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CA2329422A1 - Pyrrolidines as inhibitors of neuraminidases - Google Patents

Pyrrolidines as inhibitors of neuraminidases Download PDF

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Publication number
CA2329422A1
CA2329422A1 CA002329422A CA2329422A CA2329422A1 CA 2329422 A1 CA2329422 A1 CA 2329422A1 CA 002329422 A CA002329422 A CA 002329422A CA 2329422 A CA2329422 A CA 2329422A CA 2329422 A1 CA2329422 A1 CA 2329422A1
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Prior art keywords
pyrrolidine
acetamido
carboxylic acid
cis
propen
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CA002329422A
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French (fr)
Inventor
Clarence J. Maring
Yu-Gui Gu
Hui-Ju Chen
Yuanwei Chen
David A. Degoey
William J. Flosi
Vincent L. Giranda
David J. Grampovnik
Warren M. Kati
Dale J. Kempf
Larry L. Klein
Allan C. Krueger
Zhen Lin
Darold L. Madigan
Keith F. Mcdaniel
Steven W. Muchmore
Hing L. Sham
Kent D. Stewart
Vincent S. Stoll
Minghua Sun
Gary T. Wang
Sheldon Wang
Yibo Xu
Ming C. Yeung
Chen Zhao
April Kennedy
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Abbott Laboratories
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Individual
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Publication of CA2329422A1 publication Critical patent/CA2329422A1/en
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Abstract

Disclosed are compounds of formula (I) which are useful for inhibiting neuraminidases from disease-causing microorganisms, especially, influenza neuraminidase. Also disclosed are compositions and methods for preventing and treating diseases caused by microorganisms having a neuraminidase, processes for preparing the compounds and synthetic intermediates used in these processes.

Description

DEMANDES OU BREVETS VOLUMINEUX

COMPREND PLUS D'UN TOME_ CECI EST LE TOME ~ 02 DE
~10TE: Pour les tomes additionels, veuiilez contacter le Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS _ ~, THiS SECT10N OF THE APPUCATIONlPATENT CONTAINS MORE
THAN ONE VOLUME
THIS !S VOLUME OF
' NOTE: For additional volumes-phase contact the Canadian Patent Ofifica . ~' WO 99!54299 PCT/US99/07945 !_', AcHN. N>.,~OH
HH O
OH TFA
Ph 67B (t)-~2R 3S 5R.1'R 2'S -2-) (1-Acetamido-2-hydroxy-2-(phenylacetylen-1-yl~ ethy~cis-~ropen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound is prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-(phenylacetyien-1-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-{ 1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-carboxylic acid t butyl ester.
Example 68 (t)-(2R.3S.5R.1'R 2'R)-2-(1-Acetamido-2-hydroxy-2-(phenylacetylen-1-yl))ethyl-3-(cis-propen-1- I~yrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt i- , AcHN. N~.,~OH
H H
/ ~OH O
P h TFA
68A (t)-(2R,3S.5R.1'R.2'R)-2-(1-Acetamido-2-h dr~roxy-~phenylacetyien-1-yl))ethyl-3-(cis-propen-1-yi)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-(phenyiacetyien-1-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-( 1-acetamido-2-hyd roxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0034 g, 100%).
'H NMR (DMSO-ds) b 9.2 (bs, 1H), 8.04 (d, J=9.2 Hz, 1H), 7.45-7.35 (m, 5H), 5.50 (m, 1 H), 5.29 (m, 1 H), 4.64 (d, J=4.9, 1 H), 4.5-4.4 (m, 2H), 3.81 (m, 1 H), 3.22 (quint., J=8.5Hz, 1 H), 2.45 (dt, J=12.8,7.3Hz, 1 H), 1.89 (s, 3H), 1.74 (dt, J=12.7, 1 O.OHz, 1 H), 1.58 (dd, J=7.3,1.BHz, 3H).
MS: (M+H)+ = 357, (M+Na)+ = 379, (M-H)- = 355.
Example 69 (t)-(2R.3S,5R.1'R.2'S)-2-(1-Acetamido-2-hydroxy-3-ethyl)pen I-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN_ N~_,~ tBu H Boc ~O
69A (t)-(2R.3S.5R,1'R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-oxo-3-ether;pentyl-3-(cis-propen-1-y~~yrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 42A, substituting (t)-(2R,3S,5R,1'R,2',R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 8 mg, 81 %).
MS: (M+H}+=481, (M-H)- =479 ~OtBu O
69B (t)-(2R,3S.5R.1'R,2'S)-1-t Butoxycarbonyl-2-(1-Acetamido-2-hydrox~3-ethy~eentYl-3-(cis-propen-1-yl)-pyrrolidine-5-carbo~rlic Acid t Butyl Ester.
The title compound was prepared according to the method described in Example 42B, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (2R,3S,5R,1'R)-1-t-butoxycarbonyl 2-(1-acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 5 mg, 63%).
MS: (M+H)+=483, (M-H)- =481 / _', AcH N
N
H Boc OH
,~ H
O

AcHN.
H N
H
OH
TFA
69C (t~-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-eth~)pentyl-3-(cis-rp open-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-{1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl}-pyrrolidine-5-carboxylic acid t butyl ester (yield: 4 mg, 95%).

' H NMR (DMSO-ds) s 7.67(d, J=8.9Hz, 1 H), 5.48(m, 1 H), 5.23(m, 1 H), 4.42(m, 1 H), 4.21 (m, 1 H), 3.58(m, 2H), 3.22(m, 1 H), 2.43(m, 1 H), 1.82(s, 3H), 1.74(m, 1 H), 1.58(dd, J=6.71, 1.23 Hz, 3H), 1.52(m, 1 H), 1.38(m, 1 H), 1.29(m, 2Hz), 1.13(m, 1 H), 0.80(m, 6H) MS: (M+H)+=327, (M-H)- =325 Example 70 (t)-(2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hydroxy-3-ethyl pentyl-3-~cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ~OtBu O
70A (t)-(2R.3S.5R,1'R,2'R)-1-tButoxycarbonyl-2-(1-Acetamido-2-hydroxr-~3-ethyl)aentyl-3-(cis-proyen-1-yl)-p)rrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 41 B, substituting 3-pentyl magnesium bromide in place of ethyl magnesium bromide (yield: 13mg, 45%).
MS: (M+H)+=483, (M-H)- =481 i= , AcHN
N
H Boc ~OH

,~OH
O
70B (t)-(2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hydrox -~thyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid TrifluoroaceticAcid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-ethyl)pentyi-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (t}-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f butyl ester (yield: 3 mg, 96%).
'H NMR (DMSO-ds} 8 7.85 (d, J=9.2 Hz, 1H), 5.47 (m, 1H), 5.30 (m, 1H), 4.28 (m, 1 H}, 4.19 (m, 1 H), 3.67 (m, 1 H), 3.58 (m, 1 H), 3.17 (rn, 1 H), 2.43 (m, 1 H), 1.81 (s, 3H), 1.63 (m, 1 H), 1.58 (dd, J=6.71, 1.82 Hz, 3H), 1.40 (m, 2H), 1.28 (m, 1 H), 1.10 (m, 1 H), 1.05 (m, 1 H), 0.83 (m, 6H) MS: (M+H)+=327, (M-H)- =325 /'=', AcH N
H N
H
~OH
TFA

Example 71 {t)-(2R.3S,5R,1'R.2'R)-2-(1-Acetamido-2-h~~phenyl)eth~~cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt tBu O
71A (t)-(2R,3S,5R,1'R.2'R)-1-t-Buto~carbonyl-2-(1-Acetamido-2-hydrox phen~ ethy~cispropen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 41 B, substituting phenyl magnesium bromide in place of ethyl magnesium bromide (yield: 36 mg, 60%).
MS: (M+H)'= 489, (M+Na)+= 511, (M-H)- = 487.
,~OH
O
71 B (t)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydrox rL-2~henyi)ethYl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yi)-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-AcHN. ,.
N
H Boc ~OH
w AcHN. >..
H N
H
~OH
/ TFA

acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 5.5 mg, 100%).
'H NMR (DMSO-ds) d 7.79 (d, J= 9.2Hz, 1 H), 7.36 (m, 2H), 7.31 (m, 2H), 7.22 (m, 1 H), 5.49 (m, 1 H), 5.22 (m, 1 H), 4.94 (d, J= 3.OHz, 1 H), 4.52 (m, 1 H), 4.35 (m, 1 H), 3.62 (t, J= 8.5Hz, 1 H), 3.22 (m, 1 H), 2.46 (m, 1 H), 1.77 (m, 1 H), 1.fi5 (s, 3H), 1.57 (dd, J= 6.7, 0.8Hz, 3H).
MS: (M+H)+= 333, (M+Na)+ = 355, {M-H)- = 331.
Example 72 ,(t)-(2R 3S 5R 1'R 2'S)-2-(1-Acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-ylLpyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ,~OH
O
72A _(t)-(2R 3S 5R 1'R~1-t-Butox c~ony~1-Acetamido-2-oxo-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 42A, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (2R,3S,5R,1'R,2'R)-1-t butoxycarbonyl 2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 24 mg, 84%).
MS: (M+H}+= 487, {M+Na}+= 509, (M-H)- = 485.

AcH N .
' N
H Boc O

,~OH
O
72B (t)-(2R.3S.5R,1'R,2'S)-1-t Butoxycarbonyi-2-~1-Acetamido-2-hydrox phenyl)ethyl-3-(cis-propen-1-~)-pyrrolidine-5-carboxylic Acid t Butter.
The title compound was prepared according to the method described in Example 42B, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (2R,3S,5R,1'R)-1-t-butoxycarbonyl 2-(1-acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 7.9 mg, 52%).
MS: (M+H)+= 489, (M+Na)+= 520, (M-H)- = 487.
/-= , AcH N .
N
H Boc OH

AcHN. N~.,~OH
H H
w OH O
TFA
72~t)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-phenyl ethyl-3-(cis-proaen-1-yl)-p~rrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-{2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-{1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 7.5 mg, 100%).

'H NMR (DMSO-ds) d 7.83 (d, J= 9.2Hz, 1H), 7.36 (m, 2H), 7.32 (m, 2H), 7.25 (m, 1 H), 5.47 (m, 1 H), 5.33 (m, 1 H), 4.54 (d, J= 9.8Hz, 1 H), 4.36 (m, 1 H), 4.23 (m, 1 H), 3.78 (m 1 H), 3.20 (m, 1 H), 2.43 (m, 1 H), 1.63 (m, 1 H), 1.56 (dd, J=
6.7, l.2Hz, 3H), 1.53 (s, 3H).
MS: (M+H)+= 333, (M+Na)+= 355, (M-H)- = 331.
Example 73 Lt)-(2R.3S,5R.1'R.2'R)-2-(1-Acetamido-2-h~x~-2-(thiophen-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN. N~.,~O
H'Boc /7~'O
r OOH
S
73~t)-(2R,3S.5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-h~xy-2-thio hen-2-yl))ethyl-3-(~cispropen-1-~pyrrolidine-5-carboxylic Acid t-Butt Ester.
(t)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl 2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (40 mg, 0.098 mmol) in THF (2 mL) was added dropwise to a solution of 2-thienyllithium (1 M in THF, 0.505 mmol, 5 equivalents) in THF (1 mL) at 25 °C and reacted for 20 minutes.
The reaction was quenched with saturated aqueous ammonium chloride (2 mL) and water (5 mL) followed by extraction using dichloromethane (2 X 10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/1: ethyl acetate/hexane to provide the title compound (yield: 9.5 mg, 20%).
MS: (M+H)+= 495, (M+Na)+= 517, (M-H)- = 493.

/_~, AcHN_ N~.,~OH
w HH O
OH
S TFA
73B (t)-(2R.3S,5R,1'R.2'R)-2-(1-Acetamido-2-hydroxy-2-(thiophen-2-yl )ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carbox lid c Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41 C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetam id o-2-hyd roxy-2-(th i ophen-2-yl))ethyl-3-(cis-p ropen-1-yl)-pyrrolid ine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 4.3 mg, 100%).
'H NMR (DMSO-ds) b 7.86 (d, J= 9.8Hz, 1H), 7.63 (dd, J= 5.4, 1.0 Hz, 1H), 7.07 (m, 1 H), 6.98 (m, 1 H), 5.58 (m, 1 H), 5.43 (m, 1 H), 4.55 (m, 1 H), 4.39 (m, 1 H), 3.72 (m, 1 H), 3.11 (m, 2H), 2.43 (m, 1 H), 2.04 (s, 3H), 1.80 (m, 1 H), 1.57 (m, 3H).
MS: (M+H)+= 339, (M+Na)+ = 361, (M-H)- = 337.
Example 74 ~-(2R.3S,5R,1'R,2'S)-2-(1-Acetamido-2-~droxy-3-~4-methylthiazol-2-yl~ prowl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt i-, i-, AcHN. ~, OtBu AcHN. ,., OtBu H Boc ~ H Boc ~OH ~OH
N~ S N~ S

74A (t)-(2R,3S.5R,1'R.2'S) and (t)~2R.3S,5R.1'R.2'R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-h~idroxy 3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1- r~l -wrrolidine-5-carbox liy c Acid t-Butyl Ester.
1.6 M n-Butyllithium (0.125 mL, 0.20 mmol, 4 equivalents) was added to a solution of 2,4-dimethylthiazole (28.3 mg, 0.25 mmol, 5 equivalents) in 1 mL
of THF at -78 °C and reacted for 30 minutes. ((t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl 2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (20.5 mg, 0.050 mmol) in THF (1 mL) was added dropwise to the above solution and reacted for 30 minutes at -78 °C and then for 30 minutes at room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL) and water (5 mL) followed by extraction using dichloromethane (3 X 25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/2: ethyl acetate/hexane to provide (t)-(2R,3S,5R,1'R,2'S)-1-f butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 3.3 mg, 13%) and (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 7.5 mg, 29%).

(2R,3S,5R,1'R,2'S) MS: (M+H)+=524, (M+Na)+=546, (2M+Na)+=1069, (M-H)'=522.
(2R,3S,5R,1'R,2'R) MS: (M+H)+=524, (M+Na)+=546, (2M+Na)+=1069, (M-H)-=522.

AcHN. N~.,~ H
H H
O
OH
N ~ S TFA

74B (tL,(~2R.3S,5R,1'R,2'S)-2-(1-Acetamido-2-h~droxy-3-{4-methylthiazol-2-yl~prop~cis-proyen-1-y~-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-( 1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-carboxylic acid t-butyl ester (yield: 0.0030 g, 100%).
' H NMR (DMSO-ds) b 9.0 (bs, 1 H), 8.10 (d, J=8.3Hz, 1 H), 7.11 (d, J=1.0 Hz, 1 H), 5.48 (m, 1 H), 5.30 (m, 1 H), 4.30 (m, 1 H), 4.10 {m, 1 H), 3.88 (dt, J=9.4,2.6Hz, 1 H), 3.78 (m, 1 H), 3.25-3.15 (m, 2H), 2.93 (dd, J=15.1,8.3Hz, 1 H), 2.41 (dt, J=12.3,7.3Hz, 1 H), 2.33 (d, J=1.OHz, 3H), 1.86 (s, 3H), 1.66 (dt, J=12.7, 10.3Hz, 1 H), 1.61 (dd, J=6.8,1.SHz, 3H).
MS: (M+H)+= 368, (M+Na)+ = 390, (M-H)- = 366.

Example 75 (t)-(2R 3S 5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-3-(4-methylthiazol-2-yl)Zpropyl-3-(cis-proyen-1-~~yrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt i= , AcHN. N,.,~OH
H H
O
OH
N ~ S TFA

The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-{1-acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-( 1-acetam ido-2-hyd roxy)butyl-3-(cis-propen-1-yl)-pyrrolid ine-5-carboxylic acid t-butyl ester (yield: 0.0030 g, 100%).
' H NMR (DMSO-ds) d9.0 (bs, 1 H), 7.77 (d, J=9.3Hz, 1 H), 7.11 (s, 1 H), 5.47 (m, 1 H), 5.25 (m, 1 H), 4.45 (m, 1 H), 4.20 (m, 2H), 3.58 (t, J=9.1 Hz, 1 H), 3.19 (m, 1 H), 2.96 (m, 2H), 2.41 (m, 1 H), 2.33 (d, J=1.OHz, 3H), 1.85 (s, 3H), 1.73 (dt, J=12.7, 10.3Hz, 1H), 1.54 (dd, J=6.9,1.5Hz, 3H).
MS: (M+H)+= 368, (M+Na)+ = 390, (M-H)- = 366, (M+CF3COOH)-=480, (2M-H)-=733.
Example 76 (t)-(2R,3S.5R,1'R,2'RS)-2-(1-Acetamido-2-hydroxy-3-(thiazolin-2-yl))propyl-3-(cis-propen-1-yl)-p~olidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN. N~., OH
H Boc -OH
N~ S
U
76A (t)-(2R,3S,5R,1'R,2'RS)-1-t Butoxycarbonyi-2-{1-Acetamido-2-hydroxy-3-(thiazolin-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester (t)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl 2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (20.5 mg, 0.05 mmol) in THF (1 mL) was added dropwise to a solution of the (thiazolin-2-yl)methyl lithium (0.20 mmol, 4 equivalents, prepared from 0.025 g of 2-methylthiazoline and 0.125 mL of 1.6 M n-BuLi at -78 °C) in THF (2 mL) at -78 °C
and reacted for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) and water (5 mL) followed by extraction using dichloromethane (3 X 20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica get using 1/1: ethyl acetate/hexane to provide the title compound as a mixture of isomers (yield: 10 mg, 40%).
MS: (M+H)+= 512, (M+Na)+=534, (M-H)-=510.

!_', AcHN. N~.,~OH
H H O
-OH
N i $ TFA
U
76B (t)-(2R.3S.5R,1'R.2'RS)-2-(1-Acetamido-2-h rLdroxv-3-(thiazolin-2-yl))propel-3-(cis-propen-1-yl)-pyrrolidine-5-carbox~ Acid Trifluoroacetic Acid Salt The title compounds were prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'RS)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-(thiazolin-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-carboxylic acid t-butyl ester n place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester {yield: 0.003 g, 100%).
Major isomer' H NMR (DMSO-ds) 8 8.88 (m, 1 H), 7.76 (d, J=8.8Hz, 1 H), 5.46 (m, 1 H), 5.19 (m, 1 H), 4.69 (m, 1 H), 3.90 (m, 1 H), 3.85 (m, 1 H), 3.49 (m, 2H), 3.35 (t, J=9.OHz, 1 H), 3.29 (dd, J=17.6,5.9Hz, 1 H), 3.04 (t, J=8.9Hz, 1 H), 2.78 (dd, J=17.6,8.1 Hz, 1 H), 2.7-2.55 (m, 2H), 1.75 (s, 3H), 1.70 (m, 1 H), 1.56 (dd, J=6.8,1.5Hz, 3H).
MS: (M+H)+= 356, (M+Na)+=378, (2M+Na)+=733, (M-H)'=354.
Example 77 W~ 99/54299 PCT/US99/07945 ft)-(2R,3S.5R.1'R.2'S)-2-(1-Acetamido-2-hydroxy-3 3-difluoro-3-vin I)pro y1;3-~cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ~OtBu O
F
77A lt)-(2R.3S,5R.1'R,2'S)-1-t-Butox~rbonyl-2-(1-acetamido-2-h droxv-3 3-difluoro-3-vinyl)aropyl-3-(cis-propen-1-~)-pyrrolidine-5-carbox~rlic Acid t-Butyl Ester (t)-(2R,3S,5R,1'R)-1-f Butoxycarbonyl 2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester {41 mg, 0.10 mmol) and 1,1-difluoroallyl iodide (94 mg, 0.60 mmol, 6 equivalents) in TH1= (2 mL) was reacted with zinc dust (33 mg, 0.50 mmol, 5 equivalents) at 0°C for 5 minutes and then at room temperature for 4 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and water (15 mL) and extracted with 3 X 25 mL dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/3: ethyl acetate/hexane to provide the title compound (yield: 35 mg, 71 %}.
MS: (M+H)+=489, (M+Na)+=511, (2M+Na)+=999, (M-H)'=487.
CHI

AcHN.
H Boc ~OH

,~OH
O
F TFA
77B (t)-(2R,3S,5R.1'R.2'S)-2-(1-Acetamido-2-hydroxy-3,3-difluoro-3-vinyl)propyl-3-~cis-propen-1- rL-pyrrolidine-5-carboxylic Acid Trif)uoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t}-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxylbutyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 0.0026 g, 96%).
'H NMR (DMSO-ds) d7.68 (d, J=7.8Hz, 1 H), 5.97 (m, 1 H), 5.55-5.45 (m, 2H), 5.43 (m, 1 H), 5.23 (m, 1 H), 4.45 (m, 2H), 4.10 (m, 1 H), 3.16(quint.
J=9.1 Hz, 1 H), 2.41 (dt, J=12.8,7.3Hz, 1 H), 1.72 {s, 3H), 1.70 (dt, J=12.8, 10.3Hz, 1 H), 1.61 (dd, J=6.7,1.2Hz, 3H).
MS: (M+H)+=333, (M+Na)+=355, (M-H)-= 331, (2M-H)-=663.
Example 78 /_.', AcH N .
H N
H
~O H
F

(t)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-h d~y~3,3-difluoro-3-vinyl)propyi-3-(cis-propen-1- I~yrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN _ N ~. , OtBu H Boc O
F
78A ~t~~2R,3S.5R,1'R)-1-t Butoxycarbonyl-2-(1-Acetamido-2-oxo-3.3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 42A, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3, 3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolid ine-5-carboxylic acid t butyl ester in place of (2R,3S,5R,1'R,2'R)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester to provide (t)-(2R,3S,5R,1'R)-1-t butoxycarbonyl-2-(1-acetamido-2-oxo-3,3-difluoro-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 0.00508, 44%).
MS: (M+H)+=487, (M+Na)+=509, (M-2F)+=448, (M-H)-=485.

~Bu O
F
78B (t)-y2R.3S.5R.1'R,2'R)-1-t Butoxycarbonyl-2-(1-Acetamido-2-hydroxy-3-3-difluoro-3-vinyl)propyl-3~cis-proden-1-~pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound is prepared according to the method described in Example 42B, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo-3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (2R,3S,5R,1'R)-2-(1-acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.

AcHN_ N~.,~OH
H H
OH
F F TFA
78C (t)-ri2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-h d~ro -3,3-difluoro-3-vinyl~propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carbox~ic Acid Trifluoroacetic Acid The title compound is prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3, 3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester.
Example 79 AcHN. ).
N
H Boc OH
F

(t)-(2R,3S.5R.1'R.2'R -2-) (1-Acetamido-2-hydrox~Lis-buten-2-yl))ethy~cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN. N~., OtBu H Boc H3C ~~ 'OH

79A (tZ~2R.3S,5R.1'R.2'R)-1-t-Butox~arbon~rl-2-(1-Acetamido-2-hydrox r-L2-(cis-buten-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(t)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl 2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (30 mg, 0.073 mmol) in THF (5 mL) was reacted with cis-2-buten-2-yl lithium (0.75 mL (0.5M), 0.37 mmol) at 25°C for 45 min. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) and water (5mL) followed by extraction using dichloromethane (2 X 10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/1: ethyl acetatelhexane to provide the title compound (yield: 20 mg, 59%).
' H NMR (CDC13) 8 6.19(d, J=8.9 Hz, 1 H), 5.61 (m, 1 H), 5.35(m, 1 H), 5.27(m, 1 H), 4.48(m, 1 H), 4.18(m, 1 H), 4.77(m, 2H), 3.10(m, 1 H), 2.72(m, 1 H), 1.99(s, 3H), 1.82(m, 1 H), 1.73(m, 3H), 1.55(m, 6H), 1.47(s, 9H), 1.44(s, 9H) MS: (M+H)+= 467, (M-H)-= 465 , AcHN. N~.,~OH
H H
O
HsC ~ ~OH

79B (t)-(2R 3S 5R 1'R 2'R)-2-(1-Acetamido-2-hydroxy-2-(cis-buten-2-yl))ethyl-3-(cis'propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-(cis-buten-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxyiic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 4 mg, 96%).
' H NMR (DMSO-ds) 8 8.09(d, J=9.0 Hz, 1 H), 5.50(m, 1 H), 5.32(m, 1 H), 5.16(m, 1 H), 4.50(m, 1 H), 4.38(m, 1 H), 4.19(m, 1 H), 3.43(m, 1 H), 3.20(m, 1 H), 2.43(m, 1 H), 1.88(s, 3H), 1.74(m, 1 H), 1.70(s, 3H), 1.62(m, 3H), 1.58(m, 3H) MS: (M+H)+=311, (M-H)- =309 Example 80 (t)-(2R.3S,5R.1'R,2'R,3'R) and t,~-(2R,3S,5R.1'R,2'R,3'S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt =, i=, AcHN_ ~., OtB~ AcHN_ ~., OtBu H Boc ~ H Boc ~OH ~OH
80A (tl-12R.3S.5R.1'R,2'R,3'R and (t)-~2R,3S.5R,1'R.2'R,3'S)-1-t Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1 yl)-pyrrolidine-5-carbox~c Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (60 mg, 0.15 mmol) in THF (1 mL) was added dropwise to a solution of 2-butylmagnesium bromide (3M
in ether) (0.45 mL, 0.85 mmol) at room temperature and reacted for 40 minutes.
The reaction was quenched with saturated NH4C1 (1 mL) followed by extraction using dichloromethane (3 x 1 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/4: ethyl acetate/hexane to provide the title compounds (t)-(2R,3S,5R,1'R,2'R,3'S)-1-t-butoxycarbonyl 2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester Rf= 0.65 (1:1 ethyl acetate: hexanes) (yield: 19 mg, 27%) and (t)-(2R, 3S, 5R,1' R,2'R, 3'R)-1-t-butoxycarbonyl 2-( 1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester Rf=
0.5) (1:1 ethyl acetate: hexanes) (yield: 19 mg, 27%).
Rf= 0.65 'H NMR (CDC13) 8 5.98 (d, J=8.8Hz, 1H), 5.62 (t, J=10.5Hz, 1 H), 5.35 (m, 1 H), 4.66 (d, J=4.4Hz, 1 H), 4.16 (d, J=9.5Hz, 1 H), 3.78 (m, 3H), 3.12(m, 2H), 2.73 (m, 1 H), 2.0 (s, 3H), 1.81 (d, J=13.2Hz, 1 H), 1.54 (br s, 3H), 1.47 (s, 9H), 1.44 (s, 9H), 1.25 (m, 1 H), 0.81 {m, 6H) MS: (M-H)- = 467; (M+H)+ = 469.
Rf= 0.5 'H NMR (CDC13) 8 6.00 (d, J=10.2Hz, 1H), 5.61 (br t, 1H), 5.36 (m, 1 H), 4.58 (d, J=4.7Hz, 1 H), 4.14 (d, J=8.8Hz, 1 H), 3.82 (m, 3H), 3.13 (m, 2H), 2.73 (m, 1 H), 1.99 (s, 3H), 1.80 (d, J=13.9Hz, 1 H), 1.54 (br s, 3H), 1.46 (s, 9H), 1.44 (s, 9H), 1.43 (m, 1 H), 0.97 (d, J=6.8Hz, 3H), 0.81 (t, J=7.2Hz, 3H) MS: (M-H)- = 467; (M+H)+ = 469.

AcHN_ N~.,~OH
H H
~OH O
TFA
80B ft)-(2R,3S,5R.1'R,2'R,3'S)-2-(1-Acetamido-2-hydrox r-~3-methyl)pentyl-3-~cis-propen-1-yIZ eyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt (t)-(2R,3S,5R,1'R,2'R,3'S}-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (2.5 mg, 0.005 mmol) was reacted with trifluoroacetic acid (0.8 mL) in dichloromethane (0.2 mL) at room temperature for 6 hrs. The reaction was concentrated in vacuo overnight and triturated with acetonitrile (2 x 1 mL) to provide the title compound (yield: 2.0 mg, 100%).
1 H NMR (DMSO-d6) 8 7.68 (d, J=8.8Hz, 1 H), 5.45 (m, 1 H), 5.23 (t, J=7.3Hz, 1 H), 4.24 {br t, 1 H), 4.18 (m, 1 H), 3.52 (t, J=7.3Hz, 1 H), 3.45 (m, 1 H), 3.16 (m, 1 H), 2.38 (m, 1 H), 1.83 (s, 3H), 1.68 (m, 1 H), 1.58 (dd, J=2.0, 4.8Hz, 3H), 1.37 (m, 2H), 0.99 (m, 1 H), 0.89 (d, J=6.8Hz, 3H), 0.79 (t, J=7.4Hz, 3H) MS: (M-H)- = 311; (M+H)+ = 313, (M+Na)+ = 335.
Example 81 ~t - 2R 3SL5R 1'R 2'R,3'R?-2-l1-Acetamido-2-h dy roxy-3-methvi)penty~cis-propen-1-yl)-eyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Sait AcHN. N~.,~OH
H H
~OH O
TFA
The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R,3'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (Rf= 0.5, 1:1, ethyl acetate:hexanes) in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 1.6 mg, 76%).
' H NMR (DMSO-ds) 8 7.55 (d, J=9.3Hz, 1 H), 5.45 (m, 1 H), 5.23 (m, 1 H), 4.31 (br t, ~ H), 4.20 (t, J=8.3Hz, 1 H), 3.51 (t, J=9.3Hz, 1 H), 3.43 (d, J=7.4Hz, 1 H), 3.17 (m, 1 H), 2.40 (m, 1 H), 1.80 (s, 3H), 1.70 (m, 1 H), 1.55 (dd, J=1.4, 5.4Hz, 3H), 1.36 (m, 2H), 1.14 (m, 1 H), 0.84 (t, J=7.3Hz, 3H), 0.73 (d, J=6.9Hz, 3H) MS: (M-H)- = 311; (M+H)+ = 313, (M+Na)+ = 335.

Example 82 (tL(2R,3S 5R 1'R 2'S 3'S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-y~-pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
~0~8u O
82A (t)-(2R 3S 5R 1'R 3'RS)-1-t Butox,~,rcarbon~-2-(1-acetamido-2-oxo-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 42A, substituting (t)-(2R,3S,5R,1'R,2'R,3'RS}-1-t butoxycarbonyl-2-(1-acetamido-2-hyd roxy-3-methyl)pentyl-3-(cis-grope n-1-yl)-pyrrolid ine-5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'R) 1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl (yield: 12 mg, 63%).
i= , AcHN. ~., OtBu AcHN. ~.. O~Bu H Boc ~ H Boc' OH ; OH
82~t -(2) R 3S 5R 1'R 2'S 3'S) and (t~-{2R,3S,5R.1'R.2'S.3'R)-1-t Butoxycarbonvl-2-( 1-acetamido-2-hid roxy-3-meths,pentyl-3-(cis-propen-1-vl)-pyrrolidine-5-carboxylic Acid t Butyl Ester.
The title compounds were prepared according to the method described in Example 42B, substituting (t)-{2R,3S,5R,1'R,3'RS)-1-t butoxycarbonyl-2-(1-acetamido-2-oxo-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid AcHN_ ' N
H Boc O

t-butyl ester (Rf= 0.5 and 0.65, 1:1, ethyl acetate: hexanes) in place of (2R,3S,5R,1'R)-2-(1-acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester to give (t)-(2R,3S,5R,1'R,2'S,3'S)-1-t-butoxycarbonyl-2-( 1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (Rf= 0.15, 1:1, ethyl acetate:
hexanes) (yield: 6.0 mg, 50%) and (t)-(2R,3S,5R,1'R,2'S,3'R)-1-t-butoxycarbonyi-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester(Rf= 0.10, 1:1, ethyl acetate: hexanes) (yield: 2.5 mg, 63%).
,~ H
O
TFA
82~t)-~2R,3S.5R.1'R,2'S.3'S)-2-(1-Acetamido-2-hydroxy-3-methyl)pent)rl-3-(cis-propen-1-Yl~pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S,3'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hyd roxy-3-methyl) pentyl-3-(cis-p ro pen-1-yl)-pyrrolid i ne-5-carboxylic acid t-butyl ester (Rf= 0.15, 1:1, ethyl acetate: hexanes) in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 6.0 mg, 100%).
'H NMR (DMSO-ds) 8 7.78 (d, J=9.2Hz, 1 H), 5.42 (m, 1 H), 5.29 (t, J=10.3Hz, 1 H), 4.08 (m, 1 H), 3.96 (br t, 1 H), 3.51 (m, 2H), 3.08 (m, 1 H), 2.33 (m, 1 H), 1.78 (s, 3H), 1.56 (d, J=6.3Hz, 3H), 1.52 (m, 1 H), 1.40 (m, 1 H), 1.29 (m, 1 H), 1.21 (m, 1 H), 0.84 (t, J=7.3Hz, 3H), 0.73 (d, J=6.9Hz, 3H) MS: (M-H)~ = 311; (M+H)+ = 313, (M+Na)+ = 335.

AcH N .
H N
H
OH

Example 83 (t)-~2R 3S 5R 1'R 2'S 3'R~-2~1-Acetamido-2-h~drox~-3-methyllpentyl-3-(cis-propen-1-yl) pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN_ N~.,~ H
H H O
OH
TFA
The title compound was prepared according to the method described in Example 41C, substituting(t)-(2R,3S,5R,1'R,2'S,3'R)-1-f-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (Rf= 0.10, 1:1 ethyl acetate: hexanes) in place of (t)-(2R, 3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-( 1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 2.5 mg, 100%).
'H NMR (DMSO-dfi) 8 7.85 (d, J=8.7Hz, 1 H), 5.45 (m, 1 H), 5.29 (t, J=9.3Hz, 1 H), 4.20 (m, 2H), 3.63 (t, J=8.3Hz, 1 H), 3.42 (br d, 1 H), 3.14 (m, 1 H), 2.41 (m, 1 H), 1.79 (s, 3H), 1.62 (m, 1 H), 1.58 (d, J=5.4Hz, 3H), 1.43 (m, 2H), 1.0 (m, 1 H), 0.88 (d, J=6.8Hz, 3H), 0.80 (t, J=7.3Hz, 3H) MS: (M-H)' = 311; (M+H)+ = 3'13, (M+Na)+ = 335.

Example 84 (t)-(2R,3S,5R.1'R,2'S)-2-(1-Acetamido-2-methoxy)but~cis-propen-1- rLl)-pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN. N)., O=Bu H Boc 84A (t)-(2R.3S.5R,1'R.2'S~-1-t Butoxycarbonyl-2-(1-acetamido-2-methoxy)butyl-3-(cis-propen-1-~)-pYrrolidine-5-carboxylic Acid t-Butyl Ester (t)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (22 mg, 0.05 mmole) was reacted with methyl iodide (0.016 mL, 0.25 mmole), potassium hydroxide (14 mg, 0.25 mmole) and 18-crown-6 (0.7 mg, 0.0025 mmole) in N,N-dimethylformamide {2 mL) at room temperature for 23 hours.
Water (5 mL) was then added to the reaction mixture, followed by extraction with ether (2 x 10 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 66% ethyl acetate/hexanes to provide the title compound, as a colorless oil (yield: 5.2 mg, 23%).
MS: (M+H)+= 455, (M-H)- = 453.

AcHN. N~.,~OH
H\ H

TFA
84B (t;~~2R 3S 5R.1'R.2'S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl~pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting {t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 4.7 mg, 98%).
'H NMR {DMSO-d6) 8 7.96 (d, J= 9.2Hz, 1 H), 5.50 (m, 1 H), 5.24 (m, 1 H), 4.25 (m, 2H), 3.70 (m, 1 H), 3.23 (s, 3H), 3.19 (m, 2H), 2.40 (m, 2H), 1.86 (s, 3H), 1.68 (m, 2H), 1.62 (dd, J= 7.0, 1.BHz, 3H), 1.39 (m, 1 H), 0.77 (t, J= 7.3Hz, 3H).
MS: (M+H)+= 299, (M+Na)+= 321, (M-H)- = 297 Exam_,ple 85 St)-(2R~ 3S.5R.1 'R.2'R~-2 ~ 1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN. N~., O~Bu H Boc ~OCH3 85A (tl-(2R,3S,5R,1'R.2'R)-1-t-ButoxycarbonLrl-2-(1-acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester (t)-(2R, 3S, 5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (17 mg, 0.04 mmole) was reacted with methyl iodide (28 mg, 0.19 mmole), potassium hydroxide (8 mg, 0.19 mmole) and 18-crown-6 ( 0.002 mrnole) in N,N-dimethylformamide {1.5 mL) at room temperature for 6 hours. Water (5 mL) was then added to the reaction mixture, followed by extraction with ether (2 x 10 mL).
The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound, (yield: 5 mg, 29%).
MS: (M+H)+=455, (M-H)- =453 /= , AcHN. N~-,~ H
H H
~OCH3 O
TFA
85B (t)-(2R 3S,5R 1'R 2'Rl-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41 C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-{2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 4 mg, 95%).
1 H NMR (DMSO-d6) d 8.00(d, J=9.8HZ, 1 H), 5.57(m, 1 H), 5.35(m, 1 H), 4.42(m, 1 H), 4.28(m, 1 H),3.95(m, 1 H), 3.54(m, 1 H), 3.28(s, 3H), 2.80(m, 1 H), 2.30(m, 1 H), 1.92(s, 3H), 1.65(m, 1 H), 1.60(m, 3H), 1.43(m, 2H), 0.82(t, J=7.31 HZ, 3H).
MS: (M+H)+=299, (M-H)- =297 Example 86 (~2R 3S 5R 1'R 2'S)-2-(1-Acetamido-2-methoxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt i- , AcHN. N~., OH
H Boc 86~t~~2R 3S 5R 1'R 2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound is prepared according to the method described in Example 84A, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (~)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester.

AcHN_ N~.,~OH
H H
O

TFA
86B (t)-(2R 3S 5R 1'R.2'S)-2-l1-Acetamido-2-methoxy-3-methvl)butyl-3-(cis-propen-1_yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound is prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-~-butoxycarbonyl-2-(1-acetamido-2-methoxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-{2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-WO 99/54299 PCT/t1S99/07945 acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
Example 87 (t~-(2R.3S,5R 1'R 2'R)-2-(1-Acetamido-2-methoxy-3-methyl~tyl-3-(cispropen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN. N~., OH
H Boc ~OCH3 86A (t)-(2R.3S,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-3-meth Iy )bu_,tyl-3-(cis-propen-1- I~yrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 84A, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 6.8 mg, 33%).
MS: (M+H)+= 469, (M+Na)+= 491, (M-H)- = 467.

AcHN_ N>.,~OH
H H
~OCH3 O
TFA
87B (t)-(2R 3S.5R 1'R.2'R)-2-~1-Acetamido-2-methoxy-3-methvl)butyl-3-(cis-~ropen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolid ine-5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester. ester (yield: 6.6 mg, 100%).
' H NMR (DMSO-ds) 8 7.65 (d, J= 9.2Hz, 1 H), 5.43 (m, 1 H), 5.23 (m, 1 H), 4.42 (m, 1 H), 4.37 (m, 1 H), 3.56 (m, 1 H), 3.46 (s, 3H), 3.17 (m, 2H), 2.44 (m, 1 H), 1.80 s, 3H), 1.78 (m, 1 H), 1.70 (m, 1 H), 1.57 (dd, J= 6.7, 1.2Hz, 3H), 0.94 (d, J=
6.7Hz, 3H), 0.82 (d, J= 6.7Hz, 3H).
MS: (M+H)+= 313, (M+Na)+ = 335, (M-H)- = 311.

Example 88 (~2R 3S 5R.1'R 2'S)-2-(1-Acetamido-2-methoxy~pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt H

AcHN.
N
H Boc 88A (t)~2R.3S.5R 1'R.2'S~1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy)pentyl-3-(cis propen-1-yl)-pyrrolidine-5-carboxylic Acid t Butyl Ester The title compound was prepared according to the method described in Example 84A, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 11.9 mg, 36%).
MS: (M+H)+= 469, (M+Na)+= 491, (M-H)- = 467.

AcHN. N~.,~ H
H H

TFA
88B fit)-12R.3S.5R.1'R.2'S~ 2-(1-Acetamido-2-methoxv)pent~,(cis-~~~ropen-1-yl)-pyrrolidine-5-carboxYic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41 C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester.
(yield: 11.5 mg, 100%).
' H NMR (DMSO-ds) s 7.95 (d, J= 9.8Hz, 1 H), 5.49 (m, 1 H), 5.23 (m, 1 H), 4.25 (m, 2H), 3.68 (m, 1 H), 3.24 (s, 3H), 3.22 (m, 1 H), 3.18 (m, 1 H), 2.40 (m, 1 H), 1.85 (s, 3H), 1.66 (m, 1 H), 1.62 (m, 3H), 1.58 (m, 1 H), 1.38 (m, 1 H), 1.27 (m, 2H), 0.86 (t, J= 7.3Hz, 3H).
MS: (M+H)+= 313, (M+Na)+=335, (M-H)- = 311.
Example 89 -(2R,3S.5R,1'R,2'R~2-(1-Acetamido-2-methoxy)pent rLl-3-(cis-propen-1-y~-gyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ~OH
O

89A (t)-(2R,3S.5R,1'R.2'R)-1-t Butoxycarbonyl-2-(1-acetamido-2-methoxy)pentyl-3-(cis-propen-1~r1~-pyrrolidine-5-carboxylic Acid t Butyl Ester The title compound was prepared according to the method described in Example 84A, substituting (t)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1-acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrroiidine-5-carboxylic acid t-butyl ester (yield: 4.3 mg, 21 %).
MS: (M+H)+= 469, (M+Na)+= 491, (M-H)-= 467.

AcHN .
N
H Boc /-', AcHN_ N~.,~OH
H H
~OCH3 O
TFA
89B (t)-(2R,3S~5Ry1'R,2'R)-2-(1-Acetamido-2-methoxy~pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t butoxycarbonyl-2-(1-acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 4.8 mg, 100%).
' H NMR (DMSO-ds) 8 7.70 (d, J= 9.8Hz, 1 H), 5.45 (m, 1 H), 5.24 (m, 1 H), 4.40 (m, 1 H), 4.25 (m, 1 H), 3.57 (t, J= 8.5Hz, 1 H), 3.40 (m, 1 H), 3.35 (s, 3H), 3.17 (m, 1 H), 2.42 (m, 1 H), 1.82 (s, 3H), 1.69 (m, 1 H), 1.56 (dd, J= 7.1, 1.2Hz, 3H), 1.24 (m, 4H), 0.88 (t, J= 7.OHz, 3H).
MS: (M+H)+= 313, (M+Na)+= 335, (M-H)- = 311 Example 90 (t)-(2R,3S~5R.1'R.2'S)-2-(1-Acetamido-2-methoxy-2-all ly )ethyl-3-(cis-propen-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN. N~., OtBu H Boc 90A (t~~2R.3S.5R.1'R,2'Sl-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-allyl)ethyl-3-(cis-aropen-1-yl)-pyrrolidine-5-carboxylic Acid t-Bu I Ester The title compound was prepared according to the method described in Example 84A, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 8 mg, 31 %).
MS: (M+H)+=467, (M-H)-=465 90~t)-(2R.3S.5R.1'R,2'S)-2-(1-Acetamido-2-methox -~yl)ethyl-3~cis-propen-1 yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl}-pyrrolidine-5-carboxylic acid t-butyl ester in place of {t)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrroiidine-5-carboxylic acid f-butyl ester. ester (yield: 6 mg, 96%).
' H NMR (DMSO-d6) 8 8.02{d, J=8.6HZ, 1 H),5.75 (m, 1 H), 5.51 (m, 1 H), 5.24(m, 1 H), 5.05(m, 2H), 4.27(m, 1 H), 4.22{m, 1 H), 3.74(m, 2H), 3.26(s, 3H), 3.18(m, 1 H), 2.47(m, 1 H), 2.39(m, 1 H), 2.17(m, 1 H), 1.87(s, 3H), 1.67{m, 1 H),1.63(dd, J=6.71, 1.23 HZ, 3H).
MS: (M+H)+=311, (M-H)-=309 Example 91 {t)-(2R,3S.5R,1'R.2'R)-2-(1-Acetamido-2-methoxy-2-aIILrI ethyl-3-(cis-propen-1-I~yrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN_ ~., OtBu N
~, H Boc 91A ~t~2R.3S.5R,1'R.2'R~1-t Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-aIILrI)et~l-3-(cis-propen-1-yl)pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 84A, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (t)-{2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 4.0 mg, 16%).
MS: (M+H)+=467, (M-H)- =465 /= , AcHN. N~.,~OH
H H
/ O
~OCH3 91 B (~-(2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1- r~l -pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy-2-aliyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 3 mg, 96%).
' H NMR (DMSO-ds) 8 7.75 (d, J=9.2 HZ, 1 H), 5.75(m, 1 H), 5.47(m, 1 H), 5.24(m, 1 H), 5.06(m, 2H), 4.42(m, 1 H), 4.25(m, 1 H), 3.58(m, 1 H), 3.50(m, 1 H), 3.37(s, 3H), 3.17(m, 1 H), 2.42(m, 1 H), 2.36(m, 1 H), 1.83(s, 3H), 1.71 (m, 1 H), 1.55(dd, J=6.73, 1.83 HZ, 3H) MS: (M+H)+=311, (M-H)- =309 Example 92 (t)-(2R,3S.5R,1'R.2'S)-2-(1-Acetamido-2-h drox -~inyl)butyl-3-(cis-propen-1-yl~p rLrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .

AcHN. ~., O~B~ AcHN. ,., OtBu H Boc ~ H Boc ~OH ~OH
\ \
92A (t)-(2R.3S,5R.1'R.2'S and (t)-(2R,3S,5R 1'R.2'R)-1-t-Butoxycarbonyl-2-~1-acetamido-2-hydroxy-4-vin~~buty~cis-eropen-1- r~l)=pyrrolidine-5-carboxylic Acid t Butyl Ester.
The title compounds were prepared according to the method described in Example 41 B, substituting 1-buten-4.-yl magnesium bromide for ethyl magnesium bromide to provide (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-{1-acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 0.0030 g, 6%) and (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 0.0145 g, 28%).
(t)-(2R,3S,5R,1'R,2'S) MS: (M+H)+=467, (M+Na)+=489, (2M+Na)+=955, (M-H)-=465.
(t)-(2R,3S,5R,1'R,2'R)- MS: (M+H)+=467, (M+Na)+=489, (2M+Na)+=955, (M-H)~=465.

/= , AcHN. N~,~OH
\ HH
OH O
ZFA
92B (t)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0027 g, 100%).
~ H NMR (DMSO-ds) 8 8.93 (bs, 1 H), 7.90 (d, J=9.2 Hz, 1 H), 5.80 (m, 1 H), 5.48 (m, 1 H), 5.28 (m, 1 H), 5.00 (dd, J=17.1, 1.BHz, 1 H), 4.94 (dd, J=10.4,1.8Hz, 1 H), 4.29 (bt, J=8.3Hz, 1 H), 4.03 (m, 1 H), 3.71 (m, 1 H), 3.49 (m, 1 H), 3.15 (quint., J=8.5Hz, 1 H), 2.41 (dt, J=12.8,7.3Hz, 1 H), 2.16 (M, 1 H), 2.05 (m, 1 H), 1.83 (s, 3H), 1.79-1.75 (m, 1 H), 1.64 (m, 1 H), 1.58 (dd, J=6.7,1.BHz, 3H), 1.34 (m, 2H).
MS: (M+H)+ = 311, (M+Na)+ = 333, (M-H)~ = 309, (M+CF3C00~)'=423 Example 93 (t)-L2R,3S.5R,1'R.2'R)-2-(1-Acetamido-2-hYdroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.

AcHN_ N~,~OH
H H
O
~OH
TFA
93A (t)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-4-vinyl)but~(cis-propen-1-yl)-pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hyd roxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrol id i ne-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 0.0027 g, 100%).
' H NMR (DMSO-ds) 8 7.68 (d, J=9.6 Hz, 1 H), 5.81 (m, 1 H), 5.48 (m, 1 H), 5.25 (m, 1 H), 5.01 (dd, J=17.1, 1.BHz, 1 H), 4.95 (dd, J=10.3,1.7Hz, 1 H), 4.43 (t, J=8.5Hz, 1 H), 4.10 (m, 1 H), 3.74 (m, 1 H), 3.56 (t, J=8.9Hz, 1 H), 3.16 (quint., J=8.9Hz, 1 H), 2.42 (dt, J=12.8,7.3Hz, 1 H), 2.11 (M, 1 H), 2.07 (m, 1 H), 1.83 (s, 3H), 1.72 (dt, J=12.8, 9.8Hz, 1H), 1.55 (dd, J=6.7,1.8Hz, 3H), 1.5-1.35 (m, 2H).
MS: (M+H)+= 311, (M+Na)+= 333, (M-H)-= 309, (M+CF3C00-)-=423, (2M-H)-=619.

Example 94 (t)-(2R 3S 5R 1'R.2'S.3'S)-2-(1-Acetamido-2-methoxv-3-methyl)penty~cis-propen-1- rLl -pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt i= , AcHN.. N~., OH
H Boc 94A (t)-(2R 3S.5R,1'R,2'S.3'S)-1-t-Butoxycarbony~1-acetamido-2-methox~
3-meth)pentyl-3-(cis-propen-1-YI)-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound is prepared according to the method described in Example 84A, substituting (t}-(2R,3S,5R,1'R,2'S,3'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl}pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
,~OH
O
TFA
94B (t)-(2R.3S.5R.1'R.2'S,3'S -2-) (1-Acetamido-2-methoxy-3-methyl)pentyl-3-(cis=prohen-1~r1)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound is prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S,3'S)-1-t butoxycarbonyl-2-(1-acetamido-2-methoxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of {t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-i= , AcH N .
H N
H

acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
Example 95 (t)-(2R,3S.5R,1'RSV-2-(1-Acetamido-2-oxo-2-heptafluoropropyl)eth !-~3-(cis-propen-1- r~pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN '. , ~~Bu F F N
H Boc F3C F~ ~O
F
95A (t~~2R,3S.5R.1'RS)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-oxo-3-heptafluoroprop~rl)ethyl-3 ~cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t Butt Ester.
The title compound was prepared according to the method described in Example 42A, substituting (t)-(2R,3S,5R,1'R,2'RS)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-carboxylic acid t butyl ester for (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 6.8 mg, 88%).
MS: (M+H)+=579, (M-H)'=577.

, AcHN ~., ~OH
F F H H

F F TFA
95B (t)-(2R.3S,5R,1'RS)-2-(1-Acetamido-2-oxo-2-heptafluoropropv I)r_ethyl;3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'RS)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo-3-heptafluoropropyl)ethyl-3-(cis-propen-1- yl)-pyrroiidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0037 g, 100%).
MS: (M+H)+=423, (M-H)~=421.
Exam~~le 96 (t)-(2R 3S 5R 1'RS)-2-(1-Acetamido-2-oxo-2-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carbox rLlic Acid Trifluoroacetic Acid Salt AcHN ~. , ~OtBu F F ' N
H Boc O

F F
96A (t)-(2R 3S 5R 1'RS)-1-t Butoxycarbonyl-2-(1-Acetamido-2-oxo-3-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-ButLrl Ester.
The title compound was prepared according to the method described in Example 42A, substituting (t)-{2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-carboxylic acid t-butyl ester for (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 6.8 mg, 88%).
MS: (M+H)+=579, (M-H)-=577.

AcHN ~.,~OH
F F H H
F3C ~ O
F F TFA
96B (t)-(2R 3S 5R 1'RS)-2-(1-Acetamido-2-oxo-2-heptafluoropropyl)ethyl-3-(cis-propen-1- r~pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-heptafluoropropyl)ethyl-3-{cis-propen-1-yl)-pyrrolidine-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl 2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0037 g, 100%).
MS: (M+H)+=423, (M-H)'=421.
Example 97 ~t)-~2R,3S,5R,1'R)-2~1-Acetamido-2-oxo~~entyi-3-(cis-propen-1- I~yrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.

AcHN N>., O~Bu o Boc 97A (t)-(2R,3S 5R 1'R)-1-t-Butox)rcarbonYl-2-(1-acetamido-2-oxo)pen I-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t Butyl Ester.
The title compound was prepared according to the method described in Example 42A, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hdroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield:
14 mg, 58%).
MS: (M+H)+ = 453, (M+Na)' = 475; (M-H)' = 451.

/= , AcHN_ N~.,~ H
H~H
O O
TFA
97B (t)-(2R 3S 5R.1'R)-2-(1-Acetamido-2-oxo)pentyl-3-(cis-propen-1-YI)-~~rrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
The title compound was prepared according to the method described in Exampie41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield:
1.4 mg, 28%).
' H NMR (DMSO-ds) 8 8.31 (d, J=8.3Hz, 1 H), 5.40 (m, 1 H), 5.19 (br t, 1 H), 4.26 (t, J=6.8Hz, 1 H), 3.63 (t, J=8.3Hz, 1 H), 3.35 (m, 1 H), 2.97 (m, 1 H), 2.45 (m, 1 H), 2.34 (dt, J=3.4, 7.4Hz, 1 H), 2.20 (m, 1 H), 1.84 (s, 3H), 1.58 (dd, J=2, 4.3Hz, 3H), 1.43 (m, 3H), 0.82 (t, J=7.3Hz, 3H) MS: (M-H)- = 295; (M+H)+ = 297, (M+Na)+ = 319.

Example 98 (t)-(2R.3S,5R,1'R-,l-2-(1-Acetamido-2-oxo)butyl-3-~cis-propen-1-yi)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .

AcHN_ N~.,~OH
H H
O O
TFA
The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester prepared in Example 42A in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-( 1-acetamid o-2-hyd roxy)b utyl-3-(cis-propen-1-yl)-pyrrolid ine-5-carboxyiic acid t butyl ester (yield: 5.0 mg, 100%).
1 H NMR (DMSO-d6) 8 8.52 (d, J= 8.6Hz, 1 H), 5.47 (m, 1 H), 5.15 (m, 1 H), 4.54 (m, 1 H), 4.39 (dd, J= 11.0, 6.7Hz, 1 H), 3.84 (t, J= 9.2Hz, 1 H), 3.17 (m, 1 H), 2.50 (m, 1 H), 2.38 (m, 1 H), 2.33 (m, 1 H), 1.83 (s, 3H), 1.63 (m, 1 H), 1.58 (dd, J=
6.7, l.BHz, 3H), 0.94 (t, J= 7.5Hz, 3H).
MS: (M+H)+= 283, (M+Na)+ = 305, (M-H)' = 281.
Examples 99-115 The title compounds were prepared according to the methods described in Examples 20 and 40-42 by substituting the respective reactants.

Example 99 AcHN. N~.,~OH
H H
/ O O
TFA
~L(2R.3S.5R.1' R)-2-( 1-Acetamido-2-oxo-2-all~)ethyl-3-(cis-prohen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds) 8 8.38 (d, J= 8.5Hz, 1 H), 5.73 (m, 1 H), 5.37 (m, 1 H), 5.05 (m, 3H), 4.32 (t, J= 7.9Hz, 1 H), 3.90 (m, 1 H), 3.49 (m, 1 H), 3.13 (m, 2H), 2.98 (m, 1 H), 3.18 (m, 1 H), 1.78 (s, 3H), 1.51 (dd, J= 5.5, 1.2Hz, 3H), 1.44 (m, 1 H).
MS: (M+H)+= 295, (M-H)- = 293.
Example 100 AcHN. N>..,~OH
H H
O O
TFA
(t)-(2R.3S.5R,1'R)-2-(1-Acetamido-2-oxo-3-methyl)butyl-3-vinyl-~yrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-dfi) a 8.64 (d, J= 8.5Hz, 1 H), 5.59 (m, 1 H), 5.08 (d, J=
17.1 Hz, 1 H), 5.02 (d, J= 9.8Hz, 1 H), 4.65 (t, J= 8.6Hz, 1 H), 4.32 (m, 1 H), 3.82 (t, J= 9.2Hz, 1 H), 2.82 (m 2H), 2.36 (m, 1 H), 1.83 (s, 3H), 1.80 (m, 1 H), 1.03 (d, J=
6.7Hz, 3H), 0.97 (d, J= 6.7Hz, 3H).
MS: (M+H)+= 283, (M+Na)+ = 305, (M-H)- = 281.

Example 101 AcHN. N~.,~OH
H H
O O
TFA
{t)-f2R 3S 5R 1'R)-2-(1-Acetamido-2-oxo}propyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-ds) 8 8.96 (d, J= 7.9Hz, 1 H), 5.71 (m, 1 H), 5.27 (d, J=17.7Hz, 1 H), 5.97 (d, J= 11.OHz, 1 H), 4.38 {m, 1 H), 4.29 (m, 1 H), 3.81 (m, 1 H), 2.61 (m, 1 H), 2.22 (m, 1 H), 2.13 (s, 3H), 2.01 (s, 3H), 1.24 (m, 1 H).
MS: (M+H)+= 255, (M+Na)+ = 277, (M-H)- = 253.
Example 102 AcHN. \ OH
Fi Hue-.
O
O
TFA
{t~2R,3S.5R.1'R~-2-f 1-Acetamido-2-oxo)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds) 8 8.61 (d, J= 8.5Hz, 1 H), 5.60 (m, 1 H), 5.10 (d, J=
17.7Hz, 1 H), 5.03 (dd, J= 10.4, 1.2Hz, 1 H), 4.54 (t, J= 8.5Hz, 1 H), 4.38 (dd, J=
11.0, 6.7Hz, 1 H), 3.86 (m, 1 H), 2.84 (m, 1 H), 2.52 (m, 1 H), 2.37 (m, 2H), 1.85 (s, 3H), 1.82 (m, 1 H), 0.94 (t, J= 7.OHz, 3H).
MS: (M+H}+= 269, {M+Na)+ = 291, (M-H)- = 267.

Example 103 AcHN. N~.,~OH
H H
O
O
TFA
jt~(2R 3S 5R 1'R)-2-(1-Acetamido-2-oxo pentyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds) 8 8.60 (d, J= 9.7Hz, 1 H), 5.60 (m, 1 H), 5.07 (m, 2H), 4.65 (m, 1 H), 4.54 (m, 1 H), 4.38 (m, 1 H), 3.86 (m, 1 H), 2.84 (m, 1 H), 2.45 (m, 1 H), 2.36 (m, 1 H), 1.86 (s, 3H), 1.82 (m, 1 H), 1.47 (m, 2H), 0.87 (t, J=
5.8Hz, 3H).
MS: (M+H)'= 283, (M+Na)+= 305, (M-H)- = 281.
Example 104 AcHN. ,~ H
O
TFA
Lt)-(2R 3S 5R 1'R)-2-(1-Acetamido-2-hydroy)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds) 8 8.00 (d, J= 9.9Hz, 1 H), 5.63 (m, 1 H), 5.08 (m, 1 H), 4.98 (m, 1 H), 4.35 (m, 1 H), 4.25 (m, 1 H), 4.08 (m, 1 H), 3.55 (m, 1 H), 3.45 (m, 1 H), 3.38 (m, 1 H), 2.83 (m, 1 H), 2.33 (m, 1 H), 1.78 (s, 3H).
MS: (M+H)+= 243, (M+Na)+= 265, (M-H}- = 241.
N
H H
OH

Example 105 AcHN. N~.,~ H
H H
OH O
TFA
(t}-(2R,3S.5R,1'R,2'S~2-(1-Acetamido-2-h droxy}propyl-3-vinyl pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds) b 7.96 {d, J= 9.7Hz, 1 H), 5.74 {m, 1 H), 5.12 (m, 1 H), 5.03 (m, 1 H), 4.27 (m, 1 H), 3.96 (m, 1 H), 3.77 (m 1 H), 3.65 (m, 1 H), 2.87 (m, 1 H), 2.38 (m, 1 H), 1.82 (s, 3H), 1.80 (m, 1 H), 1.08 (d, J= 6.OHz, 3H).
MS: (M+H)+= 257, (M+Na)+= 279, (M-H)- = 255.
Example 106 AcHN. N>.,~OH
H
OH O
TFA
(t)-(2R,3S,5R.1'R.2'S}-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds) 87.99 (d, J= 9.OHz, 1 H), 5.75 (m, 1 H), 5.13 (d, J=
17.1 Hz, 1 H), 5.04 (d, J= 10.5Hz, 1 H), 4.27 (t, J= 8.4Hz, 1 H), 4.04 (m, 1 H), 3.78 (m, 1 H), 3.48 (m, 1 H), 2.89 (m, 1 H), 2.40 (m, 1 H), 1.88 (m, 1 H), 1.85 (s, 3H), 1.54 (m, 1 H), 1.28 (m, 1 H), 0.86 (t, J= 7.2Hz, 3H).
MS: (M+H)+= 271, (M+Na)+ = 293, (M-H)- = 269.

Example 107 AcHN_ N~.,~OH
H H
OH O
TFA
St)-(2R 3S 5R 1'R 2'Sl-2-(1-Acetamido-2-h dy rox )Lpentyl-3-vin r~yrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-ds) s 7.99 (d, J= 9.9Hz, 1 H), 5.75 (m, 1 H), 5.08 (m, 2H), 4.28 (m, 1 H), 4.03 (m, 1 H), 3.77 (m, 1 H), 3.52 (m, 1 H), 2.88 (m, 1 H), 2.40 (m, 1 H), 1.86 (s, 3H), 1.75 (m, 1 H), 1.45 (m, 2H), 1.25 (m, 2H), 0.87 (t, J=
5.9Hz, 3H).
MS: (M+H)+= 285, (M+Na)+= 307, (M-H)- = 283.
Example 108 AcHN_ N~.,~OH
H H
OH O
TFA
(ty-(2R 3S 5R 1'R 2'S)-2-(1-Acetamido-2-hydroxy-3-methyl)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds) 8 7.97 (d, J= 9.3Hz, 1 H), 5.75 (m, 1 H), 5.12 (d, J=
17.1 Hz, 1 H), 5.04 (d, J= 11.2Hz, 1 H), 4.24 (m, 1 H), 4.13 (m, 1 H), 3.74 (dd, J=
9.8, 6.1 Hz, 1 H), 3.44 (dd, J= 10.3, 2.OHz, 1 H), 2.87 (m, 1 H), 2.40(m, 1 H), 1.84 (m, 1 H), 1.83 (s, 3H), 1.75 (m, 1 H), 0.89 (d, J= 6.8, 3H), 0.75 (d, J=
6.8Hz, 3H).
MS: (M+H)+= 285, (M+Na)+ = 307, (M-H)- = 283.

Example 109 AcHN. N~. ~OH
H H
OH O
TFA
(t)-(2R.3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxY 2-cyclopropyl)ethyl-3-vi~l-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-ds) 8 7.81 (d, J= 10.OHz, 1 H), 5.73 (m, 1 H), 5.05 (m, 2H), 4.39 {m, 1 H), 4.20 (m 1 H), 3.90 (m, 1 H), 3.61 (m, 1 H), 3.08 (m, 1 H), 2.86 (m, 1 H), 2.42 {m, 1 H), 1.85 (s, 3H), 0.88 (m, 1 H), 0.45 (m, 1 H), 0.35 (m, 2H), 0.11 (m, 1 H).
MS: (M+H)+= 283, (M+Na)+= 305, (M-H)- = 281.
Example 110 -, AcHN. N~.,~OH
H
~OHH O
TFA
jt -) (2R,3S.5R.1'R,2'R)-2-(1-Acetamido-2-h~rdroxy)propel-3-vinyi-pyrrolidine-carbox~rlic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-ds) 8 7.77 {d, J= 9.7Hz, 1 H), 5.72 (m, 1 H), 5.07 (m, 2H), 4.40 (m, 1 H), 4.03 (m, 1 H), 3.95 (m 1 H), 3.57 (m, 1 H), 2.86 (m, 1 H), 2.43 (m, 1 H), 1.88 (m, 1 H), 1.84 (s, 3H), 1.04 (d, J= 6.OHz, 3H).
MS: (M+H)+= 257, (M+Na)+= 279, (M-H)- = 255.

Exam~~le 111 AcHN. N~.,~OH
H H
~OH O
TFA
f t~~2R, 3S.5R.1'R,2'R)-2-( 1-Acetamido-2-hydrox~butyl-3-vin~yrrolidine-5-carbo Ix iY c Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds) 87.72 (d, J= 9.8Hz, 1 H), 5.73 (m, 1 H), 5.08 (d, J=
17.1 Hz, 1 H), 5.03 (d, J= 10.4Hz, 1 H), 4.41 (m, 1 H), 4.13 (m, 1 H), 3.68 (m, 1 H), 3.63 (m, 1 H), 2.88 (m, 1 H), 2.44 (m, 1 H), 1.90 (m, 1 H), 1.83 (s, 3H), 1.38 (m, 2H), 0.84 (t, J= 7.3Hz, 3H).
MS: (M+H)+= 271, (M+Na)+ = 293, (M-H)- = 269.
Exam~~le 112 AcHN. N~.,~OH
H H
~OH O
TFA
(~2R.3S 5R.1'R.2'R)-2-f1-Acetamido-2-hydroxy)pent)rl-3-vinyl-pyrrolidine-5-carbo Ix~ic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds) s 7.72 (d, J= 9.9Hz, 1 H), 5.72 (m, 1 H), 5.06 (m, 2H), 4.42 (m, 1 H), 4.09 (m, 1 H), 3.77 (m, 1 H), 3.61 (m, 1 H), 2.87 (m, 1 H), 2.43 (m, 1 H), 1.90 (m, 1 H), 1.83 (s, 3H), 1.37 (m, 2H), 1.27 (m, 2H), 0.87 (t, J=
5.9Hz, 3H).
MS: (M+H)+= 285, (M+Na)+= 307, (M-H)- = 283.

Example 113 AcHN. N~.,~ H
H H
~OH O
TFA
(t~~2R.3Sy5R.1'R,2'R -) 2!(1-Acetamido-2-hydroxy-3-meth~rl)butyl-3-vinyl-pyrrolidine-5-carboxyiic Acid Trifluoroacetic Acid Salt ~ H NMR (DMSO-d6) 8 7.71 {d, J= 9.3Hz, 1 H), 5.70 (m, 1 H), 5.08 (d, J=
17.1 Hz, 1 H), 5.03 (d, J= 10.3Hz, 1 H), 4.42 (m, 1 H), 4.25 (m, 1 H), 3.61 (m, 1 H), 3.35 (dd, J= 8.3, 2.5Hz, 1 H), 2.90 (m, 1 H), 2.44 (m, 1 H), 1.92 (m, 1 H), 1.82 {s, 3H), 1.58 (m, 1 H), 0.95 (d, J= 6.8Hz, 3H), 0.79 (d, J= 6.4Hz, 3H).
MS: (M+H)+= 285, (M+Na)+ = 307, (M-H)- = 283.
Example 114 AcHN. N~.,~OH
H
~OH O
TFA
~2R,3S.5R.1'R.2'R)-2-(1-Acetamido-2-h droxy-2-cycloprop,~l)ethyl-3-vinyl-Pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds) b 7.94 (d, J= 9.6Hz, 1 H), 5.76 (m, 1 H), 5.12 (m, 2H), 4.40 (m, 1 H), 4.21 (m, 1 H), 3.90 (m, 1 H), 3.53 (m, 1 H), 3.13 (m, 1 H), 2.81 (m, 1 H), 2.25 (m, 1 H), 1.87 (s, 3H), 0.90 (m, 1 H), 0.47 (m, 1 H), 0.37 (m, 2H), 0.15 (m, 1 H).
MS: (M+H)+= 283, (M+Na)'= 305, (M-H)- = 281.
Example 115 AcHN. N~.,~ H
H
~OH O
TFA
(t)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy-4-meth~pentyl-3-vinyl-pyrrolidine-5-carbox~rlic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds) 8 7.71 (d, J= 9.7Hz, 1 H), 5.83 (m, 1 H), 5.06 (d, J=
17.1 Hz, 1 H), 5.02 (d, J= 10.3Hz, 1 H), 4.41 (m, 1 H), 4.06 (m, 1 H), 3_83 (m, 1 H), 3.59 (t, J= 8.8Hz, 1 H), 2.84 (m, 1 H), 2.42 (m, 1 H), 1.90 (m, 1 H), 1.82 (s, 3H), 1.71 (m, 1 H), 1.34 (m, 1 H), 1.07 {m, 1 H), 0.89 (d, J= 6.8Hz, 3H), 0.86 (d, J=
6.3Hz, 3H).
MS: (M+H)+= 299, (M+Na)+ = 321, (M-H)- = 297.

Example 116 (t)-(2R,3S 5R.1'R)-2-(1-Acetamido-2-hydroxy-2-methyl)propel-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN. N>., O~Bu OHBcc 116A (t)-(2R.3S.5R,1'R)-f-Butoxycarbonyl-2-~-Acetamido-2-hydroxy-2-methyl)propyl-3-vin rLl-pyrrofidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R, 3S,5R,1'R)-t-Butoxycarbonyl 2-(1-acetamido-2-oxo)propyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (11 mg, 0.027 mmol) was reacted with methyl magnesium bromide (3 M) ( 0.05mL, 0.134 mmol) in THF (2 mL) at 25 °C
for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL) and water (2 mL) followed by extraction using dichloromethane (2 X 5 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2/1: ethyl acetatelhexane to provide the title compound (yield: 1.9 mg, 17%).
MS: (M+H)+=427, (M-H)- =425 AcHN. N~.,~OH
H\ H
OH O
TFA
1168 (t)-(2R.3S.5R,1'R)-2-(1-Acetamido-2-hydroxy-2-methyl)propyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-methyl)propyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield:
1.6 mg, 99%).
' H NMR (DMSO-ds) 8 7.70(d, J=9.9Hz, 1 H), 5.75(m, 1 H), 5.02(m, 2H), 4.37(m, 1 H), 4.15(m, 1 H), 3.61 (m, 1 H), 2.78(m, 1 H), 2.41 (m, 7 H), 1.81 (s, 3H), 1.20(s, 3H), 1.12(s, 3H) MS: (M+H)+ =271, (M+23)+ =293, (M-H)- =269 Example 117 (t)-(2R,3S.5R.1'R)-2-(1-Acetamido-2-hydroxy-2-ethyl)bu I-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN. N,., O~Bu OH ~c 117A (t)-(2R.3S.5R.1'R)-t Butoxycarbon)rl-2-(1-Acetamido-2-hydro~-2-ethylLt~l-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Es-ter.
(t)-(2R, 3S,5R,1'R)-f-Butoxycarbonyl-2-( 1-acetamido-2-oxo)butyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (37mg, 0.087 mmol) was reacted with ethyl magnesium bromide (3 M) ( 0.15mL, 0.44rnmol) in THF (5 mL) at 25 °C for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride mL) and water (5 mL) followed by extraction using dichloromethane (2 X 10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2/1: ethyl acetate/hexane to provide the title compound (yield: 14 mg, 35%).
MS: (M+H)+= 455, (M-H)- =453 AcHN. N~.,~ H
H H
OH O
TFA
1168 (t)-(2R.3S.5R.1'R)-2-(1-Acetamido-2-hydrox -y 2-ethyl)butyl-3-viny(-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-ethyl)butyl-3vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield:
5.8 mg, 98%).
' H NMR (DMSO-ds) 8 7.62(d, J=9.6HZ, 1 H), 5.75(m, 1 H), 5.03(m, 2H), 4.39(m, 1 H), 4.31 (m, 2H), 3.87(m, 1 H), 3.38(m, 1 H), 2.88( m, 1 H), 2.40(m, 1 H), 1.83(s, 3H), 1.55-1.30(m, 4H), 0.86(m, 6H) MS: {M+H)+ =299, (M-H)- =297 Example 118 (t~2R.3S.5R,1'S)-2-(1-Acetamido)allyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN. N~., O~Bu H Boc 118A (t)-~2R.3S.5R,1'S)-1-t-Butox~carbonyl-2-(1-acetamidoLlly~cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 20K, substituting (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-2-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 15.3 mg, 61.4%).
MS: {M+H)+= 409.

AcHN. N~.,~ H
/ H H O
TFA
1188 (t)-(2R.3S.5R,1'S~,2-(1-Acetamido)allyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41 C, substituting (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido)allyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyi-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield:
13.1 mg, 100%).
'H NMR (DMSO-dg): 61.58 (dd, 3H), 1.74 (dt, 1H), 1.88 (s, 3H), 2.41 (dt, 1 H), 3.17 (m, 1 H), 3.56 (dd, 1 H), 4.35 (dd, 1 H), 4.70 (dd, 1 H), 5.22-5.30 (m, 3H), 5.51 (m, 1 H), 5.82 (m, 1 H), 8.15 (d, 1 H), 9.18 (br s, 2H).
MS: (M+H)+= 253.
Example 119 (t)-(2R 3S 5R 1'S~,-2-(1-Acetamido-2-(cis and traps)buten-1-yl)-3-(cis-propen-~~ pyrrolidine-5-carbox~rlic Acid Trifluoroacetic Acid Salt AcHN. N>., OtBU
H Boc O
119A (t)-(2R 3S 5R 1'S)-1-t Butoxycarbonyl-2-(1-Acetamido-2-(cis and traps)buten-1-yl)-3-(cis-pro.Len-1-yll ~wrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 20K, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester and ethyltriphenylphosphonium bromide for methyltriphenylphosphonium bromide (yield: 12.4 mg, 48.2%).
MS: (M+H)+= 423 /= , AcHN. N~.,~ H
H3C / N H p TFA
119B (t)-(2R.3S,5R,1'S~-2-(1-Acetamido-2-(cis and trans)buten-1-yl)-3-(cis-propen-1-yl~_pyrrolidine-5-carbox liy c Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-(cis and traps)buten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 11.8 mg, 100%).
' H NMR (DMSO-ds): 81.63 (dd, 3H), 1.66 (dd, 3H), 1.74 (m, 1 H), 1.88 (s, 3H), 2.41 (dt, 1 H), 3.17 (m, 1 H), 3.50 (dd, 1 H), 4.34 (dd, 1 H), 4.95 (m, 1 H), 5.23 (m, 1 H), 5.39 (m, 1 H), 5.53 (m, 1 H), 5.68 (m, 1 H), 8.21 (d, 1 H), 9.18 (br s, 2H).
MS: (M+H)+= 267 Example 120 {t~2R.3S,5R,1'S~ 2-(1-Acetamido-3,3-dimethyl)allyl-3-(cis-propen-1- rLl~
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN_ N~., O~Bu H Boc 120A (t)-(2R,3S,5R~1'S)-1-t Butox cy a~,rbonYl-2-(1-acetamido-3,3-dimethyl)all ~cis-propen-1-yl~-pyrrolidine-5-carboxylic Acid f-Butyl Ester The title compound was prepared according to the method described in Example 20K, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester and isopropyitriphenylphosphonium bromide for methyltriphenylphosphonium bromide (yield: 8.2 mg, 25.9%).
MS: {M+H)+= 437 AcHN_ N~.,~ H
/ H H
O
TFA
120B fit)-~2R,3S 5R.1'S)-2-(1-Acetamido-3.3-dimethyl)ally-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-3,3-dimethyi)allyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetarnido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
ester (yield: 7.5 mg, 100%).
'H NMR (DMSO-d6): 51.53 (dd, 3H), 1.57 (s, 3H}, 1.61 (s, 3H), 1.66 (m, 1 H), 1.77 (s, 3H), 2.32 (dt, 1 H), 3.07 (m, 1 H), 3.39 (dd, 1 H), 4.26 (m, 1 H), 4.75 (m, 1 H), 5.07 (d, 1 H), 5.15 (m, 1 H), 5.44 (m, 1 H), 8.06 (d, 1 H).
MS: (M+H)+= 281.
Example 121 (t) ~2R 3S 5R 1'S)-2-~1-Acetamido-2-(cis and traps)penten-1-yl)-3-lcis-propen-yl~pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt i= , AcHN. N,.,~ xBu H Boc 121A (t)-(2R 3S 5R 1'S)-1-f Butoxycarbonyi-2-(1-Acetamido -2-(cis and traps)penten-1-yl)-3-(cis-propen-1-~l-pyrrolidine-5-carboxylic Acid f-Butyl Ester The title compound was prepared according to the method described in Example substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-formyi)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-i-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid t butyl ester and ~n-butyl-triphenylphosphonium bromide for methyltriphenylphosphonium bromide (yield:
21.0 mg, 66.2%).
MS: (M+H)+= 437.

/_', AcHN. N~,~OH
/ H H
O
TFA
121B (t)-(2R,3S,5R,1'Sl-2-(1-Acetamido-2-(cis and trans)penten-1- Iy )-3~cis-propen-1-ylLp rr~ne-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-(cis and traps)penten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place ofi (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-{1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
ester (yield: 16.0 mg, 98.1 %).
'H NMR (DMSO-d6): 8 0.93 (t, 3H), 1.62 (dd, 3H), 1.75 (m, 1H), 1.87 {s, 3H), 2.07 (m, 2H). 2.40 (m, 1 H), 3.17 (m, 1 H), 3.50 (m, 1 H), 4.34 (m, 1 H), 4.94 (m, 1 H), 5.23 (m, 1 H), 5.34 (m, 1 H}, 5.53 (m, 1 H), 5.58 (m, 1 H), 8.24 (d, 1 H), 9.25 (br s, 2H).
MS: (M+H)+= 281.

Example 122 (t)-(2R.3S.5R.1'S)-2-(1-Acetamido-4-hydroxy-2-(cis and trans)buten-1-~)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN_ N~., O~Bu H Boc TBSO
122A (t)-(2R,3S.5R.1'S)-1-t-Butoxycarbonyl-2-{1-Acetamido-4-(t-butyldimeth~yloxY~2~cis and traps)buten-1-yl~cis-propen-1-~pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid t butyl ester and 4-(t-butyldimethylsilyloxy)-butyitriphenylphosphonium bromide for methyltriphenylphosphonium bromide {yield: 23.1 mg, 66.9%).
MS: (M+H)+= 567.

AcHN_ N~_,~OH
/ H H
HO O
TFA
1228 (t)-f2R.3S.5R.1'S)-2-(1-Acetamido-4-hydroxv-2-(cis and trans)buten-1-vl)-~cis-propen-1 yl~p~rrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-(cis and traps)-4-hydroxy-butenyl-2-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxyiic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 16.9 mg, >100%).
'H NMR (DMSO-d6): 61.67 (dd, 3H), 1.78 (dt, 1H), 1.91 (s, 3H), 2.44 (m, 1 H), 2.50 (m, 1 H), 2.56 (m, 1 H), 2.65 {m, 1 H), 3.23 (m, 1 H), 3.54 (m, 1 H), 4.40 (m, 1 H), 4.47 (m, 2H), 5.01 (m, 1 H), 5.26 (m, 1 H), 5.54 (m, 2H), 5.63 (m, 1 H), 8.32 (d, 1 H), 9.27 (br s, 2H).
MS: (M+H)+= 297.
Example 123 ft)~2R.3S.5R,1'S)-2~1-Acetamidolbuyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride TBDPSO-, iBu IH~ o Ph 123A (t)-(2R,3R,5R -1-Benzyl-2-vinyl-3-t-butyldiphenYlsilyioxymethYl-hyrrolidine-5-carboxylic Acid t-But~rl Ester.
(t)-(2R,3R,5R)-1-Benzyl-2-vinyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (30.8 g, 97.1 mmol) was reacted with t-butyldiphenylsilyl chloride (49.5 mL, 190.4 mmol) and imidazole in dichloromethane (650 mL) at 0 °C for 1 hour. The reaction was quenched methanol followed by extraction with dichloromethane (600 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2/1: chloroform/hexane to provide the title compound (yield: 52.9 g, 98%).
'H NMR (CDC13) 7.62-7.67 (m, 4H), 7.32-7.44 (m, 6H), 7.25-7.30 (m, 5H), 5.58-5.72 (m, 1 H), 5.06-5.14 (m, 2H), 3.90 (d, 1 H), 3.72-3.78 (m, 1 H), 3.58-3.68 (m, 2H), 3.44-3.52 (m, 2H), 2.26-2.40 (m, 1 H), 2.10-2.23 (m, 1 H), 1.68-1.78 (m, 1 H), 1.38 (s, 9H), 1.03 (s, 9H).
MS: (M+H)+=556 TBDPSO---HO N~,~O~Bu H
HO~ O
~Ph 1238 (t)-(2R,3R,y5R,1'RSl-1-Benzyl-2-(1.2-dihydroxy)eth butyld~henYlsilylo~,rmethyl-pyrrolidine-5-carboxylic Acid t-Bu I Ester.
{t)-(2R,3R,5R)-1-Benzyl-2-vinyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (22.7 g, 41 mmol) was reacted with Os04 (4%) (2.5 mL, 0.7 mol.%) and N-methyl morpholine N-oxide (18.5 g, 2.77 eq.) in acetone (500 mL) and water (60 mL) for 48h at room temperature. The reaction was quenched with 10% aqueous NaZS203 (200 mL). The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate/water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 35% ethyl acetate/hexane to provide the title compound (yield: 11 g, 55%).
'H NMR (DMSO-ds) s 7.58-7.63 (m, 5H), 7.40-7.48 (m, 7H), 7.20-7.35 (m, 3H), 4.41-4.45 (m, 2H), 3.98 (d, 1 H), 3.75-3.84 (m, 2H), 3.50-3.68 (m, 2H), 3.4-3.46 (m, 1 H), 3.16-3.25 (m, 1 H), 2.97-3.0 (m, 1 H), 2.09-2.28 (rn, 1 H), 1.62-1.89 {m, 1 H), 1.34-1.39 (m, 1 H), 1.30 (s, 9H), .98,.96 (2s, 9H).

MS: (M+H)+=590 TBDPSO~
HO N)-, ,OtBu HH pO
HO
123C (t)-(2R,3R,5R,1'RS)-2-X1,2-dihydroxy)ethy!-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3R,5R,1'RS)-1-Benzyl-2-(1,2-dihydroxy)ethyl-3-t-butyidiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (11 g, 18.7 mmol) was reacted under 1 atmosphere of hydrogen with 20% Pd(OH)2/C (5 g ) and in ethanol (40 mL) vigorously stirred for 2.5 days at room temperature.
The reaction was filtered, and the catalyst was washed with methanol (3x30 mL).
The filtrate was evaporated in vacuo to give the title compound as an oil (yield:
8 g, 94%) TBDPSO-, HO_ N,., OtBu H Boc HO
123D (t)-(2R 3R 5R 1'R)-1-t-Butoxycarbonyl-2-(1,2-dihydroxy)eth butt,rldiphenylsilyloxymethY-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 40D, substituting {t)-(2R,3R,5R,1'RS)-2-(1,2-dihydroxy)ethyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (2R,3R,5R,1'RS)-2-(1,2-dihydroxy)ethyl-3-acetoxymethyl-pyrroiidine-5-carboxylic acid t butyl ester. The residue was purified by column chromatography on silica gel using 35% ethyl acetate/hexane to provide the title compound {yield: 20.5 g, 60%).

'H NMR {DMSO-ds) 7.57-7.60 (m, 4H), 7.38-7.48 (m, 6H), 4.85,4.77 (2d, 1 H), 4.45-4.50 (m, 1 H), 4.02-4.10 (m, 1 H), 3.80-3.95 (m, 1 H), 3.73,3.68 (2s, 1 H), 3.45-3.67 (m, 2H),3.18-3.28 (m, 2H), 2.36-2.46 (m, 2H), 1:86,1.70 (2d, 1H), 1.40,1.35 (2s, 9H),1.32,1.26 (2s, 9H), 1.0,0.98 (2s, 9H).
MS: (M+H}+= 600 TBDPSO--Ms0_ N)., OtBu ~ Boc Ac0 123E (t)~2R 3R 5R 1'R)-1-t-Butoxycarbonyl-2-(1-methanesulfonyloxy-2-acetoxy)ethyl 3 t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
{t)-(2R,3R,5R,1'R)-1-t-Butoxycarbonyl-2-(1,2-dihydroxy)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (20.5 g, 34.2 mmole) was reacted with acetic anhydride (16.1 mL, 171 mmole) and triethylamine (47.7 mL, 342 mmole) in dichloromethane (360 mL) at 0°C
for 16h.
The reaction was treated with methanol (35 mL) for 10 minutes and diluted with dichloramethane (1300 mL). The organic layer was washed with water,and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was reacted with methanesulfonyl chloride (4.0 mL, 51.3 mmole) and triethylamine (14.3 mL, 103 mmole) in dichloromethane (350 mL) at 0°C for 1.5 hours.
The reaction was quenched with water (300 mL) and diluted with dichioromethane (1200 mL). The organic layer was washed with water,and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 30% ethyl acetatelhexanes to provide the title compound (yield: 23.8 g, 97%).

'H NMR (DMSO-d6) 87.58-7.62 (m, 4H), 7.38-7.50 {m, 6H), 5.12-5.26 (2m, 1 H), 4.06-4.25 (m, 3H), 4.00 (d, 1 H), 3.46-3.68 (m, 2H), 3.20,3.18 (2s, 3H), 2.40-2.48 (m, 1 H), 2.02,1.99, (2s, 3H), 1.68-1.88 (m, 1 H), 1.42,1.36 (2s, 9H), 1.31,1.25 (2s, 9H), 1.00,0.98 (2s, 9H).
MS: (M+H)+= 720, (M+NH4)+=737 TBDPSO-N ~ , ~O~Bu O H Boc O
123F (~~2R 3R 5R.1'S)-1-t Butoxycarbonyl-2-oxiranyl-3-f-butyldiphen rLlsilylox my ethyl pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3R,5R,1'S)-1-t Butoxycarbonyl-2-(1-methanesulfonyloxy-2-acetoxy)ethyl-3-t-butyidiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (23.8 g, 33.1 mmole) was reacted with potassium carbonate (10.1 g,66.2 mmole) in methanol (160 mL) and THF (160 mL) at 25 °C for 18 hours. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water,and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 25%
ethyl acetate/hexanes to provide the title compound, as an oil (yield: 16.7 g, 87%).
'H NMR (CDC13) 8 7.60-7.68 (m, 4H), 7.32-7.45 (m, 6H), 4.02-4.28 (m, 2H), 3.67-3.78 (m, 1 H), 3.52-3.62 {m, 1 H), 3.0-3.08 (m, 1 H), 2.68-2.75 (m, 1 H), 2.47-2.52 (m, 3H), 1.80-1.90 (m, 1 H), 1.48,1.42 (2s, 9H), 1.37,1.35 (2s, 9H), 1.07,1.03 (2s, 9H).
MS: (M+H)+= 582 HO-N>.,~O~Bu N Boc O
1236 (t)-(2R,3R.5R,1'S?-1-t Butoxycarbonyl-2-oxiranyl-3-hydroxymethyl-pyrrolidine-5-carbo Ix~Acid t-Butyl Ester.
(t)-(2R,3R,5R,1'S)-1-t-Butoxycarbonyl-2-oxiranyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (4.17 g, 7.2 mmole) was reacted with tetrabutylamrnonium fluoride (1 M) (14 mL, 14.0 mmole) in THF (7 mL) for 20 minutes at 0°C then for 1.5 hours at 25°C.
The reaction was concentrated in vacuo the residue was dissolved in ethyl acetate and washed with pH 7.0 buffer and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50%
ethyl acetate/hexanes to provide the title compound, as an oil (yield: 2.4 g, 97%).
' H NMR (DMSO-ds) 8 4.72-4.78 (m, 1 H), 3.94-4.05 (m, 2H), 3.35-3.47 (m, 1 H), 3.18-3.28 (m, 1 H), 3.03-3.08 (m, 1 H), 2.63-2.73 (m, 1 H), 2.37-2.44 (m, 1 H), 2.30-2.36 (m, 1 H), 2.08-2.20 (m, 1 H), 1.58-1.75 (m, 1 H), 1.40 (s, 9H), 1.37,1.34 (2s, 9H).
MS: (M+H)+= 344, (M+Na)+= 366 H
O~
N'. , ~OtBu O ~ Boc O
123H (t)-(2R.3R,5R,1'Sl-1-t-Butoxycarbonyl-2-oxiranyl-3-formyl-pyrrolidine-5-carboxylic Acid t-But)rl Ester.
(t)-(2R,3R, 5R,1'S)-1-t-Butoxycarbonyl-2-oxiranyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (2.4 g, 7.0 mmole) and triethyiamine (3.9 mL 28.0 mmole) in dichloromethane (70 mL) at 0°C was reacted with sulfur trioxide pyridine complex (3.35 g, 21.0 mmole) in dimethylsulfoxide (21 mL) by dropwise addition followed by reaction for an additional 3 hours. The reaction was quenched with water (50 mL) and diluted with ethyl acetate (200 mL). The organic layer was washed with water,and brine, dried over MgSOa, filtered and concentrated in vacuo to provide the title compound (yield: 2.2 g,).
' H NMR (DMSO-ds) (rotamers) 8 9.58 and 9.56 (2s, 1 H), 4.70 and 4.53 (2m, 1 H), 3.96 (dd, J=1.4, 9.2 Hz, 1 H), 3.25-3.20 {m, 1 H), 2.91 (m, 1 H), 2.71 (m, 1 H), 2.50-2.28 (m, 3H), 1.42, 1.37, 1.34, and 1.30 (4s, 18H) MS: (M-H)~ = 340 N ). , ~O=Bu O H Boc O
1231 (t~-(2R.3S.5R,1'S)-1-t-Butoxycarbonyl-2-oxiran I-y 3vinyl-pyrrolidine-5-carboxylic Acid t-Butyi Ester.
Triphenylphosphoranylidenemethyl ylide (17.6 mmole) prepared by reacting methyltriphenylphosphonium bromide (12.63 g, 35.4 mmole) and potassium tert-butoxide (1 M) (17.6 mL, 17.6 mmoie) in THF (70 mL) for 1 hour at 25°C. (t)-(2R,3R,5R,1'S)-1-t Butoxycarbonyl-2-oxiranyi-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester (2.2 g, 6.5 mmole) in THF (10 mL) was added to the above solution at 0°C and stirred for 0.5 hours. The reaction was quenched with saturated ammonium chloride (50 mL) and diluted with ethyl acetate (200 mL).
The organic layer was washed with water,and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 10% ethyl acetatelhexanes to provide the title compound (yield: 2 g, 84%).
'H NMR (DMSO-ds) 8 5.80-5.95 (m, 1 H), 5.08 (d, 1 H), 4.94-5.04 (1 H), 4.00-4.07 (m, 1 H), 3.59,3.90 (2t, 1 H), 3.07-3.16 (m, 1 H), 2.73-2.81 (m, 1 H), 2.65-2.72 (m, 1 H), 2.35-2.48 (m, 1 H), 1.59-1.76 (m, 1 H), 1.42 (s, 9H), 1.38,1.35 (2s, 9H).
MS: (M+H)+ = 340 Ms0 N,-, ~ tBu H Boc ~

123J (t)-(2R.3S 5R 1'R1-1-t Butoxycarbonyl-2-(1-methanesulfonyloxy-3-azido eth I-~~rl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R, 3S,5R,1'S)-1-t-Butoxycarbonyl-2-oxiranyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (1.72 g, 5.1 mmole) and ammonium chloride (1.36 g, 25.4 mmole) in ethanol (45 mL) and water (5 mL) was reacted with lithium azide (1.2 g, 24.5 mmoie) for 7 hours at 50°C. The reaction was concentrated in vacuo and diluted with ethyl acetate (200 mL). The organic layer was washed with water,and brine, dried over MgS04, filtered and concentrated in vacuo. The residue (2.15 g) was dissolved in dichloromethane (50 mL) and reacted with methanesulfonyl chloride (0.8 mL, '10.2 mmole) and triethylamine (2.8 mL, 20.4 mmole) for 0.5 hours at 0°C. The reaction was quenched with aqueous sodium bicarbonate (50 mL) and diluted with ethyl acetate (200 mL). The organic layer was washed with water,and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 10%
ethyl acetatelhexanes to provide the title compound (yield: 1.87 g, 80%).
'H NMR (DMSO-ds) s 5.77-5.98 (m, 1H), 4.94-5.11 (m, 3H), 4.12-4.19 (m, 1 H), 3.99-4.06 (m, 1 H), 3.66,3.71 (2d, 1 H), 3.25,3.22 (2s, 3H), 2.92-3.02 (m, 1 H), 2.55-2.63 (m, 1 H), 1.68-1.82 (m. 1 H), 1.45,1.42 (2s, 9H), 1.38,1.36 (2s, 9H).
MS: (M+H)+= 461 N,. , ~OtBu HN~ H goc 123K (t)-(2R,3S.5R.1'S1-1-t Butoxycarbonyl-2-aziridin I-vinyl-p r~lidine-5-carboxylic Acid t-Bu I Ester.
(t)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(1-methanesulfonyioxy-3-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (2.12 g, 4.6 mmole) was reacted with triphenylphosphine (1.81 g, 6.9 mmole) in THF (30 mL) and water (7.5 mL) at 65°C for 1 hour. The reaction was concentrated in vacuo and redissolved in ethyl acetate (200 mL). The organic layer was washed with water,and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 4% methanol in dichloromethane to provide 2 g of the crude title compound containing approximately 60% product and 40% Ph3P0 which was used directly for acylation.

' H NMR (DMSO-ds) 8 5.78-5.5.98 (m, 1 H), 4.12 (d, 1 H), 3.42,3.19 {2d, 1 H), 2.53-2.73 (m, ZH), 2.00-2.15 {m, 1 H), 1.68-1.76 (m, 1 H), 1.62-1.68 (m, 1 H), 1.41 (s, 9H), 1.37,1.36 (2s, 9H).
MS: (M+H)+ = 339, {M+Na)+ = 361 N>. , ~O~gu AcN~ H goc 0 123L (t~2R.3S 5R.1'S}-1-t-Butoxycarbonyl-~N-acetylaziridinyl -3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (1.03 g, 3.1 mmole) was reacted with acetic anhydride (.42 mL, 4.7 mmoie) and triethylamine (1.3 mL, 9.3 mmole) in dichloromethane (30 mL) at 25°C for 1 hours. The reaction was quenched with water (50 mL) and diluted with ethyl acetate (200 mL). The organic layer was washed with water,and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 20%
ethyl acetate/hexanes to provide the title compound (yield: .75 g, 64%).
' H NMR (DMSO-ds) 8 5.78-5.98 (m, 7 H}, 5.05 (d, 1 H), 4.98,4.94 (2d, 1 H), 4.12-4.20 (m, 1 H), 3.54,3.42 (2dd, 1 H), 2.54-2.98 (m, 3H), 2.40,2.49 (2d, 1 H), 2.15,2.19 (2d, 1 H), 2.02,2.04 (2s, 3H), 1.68-1.82 (m, 1 H), 1.42 (s, 9H), 1.48.1.45 (2s, 9H).
MS: (2M+Na)+= 783 AcN. N,. O~Bu H Boc 123M (tl-(2R 3S 5R 1'S)-1-t-Butoxycarbony~1-acetamido)butyl-3-vinyl-pYrrolidine-5-carboxylic Acid t-Butyl Ester.
To a suspension of copper(I) bromide-dimethyl sulfide complex (0.0518, 0.248 mmol) in THF (1.0 ml) at 0°C was added ethylmagnesium bromide (1M) (1.0 ml, 1.0 mmol) in THF. After stirring for 10 minutes at 0 °C, a portion of this solution (0.60 ml) was added dropwise to a solution of (t)-(2R,3S,5R,1'S)-1-t Butoxycarbonyl-2-(N-acetylaziridinyl)-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (0.020 g, 0.053 mmole) in THF (0.40 ml) at -78°C. After stirring for 20 minutes at -78°C, the reaction was warmed to 0 °C and stirred for 30 minutes.
The reaction was quenched with saturated ammonium chloride {1.0 mL) and diluted with ethyl acetate (10 mL). The organic layer was washed with water and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using a gradient of 0-75% ethyl acetate/hexanes to provide the title compound (yield: 0.004 g, 19%).
' H NMR (DMSO-ds) (rotamers) 8 7.48 (d, J=9.5Hz, 1 H), 5.98-5.80 (m, 1 H), 5.00-4.90 (m, 2H), 4.45-4.25 (m, 1 H), 3.96-3.91 (m, 1 H), 3.60-3.57 and 3.53-3.50 (2m, 1 H), 2.91-2.76 (m, 1 H), 2.59-2.42 (m, 1 H), 1.80 (s, 3H), 1.73-1.59 (m, 1 H), 1.42 and 1.41 (2s, 9H), 1.40-1.15 (m, 4H), 1.37 and 1.34 (2s, 9H), 0.89-0.82 {m, 3H) MS: (M-H)-= 409, (M+H)+= 411 AcHN_ N,.,~OH
H H
O
HCI
123N (t)-~2R.3S,5R,1'Sl-2-f 1-Acetamido)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloric Acid Salt The title compound was prepared according to the method described in Example 1K, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido)butyl-3-vinyl-pyrrolidine-5-carboxylic acid t butyl ester in place of (2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 3.1 mg, 99%).
'H NMR (DMSO-d6) 8 8.11 (d, J=7.3Hz, 1 H), 5.76-5.69 (m, 1 H), 5.16 (d, J=17.1 Hz, 1 H), 5.07 (dd, J=1.5, 10.3Hz, 1 H), 4.30 (dd, J=7.3, 9.8Hz, 1 H), 4.13 (m, 1 H), 3.50 (dd, J=5.9, 9.8Hz, 1 H), 2.90 (m, 1 H), 2.39 (m, 1 H), 1.92-1.85 (m, 1 H), 1.87 (s, 3H), 1.52-1.18 (m, 4H), 0.85 (t, J=7.3, 3H) MS: (M-H)-= 253, (M+H)+= 255 Examples 124-130 1. Organocuprate Otg~ AcHN_ ).,~OH
AcN~ ' N~ 'j~ 2. 6N HCI H N
H Boc O R H O
HCI
The following title compounds were prepared in two steps according to the methods described in Examples 123M and 123N, the denoted reagents and their respective methods of preparation are substituted in place of diethylcuprate and its preparation in Example 123M for step 1.
Example 124 AcHN. N~,~OH
H H
O
t~Ci (t)-(2R,3S,5R.1'S~-2-(1-Acetamido)hexyl-3-vinyl-pyrrolidine-5-carboxv iii c Acid Hydrochloric Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to the methods described in Example 123M, substituting 2M butylrnagnesium chloride for 1 M ethylmagnesium bromide.
' H NMR (MeOD-ds) 8 5.82-5.70 (m, 1 H), 5.29 (d, J=17.OHz, 1 H), 5.17 (dd, J=1.3, 10.2Hz, 1 H), 4.35 (dd, J=7.5, 10.2Hz, 1 H), 4.19 (m, 1 H), 3.65 (dd, J=3.4, 9.8Hz, 1 H), 3.01 (m, 1 H), 2.55 (m, 1 H), 2.08-1.97 (m, 1 H), 2.04 (s, 3H), 1.62-1.31 (m, 8H), 0.91 (t, J=6.4Hz, 3H) MS: (M-H)- = 281, {M+H)+ = 283 Example 125 AcHN. N~.,~OH
H H
O
HCI
(t~~2R.3S,5R.1'S -~-Acetamido-4-meth~pentyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloric Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to the methods described in Example 123M, substituting iso-butylmagnesium chloride for ethylmagnesium bromide..
' H NMR (MeOD-d3) s 5.83-5.71 (m, 1 H), 5.29 (dd, J=0.7,17.OHz, 1 H), 5.17 (dd, J=0.7, 10.2Hz, 1 H), 4.34 (dd, J=7.5, 10.2Hz, 1 H), 4.15 (m, 1 H), 3.66 (dd, J=3.4, 9.8Hz, 1 H), 3.01 (m, 1 H), 2.55 (m, 1 H), 2.08-1.97 (m, 1 H), 2.04 (s, 3H), 1.65-1.10 (m, 5H), 0.91 (d, J=6.4Hz, 3H), 0.91 (d, J=6.5Hz, 3H) (M+H)+= 283 Example 126 AcHN. N~.,~ H
H H
O
HCI
{t)-(2R 3S 5R 1'S)-2-(1-Acetamido-3.3dimethyl~bu I-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloric Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to the methods described in Example 123M, substituting 1 M tert-butylmagnesium chloride for 1 M ethylmagnesium bromide.
' H NMR (MeOD-d3) 8 5.84-5.71 {m, 1 H), 5.31 (d, J=17.OHz, 1 H), 5.19 (d, J=10.2Hz, 1 H), 4.39-4.33 (m, 2H), 3.66 (dd, J=3.4, 9.8Hz, 1 H), 3.02 (m, 1 H), 2.57 (m, 1 H), 2.08-1.97 (m, 1 H), 2.02 (s, 3H), 1.55 (dd, J=9.5, 14.6Hz, 1 H), 1.42 (dd, J=1.4, 14.6Hz, 1 H), 0.95 (s, 9H) (M+H)+ = 283 Example 127 ~OH
O
AcH N .
~ N
H
HCt (t)-(2R 3S 5R 1'S~2-(1-Acetamido-2-phen~)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloric Acid Salt Lithium diphenylcurpate was prepared according to the method described by Lipshutz, B. H. in Org.,anometallics in Synthesis; Schlosser, M., Ed.;
Wiley and Sons: New York, 1994; p.292. This cuprate was used according to the methods described in Example 123M, substituting lithium diphenylcuprate for the Grignard derived diethylcuprate complex.
'H NMR (MeOD-d3) 8 7.35-7.21 (m, 5H), 5.87-5.75 (m, 1H), 5.37 (d, J=16.6Hz, 1 H), 5.26 (dd, J=1.0, 10.2Hz, 1 H), 4.53 (m, 1 H), 4.37 (dd, J=7.5, 9.8Hz, 1 H), 3.70 (dd, J=3.7, 9.8Hz, 1 H), 3.11 (m, 1 H), 2.97 (dd, J=6.1, 14.2Hz, 1 H), 2.84 (dd, J=9.5, 14.2Hz, 1 H), 2.59 (m, 1 H), 2.08-1.99 (m, 1 H), 1.93 (s, 3H) (M-H)-= 301. (M+H)+ = 303 Example 128 ~OH
O
(t)-(2R.3S.5R,1'S)-2-(1-Acetamido-4-phenyl~butyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloric Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to the methods described in Example 123M, substituting 1 M phenethylmagnesium chloride for 1 M ethylmagnesium bromide.
~~H NMR (MeOD-d3) s 7.29-7.13 (m, 5H), 5.77-5.65 (m, 1H), 5.24 (d, J=16.6Hz, 1 H), 5.13 (dd, J=1.0, 9.8Hz, 1 H), 4.33 (dd, J=7.5, 10.2Hz, 1 H), 4.22 (m, 1 H}, 3.62 (dd, J=3.4, 9.8Hz, 1 H), 2.98 (m, 1 H}, 2.63 (m, 2H), 2.54 (m, 1 H), 2.06-1.95 (m, 1 H), 2.03 (s, 3H), 1.79-1.55 (m, 4H) (M-H)-= 329, (M+H)+= 331 Example 129 AcHN. N~.,~ H
H H
O
HCI
(t)-(2R 3S 5R 1'S)-2~1-Acetamido-3-phenyl)butyl-3-vinyl-ayrrolidine-5-carboxylic Acid Hydrochloric Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to the methods described in Example 123M, substituting 2M benzylmagnesium chloride for 1 M ethylmagnesium bromide.
'H NMR (MeOD-d~) b 7.30-7.17 {m, 5H), 5.82-5.70 (m, 1H), 5.28 (d, J=17.OHz, 1 H), 5.17 (d, J=11.2Hz, 1 H), 4.33 (dd, J=7.5, 10.2Hz, 1 H), 4.18 (m, 1 H), 3.64 (dd, J=3.4, 9.8Hz, 1 H), 3.01 (m, 1 H), 2.78 (m, 1 H), 2.66-2.50 (m, 2H), 2.07 (s, 3H1, 2.07-1.85 (m, 3H) (M-H)-= 315, (M+H)+ = 317 Example 130 {t~2R,3S.5R,1'S)-2-(1-Acetamido-2-propen-2-yl)ethyl -3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt N>.., ~OtBu BocN~ H Boc p 130A lt)-(2R.3S,5R.1'S)-1-t Butoxycarbonyl-2-(N-t Butoxycarbonylaziridin I~-3-vinyl-pyrrofidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (0.058 g, 0.17 mmole) was reacted with di-t-butyldicarbonate (95 mg, 0.44 mmole) and triethylamine (0.12 mL, 0.86 mmofe) in dichloromethane (2.0 mL) at room temperature for 1 hour. The reaction was quenched with saturated sodium bicarbonate (1.0 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with water,and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using a gradient of 0-15% ethyl acetate/dichloromethane to provide the title compound (yield: 0.060 g, 80%).
'H NMR (DMSO-d6) (rotamers) 8 5.97-5.78 (m, 1H), 5.06-4.93 (m, 2H), 4.15 (dd, J=2.0, 9.8Hz, 1 H), 3.40-3.28 (m, 1 H), 2.94-2.49 {m, 3H), 2.39 and 2.33 (2d, J=6.1, 6.4Hz, 1 H), 2.17 and 2.11 (2d, J=3.7, 3.4, 1 H), 1.81-1.69 (m, 1 H), 1.42-1.36 (m, 27H) MS: (M+Na)+= 461 (weak) BocHN. N>., O~Bu H Boc 130B (t)-(2R,3S.5R.1'S~1-f-Butoxycarbony~1-N-f-butoxycarbonylamino-2-propen-2- Iy )ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
To a suspension of copper(I) bromide-dimethyl sulfide complex (0.0268, 0.127 mmol) in THF (1.0 ml) at 0 °C was added isopropenylmagnesium bromide (0.5M) (1.0 ml, 0.50 mmol) in THF. After stirring for 10 minutes at 0 °C, the mixture was cooled to -78 °C and a solution of (t)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(N-t butoxycarbonylaziridinyi)-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (0.030 g, 0.068 mmole) in THF (1.0 ml) was added dropwise.
After stirring for 10 minutes at -78°C, the reaction was warmed to 0 °C and stirred for 2 hours. The reaction was quenched with saturated ammonium chloride (1.0 mL) and diluted with ethyl acetate (10 mL). The organic layer was washed with water,and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using a gradient of 0-10%
ethyl acetateldichloromethane to provide the title compound (yield: 0.026 g, 79%).
H NMR {DMSO-ds) (rotamers) 8 6.64 (m, 1 H), 5.96-5.76 (m, 1 H), 4.98-4.89 (m, 2H), 4.76-4.68 (m, 2H), 4.40-4.25 (m, 1 H), 3.94 (m, 1 H), 3.60-3.53 (m, 1 H), 3.02-2.86 (m, 1 H), 2.62-2.42 (m, 1 H), 2.10-1.99 (m, 2H), 1.72 and 1.70 (2s, 3H), 1.72-1.55 (m, 1 H), 1.44-1.34 (m, 27H) MS: (M-H)-= 479, (M+H)+= 481 Ac BocN. N>., O~Bu H Boc 130C (t)-(2R,3S,5R.1'S)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-propen-2-~ ethyl -3-vinyl-pyrrolidine-5-carboxylic Acid t-Butter.
{t)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2-propen-2-yl)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (0.024 g, 0.050 mmole) was reacted with lithium hexamethyldisilazide (1 M) (0.60 mL, 0.60 mmoie) in THF (2.0 mL) at -25°C for 1 hour. To the above reaction was then added acetyl chloride (0.085 mL, 1.20 mmole) at -25°C and the mixture was stirred for 30 minutes. The reaction was quenched with saturated sodium bicarbonate (2.0 mL) and stirred for 30 minutes at room temperature. The reaction was diluted with ethyl acetate (20 mL). The organic layer was washed with water,and brine, dried over MgSO4, filtered and concentrated in vacuo.
The residue was purified by chromatography on silica gel using a gradient of 0-15%
ethyl acetate/hexanes to provide the title compound {yield: 0.015 g, 58%) along with unreacted starting material.
'H NMR {DMSO-dfi) (rotamers) 8 6.01-5.84 (m, 1H), 4.99-4.89 (m, 2H), 4.76-4.58 (m, 3H), 4.33 and 4.23 (2d, J=7.8, 8.1 Hz, 1 H), 4.13-4.04 (m, 1 H), 2.69 (m, 1 H), 2.62-2.42 (m, 1 H), 2.29 (br s, 3H), 2.35-2.14 (m, 2H), 1.76-1.55 (m, 1 H), 1.60 (s, 3H), 1.50-1.35 (m, 27H) MS: (M+H)+= 523 AcHN. N~.,~OH
H H
O
TFA
130D (t)-(2R.3S,5R.1'S)-2-(1-Acetamido-2-propen-2-yl)ethyl -3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-{2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-propen-2-yl)ethyl -3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester. (yield: 12 mg, 99%).
t H NMR (MeOD-d3) 8 5.83-5.70 (m, 1 H), 5.30 (dd, J=0.7, 17.OHz, 1 H), 5.19 (d, J=10.2Hz, 1 H), 4.79 (s, 1 H), 4.71 (s, 1 H), 4.46 (m, 1 H), 4.30 (dd, J=7.8, 9.8Hz, 1 H), 3.66 (dd, J=3.7, 9.8Hz, 1 H), 3.03 (m, 1 H), 2.56 (m, 1 H), 2.40-2.19 (m, 2H), 2.08-1.96 (m, 1 H), 2.01 (s, 3H), 1.76 (s, 3H) (M-H)-= 265, (M+H)+ = 267 Examples 131-135 t. Organocuprate OtBu AcHN. ,.,~OH
2. I.iHMDS ' ~ N
BocHN~ H goc ~ 3. Acct H H
4. TFAICHzCIy R O
TFA
The following title compounds were prepared in 4 steps according to the methods described in Example 130 the denoted reagents for step 1 and their respective methods of preparation are substituted in place of isopropenyl cuprate and its preparation in 1308 Example 131 _-, AcHN_ N,.,~OH
H H

TFA
(t)-(2R 3S 5R 1'S)-2-(1-Acetamido-1-(cis and traps)-propen-1-yl)ethyl-3-vinyl-p~rrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(/) bromide-dimethyl sulfide complex according to the methods described in Example 1308, substituting 0.5M 1-propenylmagnesium bromide (mixture of cis and traps isomers) for 0.5M isopropenylmagnesium bromide.
'H NMR (MeOD-d3) (2:1 trans:cis ratio) 8 5.81-5.54 (m, 2H), 5.43-5.30 (m, 1 H), 5.33-5.27 (m, 0.33H, cis isomer), 5.31-5.25 (m, 0.66H, frans isomer), 5.20-5.15 (m, 1 H), 4.26-4.17 (m, 2H), 3.65 (dd, J=3.4, 9.8Hz, 1 H), 2.98 (m, 1 H), 2.58-2.48 (m, 1 H), 2.45-2.19 (m, 2H), 2.08-1.94 (m, 1 H), 2.02 (s, 3H), 1.68 (m, 2H, traps isomer), 1.63 (m, 1 H, cis isomer) (M-H)-= 265, (M+H)' = 267 WO 99/54299 PCTlUS99/07945 Example 132 AcHN. N~.,~ H
H H
O
TFA
!t)-f2R.3SL5R,1'S~2-~1-Acetamido-2-allyllmeth I-3-vinyl-pyrrolidine-5-carbox~c Acid Trifluoroacetic Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to the methods described in Example 1308, substituting 1 M vinylmagnesium bromide for 0.5M isopropenylmagnesium bromide.
'H NMR (Me~D-ds) 8 5.83-5.70 (m, 2H), 5.28 (d, J=17.OHz, 1 H), 5.19-5.'13 (m, 3H), 4.28 (m, 1 H), 4.19 (dd, J=8.5, 9.1 Hz, 1 H), 3.66 (dd, J=3.4, 9.5Hz, 1 H), 2.99 (m, 1 H), 2.57-2.48 (m, 1 H), 2.44-2.26 (m, 2H), 2.05-1.93 (m, 1 H), 2.01 (s, 3H) (M+H)+ = 253 Example 133 AcHN. N~.,~OH
H H
O
TFA
(t~2R,3S,5R,1'S)-2-(1-Acetamido)-2-(1-buten-2-yl)ethyl-3-vinyl-~ rroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to the methods described in Example 1308, substituting 0.5M 1-buten-2-ylmagnesium bromide for 0.5M isopropenylmagnesium bromide.
'H NMR (MeOD-d3) 8 5.81-5.73 (m, 1 H), 5.30 (d, J=17.1 Hz, 1 H), 5.19 (d, J=10.OHz, 1 H), 4.93 (s, 1 H), 4.83 (s, 1 H), 4.45 (m, 1 H), 4.31 (dd, J=7.6, 9.8Hz, 1 H), 3.69 (dd, J=3.2, 9.8Hz, 1 H), 3.03 (m, 1 H), 2.59-2.53 (m, 1 H), 2.38 (dd, J=5.9, 14.9Hz, 1 H), 2.30 (dd, J=9.5, 14.9Hz, 1 H), 2.07 (q, J=7.6Hz, 2H), 2.05-1.99 (m, 1 H), 2.01 (s, 3H), 1.05 (t, J=7.6Hz, 3H) (M+H)+= 281 Example 134 AcHN. >..,~ H

O

fit)-(2R.3S.5R 1'S)-2-(1-Acetamido-2-(trans-2-buten-2- rLl)ethyl-3-vinyl-pyrrolidine-5-carbolic Acid Trifluoroacetic Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to the methods described in Example 1308, substituting 0.5M 1-methyl-1-propenylmagnesium bromide for 0.5M isopropenylmagnesium bromide.
'H NMR (MeOD-d3) 8 5.83-5.71 (m, 7 H), 5.41 (q, J=6.8Hz, 1 H), 5.31 (d, J=17.3Hz, 1 H), 5.19 (d, J=10.2Hz, 1 H), 4.42 (m, 1 H), 4.31 (dd, J=7.5, 9.8Hz, 1 H), 3.61 (dd, J=4.0, 9.8Hz, 1 H), 3.01 (m, 1 H), 2.62-2.52 (m, 1 H), 2.46 (dd, J=9.5, 13.9Hz, 1 H), 2.26 (dd, J=5.8, 13.9Hz, 1 H), 2.09-1.99 (m, 1 H), 2.00 (s, 3H), 1.72 (s, 3H), 1.59 (d, J=6.8Hz, 3H) (M+H)+ = 281 Example 135 AcHN. N~.,~OH
H H
O
TFA
~t~-(2R 3S 5R.1'S.3'RS}-2-f 1-Acetamido-3-methyl)pentyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(I) bromide-dimethyl sulfide complex according to the methods described in Example 1308, substituting 2M sec-butylmagnesium bromide for 0.5M isopropenylmagnesium bromide.
' H NMR (MeOD-d3) (1:1 mixture of methyl isomers) 8 5.82-5.69 (m, 1 H), 5.27 (d, J=17.OHz, 0.5H), 5.25 (d, J=17.OHz, 0.5H), 5.15 (d, J=10.2Hz, 1 H), 4.33 (m, 1 H), 4.18 (dd, J=2.7, 7.5Hz, 0.5H), 4.15 (dd, J=3.0, 7.8Hz, 0.5H), 3.62 (dd, J=3.1, 9.8Hz, 0.5H), 3.57 (dd, J=4.07, 9.8Hz, 0.5H), 2.97 (m, 1 H), 2.57-2.47 (m, 1 H), 2.03-1.92 (m, 1 H), 2.03 (s, 1.5H), 2.02 (s, 1.5H), 1.72-1.06 (m, 5H), 0.95-0.86 (m, 6H) (M+H)+ = 283 Example 136 (t)-(2R 3S 5R.1'RS)-2-(1-Acetamido-1-{N-methyl-N-benzylcarbamoyl)methyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN. N~.., OtBu H Boc HO O
136A (t)-(2R.3S 5R 1'R)-1-t-Buto~rcarbonyl-2-(1-acetamido-1-carboxyl)methyl-3-vinyl-pyrrolidine-5-carboxylic Acid t Bu I Ester The title compound was prepared according to the method of Example 2B
substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-1-formyl)methyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester for (t)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester.
AcHN ~. OtBu N T~
Phi H Boc 'O
N O

1368 (t)-l2R 3S 5R.1'RS)-1-t-Butox~carbonyl-2-~1-acetamido-2-lN-methyl-N-benzylcarbamoyl meth-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester (t)-(2R, 3S,5R,1'R)-1-t-Butoxycarbonyl-2-( 1-acetamido-1-carboxyl)methyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (36 mg, 0.09 mrnole) was reacted with N-methyl-N-benzylamine (32 mg, 0.26 mmole), dimethylaminopyridine (1mg, 0.008 mmole) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30mg, 0.16mmole) in DMF (3 mL) at 25°C
for 16 hours. The reaction was quenched with water (3 mL) and diluted with ethyl WO 99!54299 PCT/US99/07945 acetate ( 20mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetatelhexanes to provide the title compound.
MS: (M+H)+=516, (M-H)- =514 AcH , ~OH
CH3 ~ O O
TFA
Ph 136C (t)-(2R.3S 5R.1'RS)-2-(1-Acetamido-1-(N-methyl-N-benzylcarbamoyl)methyl-3-vi ~I-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41 C, substituting (t)-(2R,3S,5R,1'RS)-1-t-butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-benzylcarbamoy!)methyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl}-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 7 mg, 95%).
' H NMR (DMSO-ds) 8 8.52( d, J=9.7HZ, 1 H), 7.30( m, 5H), 5.65( m, 1 H), 5.12(m, 4H), 4.62(m, 1 H), 4.40(m, 2H), 3.70(m, 1 H), 2.90(s, 3H), 2.20(m, 2H), 1.96(s, 3H), MS: (M+H)+=360, (M+23)+ =382 N
H N
H

Example 138 (t)-(2R 3S 5R 1'R)-2-(1-Acetamido-2-(N phenyl-carbonylox)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcH , ~OtBu O O
Ph.N~O
H
138A lt)-(2R 3S,5R,1'R)-1-t Butoxycarbonyl-2-(1-acetamido-2-N-phenyl-carbonyloxy)ethyl-3-vinyl:pyrrolidine-5-carboxylic Acid f Butyl Ester (t)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-vinyl-pyrroiidine-5-carboxylic acid t-butyl ester (18 mg, 0.045 mmofe) was reacted with phenylisocyanate (16 mg, 0.14 mmole) and pyridine(0.1 ml) in THF (3 mL) at 25°C for 16 hours. The reaction was quenched with water (2 mL) and diluted with ethyl acetate (10 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound (yield:7.5 rng, 33%).
MS: (M+H)+=518, (M-H)- =516 N.
N
H Boc --, AcHN. N~.,~ H
H H
O O
O"N-Ph rFA
H
138B (t)-(2R,3S.5R,1'R)-2-(1-Acetamido-1-(N-phenylcarbonyloxy)ethyl-3-vinyl pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-N-phenyl-carbonyloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 4 mg, 95%).
'H NMR (DMSO-ds) d 8.36( d, J=9.7HZ, 1 H), 7.30(m, 5H), 5.78(m, 1 H), 5.22(m, 1 H), 5.10(m, 1 H), 4.58(m, 1 H), 4.45(m, 1 H), 4.14(, 2H), 3.58(m, 1 H), 2.88( m, 1 H), 2.27(m, 1 H), 2.12(m, 1 H), 1.88(s, 3H) MS: (M+H)+=362, (M+23)+ =384, (M-H)- =360, (M+35)- =396 Example 139 (t)-(2 R, 3S, 5R,1 'R~-~-( 1-Acetamido-1-isobutyr)rloxy)ethyl-3-vinyl-p~rrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN. N,., OtBu ~Boc O
139A ~t)-(2R.3S,5R,1'R~-1-t-Butoxycarbonyl-2-(1-acetamido-2-isobutyryloxy)eth~rl-3-vinyl-p~rrrolidine-5-carboxylic Acid t-Bu I Ester (t)-(2R,3S,5R,1'R)-1-t Butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (15 mg, 0.04 mmole) was reacted with isobutyryl chloride (8 mg, 0.08 mmole) and triethylamine (8 mg, 0.08 mmole) in dichloromethane (4 mL) at 0°C for 2 hours. The reaction was quenched with water (3 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 30%
ethyl acetatelhexanes to provide the title compound (yield: 11 mg, 63%).
MS: (M+H)+=469, (M-H)- =467 AcH , ~O H
O O
TFA
O
1398 (t)-(2R,3S.5R,1'R)-2-(1-Acetamido-1-isobutyrYloxY ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-isobutyryloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield:
6.0 mg, 96%).
'H NMR (DMSO-ds) 8 8.00( d, J=9.9HZ, 1 H), 5.63(m, 1 H), 5.08(m, 1 H), 4.98(m, 1 H), 4.35(m, 1 H), 4.25(m, 1 H), 4.08(m, 1 H), 3.55(m, 1 H), 3.45(m, 1 H), 3.38(m, 1 H), 2.83(m, 1 H), 2.33(m, 1 H), 1.78(s, 3H) MS: (M+H)+ =243, (M+23)+ =265, (M-H)- =241 N.
H N
H

Example 140 (t)-(2R,3S.5R.1'R}-2 ~1-Acetamido-2-N-ethyl-thiocarbonYloxy ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt -, AcHN. N>., O~Bu H Boc O
N
S~ --~
H
140A (t)-(2R.3S,5R,1'R}-1-t Butoxycarbonyl-2-(1-Acetamido-2-N-ethyl-thiocarbonyloxy)ethyl-3-vinyl pyrrolidine-5-carbox~ic Acid t-Butyl Ester (t}-(2R,3S,5R,1'R)-1-t Butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (17 mg, 0.04 mmole) was reacted with ethylisothiocyanate ( 19 mg, 0.21 mmole) in pyridine (2 mL) at 70°C for 17 hours. The reaction was quenched with water (3 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 70% ethyl acetate/hexanes to provide the title compound (yield: 10 mg, 48%).
MS: (M+H)+=486, (M+23)' =508, (M-H)- = 485 AcH , ~ H
O O
S~N~ TFA
H
140B (t)-12R.3S.5R,1'R)-2-(1-Acetamido-2-N-ethyl-thiocarbon~y)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-N-ethyl-thiocarbonyloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 7 mg, 94%).
' H NMR {DMSO-ds) 88.30(d, J=9.7HZ, 1 H), 5.78 (m, 1 H), 5.25(m, 1 H), 5.12(m, 1 H), 4.50(m, 1 H),4.33(m, 1 H), 4.18(m, 2H), 3.72(m, 1 H), 3.55(m, 2H), 2.30(m, 1 H), 2.10(m, 1 H), 1.82(s, 3H), 1.17(m, 3H) MS: (M+H)+ =330, (M-H)- =328 N.
H N
H

Example 141 ~t~2R,3S.5R,1'S -2-) (1-Acetamido-2-amino)ethyl-3-vinyi-pyrrolidine-5-carboxylic Acid HydrochlorideSalt -, AcHN_ N~, O~Bu H Boc BocHN
141A (t)-(2R,3S.5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-t-butoxycarbonylamino ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Bu I Ester.
(t)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (9.5 mg, 0.022 mmole} was reacted with triphenylphosphine (23.5 mg, 0.090 mmole) in ethanol (180 ~L) and water (45 ~.L) at 70°C for 30 minutes. The reaction mixture was concentrated in vacuo.
The residue was dissolved in dichloromethane (220 pL) and to it was added di-tert butyl Bicarbonate (7.3 mg, 0.034 mmol) and N,N-diisopropylethylamine (11.7 mL, 0.067 mmol) at 25°C. After 1 hour the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgS04, and concentrated in vacuo. The residue was purified by chromatography on silica gel using 100% dichloromethane to 50%
dichloromethane/ethyl acetate to provide the title compound (yield: 7.5 mg, 67%).
' H NMR (DMSO-ds) (rotamers) 8 7.51 (d, J=10.5Hz, 1 H), 6.80-6.66(m, 1 H), 5.90-5.76(m, 1 H), 5.02-4.90(m, 2H), 4.38-4.19(m, 1 H), 3.98-3.94(m, 1 H), 3.68-3.62(m, 1 H), 3.09-2.73(m, 2H), 2.60-2.42(m, 1 H), 1.80(s, 3H), 1.72-1.62(m, 1 H), 1.42-1.34(m, 27H).
MS: (M+H)+=498, (M+Na)+=520, (M-H)-=496, (M+CI)--532 AcH , ~ H
H2N 2 Hci 141 B ~t)-(2R.3S.5R.1'S,)-2-(1-Acetamido-2-amino ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid DiHydrochloride The title compound was prepared according to the method described in Example 1K, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-f-butoxycarbonylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyi-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 3.65 mg, 99%).
~H NMR (DMSO-ds) 8 8.24(d, J=7.9Hz, 1 H), 5.75-5.68(m, 1 H), 5.16(d, J=17.1 Hz, 1 H), 5.06{d, J=10.4Hz, 1 H), 4.37-4.27(m, 2H), 3.60-3.16(m, 2H), 3.00-2.88(m, 2H), 2.46-2.36(m, 1 H), 1.91-1.81 (m, 1 H), 1.86(s, 3H).
MS: (M+H)+=242, (M+Na)+=264, (M-H)-=240, (2M-H)-=481 N_ H N
H

Example 142 jt)-(2R, 3S.5R,1 'Sl-2-~1-Acetamido-2-acetamido)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid H~rdrochloride AcHN. N)., O~Bu H Boc AcH N
142A (~~2R.3S.5R,1'S)-1-t Butoxycarbony!-2-(1-acetamido-2-acetamido)ethyl_ 3-vin~pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-( 1-acetamido-2-amino)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t butyl ester (9.4 mg, 0.024 mmole) was reacted with acetic anhydride (11.2 uL) and triethylamine (33.1 ~L) in dichloromethane (0.23 mL) at 0°C for 1 hour. The reaction was diluted with water (3 mL), extracted with ethyl acetate (12 mL), washed with brine, dried over MgS04, and concentrated in vacuo. The residue was purified by chromatography on silica gel using 100% ethyl acetate to 90% ethyl acetatelmethanol to provide the title compound (yield: 6.8mg, 66%).
' H NMR (DMSO-ds) {rotamers) b 7.79-7.74(m, 1 H), 7.54(d, J=9.8Hz, 1 H), 5.97-5.81 (m, 1 H), 5.01-4.91 (m, 2H), 4.36-4.27(m, 1 H), 3.97-3.90(m, 1 H), 3.68-3.63(m, 1 H), 3.21-3.15(m, 1 H), 3.10-2.76(m, 1 H), 2.88-2.78(m, 1 H), 2.58-2.45(m, 1 H), 1.81 (s, 3H), 1.78(s, 3H), 1.76-1.64{m, 1 H), 1.42-1.36(m, 18H).
MS: (M+H)+=439, (M+Na)+=462, (M-H)-=438, (M+35)-=474 AcHN , ~OH
AcHN O
HC!
142B (t)-(2R.3S,5811'S)-2-(1-Acetamido-2-acetamido)ethyl-3-vinyl-pyrrolidine-5-carbox~fic Acid Hydrochloride The title compound was prepared according to the method described in Example 1 K, substituting (t)-(2R,3S,5R,1'S)-2-(1,2-di-acetamido)butyl-3-vinyl-pyrrolidine-5-carboxylic acid Hydrochloridesalt in place of (t)(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid t butyl ester (yield: 3.30 mg, 80%).
MS: (M+H)+=284, (M-H)-=282, (M+CI)-=318 H N
H
Example 143 (t)-(2R.3S,5R,1'S)-2-(1-Acetamido-2-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride T
AcHN, N)., O~Bu H Boc 143A (t)-(2R.3S,5Ry1'S)-1-t-Butoxv cap rbonyl-2-(1-N-acetamido-2-azido)eth vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'S}-1-t-Butoxycarbonyl-2-(N-acetylaziridinyl)-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (21.6 mg, 0.064 mmole) was reacted with sodium azide (41.6 mg, 0.64 mmole) and ammoniun chloride (34.2 mg, 0.64 mmol) in ethanol (270 ~L) and water (30 ~L) at 75°C for 1 hour. The ethanol was then removed in vacuo and the remaining aqueous was extracted with ethyl acetate.
The combined organics were washed with brine, dried over MgS04, and concentrated in vaccro (crude yield: 20mg, 82%). To the crude mixture was added acetic anhydride (31 ~L, 0.33 mmol) and triethylamine (92 uL, 0.66 mmol) in dichloromethane (330 ~L) at 0°C for 30 minutes. The reaction mixture was then concentrated in vacuo. The residue was purified by chromatography on silica gel using 100% dichloromethane to 50% dichloromethanelethyl acetate to provide the title compound (yield: 10 mg, 60%).
'H NMR (DMSO-ds)(rotamers) 8 7.85 and 7.81 (d, J=9.5Hz and 9.8Hz, 1 H), 5.94-5.80(m, 1 H), 5.04-4.93(m, 2H), 4.58-4.38(m, 1 H), 4.04-3.96(m, 1 H), 3.72-3.66(m, 1 H), 3.41-3.21 (m, 2H), 3.09-2.79(m, 1 H), 2.59-2.46(m, 1 H), 1.84-1.82(m, 3H), 1.79-1.53(m, 1 H), 1.43-1.35(m, 18H).
MS: (M+H)+=424, (M+Na)+=446, (2M+Na)+=869, (M-H)-=422, (M+CI)-=458 AcHN. N~,~OH
H H

HCI
143B (t)-(2R.3S,5811'S)-2-(1-Acetamido-2-azido)ethyl-3-vinyl-pyrrolidine-5-carboxLrlic Acid Hydrochloric Salt.
The title compound was prepared according to the method described in Example 1K, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 2.94 mg, 93%).

' H NMR (DMSO-ds) 8 8.24(d, J=8.55Hz, 1 H), 5.74-5.67(m, 1 H), 5.14(d, J=17.1 Hz, 1 H), 5.06(d, J=10.4Hz, 1 H), 4.41-4.35(m, 2H), 3.57-3.36(m, 3H), 2.93-2.90(m" 1 H), 2.44-2.38(m, 1 H}, 1.96-1.84(m, 1 H), 1.84(s, 3H).
MS: (M+H)+=268, (M-H)-=266, (M+CI)-=302 Exa J~le 144 (2R.3S,5R,1'S)-2-(1-Acetamido-2-N-methylamino)ethyl-3-vinyl-pyrrolidine-5-carboxyiic Acid Dihydrochloride AcHN_ N~., OtBu H Boc HN

144A (t~(2R.3S.5R.1'S)-1-t-Butoxycarbony~1-N-acetamido-2-N-meth IaminoLethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
Methylamine (.016 g, .53 mmole) was reacted with N,O-bis-trimethylsilylacetamide (.079 g, .39 mmole) in DMSO (0.8 mL) at 0°C for 1 hour.
(t)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(N-acetylaziridinyl)-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (.040 g, .11 mmole) was then reacted with the above reagent N-trimethylsilylmethylamine at 75°C for 18 hours. The reaction was diluted with ethyl acetate (7 mL) washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using chloroform-methanol-ammonia to provide the title compound (yield: .011 g, 25%).

'H NMR (CDC13) b 5.78-5.98 (m,lH), 5.90-5.04 (2m, 2H), 4.40-4.55 (brm, 1 H), 3.90-4.02 {m, 1 H), 3.64-3.75 (2m, 1 H}, 2.25-2.40 (brm 3H), 2.83,2.85 (2d, 3H), 1.42,1.44 {2s, 9H), 1.34,1.37 (2s, 9H).
MS: (M+H)+= 412 AcHN ,~OH
HN O

1448 (t)-(~2R,3S.5R.1'S)-2-(1-Acetamido-2-N-methylamino)ethyl-3-vin~rl-pyrrolidine-5-carboxylic Acid Dih rLdrochforide Salt The title compound was prepared according to the method described in Example 1K, substituting (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-2-N-methylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid t butyl ester (yield: 7.2 mg, 99%).
H NMR (DMSO-ds) 8 8.25 (d, 1 H), 5.70 (m, 1 H), 5.10 (m, 2H), 4.50 (m,1 H), 4.40 (m,1 H), 2.55 (s, 3H), 1.85 (s, 3H).
MS: (M+H)+= 256 ~ N
H

Examples 145-164 t. RR'NH
OtBu 2. 6N HCI AcHN. ,.~ OH
~Ni_.~
AcN~ H goc ~ R'RN H H
O

The following title compounds were prepared according to the methods described in Examples 141-144 where R' is equal to hydrogen. Where R or R' are not equal to hydrogen the corresponding amine is used directly without the intermediacy of trimethylsilylation.
Example 145 AcHN. N~..,~OH
H H
~'N O
/ H 2 HCt ,fit)-(2Ry3S.5R 1'S)-2-(1-Acetamido-2-N-isopropylaminolethLrl-3-vinyl-pyrrolidine-5-carboxylic Acid Dihydrochloride Salt ' H NMR (DMSO-d6) 8 8.30 (d, 1 H), 5.70 (m, 1 H), 5.10 (m, 2H), 4.40 (br, 2H), 3.52-3.68 (br, 1 H), 3.10-3.20 (br, 1 H), 2.82-2.97 (br, 1 H), 2.37-2.47 (br, 1 H), 1.88 (s, 3H), 1.25 (d, 6H).
MS: (M+H)+= 284 Example 146 AcHN , ~OH
NN O

(t)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-N-butylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Dihydrochloride Salt ' H NMR (DMSO-ds) 8 8.25 (d, 1 H), 5.70 (m, 1 H), 5.10 (m, 2H),4.50 (m, 1 H), 4.38 (m, 1 H), 3.60 (m, 1 H), 2.90 (m, 3H), 2.40 (m, 2H), 1.87 (s, 3H), 1.62 (m, 2H), 1.33 (m, 2H), 0.90 (t, 3H).
MS: (M+H)+= 298 AcH , ~OH
HN O

Ph (t)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-N-benzylamino)ethyl-3-vinyl-pyrrolidine-5-carbox\~lic Acid HydrochlorideSalt 'H NMR (DMSO-ds) b 7.56-7.43(m, 5H), 5.74-5.67(m, 1H), 5.15-4.99(m, 2H), 4.56(m, 1 H), 4.27-3.93(m, 3H), 3.66-3.15(m, 3H), 2.91-2.88(m, 1 H), 2.64-2.34(m, 2H), 1.86(s, 3H).
MS: (M+H)+=332, (M+Na)+=354, (M-H)-=330, (2M-H)-=661 ~ N
H
Example 147 -, N.
H N
H

Example 148 AcHN. N~.,~OH
H H O
HN
Ph~ 2HC~
(t)-~2R,3S.5R.1'S?-~1-Acetamido-2-N-phenethylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Dihydrochloride Salt H NMR (DMSO-ds) 8 8.25 (d, 1 H), 7.30 (m, 5H), 5.70 (m, 1 H), 5.10 (m, 2H), 4.50 (br, 1 H), 4.35 (br, 1 H), 3.61 (m, 1 H), 3.17 (m, 3H), 2.98 (m, 3H), 2.42 (m, 1 H), 1.88 (s, 3H).
MS: (M+H)+= 346 AcH , ~OH
-N O
I 2HCi -(2R,3S.5R.1'S~-2-(1-Acetamido-2-N.N-dimethylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Dihydrochloride Salt ' H NMR (DMSO-d6) 8 8.34(d, J=9.2Hz, 1 H), 5.74-5.67{m, 1 H), 5.12(d, J=17.1 Hz, 1 H), 5.04(d, J=10.4Hz, 1 H), 4.67-4.62(m, 1 H), 4.40(dd, J=7.3, 10.4Hz, 1 H), 3.60-3.11 (m, 3H), 2.96-2.83(m, 1 H), 2.50(s, 6H), 2.44-2.38(m, 1 H), 1.92-1.84(m, 1 H), 1.84(s, 3H).
Example 149 N.
~ N
H

MS: (M+H)+=270, (M+Na)+=292, (M-H)-=268.
Example 150 AcHN , ~ H
~N O

(t)-(2R.3S.,5R,1'S)-2-(1-Acetamido-2-N,N-diethylamino)ethyl-3-vinyl-pyrrolidine-5-carbolic Acid Di~drochloride Salt 'H NMR (DMSO-ds) 8 8.23 (d, 1 H), 5.70 (m, 1 H), 5.10 (m, 2H), 4.60 (br, 1 H), 4.40 (br, 1 H), 3.12 (m, 4H), 2.88 (m, 1 H), 2.42 (rn, 1 H), 1.85 (s, 3H), 1.22 (t, 3H).
MS: (M+H)+= 298 N
H H

WO 99!54299 PCT/US99/07945 Example 151 AcHN. N~.,~ H
H H
~N O

(t)-(2R, 3S, 5R.1'S)-2-( 1-Acetamido-2-N, N-dibutylamino)ethyl-3-vinyl-pyrrolid ine-5-carboxylic Acid Dihydrochloride Salt ' H NMR (DMSO-ds) 8 8.24 (d, 1 H), 5.70 (m, 1 H), 5.08 (m, 2H), 4.48-4.62 (br, 1 H}, 4.28-4.43 (1 H), 3.05 (m, 4H), 2.77-2.92 (br, 1 H), 2.34-2.46 (br, 2H), 1.84 (s, 3H), 7.64 (m, 4H), 1.30 (m, 4H), 0.93 (t, 6H).
MS: (M+H)+= 354 Example 152 AcHN. N~.,~OH
H H
HN O
~OH zHCI
~2R,3S.5R,1'S',i-2~1-Acetamido-2-~N-2-h~yethylamino )ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Dih~drochloride Salt ' H NMR (DMSO-ds) 8 8.20 (d, 1 H), 5.70 (m, 1 H), 5.15 (d, 1 H), 5.08 (d, 1 H), 4.50 (brm, 1 H), 4.38 (brm, 1 H), 3.68 (M, 1 H), 3.0 (brm, 2H), 2.90 (m, 1 H), 2.41 (m, 1 H), 1.85 (s, 3H).

MS: (M+H)+= 286 AcH H

, ~

~N O
~OH

2HCi (t)-(2R.3S, 5R.1'S)-2-( 1-Acetamido-2-(N-2-hydroxyethyl-N-ethylamino))ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Dihydrochloride Salt 'H NMR (DMSO-dfi) s 5.81-5.74(m, 1 H), 5.38(d, J=17.1 Hz, 1 H), 5.22(d, J=1 O.OHz, 1 H), 4.92-4.88(m, 1 H), 4.48(dd, J=7.6, 9.8Hz, 1 H), 3.91 (t, J=4.9Hz, 2H), 3.85(dd, J=5.6, 1 O.OHz, 1 H), 3.63-3.53(m, 2H), 3.46-3.39(m, 4H), 3.16-3.13(m, 1 H), 2.66-2.61 (m, 1 H), 2.08(s, 3H), 2.06-2.01 (m, 1 H), 1.38(t, J=7.33, 3H).
MS: (M+H)+=314, (M+Na)+=336, (M-H)-=312, (M+CI)-=348, (2M-H)-=625 Example 153 N.
H N
H

Example 154 AcHN. N~.,~OH
H H
~N O
~OH 2tiC~
(t)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-(N-2-h dY roxyethyl-N-propylamino))eth vinyl-pyrrolidine-5-carboxylic Acid Dihydrochloride Salt ' H NMR (DMSO-d6) s 8.36(d, J=8.5Hz, 1 H), 5.75-5.68(m, 1 H), 5.13(d, J=17.1 Hz, 1 H), 5.04{d, J=10.4Hz, 1 H), 4.62(m, 1 H), 4.36(m, 1 H), 3.77(t, J=4.9Hz, 2H), 3.63-3.59(m, 1 H), 3.50-3.23(m, 3H), 3.22-3.19(m, 2H), 3.08(t, J=7.3Hz, 2H), 2.91-2.87(m, 1 H), 2.44-2.39(m, 1 H), 1.99-1.88(m, 1 H), 1.84(s, 3H), 1.75-1.70(m, 2H), 0.90(t, J=6.7Hz, 3H).
MS: (M+H)+=328, (M+Na)+=350, (M-H)-=326, (M+CI)~=362, (2M-H)'=653 Example 155 AcHN. OH
~N O
N ~ 2HC~
(t)-~2R,3S,5R,1'S)-2-(1-Acetamido-2-(imidazol-1-vl))ethyl-3-vinyl-pyrrolidine-carboxylic Acid DiHydrochloride ' H NMR (MeOD-d3) 5.9.06(s, 1 H), 7.72(s, 1 H), 7.58(s, 1 H), 5.84-5.76(m, 1 H), 5.39(d, J=17.1 Hz, 1 H), 5.23{d, J=10.25Hz, 1 H), 4.70-4.66(m, 1 H), 4.52-4.43(m, 2H), 3.92-3.89(m, 1 H), 3.20-3.17(m, 1 H), 2.67-2.62(m, 1 H), 2.11-2.04(m, 1 H), 1.95-1.89(m, 1 H), 1.91 (s, 3H).
MS: (M+H)+=293, (M-H)-=291, (M+35)+=327.
Example 156 AcHN. N~.,~ H
H H
~- N O
HO~ 2HCi ~OH
fit)-~2R, 3S.5R.1'S)-2-~1-Acetamido-2-(N, N-di-{2-hydrox~ylamino))ethyl-3-vine pyrrolidine-5-carboxylic Acid Dihydrochloride Salt MS: (M+H)+=330, (M+Na)+=352, (M-H)-=328, (M+CI)-=364 Example 157 AcHN ,~ H
AcN O
I Hci (tL{2R,3S,5R.1'S~~1-Acetarnid~N-acet~N-methylamino)eth I-3-vi~f-pyrrolidine-5-carboxylic Acid Hydrochloride Sait ' H NMR {DMSO-ds) 8 8.01,7.95 (2d, 1 H), 5.68-5.80 (m,1 H), 5.02-5.22 (m, 2H), 4.30-4.45 (brm, 2H), 3.26,3.21 (2d, 1 H), 2.82-2.95 (brm, 1 H), 2.38-2.48 (m, 1 H), 1.98,2.02 (2s, 3H),1.79,1.82 (2s, 3H).
MS: (M+H)+= 298 N
H H

Example 158 AcH , ~OH

~OH 2HCi fit)-(2R.3S 5R,1'S)-2- 1-Acetamido-2-{N-2-hydroxyethyl-N-methylamino))ethyl-3-yinyl-pyrrolidine-5-carboxylic Acid Dihydrochloride Salt 'H NMR (DMSO-ds) 8 8.35(d, J=9.15Hz, 1 H), 5.74-5.67(m, 1 H), 5.12(d, J=17.1 Hz, 1 H), 5.04(d, J=10.4Hz, 1 H), 4.70(m, 1 H), 4.39(dd, J=7.3, 10.4Hz, 1 H), 3.80-3.75(m, 3H), 3.61-3.43(m, 3H), 3.23-3.16(m, 2H), 2.91-2.82(m, 1 H), 2.82(s, 3H), 2.44-2.39(m, 1 H), 1.92-1.84{m, 1 H), 1.84(s, 3H).
MS: (M+H)+=300, (M+Na)+=322, (2M+H-HZO)+=581 Example 159 AcH , ~ H
CH3 ~ O
2iiCt (t)-(2R,3S.5R.1'S~2-(1-Acetamido-2-(N-~propyl-N-methylamino eth I-~yl-pyrrolidine-5-carboxylic Acid Dihydrochloride Salt 'H NMR (DMSO-dfi) (broad) 8 8.3(1 H), 5.7(1 H), 5.12-5.04(2H), 4.6(1 H), 4.35(1 H), 2.61-2.35(11 H), 1.9(3H), 1.78-7 .63(2H), 1.9(3H).
MS: (M+H)+=298, (M+Na)+=320, (M-H)-=296, (M+Cl)'332, (2M-H)-=593 N_ H N
H
N _ ,.
H N
H

WO 99/'54299 PCT/US99/07945 Example 160 AcH , ~OH

(t)-(2R,3S.5R,1'S)-2-(1-Acetamido-2-(N-c clue ohexyl-N-methylamino))ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride Salt ' H NMR (DMSO-dfi) b 8.26(m, 1 H), 5.75-5.65(m, 1 H), 5.08(d, J=17.1 Hz, 1 H), 5.02(d, J=10.3Hz, 1 H), 4.62(m, 1 H), 4.43-4.40(m, 1 H), 3.62-3.58(m, 1 H), 3.46-3.16(m, 2H), 2.89-2.84(m, 1 H), 2.72(s, 3H), 2.44-2.39(m, 1 H), 2.07-1.80(m, 5H), 1.81 (s, 3H), 1.63(m, 1 H), 1.45-1.06(m, 6H).
MS: (M+H)+=338, (M+Na)+=360, (M-H)~=336, (M+CI)-=372 Example 161 AcH ~ ~ H

~Ph (~2R,3S,5R.1'S)-2-(1-Acetamido-2-(N-benzyl-N-meth~amino )eth I-3-vinyl-pyrroiidine-5-carboxylic Acid Dih~chloride Salt ' H NMR (DMSO-ds) 8 8.36(m, 1 H), 7.61-7.46(m, 5H), 5.69-5.64(m, 1 H), 5.07(d, J=17.1 Hz, 1 H), 4.99(d, J=10.1 Hz, 1 H), 4.77(m, 1 H), 4.44-4.39(m, 2H), N.
H N
H
N.
H N
H

4.25(d, J=12.9, 1 H), 3.61 (m, 1 H), 3.43(m, 1 H), 3.22(m, 1 H), 2.93-2.85(m, 1 H), 2.73(s, 3H), 2.44-2.38(m, 1 H), 1.92-1.85(m, 1 H), 1.85(s, 3H).
MS: (M+H)+=346 AcH N

2HCi (t~-(2R.3S.5R.1'S~~-Acetamido-2-(N-phenethyl-N-methylamino))ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Dihydrochloride Salt 'H NMR (DMSO-ds) 8 8.34(d, J=8.55Hz, 1H), 7.37-7.26(m, 5H), 5.76-5.69(m, 1 H), 5.14(d, J=17.1 Hz, 1 H), 5_06(d, J=10.4Hz, 1 H), 4.72(m, 1 H), 4.46-4.42(m, 1 H), 3.83-3.20(m, 6H), 3.13-2.99(m, 2H), 2.86(s, 3H), 2.95-2.83(m, 1 H), 2.46-2.40(m, 1 H), 1.95-1.81 (m, 1 H), 1.86(s, 3H).
MS: (M+H)+=360 Example 162 -, H N
H

Example 163 AcHN. N~.,~OH
H H
CH3N O 2HCi (t)-(2R,3S.5R.1'S)-2-(1-Acetamido-2-(N-naphth IY methyl-N-methylamino))eth vinyl pyrrolidine-5-carboxylic Acid Dihydrochloride Salt 'H NMR (DMSO-ds) b 8.41(d, J=7.3Hz, 1H), 8.32-7.59(m, 7H), 5.60{m, 1 H), 5.04(d, J=17.1 Hz, 1 H), 4.91 (d, J=9.8Hz, 1 H), 4.97-4.73(m, 3H), 4.39(m, 1 H), 3.70-3.13(m, 3H), 2.90(m, 1 H), 2.72(s, 3H), 2.43-2.41 (m, 1 H), 2.01-1.74(m, 1 H), 1.87(s, 3H).
MS: (M+H)+=395, (M+Na)+=418, (M-H)-=394, (M+CI)-=430, (2M-H)-=789 Example 764 ,~OH
O

AcH N
H N
H
N
(t)'(2R.3S,5R,1'S)-2~1-Acetamido-2-(N-morpholinyl~~eth I-3-vinyl-tayrrolidine-carboxylic Acid Dihydrochloride Salt H NMR (DMSO-ds) 8 8.28 (d, 1 H), 5.75-5.78 (m, 1 H), 5.15 (d,1 H), 5.05 (d, 1 H), 4.65 (brm, 1 H), 4.42 (m, 1 H), 3.72-3.98 (brm, 3H), 3.62 (m, 1 H), 2.90 (m, 1 H), 2.38-2.48 (m, 1 H), 1.85 (s, 3H).
MS: (M+H)+= 312 Example 165 (t)-(2R.3S,5R.1'S.3'R~-2-(1-Acetamido-2-(N-methyl-N-t butylamino-N-oxide))eth~l-3-vinyl pyrrolidine-5-carbox,~lic Acid H~rdrochloride Salt AcHN_ ,., OtB~ AcHN_ ~ H Boc ~ ~ H Boc' 'N N
O ..CH3 O: .CHs 165A lt)-(2R.3S.5R,1'S,3'R~ and (t)-(2R,3S,5RL1'S,3'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-t-butylamino-N-oxide),leth r~yrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'S)-1-t Butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-t-butylamino))ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (37 mg, .08 mmole) was reacted with the m-chloroperoxybenzoic acid (20 mg, .08 mmole) in CH2C12 (0.9 mL) at 0°C for 1 hour. The reaction was chromatographed directly on silica gel eluting with a gradient of acetone to acetone/30% MeOH to provide the title compounds isomer (t)-(2R,3S,5R,1'S,3'R) {yield: .010 g, 27%) and isomer {t)-(2R,3S,5R,1'S,3'S) (yield: .011 g, 29%).
,~OH
O
wCH3 Hci 1658 ~)-(2R.3S,5R,1'S,3'R,~-2-~1-Acetamido-2-lN-methyl-N-t-butylamino-N-oxide))ethyl-3-vinyl pyrrolidine-5-carboxylic Acid Hydrochloride Salt The title compound was prepared according to the method described in Example 15C substituting (t)-(2R,3S,5R,1'S,3'R)-1-t-butoxycarbonyl-2-(1--, AcHN
H N
H
N

acetamido-2-(N-methyl-N-t-butylamino-N-oxide))ethyl-pyrrolidine-5-carboxylic acid t-butyl ester for (t)-(2R,3S,5R,1'S)-2-(1-acetarnido-3-ethyl)pentyl-3-(imidazol-2-yl)-pyrroiidine-5-carboxylic acid t-butyl ester (yield: 6 mg, 80%).
' H NMR (CD30D) 8 5.72-5.87 (m, 1 H), 5.40 (d, 1 H), 5.20-5.28 (m, 2H), 4.44-4.53 (dd, 1 H), 3.73-3.95 (m, 3H), 3.57 (s, 3H), 3.08-3.19 {m, 1 H), 2.59-2.72 (m, 1 H), 2.05-2.15 (m, 1 H), 2.04 (s, 3H), 1.54 (s, 9H).
MS: (M+H)+= 328 Exam~ies 166-178 1. MCPBA
2. chromatographic ACHN_ ). OH separation AcHN_ ,_, OH
3. 6 N HCI O H H
R'RN ~ R'RN
HCi The following title compounds were prepared according to the method described in Example 165.

Example 166 --, AcHN. N~.,~OH
H H
O
O.N.CH HCi (t)-(2R.3S,5R 1'S.3'R)-2-(1-Acetamido-2-(N-methyl-N-isopropylamino-N-oxide))ethyl-3-vin~pyrroiidine-5-carboxylic Acid Hydrochloride Salt 1 H NMR (MeOD-dg) 8 5.87-5.74 (m, 1 H), 5.46-5.40 (m, 1 H), 5.27-5.23 (m, 1 H), 5.21-5.18 (m, 1 H), 4.50 (dd, J=8.1, 9.8Hz, 1 H), 4.04-3.87 (m, 4H), 3.54 (s, 3H), 3.20-3.14 (m, 1 H), 2.69-2.60 (m, 1 H), 2.12-2.01 (m, 1 H), 2.05 (s, 3H), 1.50 (d, J=6.4Hz, 3H), 1.48(d, J=6.4Hz, 3H).
MS: (M+H)+=314, (M+Na)+=336, (2M+1 )+= 627, (2M+Na)+=649.
Example 167 AcHN_ N~.,~ H
H H
O
N~-CH3 Hci O
(t)-(2R.3S, 5R.1 'S, 3'S~-~ 1-Acetamido-2-(N-methyl-N-propylamino-N-oxideethyl-3-vinyl-pyrroiidine-5-carboxyiic Acid HydrochlorideSalt ~ H NMR (MeOD-d3) 8 5.87-5.74 (m, 1 H), 5.46-5.40 (m, 1 H), 5.27-5.23 (m, 1 H), 5.21-5.18 (m, 1 H), 4.50 (dd, J=8.1, 9.8Hz, 1 H), 4.04-3.87 (m, 4H), 3.54 (s, 3H), 3.20-3.14 (m, 1 H), 2.69-2.60 (m, 1 H), 2.12-2.01 (m, 1 H), 2.05 (s, 3H), 1.50 (d, J=6.4Hz, 3H), 1.48(d, J=6.4Hz, 3H).
MS: (M+H)+=314, (M+H-H20)-=295 AcH , ~OM
O
N
O ..CHs {tLf2R.3S.5R.1'S.3'S -Z 2-(1-Acetamido-2-(N-meth-N-ethylamino-N-oxide) ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid HydrochlorideSalt 1 H NMR (MeOD-d3) 8 5.82-5.75 (m, 1 H), 5.44{d, J=17.1 Hz, 1 H), 5.26(d, J=10.4Hz, 1 H), 5.14-5.11 (m, 1 H), 4.48-4.45(m, 1 H), 4.9(d, J=4.9Hz, 2H), 3.87(dd, J=4.9, 10.4Hz, 1 H), 3.76(q, J=6.7Hz, 2H), 3.54(s, 3H), 3.17-3.09(m, 1 H), 2.68-2.62 (m, 1 H), 2.06(s, 3H), 2.09-2.03 (m, 1 H), 1.45(t, J=7.3Hz, 3H).
MS: (M+H)+=300, (M+Na)+=322, (M+H-H20)+=282 Example 168 N.
H -N
H

Example 169 AcHN. N~,~OH
H H
O
O'N~ CHg HCI
jt~-~2R 3S 5R.1'S)-2-~1-Acetamido-2-(N,N-dimethylamino-N-oxide)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride Salt ' H NMR (DMSO-ds) 8 8.58 (d, 1 H), 5.67-5.78 (m, 1 H), 5.20 (d, 1 H), 5.08 (d, 1 H), 4.62-4.78 (brm, 1 H), 4.25-4.42 (brm, 1 H), 4.06 (d, 1 H), 3.85-3.95 (brm, 1 H), 3.88-3.98 (brm, 1 H), 3.35-3.50 (brs, 6H), 2.36-2.48 (m, 1 H), 1.92 (m, 1 H), 1.85 (s, 3H).
MS: (M+H)+= 286 Example 170 AcHN. N~.,~ H
H H
O
Ph~N HCi p ~CH3 (t)-(2R.3SL5R,1'S.3'S)-2-(1-Acetamido-2-(N-methyl-N-benzylamino-N-oxidelyethyl-3-vinyl-pyrrolidine-5-carboxylic Acid HydrochlorideSalt ' H NMR (MeOD-d3) 8 7.60-7.47(m, 5H), 5.75-5.65(m, 1 H), 5.39(d, J=6.35Hz, 1 H), 5.21 (d, J=8.8Hz, 1 H), 5.18-5.11 (m, 1 H), 5.00-4.70(m, 2H), 4.35-4.27(m, 1 H), 4.00-3.94(m, 2H), 3.86-3.79(m, 1 H), 3.20(s, 3H), 3.14-3.05(m, 1 H), 2.77-2.50(m, 1 H), 2.08(s, 3H), 2.10-2.94(m, 1 H).
MS: (M+H)+=362, (M+Na)+=385, (M-H)~=360, (M+35)-=396 Example 171 AcHN. N~.,~ H
H H
O
O~N'CH3 HCi (t)-(2R,3S.5R.1'S.3'S)-2-(1-Acetamido-2-(N-methyl-N-t-butylamino-N-oxide)ethyl-3-vinyl-uyrrolidine-5-carboxLrlic Acid HydrochlorideSait 'H NMR (CD30D) b 5.80 (m, 1 H), 5.44 (d, 1 H), 5.27 (d, 1 H), 5.08 (m, 1 H), 4.34-4.44 (dd, 1 H), 3.83-3.94 (m, 3H), 3.38 (s, 3H), 3.02-3.18 (m, 1 H), 2.58-2.72 (m, 1 H), 2.08 (s, 3H1, 1.97-2.08 (m, 1 H), 1.55 (s, 9H).
MS: (M+H)+= 328 Example 172 AcHN_ N~.,~ H
H H
O
N
O~ 'CH3 ~ci (t)-(2R.3S.5R,1'S,3'S)-2~1-Acetamido-2-(N-meth i-rL N-isoprowlamino-N-oxide))ethyl-3-vinyl-p~rrolidine-5-carboxylic Acid Hydrochloride Salt 1 H NMR (MeOD-d3) 8 5.86-5.74 (m, 1 H), 5.53-5.47 (m, 1 H), 5.29-5.25 (m, 1 H), 5.22-5.19 (m, 1 H), 4.50 (dd, J=8.1, 9.5Hz, 1 H), 4.13-4.04 (m, 2H), 3.96 (dd, J=4.1, 10.5Hz, 1 H), 3.87-3.82 (m, 1 H), 3.39 (s, 3H), 3.23-3.17 (m, 1 H), 2.70-2.61 (m, 1 H), 2.11 (s, 3H), 2.08-2.00 (m, 1 H), 1.50 (d, J=6.4Hz, 3H), 1.49(d, J=6.4Hz, 3H).
MS: (M+H)+=314, (M+Na)+=336, (2M+1 )+=627, (2M~Na)+=649.
Example 173 AcHN. N~.,~OH
H H
O
O~N~CH3 Hci t - 2R.3S.5R,1'S.3'R)-2-(1-Acetamido-2-(N-methyl-N-propylamino-N-oxide))ethyl-3-vial-pyrrolidine-5-carboxylic Acid Hydrochloride Salt 'H NMR (MeOD-d3) 8 5.82-5.75(m, 1 H), 5.45(d, J=17.1 Hz, 1 H), 5.26(d, J=10.4Hz, 1 H), 5.07-5.13(m, 1 H), 4.48-4.42(m, 1 H), 3.98(d, J=5.5Hz, 2H), 3.86(dd, J=4.3, 9.8Hz, 1 H), 3.67-3.64(m, 2H), 3.46(s, 3H), 3.16-3.01 (m, 1 H), 2.68-2.62(m, 1 H), 2.09-2.02(m, 1 H), 2.06(s, 3H), 1.92-1.86(m, 2H), 1.04(t, J=7.3Hz, 3H).
MS: (M+H)+=314, (M+H-H20)-=295 AcH
O
ON'OH3 Hc~
(t;y(2R.3S,5R.1'S,3'R)-2-(1-Acetamido-2-(N-methyl-N-ethylamino-N-oxide) ethyl-3-vin ELI-pyrrolidine-5-carboxylic Acid Hydrochloride Salt 1 H NMR (MeOD-d3) 8 5.82-5.75(m, 1 H), 5.45(d, J=17.1 Hz, 1 H), 5.26(d, J=10.4Hz, 1 H), 5.13-5.10(m, 1 H), 4.48-4.44(m, 1 H), 4.02-3.94(m, 2H), 3.89 (dd, J=4.3, 9.8Hz, 1 H), 3.82(q, J=7.3Hz, 2H), 3.46(s, 3H), 3.18-3.10(m, 1 H), 2.68-2.62 (m, 1 H), 2.09(s, 3H), 2.07-2.02(m, 1 H), 1.46(t, J=7.3Hz, 3H).
MS: (M+H)+=300, (M+Na)+=322, (M+H-H20)+=282 Example 174 N.
H -N
H

Example 175 AcHN. N~.,~OH
H H
O
Ph O~N~CH Hci (t)-(2R,3S.5R,1'S.3'S)2-(1-Acetamido-2-(N-methyl-N-benzLrlamino-N-oxideLhyl-3-vin rLi-p rr~ne-5-carboxylic Acid HydrochlorideSalt 'H NMR (MeOD-d3) S 7.60-7.47(m, 5H), 5.75-5.65(m, 1 H), 5.39(d, J=6.35Hz, 1 H), 5.21 (d, J=8.8Hz, 1 H), 5.18-5.11 (m, 1 H), 5.00-4.70(m, 2H), 4.35-4.27(m, 1 H), 4.00-3.94(m, 2H), 3.86-3.79(m, 1 H), 3.40(x, 3H), 3.14-3.05(m, 1 H), 2.77-2.50(m, 1 H), 2.08(s, 3H), 2.10-2.94(m, 1 H).
MS: (M+H)+=362, (M+Na)'=385, (M-H)'=360, (M+35)~=396 Example 176 AcHN. N,.,~OH
H H
O
~N
O
t - 2R.3S.5R,1'S)-2-(1-Acetamido-2-~N,N-diethylamino-N-oxide))eth I-~yl-pyrrolidine-5-carboxylic Acid Hydrochloride Salt 1 H NMR (MeOD-dg) 8 5.84-5.78(m, 1 H), 5.45(d, J=16.85Hz, 1 H), 5.26(d, J=10.OHz, 1 H), 5.09-5.05(m, 1 H), 4.45-4.42(m, 1 H), 3.96-3.86(m, 3H), 3.76(q, J=6.6Hz, 2H), 3.70(q, J=7.3Hz, 2H), 3.15-3.11 (m, 1 H), 2.68-2.62(m, 1 H), 2.08-2.02(m, 1 H), 2.08(s, 3H), 1.44-1.38(m, 6H}.
MS: (M+H)+=314, (M+Na)+=336, (M+2Na)+=358 Example 177 AcHN. N~.,~ H
H H
O
N
O
(t)-(2R.3S.5R,1'S.3'R)-2-(1-Acetamido-2-(N-pyrrolidinyl-N-oxide))ethyl-3-vinyl-pyrrolidine-5-carbox I~Acid Hydrochloride Salt ~ H NMR (DMSO-ds) 8 8.74 (d, 1 H), 5.65-5.80 (m,1 H), 5.28 (d, 1 H), 5.10 {d,1 H), 4.82 (m, 1 H), 4.40-4.50 (dd, 1 H), 4.30 (d, 1 H), 3.60-4.12 (brm, 5H), 2.98-3.15 (m, 1 H), 2.38-2.48 (m, 1 H), 2.05-2.20 (brm, 5H), 1.88-1.98 {m, 1 H), 1.87 (s, 3H).
MS: (M+H)+= 312 Example 178 AcH , ~ H
O
Hc~
(t)-(2R.3S, 5R,1'S)-2-( 1-Acetamido-2-(N-morpholin~oxide~ethyl-3-vinyl-~yrrolidine-5-carboxylic Acid Hydrochloride Salt 'H NMR (DMSO-ds) b 8.65 (d, 1 H), 5.66-5.80 (m, 1 H), 5.22 (d, 1 H), 5.09 (d, 1 H), 4.78 (brs, 1 H), 4.32-4.42 (dd, 1 H), 4.10-4.17 (brm, 2H), 3.50-4.02 (brm, 9H), 2.92-3.04 (brrn, 1 H), 2.37-2.48 (m, 1 H), 1.88-1.96 (m, 1 H), 1.87 (s, 3H).
MS: (M+H)+= 328 N. ,.
H N
H
Example 179 t - 2R 3S,5R,1'S,3'S)-2-(1-Acetamido-2-~,N-ethyl-N-methylamino-N-oxide))ethyl-~cis-propen-1_yl)-pyrrofidine-5-carboxyiic Acid HydrochlorideSalt N>.,~OtBu O H Boc ~
179A (t)-i(2R.3S,5R.1'S)-1-t Butox~carbon~,rl-2-oxiranyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Bu I Ester.
The title compound was prepared according to the method described in Example 1231, substituting ethyltriphenylphosphonium bromide in place of methyltriphenylphosphonium bromide (yield: 350 mg, 77%).

'H NMR (CDC13) (rotamers) s 5.55-5.43 (m, 2H), 4.13-4.04 (m, 2H), 3.14-3.11 (m, 2H), 2.76-2.50 (m, 3H), 1.75-1.70 (m, 1 H), 1.64(d, 3H), 1.48-1.43(m, 18H).
MS: (M+H)+=354, (M+Na) +=376, (2M+Na)+=729 Ms0 N,-, ~ tBu H Boc 0 179B (tl-(2R.3S.5R,1'R)-1-t-Butoxycarbonyl-2-(1-methanesulfonylox r-~3-azido)ethyl-3-(cis-proyen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 1231, substituting (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-oxiranyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido)butyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 1.08 g, 84%).
'H NMR (DMSO-ds) (rotamers) b 5.53-5.33 (m, 2H), 5.05-4.93 (m, 1H), 4.20-3.90 (m, 2H), 3.76-3.62 (m, 2H), 3.24 (s, 3H), 2.59-2.49(m, 1 H), 1.64-1.55(m, 51-;), 1.43-1.36(m, 18H).
MS: (M+H)+=475, (M+Na)+=497, (2M+Na)+=971 N>..,~ 1Bu HN~ H goc 0 179C (t)-(2R,3S 5R 1'S)-1-t-Butoxycarbonyl-2-aziridinyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 123K, substituting (2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-methanesulfonyloxy-3-azido)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(1-methanesulfonyloxy-3-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester(crude yield: 564 mg, 71 %).
'H NMR(DMSO-ds) (rotamers) 8 5.45-5.30 (m, 2H), 4.15-3.99 {m, 1 H), 3.30-3.08 (m, 1 H), 3.07-2.84 (m, 1 H), 2.68-2.51 (m, 1 H), 2.13-1.85(m, 1 H), 1.80-1.05(m, 3H), 1.57(d, J=5.4Hz, 3H), 1.41-1.35(m, 18H).
MS: (M+H)+=352, (M+23)+=375, (2M+H)+=705, (2M+23)+=727 N,.,~O~Bu AcN~ H goc 0 179D yt)-(2R.3S,5R,1'S)-1-t-Butoxvcarbonyl-2-lN-acetylaziridin ly )-3-(cis-propen-1-YI)-pYrrolidine-5-carboxylic Acid t-Butvl Ester.
The title compound was prepared according to the method described in Example 123L, substituting (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-aziridinyl-(cis-propen-1-yl}-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester(yield: 455 mg, 72%).
'H NMR(DMSO-ds} (rotamers) 8 5.74-5.34(m, 2H), 4.17(dd, J=2.4, 6.35Hz, 1 H), 3.41 (dd, J=1.95, 6.35Hz, 1 H), 3.14-2.99(m, 1 H), 2.73-2.58(m, 2H), 2.40(d, J=6.35Hz, 1 H), 2.17-2.12(m, 1 H), 2.05-2.00(m, 3H), 1.66-1.55(m, 1 H), 1.56(d, J=6.8Hz, 3H), 1.41-1.31 (m, 18H).
MS: (M+H)+=395, (M+Na)+=417, (M+H+Na)+=418, ~OtBu O
I
179E fit)-f~2R,3S,5R.1'S)-1-t Butoxycarbon rLl-2~1-acetamido-2-N-ethyl-N-met~lamino)ethyl-3~cis-propen-1-y~pyrroiidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 150, substituting N-ethyl-N-methyl-amine in place of diethylamine (yield:
30 mg, 87%).
MS: (M+H)+=454, (M+Na)+=476, (M-H)-=452, (M+35)-=488 AcN. >.
N
H Boc N

AcN _ )_ , OiBu AcN. ).. , O~Bu H Boc ~ ~ H Boc O,N~-CH3 O'~N'CH3 179E (t)-~2R,3S,5R,1'S,3'R) and (t)-(2R,3S.5R,1'S.3'S)-1-t Butoxycarbonyl-2-1-acetamido-2-(N-ethyl-N-methyiamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 165A, substituting (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-2-(N-ethyl-N-methylamino))ethyl-3-{cis-propen-1-yl)-pyrrolidine-5-carboxyiic acid t-butyl ester in place of (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-2-N-methyl-N-t-butylamino)ethyl-3-{cis-propen-1-yl)-pyrrolidine-5-carboxyiic acid t-butyl ester (yield: 15.2 mg, 51 %).

AcHN. N~, ~ H
H H
O
~ N ~'CH HCi () 3 179F (t~-(2R,3S.5R,1'S,3'R)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))et~l-3-(cis-~roaen-1-y~-pyrrolidine-5-carboxylic Acid Hydrochloride Salt The title compound was prepared according to the method described in Example 1K, substituting (t)-(2R,3S,5R,1'S,3'R)-1-t-butoxycarbonyl-2-{1-acetamido-2-(N-methyl-N-ethyl-N-oxide))ethyl-pyrrolidine-5-carboxylic acid t-butyl ester for (t)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 8.7 mg, 29%).
~ H NMR (MeOD-d3) 8 5.75-5.69(m, 1 H), 5.37-5.30(m, 1 H), 5.07-5.04(m, 1 H), 4.49(dd, ,l=7.8, 10.2Hz, 1 H), 4.05-3.74(m, 4H), 3.61-3.32 (m, 1 H), 3.55(s, 3H), 2.69-2.60(m, 1 H), 2.04(s, 3H), 1.95-1.84(m, 1 H), 1.75(dd, J=2.0, 7.1 Hz, 3H), 1.44 (t, J=7.1 Hz, 3H).
MS: (M+H)+=314, (M+35)+=348 Examples 179-184 1. MCPBA
2. chromatographic AcHN_ ,., OH separation AcHN_ ,., OH
3. s N Hcc O H H
R'RN O R'RN O
HCI
The following title compounds were prepared according to the method described in Example 179.
Example 180 /=, AcHN_ N~.,~OH
H H
O
~N Hci O~ ~CH3 (tl-(2R.3S 5R 1'S 3'S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))eth~
3-lcis=propen-1-yl)-pyrrolidine-5-carboxylic Acid Hydrochloride Salt ' H NMR (MeOD-d3) 8 5.75-5.69(m, 1 H), 5.38-5.30(m, 1 H), 5.02-4.98(m, 1 H), 4.47(dd, J=7.8, 9.8Hz, 1 H), 4.02-3.77(m, 4H), 3.56-3.39(m, 1 H), 3.47(s, 3H), 2.69-2.59(m, 1 H), 2.07(s, 3H), 1.95-1.84(m, 1 H), 1.76(dd, J=1.7, 7.1 Hz, 3H), 1.46(t, J=7.1 Hz, 3H).
MS: (M+H)+=314, (M+35)+=348 Example 181 ,~ H
O
O~ ~~CH3 /= , AcH N .
H N
H
N HC~
~t)~2R 3S 5R 1'S 3'R)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxyiic Acid Hydrochloride Salt ' H NMR (MeOD-d3) S 5.76-5.66(m, 1 H), 5.39-5.31 (m, 1 H), 5.17-5.11 (m, 1 H), 4.51 (dd, J=7.5, 10.2Hz, 1 H), 4.07-3.76(m, 4H), 3.55(S, 3H), 3.52-3.39(m, 1 H), 2.69-2.60(m, 1 H), 2.02 (S, 3H), 2.08-1.84(m, 1 H), 1.75(dd, J=1.7, 7.1 Hz, 3H), 1.50(d, J=6.1 Hz, 3H), 1.48(d, J=6.4Hz, 3H).
MS: (M+H)+=314, (M+35)'=348 Example 182 ,~OH
O
O~ ~CH3 /~, AcHN.
H N
H
N HCi (t)-(2R.3S 5R 1'S 3'S)-2-(,1-Acetamido-2~N-isopropyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1~rlLp~rrrolidine-5-carbox~c Acid Hydrochloride Salt ' H NMR (MeOD-d3) b 5.76-5.68(m, 1 H), 5.39-5.31 (m, 1 H), 5.10-5.05(m, 1 H), 4.49(dd, J=7.8, 9.8Hz, 1 H), 4.12-3.84(m, 4H), 3.55-3.44(m, 1 H), 3.41 (S, 3H), 2.69-2.60(m, 1 H), 2.08(S, 3H), 2.07-1.84(m, 1 H), 1.76{dd, J=1.7, 6.8Hz, 3H), 1.51{d, J=2.4Hz, 3H), 1.49(d, J=2.4Hz, 3H).
MS: (M+H)+=314, (M+35)+=348 Examele 183 ', AcHN. N,.,~OH
H H
O
NCH HCi (t)-(2R 3S 5R 1'S 3'S~~1-Acetamido-2-(N-isobutyl-N-methylamino-N-oxide))ethyl-3-(cis-eropen-1-yl)-pyrrolidine-5-carboxylic Acid Hydrochloride Salt ' H NMR (MeOD-d3) 8 5.75-5.69(m, 1 H), 5.38-5.31 (m, 1 H), 5.18-5.12(m, 1 H), 4.53(dd, J=7.5, 9.8Hz, 1 H), 4.25-3.42(m, 6H), 3.65 (s, 3H), 2.68-2.58(m, 1 H), 2.44-2.36(m, 1 H), 2.05(s, 3H), 1.94-1.87(m, 1 H), 1.76(d, J=2.7Hz, 3H), 1.14 (d, J=6.8Hz, 6H).
MS: (M+H)+=342, (M+Na)+=364, (M-H)-=340 Example 184 /= , AcHN. N~., ~OH
H\ H
O
~N ~CH

(t)-(2R 3S 5R 1'S 3'R~-2-(1-Acetamido-2-(N-isobutyl-N-methvlamino-N-oxide))eth_yl-~cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Hydrochloride Salt ~ H NMR (MeOD-d3) s 5.75-5.69(m, 1 H), 5.38-5.31 (m, 1 H), 5.06-5.02(m, 1 H), 4.48(dd, J=7.5, 9.8Hz, 1 H), 4.08-3.85(m, 3H), 3.70-3.57 (m, 2H), 3.52(s, 3H), 3.48-3.41 (m, 1 H), 2.70-2.60(m, 1 H), 2.40-2.36(M, 1 H), 2.08(s, 3H), 1.95-1.84(m, 1 H), 1.75(dd, J=1.7, 7.1 Hz, 3H), 1.14 (d, J=6.8Hz, 6H).
MS: (M+H)+=342, (M+Na)+=364, (M-H)-=340 Example 185 (t)-(2R,3S 5R 1'S)-2-(1-Acetamido-2-(N-isopropyl-N-hydroxyamino))ethyl-3-vinyl-p~rrolidine-5-carboxylic Acid HydrochlorideSalt AcHN. N>., O~Bu H Boc ~N
i OH
165A (t)-12R,3S,5R.1'S~1-t-Butoxycarbonyl-2-(1-acetamido-2-lN-isopropyl-N-hydroxyamino eth rLl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'S)-1-t Butoxycarbonyl-2-(1-acetamido-2-isopropylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (21 mg, 0.048 mmole) was dissolved in 0.95 mL of acetone. It was then titrated with 0.14 mL of a solution of dimethyldioxirane (0.1 M) in acetone at -45°C for 0.5 hour.
The reaction was stopped by concentrating the mixture in vacuo. The residue was purified by chromatography on silica gel using 100% dichloromethane to 90% dichloromethanelmethanol to provide the title compound (yield: 5.3 mg, 24%) and recovered starting material (yield 12 mg, 57%).
1 H NMR (MeOD-dg) 8 5.95-5.89(m, 1 H), 5.08-4.94(m, 2H), 4.75-4.68(m, 1 H), 4.13-3.83(m, 2H), 2.85-2.47(m, 4H), 1.96(s, 3H), 1.82-1.76(m, 1 H), 1.52-1.44(m, 18H), 1.45-1.29(m, 1 H), 1.07-1.04(m, 6H).
MS: (M+H)+=456, (M+Na)+=478, (M-H)-=454, (M+35)-=490.

,~ H
O
OH
1858 ~t)-(2R.3S.5R.1'S)-2-(1-Acetamido-2-(N-isopropyl-N-h~xyamino))ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride Salt The title compound was prepared according to the method described in Example 1K, substituting (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-{1-acetamido-2-(N-isopropyl-N-hydroxyamino))ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid t butyl ester (yield: 3.0 mg, 87%).
1 H NMR (MeOD-d3) b 5.83-5.71 (m, 1 H), 5.40(d, J=17.3Hz, 1 H), 5.24(d, J=10.2Hz, 1 H), 4.48(dd, J=7.8, 10.2Hz, 1 H), 3.88-3.59(m, 4H), 3.17-3.10(m, 1 H), 2.67-2.58(m, 1 H), 2.10-1.99(m, 1 H), 2.09(s, 3H), 1.33-1.17(m, 1 H), 1.38(d, J=6.4Hz, 6H).
MS: (M+H)+=300, (M-H)-=298, (2M-H)-=597 , AcHN.
H N
H
N

Example 186 AcHN. N~.,~ H
H H

/ TFA
(t)~2R 3S 5R 1'R~,-2-(1-Acetamido-2-oxo-2-phenyl)ethyl-3-(cis-aropen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting {t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-oxo-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f butyl ester (yield: 5.9 mg, 100%).
'H NMR (DMSO-ds) s 8.62 (d, J= 9.8Hz, 1H), 7.93 (m, 2H), 7.68 (m, 1H), 7.55 (t, J= 7.9Hz, 2H), 5.61 (m, 1 H), 5.48 (m, 1 H), 5.19 (m, 1 H), 4.50 (rn, 1 H), 3.98 {t, J= 9.8Hz, 1 H), 3.30 (m, 1 H), 2.38 (m, 1 H), 1.73 (m, 1 H), 1.71 (s, 3H), 1.59 (m, 3H).
MS: (M+H)+= 331, (M+Na)+= 353, (M-H)- = 329.

Example 187 (t) ~2R 3S 5R 1'R 2'R)-2-(1-Acetamido-2-methoxy-4-vin rLl)butyl-3-(cis-propen-Lrl~-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
~OtBu O
187A (tL{2R 3S.5Rs1'R.2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methox~
viny_I)but~rf-3-fcis-propen-1-~)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound is prepared according to the method described in Example 84A, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yi)-pyrrolidine-5-carboxylic acid t butyl ester for (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester.
,~ H
O

TFA
187B (t)-(2R 3S.5R.1'R.2'R)-2-(1-Acetamido-2-methoxv-4-vinyl)butvl-3-(cis-propen-1-~pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound is prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy-4-vinyl)butyl-3-{cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-{2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.

AcHN
N
H Boc ~OCH3 AcHN_ ~.
H N
H

WO 99!54299 PCT/US99/07945 Example 188 {t) ~2R 3S 5R 1'R 2'S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-YI)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
, AcHN. N~., OtBu H Boc 188A (t)-(2R 3S 5R 1'R 2'S)-1-t-Butoxvcarbonyl-2-(1-acetamido-2-methoxv-4-vinylbutyl-3-{cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 84A, substituting (t)-(2R,3S,5R,1'R,2'S)-1-f butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester for (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-{1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield:
0.0044 g, 22%).
MS: (M+H)+=481, (M-H)-=479.
,~OH
O

TFA

AcHN.
H N
\ H
188B (t)-~2R 3S 5R 1'R 2'Sl-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-p~rrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-{2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yf)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0031 g, 100%).
' H NMR (DMSO-ds) b 7.93 (d, J=9.2Hz, 1 H), 5.81 (m, 1 H), 5.49 (m, 1 H), 5.26 (m, 1 H), 5.1-4.9 (m, 2H), 4.29 (m 1 H), 4.03 (m, 2H), 3.68 (m, 1 H), 3.26 (m, 1 H), 3.25 (s, 3H), 3.18 (quint., J=8.5Hz, 1 H), 2.40 (dt, J=12.7,7.3Hz, 1 H), 2.32 (M, 1 H), 2.20 (m, 1 H), 2.02 (m, 1 H), 1.85 (s, 3H), 1.68 (m, 1 H), 1.64 (m, 1 H), 1.61 (dd, J=6.7,1.8Hz, 3H), 1.55-1.40 (m, 2H).
MS: (M+H)+=325, (M+Na)+=347, (M-H)'=323.
Example 189 (t)-LR.3 R.5 R.1 ' R,2'S)-2-( 1-Aceta mid o-2.3-d ihyd roxy~~ropyl-3-(cis-propen-1-yl)-~yrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt TBDPSO-Ms0 N~,~OtBu H Boc O

189A (t)-(2R.3R.5R.1'S)-1-t Butoxycarbony!-2-(1-methanesulfon~x~ 3-azido)ethyl-3-t-but~diphenylsilyloxymethYl pyrrolidine-5-carboxylic Acid t-ButLrl Ester.
The title compound was prepared according to the method described in Example 123J substituting (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-oxiranyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t butyl ester in place of (2R,3S,5R,1'S)-2-oxiranyl-3-vinyl-pyrrolidine-5-carboxylic acid t butyl ester (yield:
9.0 g, 90%).

'H NMR (DMSO-ds) (rotamers) 8 7.62-7.58 (m, 4H), 7.49-7.38 (m 6H), 4.97-4.79 (m, 1 H), 4.19-4.02 (m, 2H), 3.79-3.48 (m, 2H), 3.15 and 3.13 (2s, 3H), 2.49-2.39 (m, 2H), 1.98-1.74 {m, 1 H), 1.43-1.25 (m, 18H), 1.02 and 1.00 (2s, 9H) MS: (M+H)+= 703, (M+Na)+= 725 TBDPSO-, N)., ~O~Bu HN~ H goc O
1898 (t}-(2R.3R.5R.1'S)-1-t-butoxycarbonyl-2-aziridinyl-3-t-butyldiphenylsil~x~methyl_pyrrolidine-5-carboxylic acid t butyl ester The title compound was prepared according to the method described in Example 123K substituting(t)-(2R,3R,5R,1'S)-1-t-butoxycarbonyl-2-(1-methanesulfonyloxy-3-azido)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t}-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-methanesulfonyloxy-3-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester(yield: 5.9 g, 79%).
'H NMR (DMSO-ds) (rotamers) 8 7.60-7.56 (m, 4H), 7.49-7.39 (m 6H), 4.11-4.05 (m, 1 H), 3.67-3.48 (m, 2H}, 3.42-3.30 {m, 1 H), 2.49-2.39 (m, 1 H), 2.25-1.61 (m, 5H), 1.40, 1.35, 1.33, and 1.27 (4s, 18H), 0.99 and 0.98 (2s, 9H) MS: (M+H)+ = 581, (M+Na)+ = 603 TBDPSO-, N ). , ~OtBu AcN~ H Boc O
189C (~)-(2R.3R.5R,1'Sl-1-t-Butoxycarbonyl-2-N-acetylaziridinyl-3-t-butyldiphenyisilylox~methyt-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 123L substituting (t)-(2R,3R,5R,1'S)-1-t-butoxycarbonyl-2-aziridinyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 3.1 g, 96%).
'H NMR (DMSO-ds) (rotamers) 8 7.60-7.57 (m, 4H), 7.49-7.39 (m 6H), 4.18-4.11 (m, 1 H), 3.71-3.51 (m, 3H), 2.76-2.68 (m, 1 H), 2.58-2.45 (m, 1 H), 2.46 and 2.39 (2d, J=6.1, 6.1 Hz, 1 H), 2.40 and 2.47 (2m, 1 H), 2.08 and 2.05 (2d, J=3.1, 3.1 Hz, 1 H), 2.02 and 1.99 (2s, 3H), 1.94-1.79 (m, 1 H), 1.41, 1.36, 1.35 and 1.29 {4s, 18H), 0.99 and 0.98 (2s, 9H) MS: (M+H)+ = 623, (M+Na)+ = 645 TBDPSO-AcHN- N~,~OtBu Ac0 H Boc 189D {t~2R,3R.5R,1'R)-1-t Butoxycarbonyl-2-(1-acetamido-2-acetox )Lthyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester (t)-(2R,3R,5R,1'S)-1-t-butoxycarbonyl-2-N-acetylaziridinyl-3-t-butyldiphenylsilyloxyrnethyl-pyrrolidine-5-carboxylic acid f-butyl ester (2.75g, 4.40 mmole) was reacted with potassium acetate (2.49 g, 25.37 mmole) and acetic acid (1.45 mL, 25.37 mmole) in DMSO (45 mL) at 100°C for 16 hours. The reaction was quenched with 1 N NaHC03 (100 mL) and diluted with ethyl acetate (300 mL). The organic layer was washed with water,and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chramatography on silica gel using 100% dichloromethane to 50%
dichloromethane/ethyl acetate to provide the title compound (yield: 2.45g, 81 %).
MS: (M+H)+=683, (M+Na)+=705, (M-H)-=681, {M+CI)'=717 TBOPSO--AcHN- N~.~ ~B~
HO H Boc 189E (t)-(2R,3R,5R,1'R)-1-t Butox~arbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-t butyld~henylsilyloxvmethYl_pyrroiidine-5-carboxylic Acid t Butyl Ester (t)-(2R, 3R,5R,1'R)-1-t-Butoxycarbonyl-2-( 1-acetamido-2-acetoxy)ethyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t butyl ester (2.45 g, 3.58 mmole) was reacted with potassium carbonate (1.48 g, 10.73 mmole) in methanol (18 mL) and THF (l8mL) at 25°C for 45 minutes. The reaction was quenched with water (100 mL) and diluted with ethyl acetate (200 mL). The organic layer was washed with water,and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 85%
dichloromethanelethyl acetate to 100% ethyl acetate to provide the title compound {yield: 2.05 g, 90%).
MS: (M+H)+=641, (M+Na)+=663, (2M+Na+H)+=1304, (M-H)'=639, (M+CI)' =675 ~01-TBDPSO-.
, AcHN- N~, O H'Boc O
189F (t)-(2R.3R 5R 1'R~-1-t-Butoxycarbonyl-2;~1-acetamido-2-formyl)ethyl-3-f butyldiphen~silyloxymethy!-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 41A substituting (t)-{2R,3R,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R)-1-t butoxycarbonyl 2-(1-acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
'H NMR (DMSO-ds) (rotamers) 9.49(4, J=16.3, 1H), 8.33 and 8.29(24, J=8.8 and 8.8Hz, 1 H), 7.58-7.38(m, 1 OH), 4.94 and 4.84(244, J=4.4, 8.8Hz and 4.4, 8.8Hz, 1 H), 4.26-3.37(m, 4H}, 2.47-2.30(m, 1 H), 1.97-1.83(m, 1 H), 1.92(s, 3H), 1.42-1.18(m, 18H), 1.42-1.18(m, 1 H), 1.00-0.97(m, 9H).
MS: (M+H)+=639, (M-H)'=637 TBDPSO-AcHN- N~.
.~ H Boc O
189G {t?-(2R.3R.5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-1-vinyl)methyl-3-t butyldiphen~IsilYlox~rmethyl-pyrrolidine-5-carboxylic Acid t Buty! Ester The title compound was prepared according to the method described in Example 118A substituting (t)-{2R,3R,5R,1'R)-1-t butoxycarbonyl-2-(1-acetamido-2-formyl)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R)-1-t butoxycarbonyl 2-(1-acetamido-2-forrnyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
'H NMR (DMSO-ds) (rotamers) 7.99-7.74(m, 1H), 7.59-7.39(m, 10H), 5.80-5.68(m, 1 H), 5.21-5.01 (m, 3H), 3.97-3.31 (m, 1 H), 3.78-3.74(m, 1 H), 3.60-3.46(m, 2H), 2.53-2.37(m, 1 H), 2.09-1.72(m, 1 H), 1.87(s, 3H), 1.42-1.23(m, 19H), 1.00-0.99(m, 9H).
TBDPSO-~ TBDPSO-AcHN- N~.~OtB~ AcHN- , N~,~O~Bu H Boc [O H Boc O
~OH OH
OH OH
189H (t -(~ 2R,3R,5R 1'R.2'R) and (t)-(2R,3R.5R.1'R,2'S)-1-t-Butoxycarbon (,1-acetamido-2.3-dih~drox~propyl-3-t-butyldiphenylsilyioxymethyl-pyrrolidine-carboxylic Acid t Bu I Ester The title compounds were prepared according to the method described in Example 20A substituting (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-2-vinyl)ethyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R)-1-benzyl-2-vinyl-3-t-butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (t}-(2R,3R,5R,1'R,2'S) isomer (yield:
311mg, 24%) (t)-(2R,3R,5R,1'R,2'R) isomer (yield: 700 mg, 54%).
(t)-(2R,3R,5R,1'R,2'S) 'H NMR (DMSO-dfi) (rotamers) 7.62-7.39(m, 11 H), 4.56 and 4.51 (d, J=4.8, 1 H), 4.46-4.39(m, 2H), 3.97-3.82(m, 1 H), 3.74-3.47(m, 3H), 3.28-3.21 (m, 2H), 2.89-2.64(m, 1 H), 2.51-2.45(m, 1 H), 2.05-1.8(m, 1 H), 1.87-1.86(m, 3H), 1.43-1.23(m, 19H), 0.99-0.98(m, 9H).
(t)-(2R,3R,5R,1'R,2'R) 'H NMR (DMSO-d6) (rotamers) 7.63-7.40(m, 11 H), 4.56-4.54(d, J=4.8, 1 H), 4.47-4.33(m, 2H), 3.94-3.80(m, 1 H), 3.85-3.80(m, 1 H), 3.76-3.68(m, 1 H), 3.60-3.51 (m, 1 H), 3.44-3.35(m, 1 H), 3.30-3.21 (m, 1 H), 2.78-2.62(m, 1 H), 2.46-2.31 (m, 1 H), 2.07-1.98(m 1 H), 1.83(s, 3H), 1.39-1.29(m, 19H), 1.00-0.99(m, 9H).
TBDPSO-AcHN- N,-,~ tBu H Boc O
~O
O
1891 ltl-(2R.3R.5R.1'R.2'S)-1-t Butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1.3-dioxolan-4~yl), methyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-carbox~lic Acid t Butyl Ester (t)-(2R,3R,5R,1'R,2'R)-1-t-Butoxycarbonyl-2-( 1-acetamido-2,3-dihydroxy)propyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester was reacted with 2,2-dimethoxypropane (1.1 ml, 9.09 mmole) and p-Toluenesulfonic acid (4.3 mg, 0.023 mmole) in tetrahydrofuran (4.5 mL) at 25°C
for 45 minutes. The reaction was quenched with triethylamine (3 mL). Stirring was continued for an additional 10 minutes. The reaction was then diluted with 10% NaHC03(15 mL) and extracted with ethyl acetate (45 ml). The organic layer was washed with water,and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was carried over to the next step. purified by chromatography on silica gel using 100% dichlormethane to 94%
dichloromethane/methanol to provide the title compound {yield: 194 mg, 91%).

HO~
AcHN- N~,~OtBu H Boc O
~O
O
189J (t~-(2R 3R 5R.1'R.2'S -1-) t-Butoxvcarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1 3-dioxolan-4-yl))methyl-3-hydroxymethyLpyrrolidine-5-carbox liy c Acid t Butyl Ester The title compound was prepared according to the method described in Example 1236 substituting (t)-(2R,3R,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester for (t}-(2R,3R,5R,1'S)-1-t-butoxycarbonyl-2-oxiranyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester. The resulting residue was purified by chromatography on silica gel using 100% dichlormethane to 94%
dichloromethanelmethanol to provide the title compound (yield: 194 mg, 91%).
H
O
AcHN- N~.~OtBu H Boc O
~O
O
189JJ (t)-(2R 3R 5R.1'R.2'Sl-1-t ButoxycarbonYi-2-(1-acetamido-1-(2.2-dimethyl-1,3-dioxolan-4 yl))methyl-3-formyl-pyrrolidine-5-carboxylic Acid t Butyl Ester The title compound was prepared according to the method described in Example 123H substituting (t)-(2R,3R,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester for (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-oxiranyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.

AcHN- N~..~ tBu H Boc O
~O
O
189K (t)-(2R.3S,5R,1'R,2'S)-1-t Butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-~ I)~ )methyl-3-(cis-propen-1- I~yrrolidine-5-carboxylic Acid t-Bud Ester The title compound was prepared according to the method described in Example 35A substituting (t)-(2R,3R,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid t butyl ester (yield: 11.5 mg, 59%).
' H NMR (CDC13): b 6.62 (d, 1 H), 5.56 (m, 1 H), 5.40 (m, 1 H), 4.43 (m, 1 H), 4.25 (m, 1 H), 4.16 (m, 1 H}, 4.02 (m, 1 H), 3.88 (m, 1 H), 3.54 (m 1 H), 3.14 (m, 1 H), 2.54 (m 1 H), 2.04 (s, 3H), 1.71 (m 1 H), 1.60 (dd, 3H), 1.46 (s, 9H), 1.45 (s, 9H), 1.40 (s, 3H}, 1.32 (s, 3H).
MS: (M+H)+=483 /= , AcHN. N~.,~OH
H H
O
~OH
OH TFA
189L (t)-(2R,3S,5R.1'R.2'S)-2-(1-Acetarnido-2,3-dih dy roxy)prop~-3-(cis-proper-1-yl}-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-(cis-proper-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-{ 1-acetam ido-2-hyd roxy)butyl-3-(cis-proper-1-y!)-pyrrolidine-5-carboxylic acid t butyl ester.
' H NMR (DMSO-ds): 8 7.84 (d, J=9Hz, 1 H), 5.49 (m, 1 H), 5.27 (m, 1 H), 4.47 (m, 1 H), 4.25 (m, 1 H), 4.17 (m, 1 H), 3.75 (rn, 1 H), 3.59 (m, 1 H}, 3.35 (m, 1 H), 3.18 (m, 1 H), 2.43 (m, 1 H), 1.81 (s, 3H),1.55 (dd, 3H).
MS: (M+H)+=287 Example 190 (t)-(2 R, 3R.5R,1' R, 2'R)-2-( 1-Acetamido-2.3-dihyd roxY)propYl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt TBDPSO-AcHN- N~,~O~Bu H Boc O
O
O
190A (t)-(2R.3R,5R,1'R,2'R)-1-t-Butoxycarbony~1-acetamido-1-(2.2-dimetf~l-1,3-dioxolan-4-y~)methyl-3-t bu Idiphenylsilyloxyrnethyl-pyrrolidine-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 1891 substituting (t)-(2R,3R,5R,1'R,2'R)-1-t butoxycarbonyl-2-(1-acetamido-2,3-dihydroxy)propyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'R,2'S)-1-t-B utoxycarbonyl-2-( 1-acetamido-2, 3-d ihyd roxy)propyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.

HO-AcHN- N,-. ~ tBu H Boc ~
O
O
190B (t)-(2R,3R,5R,1'R,2'R)-1-t Butoxycarbonyl-2-(1-acetamido-1-(2.2-dimeth,/1-1.3-dioxolan-4-yIZ methyl-3-hydroxymethyl-gyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 1236 substituting (t)-(2R,3R,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester for (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-oxiranyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.
H
O
AcHN- N,.,~OtBu H Boc O
O
O
190C (t)-(2R.3R,5R.1'RL2'R)-1-t Butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4yl))methyl-3-formylpyrrofidine-5-carboxylicAcid t Butyl Ester The title compound was prepared according to the method described in Example 123H substituting (t)-(2R,3R,5R,1'R,2'R)-1-t butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-hydroxymethyi-pyrrolidine-5-carboxylic acid t-butyl ester for (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-oxiranyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.

AcHN
N T~
H Boc 'O
-o o~
190D (t)-~2R 3S 5R.1'R.2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(2.2-dimethyl-1.3-dioxolan-4.-yl))methyl-3-(cis-propen-1-yl)Lpyrrolidine-5-carboxylic Acid t Butyl Ester The title compound was prepared according to the method described in Example 35A substituting (t)-(2R,3R,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 42 mg, 61 %).
' H NMR (CDC13): 8 7.88 (d, 1 H), 5.52 (m, 1 H), 5.34 (m, 1 H), 4.33 (m, 1 H), 4.21 (m, 1 H), 3.96 (m, 2H), 3.83 (m, 1 H), 3.60 (m, 1 H), 3.40 (m, 1 H), 2.53 (m, 1 H), 1.98 (s, 3H), 1.66 (dd, 3H), 1.46 (s, 9H), 1.44 (s, 9H), 1.41 (s, 3H), 1.33 (s, 3H).
MS: (M+H)+=483 /_', AcHN_ N~,~OH
H H
O
OH
OH TFA
190E ~t~~2R 3S 5R 1'R 2'R)-2-(1-Acetamido-2.3-dihy_droxy)propyl-3-(cis-pro en-1-yly-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41 C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-y!))methyl-3-(cis-propen-1-yl))-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-( 1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-carboxylic acid t-butyl ester.
' H NMR (DMSO-ds): 8 7.98 (d, J=9Hz, 1 H), 5.48 (m, 1 H), 5.29 (m, 1 H), 4.60 (m, 1 H), 4.30 (m, 1 H), 4.12 (m, 1 H), 3.76 (m, 1 H), 3.52 (m, 1 H), 3.46 (m, 1 H), 3.32 (m, 1 H), 3.18 (m, 1 H), 2.40 (m, 1 H), 1.84 (s, 3H), 1.60 (dd, 3H).
MS: (M+H)+=287 ~11-Example 193 (~2R.3S 5R 1'R 2'S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN. N,.,~ ~Bu H Boc O
O
193A (tL(2R,3S,5R.1'R.2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-ethoxy~pentyl-3-(cis-proyen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 88A, substituting ethyl iodide for methyl iodide (yield: 3.6 mg, 28%).
MS: (M+H)+= 483, (M+Na)+= 505, (M-H)- = 481.
/_.:.

AcHN, N~_.,,~~ H
H fO
'O
I TFA
1938 (t)-~2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-ethoxv)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
ester (yield: 3.2 mg, 100%).

'H NMR (DMSO-ds) b 7.92 (d, J= 9.2Hz, 1 H), 5.47 (m, 1 H), 5.25 (m, 1 H), 4.25 (m, 2H), 3.70 (m, 1 H), 3.52 (m, 1 H), 3.33 (m, 2H), 3.18 (m, 1 H), 2.39 (m, 1 H), 1.85 (s, 3H), 1.66 (m, 1 H), 1.61 (dd, J= 6.7, 1.8Hz, 3H), 1.56 (m, 1 H), 1.37 (m, 1 H), 1.28 (m, 2H;1, 1.13 {m, 3H), 0.86 (t, J= 7.3Hz, 3H).
MS: (M+H)+= 327, (M+Na)+= 349, (M-H)- = 325.
Example 194 (t)-(2R,3S,5R.1'R.2'R)-2-f 1-Acetamido-2-ethox)ilpentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ~O~Bu O O

AcHN.
N
H Boc 194A (t)~2R.3S.5R 1'R.2'Ry-1-t Butox~rcarbonyl-2-(1-acetamido-2-ethoxy pentyl-3-(,cis-propen-1 ~il~pyrrolidine-5-carboxylic Acid t Butyl Ester The title compound is prepared according to the method described in Example 88A, substituting ethyl iodide for methyl iodide.

AcHN OH
N> ,~~~~
H H O
~~~'O
TFA
194B (t) ~2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-ethoxy~pentyl-3-(cis~r~oen-1-yl)-pyrrolidine-5-carboxyic Acid Trifluoroacetic Acid Salt The title compound is prepared according to the method described in Example 41 C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrroiidine-5-carboxylic acid t-butyl ester.
Examele 195 {2R.3S.5R.1'S)-2-(1-Acetamido-2-hydroxy)ethyl-3-vinyl-~yrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt _ ~.
AcHN OH
N ~ .~'~~
HH O
HO
TFA
The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester {yield: 19.9 mg, 100%).

'H NMR (DMSO-ds) 8 7.80 (d, J= 8.8Hz, 1 H), 5.76 (m, 1 H), 5.23 (d, J=
17.1 Hz, 1 H), 5.15 (m, 1 H), 4.31 (m, 1 H), 4.03 {m, 1 H), 3.62 (m, 1 H), 3.53 (m, 2H), 2.79 (m, 1 H), 2.42 (m, 1 H), 1.90 (s, 3H), 1.85 (m, 1 H).
MS: (M+H)+= 243, (M+Na)+= 265, (M-H)- = 241.
Example 196 (t)-(2R,3S,5R,1'R.~2'S~-2-(1-Acetamido-2-hydroxv-3-dimethylphosphonyl)pro~,yl-3-(cis-propen-1-yl~~ayrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt i= , AcHN_ )., O~Bo AcHN. ,., OtBu H Boc ~ H Boc OOH ~OH
O=P-OCH3 O=P-OCH3 196A (t)-(2R,3S.5R,1'R,2'S) and ~t~-(2R.3S.5R,1'R,2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-dimeth I~phosphonyl)~ropyl-3-(cis-propen-1-yl~
pyrrolidine-5-carboxylic Acid t-Butyi Ester.
(t)-(2R,3S,5R,1'R)-1-t Butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (78 mg, 0.19 mmoi) in THF (5 mL) was added dropwise to a solution of dimethylphosphonylmethyl lithium (3M) (0.32 mL, 0.95 mmoi) in THF (20 mL) at -78°C and reacted for 40 minutes. The reaction was quenched with water (10 mL) and saturated aqueous ammonium chloride (10 mL) followed by extraction using dichloromethane (2 x 50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 5-7 0% methanol in dichloromethane to provide the title compounds (t)-{2R,3S,5R,1'R,2'R) isomer (yield: 27 mg, 27%) and (t)-(2R,3S,5R,1'R,2'S) isomer (yield: 5.5 mg, 6%).
(t)-(2R,3S,5R,1'R,2'R) _ ' H NMR (CDC13) 8 5.98 (m, 1 H), 5.58(m, 1 H), 5.35(m, 1 H), 4.94(m, 1 H), 4.14(m, 2H), 3.74(m, 8H), 3.06(m, 1 H), 2.64{m, 1 H), 2.03(s, 3H), 1.95(m, 1 H), 1.83(m, 3H), 1.53(s, 9H), 1.46(s, 9H) MS: (M+H)+=535, (M-H)- =533 (t)-(2R,3S,5R,1'R,2'S) MS: (M+H)+=535, (M-H)-=533 AcHN_ N~.,~OH
H H
OH O
O=P-OCH3 TFA

1968 ~t)-(2R.3S.5R.1'R,2'S)-2-{1-Acetamido-2-hydroxy-3-dimethylphosphonyfZpropyl-3-(cis-propen-1-yl)-ayrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-f butoxycarbonyl-2-(1-acetamido-2-hydroxy-dimethylphosphonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)- 1-t-butoxycarbonyl-2-{1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-carboxylic acid t-butyl ester (yield: 3 mg, 96%).
' H NMR {DMSO-d6) b 7.98(d, J=9.2 HZ, 1 H), 5.48(M, 1 H), 5.28(m, 1 H), 4.36(m, 1 H), 4.30(m, 1 H), 4.08(m, 2H), 3.70(m, 2H), 3.60(m, 6H), 3.18(m, 1 H), 2.40(m, 1 H), 2.05(m, 1 H), 1.85(s, 3H), 1.60(dd, J=6.2, 1.2 HZ, 3H) MS: (M+H)+=379, (M-H)' =377 Example 197 AcHN. N~.,~OH
HH O
~OH
O=P-OCH3 TFA

-(2R.3S.5R.1'R.2'R}-~1-Acetamido-2-hydroxy-3-dimethylphosphon r~1 propyl-~cis-propen-1-yl) pYrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-dimethylphosphonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-( 1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolid ine-5-carboxylic acid t butyl ester (yield: 13 mg, 96%).
' H NMR (DMSO-d6) 8 7.72 (d, J=9.2 HZ, 1 H), 5.48(m, 1 H), 5.24(m, 1 H), 4.44(m, 1 H), 4.15(m, 2H), 3.62(m, 7H), 3.54(m, 1 H), 3.15(m, 1 H), 2.40(m, 1 H), 1.95(m, 1 H), 1.82(s, 3H), 1.72(m, 1 H), 1.54(dd, J=6.7, 1.2 HZ, 3H) MS: (M+H)+= 379, (M-H)' = 377 Example 198 {t)-{2R 3S 5R 1'S)-2-~1-Acetamido-3-hydroxY)propel-3-(cis-propen-1-~~
pyrrolidine-5-carboxyiic Acid Triffuoroacetic Acid Salt AcHN. N,., O~Bu H Boc 198A (t)-(2R.3S 5R 1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(cis and traps-2-methoxyvinyl))methyl-3-(cispropen-1-YI)-pyrrolidine-5-carboxylic Acid t Butt Ester (t)-(2R,3S,5R,1'R)-1-t Butoxycarbonyl-2-{1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (113 mg, 0.28 mmol) was added to a solution of (methoxymethyl)triphenylphosphonium bromide (240 mg, 0.70 mmof) and potassium t-butoxide (0.56 mL, 0.56 mmol, 1 M in THF) in toluene (3 mL) at 0°C for 15 minutes. The reaction was quenched with saturated aqueous ammonium chloride (3 mL) followed by extraction using dichloromethane (2 X 3 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica get using 1 /4: ethyl acetatelhexane to provide the title compounds ' H NMR (CDC13) 8 8.65 (br d, 1 H) 6.01 (d, J=5.7Hz, 1 H), 5.40 (m, 3H), 5.11 (br t, 1 H), 4.15 (m, 2H), 3.72 (m, 1 H) 3.61 (s, 3H), 3.00 (m, 1 H), 2.42 (m, 1 H), 1.94 (s, 3H), 1.64 (dd, J=1.4, S.OHz, 3H), 1.45 (m, 9H), 1.25 (m, 9H) MS: (M+H)+= 439.

!-= , AcHN. N~.,~ ~Bu p H Boc p H
198B (t)-(2R.3S.5R.1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-formyt)ethLrl-3-(cis-propen-1- r~pyrrolidine-5-carboxylic Acid t-Butyl Ester (t)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-(cis and traps-2-methoxyvinyi))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (21 mg, 0.048 mmol) was reacted with Liar (37 mg, 0.43 mmol) and AG50W-X2 ion exchange resin in CH3CN (2 mL) and water (0.1 mL) at room temperature for 45 minutes. The reaction was filtered and quenched with saturated aqueous sodium bicarbonate (1 mL) followed by extraction using dichloromethane (2 X 1 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/4: ethyl acetate/hexane to provide the title compound.
' H NMR (CDC13) s 9.70 (dd, J=1.3, 2.4Hz, 1 H), 8.11 (d, J=7.8Hz, 1 H), 5.54 (m, 1 H), 5.41 (t, J=5.8Hz, 1 H), 4.52 (m, 1 H), 4.13 (dd, J=4.4, 4.8Hz, 1 H), 3.75 (dd, J=2.7, 3.1 Hz, 1 H), 2.86 (m, 1 H), 2.47 (m, 3H), 1.99 (s, 3H), 1.63 (dd, J=1.6, 5.1 Hz, 3H), 1.46 (s, 9H), 1.45 (m, 1 H), 1.44 (s, 9H) MS: (M+H)+= 425; (M-H)- = 423.

/~, AcHN. N~., OtBu H Boc OH
198C (t)-~2R.3S.5R.1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-hydroxy)propyl-3-(cis-propen-1-~p~rrolidine-5-carboxylic Acid t-Bu I Ester (t)-(2R, 3S, 5R,1'S)-1-t-Butoxycarbonyl-2-( 1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (9 mg, 0.02 mmol) was reacted with sodium borohydride (1 mg, 0.02 mmol) in methanol (0.1 mL) at room temperature for 20 minutes. The reaction was quenched with saturated aqueous ammonium chloride (1 mL) followed by extraction using dichloromethane (2 X 1 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/4: ethyl acetate/hexane to provide the title compound.
' H NMR {CDC13) b 8.45 (d, J=7.5Hz, 1 H), 5.55 (m, 1 H), 5.34 (t, J=7.8Hz, 1 H), 4.20 (dd, J=3.0, 5.4Hz, 2H), 3.71 (d, J=6.1 Hz, 1 H), 3.62 (m, 1 H), 3.50 (t, J=9.1 Hz, 1 H), 2.92 (m, 1 H), 2.41 (m, 1 H), 2.04 (s, 3H), 1.66 (dd, J=2.0, 5.1 Hz, 3H), 1.62 (m, 1 H), 1.47 (s, 9H), 1.45 (m, 1 H), 1.43 (s, 9H), 1.22 (m, 2H) MS: (M+H)+ = 427; (M-H)- = 425.

/= , AcHN_ N~,~OH
H H
O
OH TFA
198D Ct)-f2R 3S 5R 1'S)-2-!1-Acetamido-3-h dY roxy_)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-hydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)- 1-f butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester.
ester (yield: 4.6 mg, 100%).
~ H NMR (DMSO-ds) 8 9.25 (br s, 1 H), 8.13 (d, J=7.3Hz, 1 H), 5.52 (m, 1 H), 5.28 (br t, 1 H), 4.32 (br t, 1 H), 4.22 (m, 1 H), 3.49 (m, 4H), 3.18 (m, 1 H), 2.40 (m, 1 H), 1.90 (s, 3H), 1.73 (m, 1 H), 1.63 (dd, J=1.8, 5.5Hz, 3H), 1.57 (m, 1 H) MS: (M-H)- = 269; (M+H)+ = 271.

Example 199 !t)-(2R.3S,5R,1'S,3'S)-2-(1-Acetamido-3-h droxY)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN_ ,., OtB~ AcHN_ )., O~Bu H Boc ~ H Boc OH OH
199A (~2R.3S.5R,1'S.3'S) and (t)-(2R,3S,5R,1'R.3'R)-1-t-Butoxycarbonyl-2-(1-acetamido-3-h~droxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid (-Butyl Ester (t)-(2R,3S,5R,1'S)-1-t Butoxycarbonyl-2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (26 mg, 0.061 mmol) was reacted with ethylmagnesium bromide (3.0 M) (0.122 mL, 0.367 mmol) in THF (4 mL) at room temperature for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride (10 mL) and water (10 mL) followed by extraction using ethyl acetate (3 X 25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/1 ethyl acetate/hexane followed by 2/1 ethyl acetate/hexane to provide the title compounds (t)-(2R,3S,5R,1'S,2'S) (yield: 6.7 mg, 24%) and (t)-(2R,3S,5R,1'S,2'R) (yield: 6.8 mg, 24%).
(t)-(2R,3S,5R,1'S,2'S) MS: (M+H)+=455, (M+Na)+=477, (M-H)'=453.
(t)-(2R,3S,5R,1'S,2'R) MS: (M+H)+=455, (M+Na)+=477, (M-H)-=453.

AcHN. N~,~OH
H H
O
OH TFA
199B ~t)-(2R,3S.5R.1'S.3'S)-2-(1-Acetamido-3-h~droxy)pentyl-3-(cis-propen-1-~pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'S,3'S}-1-t butoxycarbonyl-2-(1-acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-{cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
ester (yield: 6.2 mg, 100%).
' H NMR (DMSO-ds) 8 9.20 (bs, 1 H), 8.18 (d, J=7.3 Hz, 1 H), 5.51 (m, 1 H), 5.27 (m, 1 H), 4.30 (m, 1 H), 4.25 (m, 1 H), 3.58 (m, 1 H), 3.41 (m, 1 H), 3.18 (m, 1 H), 2.39 (m, 1 H), 1.90 (s, 3H), 1.75 (m, 1 H), 1.64 (dd, J=7.5,1.SHz, 3H), 1.51 (M, 1 H), 1.38 (m, 1 H), 1.32 (m, 1 H), 0.83 (t, J=7.3Hz, 3H).
MS: (M+H)+ = 299, (M+Na)+ = 321, (M-H)' = 297, (2M-H)-=595.

Example 200 f~2R,3S.5R.1'S,3'R~ 2-(1-Acetamido-3-hydroxy)pen I-3-(cis-propen-1=yl)-pyrrolidine-5-carbolic Acid Trifluoroacetic Acid Salt '=, AcHN. N,.,~ H
H H
O
OH TFA
The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'S,3'R)-1-t-butoxycarbonyl-2-(1-acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
ester (yield: 6.5 mg, 100%).
' H NMR (DMSO-ds) 8 9.25 (bs, 1 H), 8.15 (d, J=7.3 Hz, 1 H), 5.52 (m, 1 H), 5.27 (m, 1 H), 4.31 (m, 2H), 3.52 (m, 1 H}, 3.36 (m, 1 H), 3.19 (quint., J=8.5Hz, 1 H), 2.38 (m, 1 H), 1.92 (s, 3H), 1.75 (m, 1 H), 1.64 (dd, J=7.3,1.SHz, 3H), 1.48 (m, 1 H), 1.33 (m, 2H), 0.85 (t, J=7.3Hz, 3H).
MS: (M+H)' = 299, (M+Na)+ = 321, (M-H)- = 297, (2M-H)-=595.
Example 201 it~2R 3S 5R 1'R)-2-j1-Acetamido-2-oxo-3.3-difluoro-3-vinyl)propyl-3-(cis-propen-1-y~-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt H
O
TFA
The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t butoxycarbonyl-2-(1-Acetamid o-2-oxo-3, 3-d ifl uoro-3-vinyl)propyl-3-( cis-p rope n-1-yl)-pyrrol id ine-5-carboxylic Acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-( 1-acetamido-2-hyd roxy) butyl-3-(cis-propen-1-yl)-pyrrol id ine-5-carboxylic acid t butyl ester (yield: 0.0050 g, 100%).
' H NMR (DMSO-ds) 8 8.67 (d, J=8.5Hz, 1 H), 6.1-5.95 (m, 1 H), 5.78 (dd, J=17.1, 2.4Hz, 1 H), 5.71 {d, 11.OHz, 1 H), 5.45 (m, 1 H), 5.12 (m, 1 H), 4.94 (t, J=9.2Hz, 1 H), 4.51 (dd, J=12.2,6.1 Hz, 1 H), 3.98 (m, 1 H), 3.24 (m, 1 H), 2.32 (m, 1 H), 1.73 {s, 3H), 1.66 (q, J=11.9Hz, 1 H), 1.57 (dd, J=6.7,1.BHz, 3H).
MS: (M+H)+ = 331, (M+H20)+=349, (M+Na)+ = 353, (M-H)- = 329, (2M-H)-=659.

AcH N
H N
H
~O

Example 202 TBDPSO-, TBDPSO--t t AcHN- N~_~ Bu AcHN- N~,~ Bu H Boc pO H Boc ~OH ~OH
202A (t)-(2R,3R.5Ry1'R,2'S) and (t)-(2R,3R,5R.1'R,2'R)-1-t Butoxycarbon (1-acetamido-2-hydroxy~lbutyl-3-t but~ldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid t-ButLrl Ester The title compounds were prepared according to the method described in Example 41 B substituting (t)-(2R,3R,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-formyl)ethyl-3-t butyldiphenylsilyloxymethyi-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester to provide (t)-(2R,3R,5R,1'R,2'S) isomer (yield: 370 mg, 17%) and (t)-(2R,3R,5R,1'R,2'R) isomer (yield: 1.2 g, 55%).
(t)-(2R,3R,5R,1'R,2'S) 1H NMR(d6-DMSO) 8 7.4-7.65 (m, 10H), 4.47 (d, 1 H), 4.32 (m, 1 H), 3.87 (m, 2H), 3.68 (m, 1 H), 3.55 (m, 1 H), 3.25 {m, 1 H), 2.7 (m, 1 H), 2.45 (m, 1 H), 2.0 (m, 1 H), 1.83 (d, 3H), 1.28-1.4 (m, 18H), 0.95 (d, 9H), 0.83 (dt, 3H) MS: (M-H)- = 667, (M+35)+ = 703; (M+H) + = 669, (M+Na) + = 691 (t)-(2R,3R,5R,1'R,2'R) 1 H NMR(d6-DMSO) 8 7.4-7.65 (m, 10H), 4.40 (dd, 1 H), 4.12-4.32 (m, 1 H), 3.82-3.96 (m, 1 H), 3.66 (m, 2H), 3.52 (t, 1 H), 2.6-2.8 (m, 1 H), 2.45 (m, 1 H), 1.76-2.0 (m, 1 H), 1.87 (d, 3H), 1.25-1.4 (m, 18H), 0.95 (d, 9H), 0.83 (dt, 3H).
MS: (M-H)- = 667, (M+35)+ = 703; (M+H) + = 669, (M+Na) + = 691 TBDPSO-AcHN- N~,~O~Bu H Boc O
OI
~O
I
202B (t)-(2R 3R 5R 1'R,2'S -) 1~t-Butoxycarbonyl-2-(1-acetamido-2-metho~methYloxy}butyl-3-t butyldiphenYlsilyloxyrnethyl-pyrrolidine-5-carboxylic Acid t Butyl Ester (t)-(2R,3R, 5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t butyl ester (0.58 g,0.87 mmole) was reacted with methoxymethyl chloride (1.15 mL, 10.07 mmole) and diisopropylethylamine (3.5 mL, 20.1 mmole) in dichloromethane (1 mL) at room temperature for 5 hours. The reaction was quenched with saturated NH4C1 (100 mL) and diluted with ethyl acetate (200 mL).
The organic layer was washed with water, and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% methanoi/methylene chloride to provide the title compound (yield: 0.64 g, 98%).
1 H NMR(d6-DMSO) 8 7.4-7.65 (m, 1 OH), 4.70 (s, 1 H), 4.62 (s, 1 H), 4.35-4.55 (m, 2H), 3.75-3.95 (m, 2H), 3.68 (m, 1 H), 3.55 (m, 1 H), 3.25 (m, 1 H), 3.24 (s, 3H), 2.55 (m, 1 H), 2.45 (m, 1 H), 2.0 (m, 1 H}, 1.85 (s, 3H), 1.28-1.4 (m, 18H), 0.99 (d, 9H), 0.8 (dt, 3H) MS: (M-H)- = 755, (M+35)+ = 791; (M+H) + = 757, (M+Na) + = 779 HO-AcHN- N~,~OtSu H Boc ~(O
O
~O
I
202C (tl~2R 3R 5R,1'R 2'S)-1-t Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butt'l-3-hydrox~methyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 1236 substituting (t)-(2R,3R,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-oxiranyl-3-t butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.416 g, 95%).
1 H NMR(d6-DMSO) 8 7.45 (t, 1 H), 4.62-4.74 (m, 3H), 4.48 (m, 1 H), 3.85 (m, 2H), 3.55-3.6 (m, 2H), 3.45 (t, 1 H), 3.2-3.4 (m, 2H), 3.25 (d, 3H), 2.4 (m, 2H), 1.82 (d, 3H), 1.58 (m, 3H), 1.32-1.45 (m, 18H), 0.82 (dt, 3H).
MS: (M-H)- = 517, (M+35)+ = 553; (M+H) + = 519, (M+Na)+ = 541 H
O~
AcHN- N~.~ ~B~
H Boc O
O
~O
I
202D (t)-(2R.3R 5R,1'R.2'S)-1-t-Butoxycarbon~r4-2-(1-acetamido-2-methoxymethyloxy)butyl-3-formyl-pyrrolidine-5-carboxylic Acid t-Bu I Ester The title compound was prepared according to the method described in Example 123H substituting (t)-(2R,3R,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-oxiranyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.335 g, 80.8%).
1 H NMR(dg-DMSO) 8 9.55 (d, 1 H), 7.48 (m, 1 H), 4.55-4.72 (m, 4H) 3.9 (d, 1 H), 3.6 (m, 2H), 3.45 (m, 3H), 3.32 (s, 3H), 3.05 (t, 1 H), 2.25-2.45 (m, 4H), 1.83 (s, 3H), 1.58 (m, 3H), 1.30-1.45 (m, 18H), 0.86 (dt, 3H).
MS: (M-H)- = 515, (M+35)+= 551; (M+H)+ = 517 OH
AcHN- N~.
H Boc ~O
O
~O
I
202E (t)-(2R.3R,5R.1'R,2'S.1"RS)-1-t Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)buyl-3-(1-h dY roxy-2-propyn-1yl)-pyrrolidine-5-carboxYlicAcid t-Butyl Ester The title compound was prepared according to the method described in Example 38A substituting (t)-(2R,3R,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyioxy)butyl-3-formyl-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.27 g, 83%).
MS: (M-H)- = 541, (M+35)+ = 577; (M+H)+ = 543, (M+Na)+ = 565 AcHN- N~.,~O~Bu H Boc O
O
~O
I
202F (t)-(2R.3R,5R.1'R.2'S)-1-t-Butox~carbony!-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylic Acid t Bu 1 Ester The title compound was prepared according to the method described in Example 38B substituting (t)-(2R,3R,5R,1'R,2'S,1"RS)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-( 1-hydroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S,1"RS)-1-t-butoxycarbonyl-2-( 1-acetamido-3-methyl)butyl-3-( 1-hydroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.2 g, 74%).
1 H NMR(dg-DMSO) 87.49 (br d, 1 H), 5.0 (d, 1 H), 4.7 (br s, 1 H), 4.55-4.7 (m, 3H), 3.88 (br d, 1 H), 3.5-3.7 (m, 2H), 3.43 (t, 2H), 3.2-3.4 (m, 2H), 3.24 (s, 3H), 2.4-2.7 (m, 2H), 1.84 (s, 3H), 1.5-1.7 (m, 2H), 1.30-1.45 (m, 18H), 0.86 (dt, 3H) MS: (M-H)' = 539, (M+35)+ = 575; (M+H)+ = 541, (M+Na)+ = 563 HN
N
AcHN- ~ O~Bu N
H Boc' -O
~O
I
2026 (t)-(2R 3R 5R 1'R 2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methox)rmethyloxY~ut)rl-3-(pyrazol-3-YI~-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 38C substituting (t)-(2R,3R,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 180 mg, 87%).

1 H NMR(dg-DMSO) ~ 7.57 (br t, 2H), 6.1 (d, 1 H), 4.50-4.7 (m, 4H) 3.95 (m, 1 H), 3.4-3.6 (m, 3H), 3.3-3.4(m, 3H), 3.22 (d, 3H), 2.55-2.65 (m, 1 H), 2.2 (m, 1 H), 1.85 (s, 3H), 1.5-1.7 (m, 2H), 1.15-1.45 (m, 18H), 0.86 (dt, 3H).
MS: {M-H)- = 553, (M+35)+ = 589; (M+H)+ = 553, (M+Na)+ = 577 HN
N
AcHN. N~.,~OH
H H
OH O
TFA
202H (t -(~ 2R,3R.5R.1'R,2'S~-~1-Acetamido-2-h r~droxY~but~pyrazol-3-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 1K, substituting (t)-(2R,3R,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place (t)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester. Chromatography on silica gel with 2-propanol:acetic acid:ethyl acetate:water 1:1:3:1 followed by the addition of 0.1 % trifluoroacetic acid gave the title compound (yield: 15 mg, 55%}.
1 H NMR(dg-DMSO) 8 7.95 (d, 1 H), 7.65 (br s, 1 H), 6,18 (d, 1 H), 4.37 (m, 1 H), 4.23 (m, 1 H), 4.38 (m, 1 H), 4.56 (m, 1 H), 2.63 (m, 1 H), 2.10 (m, 1 H), 1.78 (s, 3H}, 1.50 (m, 1 H), 1.25 (m, 1 H), 0.83 (t, J=7.46 Hz, 3H).
MS: (M-H)- = 309, (M+35)+ = 345; (M+H) + = 311, (M+Na) + = 333 Example 203 (t)-(2R.3R,5R,1'R.2'R~2-~1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt TBDPSO-, AcHN- ,- OtBu ~N
N Boc '~
~O
203B (t)-(2R,3R,5R.1'R.2'R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxY)butyl-3-t butyidiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compounds were prepared according to the method described in Example 202B substituting (t)-(2R,3R,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'R,2'S)-1-t-butoxycarbonyl-2-( 1-acetamido-2-hydroxy)butyl-3-t-butyld iphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t butyl ester (yield: 0.217 g, 96%).
1 H NMR(dg-DMSO) 87.4-7.65 (m, 10H), 4.70 (s, 1 H), 4.62 (s, 1 H), 4.35-4.55 (m, 2H), 3.75-3.95 (m, 2H), 3.68 (m, 1 H), 3.55 (m, 1 H}, 3.25 (m, 1 H), 3.24 (s, 3H), 2.55 (m, 1 H), 2.45 (m, 1 H), 2.0 (m, 1 H), 1.85 (s, 3H), 1.28-1.4 (m, 18H), 0.99 (d, 9H), 0.8 (dt, 3H).
MS: (M-H)- = 755, (M+35)+ = 791; (M+H} + = 757, (M+Na) + = 779 HO--AcHN- N~,~OtBu H Boc O
~O
'O
I
203C (t)-(2R,3R,5R,1'R,2'R)-1-t Butoxycarbonyl-2-(1-acetamido-2-methoxymeth~)butyl-3-hydroxymethyl pyrroiidine-5-carboxylic Acid t Butt Ester The title compound was prepared according to the method described in Example 1236 substituting (t)-(2R,3R,5R,1'R,2'R)-1-t butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-t-butyldiphenylsiiyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t-butoxycarbonyl-2-oxiranyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.124' g, 83%).
1 H NMR(dg-DMSO) 8 7.42 (dd, 1 H), 4.62-4.8 (m, 3H), 4.48 (m, 1 H), 3.6-3.85 (m, 3H), 3.35-3.6 (m, 4H), 3.25 (s, 3H), 2.25 (m, 1 H), 2.4 (m, 1 H), 2.28 (m, 1 H), 1.82 (s, 3H), 1.58 (m, 3H), 1.32-1.45 (m, 18H), 0.9 (dt, 3H).
MS: (M-H)- = 517, (M+35)+ = 553; (M+H)+ = 519, (M+Na)+ = 541 H
O~
, AcHN- N,-, ~O~Bu H Boc O
~O
'O
203D ~t~-(2R 3R 5R 1'R.2'R)-1-t-ButoxycarbonLrl-2-(1-acetamido-2-methoxymethyloxY)butyl-3-formyl-pyrrolidine-5-carboxyiic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 123H substituting (t)-(2R,3R,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyfoxy)butyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-t butoxycarbonyl-2-oxiranyl-3-hydroxymethyl-pyrroiidine-5-carboxylic acid t-butyl ester (yield: 0.106 g, 86%).
1 H NMR(d6-DMSO) 89.58 (d, 1 H), 7.58 (dd, 1 H), 4.6-4.72 (m, 3H), 4.48(d, 1 H), 3.88 (d, 1 H), 3.4-3.65 (m, 5H), 3.24 (s, 3H}, 3.15 (dd, 1 H), 2.20-2.48 (m, 4H), 1.86 (s, 3H), 1.58 (m, 3H), 1.30-1.40 (m, 18H), 0.86 (t, 3H).
MS: (M-H)- = 515, (M+35)+ = 551; (M+H)+ = 517 OH
AcHN~ N~,~O~Bu H Boc O
~O
~O
I
203E (t~~2R 3R 5R~1'R 2'R 1"RS)-1-f-Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(1-hydroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester The title compound was prepared according to the method described in Example 38A substituting (t)-(2R,3R,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S,1"RS)-1-f-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid t butyl ester (yield: 32 mg, 76%).
MS: (M-H)' = 541, (M+35)+ = 577; (M+H)+ = 543, (M+Na)' = 565 AcHN- N~,~OzBu H Boc O
~O
'O
I
203F (t)-(2R 3R 5R 1'R 2'R~,-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(1-oxo-2propyn-1-girl)-pyrrolidine-5-carboxylicAcid t Butyl Ester The title compound was prepared according to the method described in Example 38B substituting (t)-(2R,3R,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-( 1-hydroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (t)-{2R,3R,5R,1'S,1 "RS)-1-t butoxycarbonyl-2-( 1-acetamido-3-methyl)butyl-3-( 1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 25 mg, 78%).
1 H NMR(d6-DMSO) s 7.49 (br d, 1 H), 5.0 (d, 1 H), 4.7 (br s, 7 H), 4.55-4.7 (m, 3H) 3.88 (br d, 1 H), 3.5-3.7 (m, 2H), 3.43 (t, 2H), 3.2-3.4 (m, 2H), 3.24 (s, 3H), 2.4-2.7 (m, 2H), 1.84 {s, 3H), 1.5-1.7 (m, 2H), 1.30-1.45 (m, 18H), 0.86 (dt, 3H).
MS: (M-H)~ = 539, (M+35)+ = 575; (M+H)+ = 541, (M+Na)+ = 563 HN
~(N
AcHN- ,- C~Bu N
H Boc ' ~O
'O
I
203~t)-(2R,3R,5R,1'R,2'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2-methox~yloxylbutyl-3-(pyrazol-3-yl)-~rrrolidine-5-carboxylic Acid t-Butt' Ester The title compound was prepared according to the method described in Example 38C substituting (t)-(2R,3R,5R,1'R,2'R)-1-t butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylic acid f butyl ester in place of (t)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-{1-acetamido-3-methyl)butyl-3-{1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 18 mg, 72%).

1 H NMR(d6-DMSO) 8 7.57 (m, 2H}, 6.1 (d, 1 H), 4.40-4.7 (m, 4H) 3.93 (m, 1 H), 3.4-3.6 (m, 3H), 3.3-3.4(m, 3H), 3.22 (d, 3H), 2.55-2.65 (m, 1 H), 2.2 (m, 1 H), 1.85 (s, 3H), 1.5-1.7 (m, 2H), 1.15-1.45 (m, 18H), 0.86 (m, 3H).
MS: (M-H)- = 553, (M+35)+ = 589; (M+H)+ = 553, (M+Na)+ = 577 H N
N
AcHN_ N~_,~OH
H H
~OH O
TFA
203H (t)-(2RL3R~5R,1'R,2'R)-2-(1-Acetamido-2-hydroxY~butyl-3-(p rLrazol-3-y_I}-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 15B, substituting (t)-(2R,3R,5R,1'R,2'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
Chromatography on silica gel with 2-propanol:acetic acid:ethyl acetate:water 1:1:3:1 followed by the addition of 0.1 % trifluoroacetic acid gave the title compound (yield: 4 mg, 45%).
1 H NMR(d6-DMSO) b 7.65 (d, 1 H), 7.64 (d, 1 H), 6,16 (d, 1 H), 4.37 (m, 1 H), 4.23 (m, 1 H), 4.38 (m, 1 H), 4.56 (m, 1 H), 2.63 (m, 1 H), 2.10 (m, 1 H), 1.74 (s, 3H), 1.25-1.40 (m, 2H), 0.83 (t, J=7.46 Hz, 3H).
MS: (M-H)- = 309, (M+35)+ = 345; (M+H)+ = 311, (M+Na)+ = 333 Example 204 (t)-~2R,3R,5R)-2-Acetamidomethyl-3-methoxycarbonyl-pyrrolidine-5-carbolic Acid Hydrochloride.
TBDMSO~
H2N ~ , OtBu O
Ph 204A {t)-(2R.3R,5R)-1-Benzyl-2-aminomethyl-3-t butyldimethylsilyloxymeth r~l-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound is prepared according to the method described in Example 1 F, substituting (t)-(2R,3R,5R)-1-benzyl-2-formyl-3-t butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t butyl ester in place of (t)-(2R, 3R, 5 R)-1-benzyl-2-( 1-oxo-3-ethyl)pentyl-3-t-butyld imethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.
MS: (M+H)+= 435 TBDMSO-AcNH~., OtBu O
Ph 2048 (t)-(2R.3R 5R)-1-Benzyl-2-acetamidomethyl-3-t-butyldimeth isilylox~methYl-~~rolidine-5-carboxylic Acid t-Butyl Ester The title compound is prepared according to the method described in Example 1 G, substituting (t)-(2R,3R,5R)-1-benzyl-2-aminomethyl-3-t-butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'R)- and (t)-(2R,3R,5R,1'S)-1-benzyl-2-(1-amino-3-ethyl)pentyl-t-butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.

WO 99!54299 PCT/US99/07945 'H NMR (CDC13): 8 7.2-7.35 (m, 5H), 6.14 (br, 1H), 3.86 (dd, J=18Hz, 13.5Hz, 2H), 3.67 (m, 1 H), 3.60 (m, 1 H), 3.49 (m, 1 H), 3.28 (m, 1 H), 3.06 (m, 1 H), 2.19 (m, 2H), 1.95 (s, 3H), 1.45 (s, 9H), 0.91 (s, 9H), 0.07 (s, 6H).
MS: (M+H)+= 477 HO-AcNH~., OtBu HN
O
Ph 204C ft)-(2R 3R 5R)-1-BenzLrl-2-acetamidomethyl-3-hydroxymethyl-pyrrolidine-5-carboxylic Acid t Butyl Ester The title compound was prepared according to the method described in Example 1 H, substituting (t)-(2R,3R,5R)-1-benzyl-2-acetamidomethyl-3-f-butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-f-butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.
O
H "~
AcNH~~, OtBu ~ N
O
Ph 204D (t)-!2R 3R,,5R)-1-Benzvl-2-acetamidomethyl-3-formyl-pyrrolidine-5-carboxylic Acid t But)rl Ester The title compound was prepared according to the method described in Example 2A, substituting (t)-(2R,3R,5R)-1-benzyl-2-acetamidomethyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-hydrxoxymethyl-pyrrolidine-5-carboxylic acid f butyl ester.

' H NMR (CDC13): b 9.70 (s, 1 H), 7.22-7.36 (m 5H), 5.82 (br, 1 H), 3.83 (dd, J= 3.3Hz, 13.5Hz, 2H), 3.74 (m, 1 H), 3.56 (d, J= 9Hz, 1 H), 3.15 (m, 1 H), 2.73 (m, 1 H), 2.36-2.10 (m, 2H), 1.98 (s, 3H), 1.45 (s, 9H).
MS: (M+H)+= 361 CH30"
AcNH~., OtBu H N
O
Ph 204E fit)-(2R.3R.5R -1-Benz~l-2-acetamidomethyl-3-methoxycarbonyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 2B and 2C, substituting (t)-(2R,3R,5R)-1-benzyl -2-acetamidomethyl-3-formyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylic acid t butyl ester.
'H NMR (CDC13): 8 7.45-7.20 (m, 5H), 5.96 (br, 1 H), 3.90-3.73 (m, 4H), 3.71 (s, 3h-.), 3.52 (dd, J=9Hz, 2Hz, 1 H), 3.13 (m, 1 H), 2.84 (m, 1 H), 2.36 (m, 1 H), 2.18 (m, 1 H), 1.97 (s, 3H), 1.45 (s, 9H).
MS: (M+H)+= 391 O

AcNH~~ OtBu MN
H O
204F (t~-(2R.3R,5R~2-Acetamidomethyl-3-methoxycarbonyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester The title compound was prepared according to the method described in Example 2D, substituting (t)-(2R,3R,5R)-1-benzyl-2-acetamidomethyl-3-methoxycarbonyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxycarbonyl-pyrrolidine-5-carboxylic acid t-butyl ester.
'H NMR (CDC13): b 6.19 (br, 1H), 3.72 (m, 2H), 3.70 (s, 3H), 3.43 (m, 1H), 3.28 (m, 1 H), 2.74 (m, 1 H), 2.44 (m 1 H), 2.21 (m, 1 H), 2.00 (s, 3H), 1.48 (s, 9H).
MS: (M+H)+= 301 CH30"~
AcNH~~, OH
HN
H O
HCI
204G (t)-(2R,3R.5R)-2-Acetamidomethyl-3-methoxycarbon~yrrolidine-5-carboxylic Acid Hydrochloride.
The title compound was prepared according to the method described in Example 2E substituting (t)-(2R,3R,5R)-2-acetamidomethyl-3-methoxycarbonyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxycarbonyl-pyrrolidine-5-carboxylic acid t-butyl ester.

' H NMR (D20): b 4.42 (t, J=8.25Hz, 1 H), 4.22 (m, 1 H), 3.83 (m, 1 H), 3.75 (s, 3H), 3.70-3.60 (m, 2H), 3.26 (m, 1 H), 2.78 (m, 1 H}, 2.43 (m, 1 H), 2.03 (s, 3H).
MS: (M+H)+= 245 Examples 205-213 HO-AcHN~. OtBU AcHN~., OH
Boc Example 204C
The following title compounds were prepared according to the methods described in Examples 1-39 from the common intermediate prepared as described in Example 204C.
Example 205 AcHN~.,,, OH
H N
H O
TFA
~t)-(2R,3R,5R)-2-Acetamidomethyl-3-ethoxycarbonyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
'H NMR (D20) 8 4.30 (t, J=8.2Hz, 1 H), 4.21 (m, 3H), 3.62 (dd, J=2.4, 3.4Hz, 2H), 3.23 (m, 1 H), 2.74 (m, 1 H), 2.38 (m, 1 H), 2.02 (s, 3H), 1.2fi (m, 3H) MS: (M+H)' = 259; (M-H)- = 257.

Example 206 ~N
HN
AcHN ~.., OH
H H ,, HCI
(t)-(2R,3R.5R~-2-Acetamidomethyl-3-(imidazol-2 yl)-pyrrolidine-5-carbox~iic Acid Hydrochloride 'H NMR (Dz0): 8 7.46 (s, 2H}, 4.53 (dd, J=9.5Hz, J=8.5 Hz, 1H), 4.28 (rn, 1 H), 3.96 (m, 1 H), 3.65 (m, 2H), 3.03 (dt, J=13.5Hz, J=7.6Hz, 1 H), 2.46 (m, 1 H), 1.94 (s, 3H).
MS: (M-~H)+=253, {M-H)'=251 Example 207 _ -.
AcHN ~.,, OH
H N ~~
H O
TFA
(t)-(2R,3S.5R~2-AcetamidomethLrl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
' H NMR (D20) 8 5.74 (m, 1 H), 5.24 (m, 2H), 4.20 {dd, J=1.7, 8.1 Hz, 1 H), 3.65 (m, 2H), 3.50 (m, 1 H), 2.84 (m, 1 H), 2.61 (m, 1 H), 2.03 (s, 3H), 1.95 (m, 1 H) MS: (M+H)+= 213.
Example 208 .;.

AcHN~.,,, OH
H N
H O
TFA
(t~~2R 3R 5R)-2-Acetamidomethyl-3-(2.2-dimethyl-vinyl)-pyrrolidine-5-carbox Acid Trifluoroacetic Acid Salt.
' H NMR (D20) 8 5.01 (br d, 1 H), 4.18 (dd, J=2.1, 8.1 Hz, 1 H), 3.53 (m, 3H), 3.04 (m, 1 H), 2.55 (m, 1 H), 2.0 (s, 3H), 1.75 (m, 1 H), 1.72 (s, 3H), 1.67 (s, 3H) MS: (M+H)+= 241, (M+Na)+ = 263; (M-H)- = 239.
Example 209 H3CN_!O

OH
N ~~~
AcHN H H O
HCI
(t)-(2R 3R 5R)-2-Acetamidomethyl-3-(N,N-dimethylcarbamoyl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
'H NMR (D20) s 4.60 (t, J=8.4Hz, 1H), 4.23 (m, 1H), 3.56 {d, J=5.8Hz, 2H) 3.50 (m, 1 H), 3.10 (s, 3H), 2.94 (s, 3H), 2.88 (m, 1 H), 2.19 (m, 1 H), 2.00 {s, 3H) MS: (M+H)+= 258, (M-H)- = 256.

Example 210 H3C, O
HN~~
N I
AcHN H ti O
TFA
~)-(2R 3R 5R~ 2-Acetamidomethyl-3-lN-methylcarbamoyl)-pyrrolidine-5-carboxytic Acid Trifluoroacetic Acid Salt.
'H NMR (Dz0) 4.49 (t, J=8.5Hz, 1 H), 4.10 (m, 1 H), 3.57 (d, J=5.8Hz, 2H), 3.03 (m, 1 H), 2.76 (m, 1 H), 2.74 (s, 3H), 2.29 (m, 1 H), 2.00 (s, 3H) MS: (M+H)+ = 244.
Example 211 Hs ~O
~.,,~~~OH
NN
AcHN H hi O
TFA
(t)-(2R 3R 5R)-2-Acetamidomethyl-3-propionyl-pyrrolidine-5-carboxyiic Acid Trifluoroacetic Acid Salt.
' H NMR (D20) 8 4.24 (m, 2H), 3.55 (d, J=4.7Hz, 1 H), 3.40 (m, 1 H), 2.85 (m, 1 H), 2.64 (m, 3H), 2.16 (m, 1 H), 2.01 (s, 3H), 1.02 (t, J=7.1 Hz, 3H) MS: (M+H)+ = 243; (M-H)- = 241.

Example 212 O-OH
AcHN H H O
HCI
(t)-(2R 3R 5R)-2-Acetamidomethyl-3-methoxymethyl-~pyrrolidine-5-carboxylic Acid Hydrochloride ' H NMR (D20): b 4.44 (t, J=6Hz, 2H), 3.77 (m, 1 H), 3.65-3.48 (m, 3H), 3.35 (s, 3H), 2.64 (m, 1 H), 2.56 (m, 1 H), 2.03 (s, 3H), 2.00 (m, 1 H).
MS: (M+H)+= 231, (M-H)- = 229 Example 213 H3C;
OH
N I ~~~
AcHN H H O
TFA
(t)-(2R 3S 5R)-2-Acetamidomethyl-3-methyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
' H NMR (D20) 8 4.30 (m, 1 H), 3.fi4 (m, 1 H), 3.48 (m, 1 H), 3.20 (m, 1 H), 2.64 (m, 1 H), 2.03 (s, 3H), 1.7fi (m, 1 H), 1.32 (br t, 1 H), 1.12 (m, 4H) MS: (M+H)+= 201, (M+Na)+ = 223.

Example 214 (t)-(2R 3S 5R 1'R)-2-~1-Acetamido-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carbox~rlic Acid Trifluoroacetic Acid Salt BocHN, N,., OtBu H Boc S
214A (t)- 2R 3S 5R 1'R)-1-t-ButoxLrcarbonyl-2-(1-t butoxycarbonylamino-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
To a solution of ethanethiol (0.047 mL, 0.63 mmol) in THF (2 mL) at 0°C
was added 2.5 M n-BuLi/hexane (0.248 mL, 0.62 mmol). The reaction mixture was stirred for 45 minutes and a solution of (t)-(2R,3S,5R,1'S)-1-t-butoxycarbonyl-2-(N-t-butoxycarbonylaziridinyl)-3-vinyl-pyrroiidine-5-carboxylic acid t-butyl ester (0.08 g, 0.182 mmole) in THF (0.5 mL) was added followed by DMF (1.5 mL) and stirred at room temperature for 2 hours. The reaction was quenched with 1 N NaHC03 (10 mL) and diluted with ethyl acetate (20 mL). The organic laysr was washed with water,and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound (yield: 61 mg, fi7%).
1 H NMR(dg-DMSO) b 6.74 (br d, 1 H), 5.85 (m, 1 H), 4.9-5.0 (m, 2H), 4.20 (m, 1 H), 3.95 (m, 1 H), 3.75 (d, 1 H), 2.8-3.0 (dd, 1 H), 2.5 (m, 3H), 1.fi5 (m, 1 H), 1.32-1.45 (m, 27H), 1.17 (dt, 3H).
MS: (M-H)- = 499; (M+H)+ = 501, (M+Na)+ = 523 Ac BocN. N~, OtBu H Boc S
214B (t)-(2R 3S 5R 1'R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonvlacetamido-2-et~lthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'R)-1-t Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (58 mg, 0.116 mrnole) was reacted with lithium hexamethyfdisilazide (1 M) (1.16 mL, 1.16 mmoie) in THF (3 mL) at -78 °C. After 0.5 hour at -78 °C and 1 hour at -40 °C, the above reaction mixture was reacted with acetyl chloride (0.166 mL, 2.33 mmole) at -30 °C for 0.3 hours. The reaction was quenched with 1 N NaHCO3 (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with water,and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 10% ethyl acetatelhexanes to provide the title compound (yield: 28 mg, 44%).
1 H NMR(dg-DMSO) 8 5.88 (m, 1 H), 4.9-5.0 (m, 2H), 4.52 (m, 1 H), 4.33 (m, 1 H), 4.1 (m, 1 H), 2.78 (dd, 1 H), 2.3-2.5 (m, 6H), 1.7 (m, 1 H), 1.32-1.5 (m, 27H), 1.11 (t, 3H).
MS: (M+H) + = 543.

AcHN OH
' N' .~~1~
HH O
S
TFA
214C (t)-(2R 3R 5R 1'R1-2-(1-Acetamido-2-ethylthio)eth I-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-N-t butoxycarbonylacetamido-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 7 mg, 95%).
1 H NMR(d6-DMSO) 8 8.15 (d, 1 H), 5.72 (m, 1 H), 5.05-5.2 (m, 2H), 4.2-4.4 (m, 2H), 4.33 (m, 1 H), 2.93 (m, 1 H), 2.7-2.8 (2d, 1 H), 2.3-2.6(m, 3H), 1.85-1.95 (m, 1 H), 1.93 (s, 3H), 1.17 (t, J=7.46 Hz, 3H) MS: (M+H) + = 287.

Example 215 (t)-(2R,3S.5R.1'R.3'S)-2-(1-Acetamido-2-ethylsulfin I~ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt _~ Ac BocN. ,/ OtBu Bo N, _ OtBu N~,~ ~N~ ,~
H Boc O ~ H Boc O
S S
O O
215A (~-~2R 3S,5R,1'R.3'S) and (t)-(2R,3S,5R,1'R,3'R)-1-t-Butoxycarbon ~1-N-t-butox~rbonyiacetamido-2-ethylsulfinyl)ethyl-3-vin rLl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (72 mg, 0.132 mmole) was reacted with 55% m-chloroperoxybenzoic acid (41 mg, 0.132 mmole) in CHC13 (1.5 mL) at -40 °C for 30 minutes. The reaction was concentrated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate to provide the title compounds (t)-(2R,3S,5R,1'R,3'S) isomer (yield:

mg, 18.9%) and (t)-(2R,3S,5R,1'R,3'R) (yield: 45 mg, 60.7%).
(2R,3S,5R,1'R,3'S) 1H NMR(dg-DMSO) s 5.88 (m, 1H), 4.9-5.0 (m, 2H), 4.50 (m, 1 H), 4.0-4.15 (m, 1 H), 2.7-2.9 (m, 3H), 2.55 (m, 1 H), 2.37 (s, 3H), 1.7 (m, 1 H), 1.32-1.5 (m, 27H), 1.12 (t, 3H) MS: (M+H) + = 559, (M+Na) + = 581 (2R,3S,5R,1'R,3'R) 1 H NMR(dg-DMSO) 8 5.88 (m, 1 H}, 4.9-5.0 (m, 2H), 4.50 (m, 1 H), 4.03-4.15 (m, 1 H), 3.2 (m, 1 H) 3.1 (dd, 1 H), 2.5-2.7(m, 2H), 2.38 (s, 3H), 1.75 (m, 1 H), 1.32-1.5 (m, 27H), 1.12 (t, 3H) MS: (M+H) + = 559, (M+Na) + = 581 _ ~.
AcHN ' OH
H N ~ I
_H O
S
p TFA
2158 ~t~,~2R.3S,5R,1'R.3'S)-2-~1-Acetamido-2-ethylsulfinyl)eth !-y 3winyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,3'S)-1-t-butoxycarbonyl-2-(1-N-t butoxycarbonylacetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester. ester (yield: 9 mg, 86%).
1 H NMR(dg-DMSO) 8 8.39 (d, 1 H), 5.72 (m, 1 H), 5.15-5.2 (dd, 2H), 4.5 (m, 1 H), 4.37 (m, 1 H), 3.65 (m, 1 H), 2.85-3.04 (m, 3H), 2.6-2.85 (m, 2H), 2.4 (m, 1 H), 1.83-1.95 (m, 1 H), 1.86 (s, 3H), 1.20 (t, J=7.46 Hz, 3H).
MS: (M-H)- =301; (M+H)+ = 303, (M+Na)+ = 325 WO 99/54299 PCT/US99l07945 Example 216 ,fit)-(~2R 3S 5R.1'R 3'R)-2-(1-Acetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN OH
N > ~~~~I~
H H O
S
p TFA
The title compound was prepared according to the method described in ExampIe41C, substituting (t)-(2R,3S,5R,1'R,3'R}-1-t-butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl 2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 12 mg, 94%).
1 H NMR(d6-DMSO) 5 8.39 (d, 1 H}, 5.72 (m, 1 H), 5.15-5.2 (dd, 2H), 4.53 (m, 1 H), 4.41 (t, 1 H), 3.65 (m, 1 H), 3.2 (dd, 1 H), 2.9-3.0 (m, 2H), 2.65-2.9(m, 2H), 2.4(m, 1 H), 1.83-1.95 (m, 1 H), 1.83 (s, 3H), 1.20 (t, J=7.46 Hz, 3H) MS: (M-H)- =301; (M+H) + = 303, (M+Na) + = 325 Example 217 ~t)-(2R.3S.5R.1'Rl-2~1-N-t-butoxycarbonylacetamido-2-ethylsulfonyl)ethyl-3-vinyl pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt Ac BocN. N~, O~Bu H Boc O S, O
217A ft)~2R,3S.5R,1'R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-ethylsulfonyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1' R, 3'R)-1-t-Butoxycarbonyi-2-( 1-N-t-butoxycarbonylacetamido-2-ethylsuffinyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (25 mg, 0.0448 mmole) was reacted with 55% m-chloroperoxybenzoic acid (14 mg, 0.0448 mmofe) in CHC13 (1.5 mL) at 0 °C for one hour. The reaction was concentrated in vacuo. The residue was purified by chromatography on silica gel using 25% ethyl acetatelhexane to provide the title compound (yield: 23.7 mg, 92%).
~ H NMR(dg-DMSO) b 5.88 (m, 1 H), 4.85-5.0 (m, 2H), 4.38 (m, 1 H), 4.15 (m, 1 H), 3.7 (m, 1 H) 3.45 (dd, 1 H), 2.9-3.2 (m, 3H), 2.5-2.7 (m, 1 H), 2.3-2.4 (m, 3H), 1.6-2.04 (m, 1 H), 1.35-1.55 (m, 27H), 1.15 (t, 3H) MS: (M~H)+ = 575 AcHN OH
~ O
~S~
O O TFA
29-7B (t)-(2R 3S 5R 1'R)-2-(1-Acetamido-2-ethylsulfonyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Exampie41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-N-t butoxycarbonylacetamido-2-ethylsulfonyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 12 mg, 94%).
1 H NMR(d6-DMSO) 8 8.34 (d, 1 H), 5.72 (m, 1 H), 5.05-5.25 (dd, 2H), 4.68 (m, 1 H), 4.39 (dd, 1 H), 3.7 (2d, 1 H), 3.48 (dd, 1 H), 3.3-3.4 (dd, 2H), 3.08 (q, 2H), 2.95 (m, 1 H), 2.42 (m, 1 H), 1.9 (m, 1 H), 1.84 (s, 3H), 1.23 (t, J=7.46 Hz, 3H).
MS: (M-H)- = 317, (M+35)+ = 353; (M+H)+ = 319, (M+Na)+ = 341 Examples 218. 220 1. RSH
gu - AcHN. ,.,~OH
N ~ ~ ~ 2. LiHMDSIAcCI ' ~ N
BocHN~ H goc O 3. TFAICHpCIz H H O
RS
TFA
The following title compounds were prepared in 3 steps according to the methods described in Example 214.

Example 218 (t)-(2R,3S.5R,1'R)-2-(1-Acetamido-2-isoprop l~ eth I-y 3-v_in.~pyrrolidine-5-carbox~rlic Acid Trifluoroacetic Acid Salt -, BocHN, N~, O~Bu H Boc S
218A (t}-(2R.3S.5R,1'R)-1-t Butoxycarbanyl-2-(1-N-f-butoxycarbonylamino-2-isopropylthio)ethyl-3-vinyl-eyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 214A, substituting isopropylthiol in place of ethanethiol (yield: 22 mg, 62%).
1 H NMR(dg-DMSO) 8 6.73 (d, 1 H), 5.85 (m, 1 H), 4.9-5.0 (m, 2H), 4.18 {m, 1 H), 3.95 (m, 1 H), 3.75 (br d, 1 H), 2.8-3.0 (m, 2H), 1.65 (m, 1 H), 1.32-1.45 {m, 27H), 1.18 (dd, 6H) MS: (M-H)- = 513; (M+H) + = 515, (M+Na) + = 537 Ac BocN. N,., OtBu ~,~.,~ H Boc ~S
218B (t)-(2R.3S,5R,1'R}-1-f-Butoxycarbonyl-2-(1-(N-f-butoxycarbonyl-N-acetamido)-2-isoprapylthio)ethyl-3-vinyl-p,~rrrolidine-5-carboxylic Acid t-But~rl Ester.
The title compound was prepared according to the method described in Example 214B, substituting (t)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl-2-(1-N-t butoxycarbonylamino-2-isoproylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 12 mg, 50%).
1 H NMR(dg-DMSO) 8 5.86 (m, 1 H), 4.88-5.0 (m, 2H), 4.54 (m, 1 H), 4.33 (m, 1 H), 4.13 (d, 1 H), 3.05 (m, 1 H), 2.73-2.84 (m, 2H), 2.38 (br s, 3H), 1.72 (m, 1 H), 1.32-1.5 (m, 27H), 1.14 (dd, 6H).
MS: (M+H) + = 557, (M+Na) + = 579 _ -.
AcH N OH
N > .~~' O
S
TFA
218C (tL(2R.3S,5R,1'R)-2-(1-Acetamido-2-isopropylthio)ethyl-3-vinyl-pyrrofidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 15B, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-N-t butoxycarbonylacetamido-2-isopropylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 8 mg, 97%).
1 H NMR(dg-DMSO) b 8.14 (d, 1 H), 5.72 (m, 1 H), 5.05-5.2 (dd, 2H), 4.2-4.4 (m, 2H), 3.68 (dd, 1 H), 2.93 (m, 2H), 2.74 (dd, 1 H), 2.58 (dd, 1 H), 1.93 (m, 1 H), 1.87 (s, 3H), 1.2 (t, 6H) MS: (M-H)- = 299; (M+H) + = 301, (M+Na) + = 323 Example 219 St)-(2R 3S 5R 1'R~-2-(1-Acetamido-2-phenylthio~ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride H2N. ) ,, O~Bu H Boc ' ",- S
219A (t)-(2R 3S 5R 1'R)-1-t-Butoxycarbonyl-2-(1-amino-2-phenylthio)ethyl-3-vinvl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(t)-(2R,3S,5R,1'S)-1-t-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (20.3 mg, 0.06 mmole) was reacted with the phenylthiol (19.9 mg, 0.18 mmol) and triethylamine (0.047 mL, 0.34 mmol) in MeOH (0.06 mL) at ambient temperature for 3.5 hours. The reaction solution was concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel using ethyl acetate/methanol/ammonium hydroxide, 99/0.05/0.05, to provide the title compound (yield: 20.7 mg, 77%).
1 H NMR (ds-DMSO) S 7.31 (m, 4H), 7.17 (m, 1 H), 5.87 (m, 1 H), 5.03 (d, J=l7Hz, 0.4H), 5.01 (d, J=17Hz, 0.6H), 4.91 (d, J=11 H, 0.4H), 4.90 (d, J=11 Hz, 0.6H), 4.15 (m, 1 H), 3.82 (m, 0.6H), 3.76 (m, 0.4H), 3.39(m, 1 H), 2.92 (m, 2H), 2.55 (m, 1 H), 1.64 (m, 2H), 1.42 (s, 5.4H), 1.37 (s, 3.6H), 1.34 (s, 5.4H), 1.22 (s, 3.6H) MS: (M+H)+ = 449, (M+Na)+ = 471 AcH N
,.
H Boc S
219B (t)-(2R.3S.5R.1'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2-phenyithio)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Bu I Ester.
(t)-(2R,3S,5R,1'R)-1-t Butoxycarbonyl-2-(1-amino -2-phenylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (17.2 mg, 0.04 mmole) was reacted with the acetic anhydride (0.011 mL, 0.11 mmol) and triethylamine (0.032 mL, 0.23 mmol) in CH2C12 (0.3 mL) at rt for 4.25 hours. The reaction solution was concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica get using 5% methanol/dichloromethane to provide the title compound.
'H NMR (ds-DMSO) d 7.75 (d, J=9Hz, 0.6H), 7.73 (d, J=9Hz, 0.4H), 7.32 (m, 4H), 7.19 (m, 1 H), 5.87 (m, 1 H), 5.04 (d, J=17Hz, 0.4H), 5.00 (d, J=17Hz, 0.6H), 4.95 (d, J=10Hz, 0.6H), 4.93 (d, J=10Hz, 0.4H), 4.59 (m, 0.4H), 4.45(m, 0.6H), 3.99 (dd, J=10Hz, 2Hz, 0.6H), 3.94 (dd, J=10Hz, 2.5Hz. 0.4H), 3.84 (m, 0.6H), 3.77 (m, 0.4H), 3.07 (dd, 13Hz, 5Hz, 0.6H), 2.95 (m, 1.8H), 2.83 (br t, J=8Hz, 0.6H), 2.48 (m, 1 H), 1.84 (s, 1.2H), 1.81 (s, 1.8H), 1.68 (m, 1 H), 1.41 (s, 5.4H), 1.36 (s, 3.6H), 1.34 (s, 5.4H), 1.26 (s, 3.6H) MS: (M-H)- = 489, (M+35)-; (M+H)+ = 490, (M+Na)+ = 513 - -.
AcHN OH
w O
HCI
219C (t)-l 2R.3S.5R.1'R)-2-l1-Acetamido-2-phenvlthio)et~-3-vinvl-pvrrolidine-5-carboxylic Acid Hydrochloride The title compound was prepared according to the method described in Example 1K, substituting (t)-(2R,3S,5R,1'R)-1-t butoxycarbonyl-2-(1-acetamido-2-phenylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3R,5R,1'S)-2-( 1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 14.6 mg, 100%.) 1 H NMR(d4-methanol) 8 7.43 (m, 2H), 7.31 {m, 3H), 5.75 (ddd, J=17Hz, 10Hz, 8Hz, 1 H), 5.32 (br d, J=17Hz, 1 H), 5.19 (dd, J=10Hz, 1.4Hz, 1 H), 4.58 (m, 2H), 3.89 (dd, J=10Hz, 3Hz, 1 H), 3.19 (dd, J=14Hz, 6Hz, 1 H), 3.09 (dd, J=14Hz, 9Hz, 1 H), 3.04 {m, 1 H), 2.57(dt, J=13Hz, 7Hz, 1 H), 2.04 (s, 3H), 2.03 (m, 1 H) MS: (M-H}- = 333; (M+H)+ = 335, (M+Na)+ = 357 Example 220 (t)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-Benz I~ ethyl-3-viny pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt -, BocHN. N)., OtBu -H Boc ~S
220A (t)-(2R,3S.5R,1'R)-1-t-Butoxycarbonyl-2-(1-N-f butoxycarbonylamino-2-benzylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-But)rl Ester The title compound was prepared according to the method described in Example 214A, substituting benzylmercaptan in place of ethanethiol (yield: 28 mg, 72%).
1 H NMR(d6-DMSO) 8 7.2-7.35 (m, 5H), 6.80 (br d, 1 H), 5.84 (m, 1 H), 4.86-4.96 (m, 2H), 4.25(m, 1 H), 3.95 (m, 1 H), 3.7-3.8 (m, 3H), 2.76-2.94 (m, 1 H), 2.35-2.45 (m, 2H), 1.65 (m, 1 H), 1.32-1.45 (m, 27H) MS: (M-H)- = 561; (M+H) + = 563, {M+Na) + = 585 Ac BocN. N,., OtBu H Boc S
220B (t)-(2R.3S,5R.1'R)-1-t-Butoxycarbonyl-2-(1-(N-t butoxycarbonyl-acetamido)-2-benzylthio~ethyi-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 2148, substituting (t)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2-benzylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R)-1-t-Butoxycarbonyl-2-(1-N-t butoxycarbonylamino-2-ethylthin)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 3.3 mg, 61 %).
1 H NMR(d6-DMSO) ~ 7.2-7.35 (m, 5H), 5.84 (m, 1 H), 4.86-4.96 (m, 2H), 4.55(m, 1 H), 4.32 (d, 1 H), 4.05 (d, 1 H), 3.56-3.65 (m, 2H), 2.9 (m, 1 H), 2.3-2.65 (m, 3H), 2.42 (s, 3H), 1.76 (d, 1 H), 1.25-1.55 (m, 27H) MS: (M+H) + = 605, (M+Na) + = 627 AcHN OH
' N~ ~~~1~
HH O
S
TFA
220C (t)-(2R,3S.5R.1'R)-2-(1-Acetamido-2-benzylthio)ethyl-3-vinyl-pyrrolidine-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-N-t butoxycarbonylacetamido-2-benzylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-{1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 2.2 mg, 95%).
1 H NMR(d6-DMSO) 8 8.18 (d, 1 H), 7.2-7.32 (m, 5H), 5.68(m, 1 H), 5.02-5.2 (m, 2H), 4.3-4.45 (m, 2H), 3.76 (s, 2H), 3.68 (dd, 1 H), 2.92 (m, 1 H), 2.62 (dd, 1 H), 2.32-2.55(m, 2H), 1.85-1.95 (m, 1 H), 1.89 (s, 3H).
MS: (M-H)' = 347; (M+H)+ = 349, (M+Na)+ = 371 Example 221 AcHN OH
w N / ~ H H ~ .,~~I~
O

(t)-f2R 3S 5R 1'R)-2-(1-Acetamido-2-(4-p~idinethio ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid DihYdrochloride.
The title compound was prepared according to the method of Example 219A-C substituting 4-thiopyridine for thiophenol as the reagent in Example 219A.
'H NMR(d4-methanol) d 8.57 (d, J=7Hz, 2H), 7.97 (d, J=7Hz, 2H), 5.85 (ddd, J=17Hz, 1 OHz, 9Hz, 1 H), 5.40 (br d, J=17Hz, 1 H), 5.25 (dd, J=17Hz, 10Hz, 1 H), 4.67 (dt, J=10Hz, 4Hz, 1 H), 4.47 (dd, J=10Hz, BHz, 1 H), 4.01 (dd, J=1 OHz, 4Hz, 1 H), 3.68 (dd, J=14Hz, 5Hz, 1 H), 3.45 (dd, J=14Hz, 10Hz, 1 H), 3.16 (m, 1 H), 2.65 (dt, J=14Hz, 7Hz, 1 H), 2.07 (m, 1 H), 2.04 (s, 3H) MS: (M-H)- = 334; (M+H)+ = 336, (M+Na)+ = 358 Example 222 /-.:.

AcHN~,, ~., OEt H N ~~
H O
OH
(t)-(2R 3S 5R.1'R 2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-~yrrolidine-5-carboxylic Acid Ethyl Ester.
Thionyl chloride (1.49 mL, 20.5 mmol) was reacted with ethanol (25 mL) at 0°C for 10 minutes. (t)-(2R,3S,5R,1'R,2'S)-2-{1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (815 mg, 2.05 mmol) in ethanol (50 mL) was added to the above solution and reacted at room temperature for 17 hours. The reaction was concentrated in vacuo and the residue was purified by chromatography on silica gel with 90/10/0.5 dichloromethane I methanol I ammonium hydroxide to provide the title compound as a white solid (yield: 462 mg, 72%).
' H NMR (DMSO-ds) 8 7.49 (d, J = 9.8 Hz, 1 H), 5.31 (m, 2H) 4.11 (m, 2H), 3.72 (t, J = 7.7 Hz, 1 H), 3.69 (m, 1 H), 3.42 (m, 1 H), 3.07 (m, 1 H), 2.85 (m, 1 H), 2.22 (m, 1 H), 1.76 (s, 3H), 1.54 (d, J = 5.6 Hz, 3H), 1.45 (m, 1 H), 1.39 (m, 1 H), 1.21 (m, 1 H), 1.19 (t, J = 7.0 Hz, 3H), 0.83 (t, J = 7.3 Hz, 3H).
MS: (M+H)+= 313, (M+Na)+= 335, (M-H)~ = 311.

Example 223 HN
../N
AcHN, OEt N > .~~~I~
HH O
OH
~t)-(2R.3R.5R.1'R.2'S)-2-(1-Acetamido-2-hydroxy)butyl-3- pyrazol-3-y1)-pyrrofidine-5-carbox rLlic Acid Ethyl Ester The title compound is prepared according to the method described in Example 222, substituting (t)-(2R,3R,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in place of (t)-(2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic trifluoroacetic acid salt (yield: 32 mg, 52%).
1 H NMR(d6-DMSO) 8 7.6 (br s, 1 H), 6.1 (br s, 1 H), 4.08 (q, J=7.12Hz, 2H), 3.78 (m, 1 H), 3.65 (m, 1 H), 3.55 (m, 1 H), 3.45 (m, 1 H), 3.25 (m, 1 H), 3.45 (m, 1 H), 1.72 (s, 3H), 1.45 (m, 1 H), 1.2 (m, 1 H), 1.16 (t, J=7.12 Hz, 3H), 0.82 (t, J=7.46 Hz, 3H).
MS: (M-H)- = 337, (M+35)+ = 373; (M+H)+ = 339, (M+Na)+ = 361 Example 224 AcHN. ~..,, OEt ~~ H H O
/ ~ N.CH3 O
(t)-(2R.3S 5R 1'S 3'S)-2-t1-Acetamido-2- N-isopropyl-N-methylamino-N-oxidel)ether(cis-~~en-1-y~-pyrrofidine-5-carboxylic Acid Ethyl Ester The title compound is prepared according to the method described in Example 222, substituting (t)-(2R,3S,5R,1'S,3'S)-2-(1-acetamido-2-(N-isopropyl)-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in place of (t)-(2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 25 mg, 34%).
1 H NMR (MeOD-d3) S 5.51-5.43(m, 1 H), 5.34-5.27(m, 1 H), 4.36-4.30(m, 1 H), 4.18(q, J=7.1 Hz, 2H), 3.88(dd, J=6.8, 8.8Hz, 1 H), 3.82-3.67(m, 2H), 3.49-3.42(m, 1 H), 3.34(s, 3H), 3.14-2.96(m, 1 H), 2.42-2.33(m, 1 H), 1.92(s, 3H), 1.64-1.52(m, 1 H), 1.63(dd, J=1.7, 6.8Hz, 3H}, 1.41-1.24(m, 1 H}, 1.39(d, J=6.4Hz, 3H), 1.31 (d, J=6.4Hz, 3H), 1.26(t, J=7.1 Hz, 3H).
MS: (M+H)+=356, (M+Na)+=378, (M-H)-=354, (M+35)+=390.

Example 225 AcHN. ~.,,, OEt H ~IO~
~t)-(2R,3S.5R.1'S)-2-(1-Acetamido-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Ethyl Ester The title compound is prepared according to the method described in Example 222, substituting (t)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in place of (t)-(2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 838 mg, 94%).
1 H NMR (CDC13): 8 5.50 (m, 1 H), 5.41 (m, 1 H), 5.28 (m, 1 H), 4.21 (q, J=7.5Hz, 2H), 4.06 (m, 1 H), 3.87 (t, J=7.5Hz, 1 H), 3.10 (m, 1 H), 2.97 (m, 1 H), 2.39 (m, 1 H), 1.97 (s, 3H), 1.66 (dd, 3H), 1.60 (m, 1 H), 1.40 (m, 2H), 0.94 (d, J=7.5Hz, 3H), 0.93 (d, J=7.5 Hz, 3H).
MS: (M+H)+=311 Example 226 c~
AcHN. N>..,,~I~ Et H'H lO
(t)-(2R.3S.5R 1'S~-2~1-Acetamido-3-methyl)butyl-3-(cis-2-chioro-vin-1-Lrl pvrrolidine-5-carboxylic Acid Eth I~Ester The title compound is prepared according to the method described in Example 222, substituting (t)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in place of (t)-(2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 28 mg, 46%).
' H NMR (CDC13): 8 6.05 (d, J=7.5Hz, 1 H), 5.90 (dd, J1=9 Hz, J2=6Hz, 1 H), 5.31 (d, J=9Hz, 1 H), 4.19 (q, J=7.5Hz, 2H), 4.06 (m, 1 H), 3.82 (t, J=7.5Hz, 1 H), 3.17 (m, 2H), 2.45 (m, 1 H), 1.98 (s, 3H), 1.67 (m, 1 H), 1.60 (m, 1 H), 1.37 (m, 2H), 1.27 (t, J=7.5Hz, 3H), 0.91 (d, J=7.5Hz, 3H), 0.89 (d, J=7.5Hz, 3H).
MS: (M+H)+= 331 Example 227 Intentionally blank.
-4.68-Example 228 F~/' F
AcHN. ~.,,, OEt (tL~2R 3S 5R 1'S)-2-(1-Acetamido-3-methyl)butyl-3-(2.2-difluoro-vine pyrrolidine-5-carboxylic Acid Ethyl Ester The title compound is prepared according to the method described in Example 222, substituting (t)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(2,2-difluoro-vinyl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in place of (t)-(2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 28 mg, 57%).
' H NMR {CDC13): 8 4.22 (q, J=7.5 Hz, 2H), 4.14 (m, 1 H), 4.03 (m, 1 H), 3.29 (br, 1 H), 2.85 (m, 1 H), 2.52 (m, 1 H), 2.01 (s, 3H), 1.77 (m, 2H), 1.64 (m, 2H), 1.49 (m, 1 H), 1.38 (m, 1 H), 1.29 (t, J=7.5Hz, 3H), 0.93 (d, J=7.5Hz, 3H), 0.90 (d, J=7.5Hz, 3H).
MS: (M+H)+= 333 Example 229 HN
N
AcHN. N~ .,,I~OEt H'H
O
(t)~2R,3R.5R,1'S)-2-C 1-Acetamido-3-methyl)butyl-3-tpyrazol-3-yl)-pyrrolidine-carboxylic Acid Ethyl Ester The title compound is prepared according to the method described in Example 222, substituting (t)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in place of (t)-(2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 48 mg, 75.5%).
' H NMR (CDC13): 8 7.49 (d, 1 H), 7.26 (s, 1 H), 6.18 (d, 1 H), 4.18 (q, J=7.5Hz, 2H), 4.12 (m, 1 H), 3.91 (t, J=7.5Hz, 1 H), 3.51 (t, J=7.5Hz, 1 H), 3.40 (q, J=9Hz, 1 H), 2.64 (m, 1 H), 2.00 (m, 1 H), 1.82 (s, 3H), 1.75 (m, 1 H), 1.36 (m, 1 H), 1.26 (t, J=9Hz, 3H), 0.855 (d, 3H), 0.84 (d, 3H).
MS: (M+H)+= 337 Example 230 (t)~2R,3S.5R 1'R~2-~1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
i- , AcHN. N~., O~Bu OH cc 230A (t)-(2R.3S.5R,1'R~1-t-Butoxvcarbonyl-2-(1-acetamido-2-ethyl-2-hydroxy)butyl-3-(cispropen-1-yl)-pyrrolidine-5-carboxylic Acid t-Bu I Ester.
The title compound was prepared according to the method described in Example 418, substituting (t)-(2R,3S,5R,1'R)-1-t butoxycarbonyl-2-(1-acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester for (t)-(2R, 3S, 5R,1'R)-1-t-butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester to provide the title compound {yield: 0.021 g, 51 %).
MS: (M+H)+= 469, (M+Na)+ = 491, (2M+Na)+=959, (M-H)- = 467.

AcHN. N~.,~OH
H' H O
~OH
TFA
2308 (t)-(2R,3S.5R,1'R)-2-(1-Acetamido-2-eth~ydroxy)bu~l-3-(cis-prohen-1-yIZ pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1--4.71-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0039 g, 100%).
'H NMR (DMSO-ds) s7.52 (d, J=10.3Hz, 1 H), 5.45 (m, 1 H), 5.28 (m, 1 H), 4.32 (m, 2H), 3.68 (t, J=8.8Hz, 1 H), 3.16 (quint., J=8.5Hz, 1 H), 2.41 (dt, J=13.2,8.3Hz, 1 H), 1.81 (s, 3H), 1.59 (m, 1 H), 1.53 (dd, J=6.8,1.SHz, 3H), 1.52-1.42 (rn, 3H), 1.30 (m, 1 H), 0.86 (t, J=7.3Hz, 3H), 0.83 (t, J=7.3Hz, 3H).
MS: (M+H)+ = 313, (M+Na)+ = 335, (M-H)' = 311, (2M-H)- = 623.
Example 231 (t)-(2R.3S 5R 1'R 2'S)-2-(1-Acetamido-2-hydrox rL-2-methyl)pen I-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
~O~Bu OH O
231A (t~-{,2R 3S.5R.1'R.2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-~)-pyrroiidine-5-carboxylic Acid t Butyl Ester.
The title compound was prepared according to the method described in Example 41B, substituting (t)-{2R,3S,5R,1'R)-1-t butoxycarbonyl-2-(1-acetamido-2-oxo)pentyl-3-(cis-propen-1-yl)-pyrroiidine-5-carboxylic acid t butyl ester for (t)-(2R,3S,5R,1'R)-1-t Butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester and methyimagnesium bromide for ethylmagnesium bromide to provide the title compound (yield:
0.0285 g, 45%).
MS: (M+H)+= 469, (M+Na)+ = 491.

AcHN. ).
N
H Boc WO 99154299 PCT/US99/0'7945 , AcHN. N~.,~OH
H\ H
OH O
- TFA
231 B (tL(2R.3S.5R,1'R,2'S)-2-(1-Acetamido-2-h~roxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pYrrolidine-5-carbox~ic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-methyl)pentyl-3-{cis-propen-1- yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (yield: 0.0040 g, 100%).
' H NMR (DMSO-ds) 89.25 (bs, 1 H), 8.75 (bs, 1 H), 7.54 (d, J=10.3Hz, 1 H), 5.45 (m, 1 H), 5.29 (m, 1 H), 4.37 (bt, J=8.3Hz, 1 H), 4.22 (t, J=9.7Hz, 1 H), 3.62 (t, J=8.8Hz, 1 H), 3.12 (quint., J=8.5Hz, 1 H), 2.41 (dt, J=12.7,7.8Hz, 1 H), 1.78 (s, 3H), 1.59 (m, 1 H), 1.53 (dd, J=6.8,2.OHz, 3H), 1.4-1.25 (m, 4H), 1.17 (s, 3H), 0.81 (t, J=6.5 Hz, 3H).
MS: (M+H)+= 313, (M+Na)+ = 335, (M-H)- = 311, (2M-H)~ = 623 Example 232 (t)-(2R 3S 5R 1'R 2'S)-2-(1-Acetamido-2-ethyl-2-hydroxY)pentyl-3-(cis-propen-1-yl~wrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
~O~Bu OH O
232A (t~~2R 3S.5R.1'R,2'S)-1-t-Butoxycarbonvl-2-(1-acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl~-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 41B, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester for (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester to provide the title compound (yield: 0.0222 g, 33%).
MS: (M+H)+= 483, (M+Na)+ = 505, (M-H)-=481.

AcHN _ >.
N
H Boc AcHN. N~.,~ H
HH ~O
OH
/ TFA
232B (t)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yi)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0035 g, 100%).
'H NMR (DMSO-dfi) ~ 9.1 (bs, 1 H), 8.75 (bs, 1 H), 7.53 (d, J=9.8Hz, 1 H), 5.44 (m, 1 H), 5.28 (m, 1 H), 4.35-4.25 (m, 2H), 3.67 (m, 1 H), 3.16 (quint., J=8.5Hz, 1 H), 2.41 (dt, J=12.8,7.9Hz, 1 H), 1.81 (s, 3H), 1.60 (m, 1 H), 1.53 {dd, J=6.7,1.8Hz, 3H), 1.46 (m, 2H), 1.4-1.20 (m, 4H), 0.86 (t, J=7.3Hz, 3H), 0.82 (t, J=6.7 Hz, 3H).
MS: (M+H)+= 327, (M-H)- = 325, (M+CF3COOH)-=439, (2M-H)' = 651 Example 233 i- , AcHN_ N~..,~OH
H
OHH O
TFA
~)-(2R 3S 5R 1'R)-2-(1-Acetamido-2-progyl-2-hydroxy)pent-3-(cis_propen-1-vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 232 substituting propyl magnesium bromide for ethyl magnesium bromide.
'H NMR (DMSO-d6): 8 0.81 (t, 3H), 0.91 (t, 3H), 1.24-1.49 (m, 8H), 1.54 (dd, 3H), 1.60 (m, 1 H), 1.81 (s, 3H), 2.41 (m, 1 H), 3.15 (m, 1 H), 3.69 (t, 1 H), 4.28 (t, 1 H), 4.35 (t, 1 H), 5.17 (br s, 1 H), 5.28 (td, 1 H), 5.45 (dq, 1 H), 7.54 (d, '! H), 8.80 (br s, 1 H), 9.12 {br s, 1 H).
MS: (M+H)+= 341.

Example 234 (t)-(2 R.3S, 5 R.1 ' R)-2-( 1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1~1)-pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN_ N~., OtBu H Boc J _o~
S-234A (t)-~2R.3S.5R.1'R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-ethyl-2-(methylthio)methyloxy)butyl-3-(cis-propen-1-yl) pyrrolidine-5-carboxylic Acid t-Bu I Ester (t)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester was reacted with dimethylsufoxide and acetic anhydride according to the method of Marshall, J. A. in J. Org. Chem. 1979, vol. 44, p 2994 to provide the title compound.
i- , AcHN_ N~_, OtBu H Boc J -ocH3 234A (t)-(2R,3S.5R.1'R.2'S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl~~ayrrolidine-5-carboxylic Acid t-Butyl Ester (t)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-ethyl-2-(methylthio)methyloxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester is reacted with Raney Nickel according to the procedure of Marshall, J.
A. in J. Org. Chem. 1979, vol. 44, p 2994 to provide the title compound.
/=.:.
H C
Ac~~-IN _ OH
~N~ ~~~I~
HH O
'OCH3 TFA
(~2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1=
yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound is prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-rnethoxy)butyl-3-(cis-propen-1-yl)-pyrrolid ine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester.
Example 235 ...
HsC~
AcH N O H

TFA
~t)-(2R,3S.5R.1'R.2'S)-2-(1-Acetamido-2-ethyl-2-methoxy)pen /I-3-(cis-propen-1-yl~pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound is prepared according to the method described in Example 234 substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester for (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester in 234A.
Example 236 (t)-(2R.3S.5R,1'R.2'S)-2-(,1-Acetamido-2-hydroxymethyl-2-hydroxy~pen I-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt AcHN. N~.,, OtBu OHBoc/ ~~
~o o~
236A (t)-(2R.3S.5R.1'R.2'S -1-t-Butoxycarbonyl-2-(1-Acetamido-2-((1-ethoxy)ethyloxymethyl)-2-h_ydrox~pentyl-3-(cis-propen-1- rLpyrrolidine-5-carboxylic Acid t-Butyl Ester (t)-(2R, 3 S, 5R,1 ' R, 2'S)-1-t-Butoxycarbonyl-2-( 1-acetamid o-2-oxo)pentyl-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (50 mg, 0.11 mmole) was reacted with (ethoxyethyloxymethyl)tributylstannane (260 mg, 0.66 mmole) according to the method of Stifl, W. C. (J. Am. Chem. Soc., 100, 1481(1978)) to provide the title compound (yield: 26.8 mg, 43.8%).
'H NMR (CDC13): s 0.89 (t, 3H), 1.19 (m, 3H), 1.29 (dd, 3H), 1.45 (s, 9H), 1.46 (s, 9H), 1.52-1.73 (m, 8H), 1.99 (s, 3H), 2.44 (m, 1 H), 3.24-3.74 (m, 5H), 3.91-4.22 (m, 3H), 4.49 (m, 1 H), 4.62 (m, 1 H), 5.37 (m, 1 H), 5.64 (m, 1 H), 5.97-6.41 (m, 1 H).
MS: (M+H)+= 557.

~.

AcHN, N~.,, OH
H H
OH O
OH TFA
2368 (t)-(2R 3S 5R,1'R 2'Sl-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(cis-prJ~en-1-Y)-pyrrolidine-5-carbox~ic Acid Trifluoroacetic Acid Salt (t)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-(1-ethoxy-2-ethoxymethyl)-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester (13.5 mg, 0.024 mmol) was dissolved in THF (1 mL) and treated with 0.5 N HCI ( 1 mL) at room temperature for 1 hr. The solvents were removed and the resulting white solid was reacted with trifluoroacetic acid (0.8 mL) in dichloromethane (0.2 mL) at room temperature for 6 hours. The reaction was concentrated in vacuo overnight to provide the title compound (yield: 10.7 mg) as a off white solid.
'H NMR (DMSO-ds): 8 0.81 (t, 3H), 1.24-1.38 (m, 4H), 1.52 (dd, 3H), 1.62 (rn, 1 H), 1.78 (s, 3H), 2.41 (m, 1 H), 3.11 (m, 1 H), 3.51 (qAB, 2H), 3.77 (t, 1 H), 4.23 (t, 1 H), 4.40 (m, 1 H), 5.27 (t, 1 H), 5.45 (m, 1 H), 7.55 (d, 1 H), 8.87 (br s, 1 H), 9.26 (br s, 1 H).
MS: (M+H)+= 329 Example 237 (t~(2R,3S 5R 1'R 2'S)-2-(1-Acetamido-2-allyloxy-2-vin I~)ethyl-3-(cis-propen-1-yl} pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt /_ =:
H3C~
AcHN OtBa N~..,, O Boc 0 237A (t)-(2R,3S.5R 1'R.2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-allylox~2-vinyl)ethyl-3-(cis-propen-1-ylLpyrrolidine-5-carboxylic Acid t-Butyl Ester (2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester was reacted according to the method described in Example 84A substituting allyl iodide for methyl iodide (yield: 28 mg, 80%).
MS: (M+H)+= 479, (M-H)- = 477 /_ :.
H3C~
AcHN OH
H N / II~
H O
TFA
2378 (t)-(2R,3S.5R.1'R.2'S)-2-(1-Acetamido-2-alylox -y 2-vinyl)ethyl-3-(cis-propen-1 yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41 C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-allyloxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester. (yield: 4 mg, 100%).
'H NMR (DMSO-d6) 8 7.98 (d, J=7.8 Hz, 1 H), 5.90 (m, 1 H), 5.55 (m, 1 H), 5.48 (m, 1 H), 5.32 (m, 2H), 5.26 (m, 2H), 5.16 (m, 1 H), 4.28 (m, 2H), 3.96 (m, 1 H), 3.79 (m, 1 H), 3.73 (m, 1 H), 3.66 (m, 1 H), 3.26 (m, 1 H), 2.40 (m, 1 H), 1.81 (s, 3H), 1.70 (m, 1 H), 1.64 (dd, J=6.9, 1.5 Hz, 3H).
MS: (M+H)+= 323, (M-H)' = 321.
Example 238 {t)-,~2R.3S.5R.1'R 2'S -) 2i(1-Acetamido-1-(2,5-dihydrofuran-2- rLl) methy~cis-propen-1- ly )ip~rrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt /_ :.

AcHN, N~.,, OtBu o Soc '~~
238A ~t)-(2R.3S35R.1'R,2'S)-2-(1-Acetamido-1-(2,5-dihydrofuran-2-yl))methyl-3-Scis-propen-1-yl)-pyrroiidine-5-carboxylic Acid t-Butyl Ester (t)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-{1-acetamido-2-allyloxy-2-vinyl)ethyl-3-{cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester (21 mg, 0.044 mmole) prepared according to the procedure of Example 237A was reacted with bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride [Grubb's catalyst] (7.5 mg, 0.009 mmole) in methylene chloride (5 mL) at 25°C
for 2 hours under a nitrogen atmosphere. The reaction was concentrated in vacuo and the resulting residue purified by chromatography on silica gel using 75% ethyl acetatelhexanes to provide the title compound (yield: 18 mg, 90%).

MS: {M+H)+= 451, (M-H)~ = 449.
/_ ,,.
H C
Ac~N OH
N / I,'~
H H O
TFA
2388 (t)-f,2R,3S,5R.1'Rj,2'S)-2-(1-Acetamido-1-(2.5-dihydrofuran-2-yl))methyl-(cis-~ropen-1-yl~wrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-1-(2,5-dihydrofuran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester. (yield: 7 mg, 100%).
' H NMR (DMSO-d6) b 8.09 (d, J=8.8 Hz, 1 H), 6.10 (m, 1 H), 5.87 (m, 1 H), 5.50 (m, 1 H), 5.27 (m, 1 H), 4.68 (m, 2H), 4.58 (m, 1 H), 4.33 (m, 1 H), 4.06 (m, 1 H), 3.68 (m, 1 H), 3.18 (m, 1 H), 2.40 (m, 1 H), 1.85 (s, 3H), 1.68 (m, 1 H), 1.60 (dd, J=6.8, 1.5 Hz, 3H), MS: (M+H)+= 295, (M-H)- = 293.

Example 239 (t)-~ R, 3S, 5R,1'R.2'S)-2-(1-Acetamido-2-allyloxy-2-allyl)ethyl-3-(cis-propen-1_yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt /_.:.
HC
Ac~HN OtSu '~Ni..~.
B~C O
239A (t)-(2Ry3S.5R,1'R.2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-allyloxy-2-all~rl~thyl-3-(cispro~en-1 yl~pyrrolidine-5-carboxylic Acid t-Buyl Ester (2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester was reacted according to the method described in Example 84A substituting allyl iodide for methyl iodide iodide (yield: 19 mg, 36%).
MS: (M+H)+= 493, (M-H)- = 491.
/_ =.
H C
Ac~HN OH
H N / I~
_ H O
TFA
239B (t)-(2R,3S.5R.1'R.2'S)-2-(1-Acetamido-2-allylox -y tall r~l ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-Acetamido-2-allyloxy-2-allyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester. (yield: 5.7 mg, 100%).
' H NMR (DMSO-d6) b 8.06 (dd, J= 8.8 Hz, 1 H), 6.92 (m, 1 H), 6.77 (m, 1 H), 5.50 (m, 1 H), 5.29 (m, 2H), 5.17 (m, 1 H), 5.05 (m, 2H), 4.27 (m, 2H), 4.10 (dd, J= 12.2, 5.4 Hz, 1 H), 3.83 (m, 1 H), 3.78 (m, 1 H), 3.40 (m, 1 H), 3.20 (m, 1 H), 2.46 (m, 1 H), 2.38 (m, 1 H), 2.20 (m, 1 H), 1.88 (s, 3H), 1.69 (m, 1 H), 1.63 {dd, J=
6.8, 1.5 Hz, 3H).
MS: (M+H)+= 337, (M+Na)+= 359, (M-H)- = 335.

Example 240 t~j2R.3S,5R.1'R,2'S)-2-{1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-jcis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt /_.:.

AcHN N~ ,,, OtBu O Boc ~~
240A (t)-(2R,3S,5R.1'R.2'S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-p ry an-2-yl))methyl-3-(cis-proyen-1-yl)-pyrrolidine-5-carboxylic Acid t-But I Ester (t)-{2R,3S,5R,1'R,2'S)-1-t Butoxycarbonyl-2-(1-Acetamido-2-allyloxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (11.5 mg, 0.023 mmole) prepared according to the procedure of Example 239A was reacted with bis(tricyclohexylphosphine)benzylidine ruthenium(I~ dichloride [Grubb's catalyst]
(3.8 mg, 0.005 mmole) in methylene chloride (3 mL) at 25°C for 3 hours under a nitrogen atmosphere. The reaction was concentrated in vacuo and the resulting residue purified by chromatography on silica gel using 75% ethyl acetate/hexanes to provide the title compound (yield: 5.7 mg, 53%).
MS: (M+H)+= 465, (M+Na)+= 487, (M-H)- = 463 /_.:.
H C
Ac~-IN OH
H N/ ,/~~I~
_ H O
TFA
240B (t)-(2R.3S.5R,1'R.2'S)-2!1-Acetamido-1-X3,6-dih d~-H-pyran-2-yl) methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-(cis-propen-1-yl)-pyrroiidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t butyl ester. (yield: 5.9 mg, 100%).
'H NMR (DMSO-d6) 8 8.04 (d, J= 8.8Hz, 1 H), 5.77 (m, 2H), 5.50 (m, 1 H), 5.25 (m, 1 H), 4.21 (m, 2H), 4.14 (m, 1 H), 4.04 (m, 1 H), 3.81 (m, 1 H), 3.40 (m, 1 H), 3.23 (m, 1 H), 2.41 (m, 1 H), 2.09 (m, 1 H), 1.88 (s, 3H), 1.83 (m, 1 H), 1.70 (m, 1 H), 1.63 (d, J= 6.8Hz, 3H).
MS: (M+H)+ = 309, (M+Na)+ = 331, (M-H)- = 307 The following compounds were synthesized according to the methods previously described in Examples 1-240 Exam~ole 241 ...
H C
Ac~iN OH
H N/ ,/~
H O
~ TFA
it)~2R.3S,5R,1'R,2'R)-2-(1-Acetamido-1-(3.6-dihydro-2-H-pLrran-2- I)~p~-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Satt 1 H NMR (DMSO-d6) 8 7.90 (d, 9.1 Hz, 1 H), 5.79 (m, 2H), 5.48 (m, 1 H), 5.23 (m, 1 H), 4.43 (m, 1 H), 4.24 (m, 2H), 4.17 (m, 2H), 3.73 (m, 1 H), 3.64 (m, 1 H), 3.19 (m, 1 H), 2.42 (m, 1 H), 2.02 (m, 1 H), 1.85 (s, 3H), 1.78 (m, 1 H), 1.75 (m, 1 H), 1.56 (dd, J= 7.5, 1.5 Hz, 3H).
MS: (M+H)+ = 309, (M+Na)+ = 331, (M-H)- = 307.

Example 242 /= ~.
H~C~
AcllN OH
N~ .~~' HH O
'OH
TFA
{t)-(2R,3S 5R 1'S 2'RS)-2-(1-Acetamido-2-hvdroxy)pentvl-3-(cis-propen-1-vl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO) 8 7.7 (d, J= 9.8 Hz, 1 H), 5.61 (m, 1 H), 5.19 (dt, J= 1.8, 11.0 Hz, 1 H), 4.33 (dd, J= 6.7, 10.3 Hz, 1 H), 3.81 (m, 1 H), 3.70 (dd, 1.8, 10.3 Hz, 1 H), 3.54 (q, J= 6.1 Hz, 1 H), 3.10 (m, 1 H), 2.35 (dt, J= 12.8, 6.8 Hz, 1 H), 1.90 (s, 3H), 1.7 (m, 1 H), 1.59 (dd, J= 0.7, 7.3 Hz, 3H), 1.4 (m, 3H), 1.2 (m, 2H), 0.90 (t, J= 6.7 Hz, 3H).
MS: (M+H)+= 299 Example 243 H C
Ac~-IN OH
E., N~ ~~~'I~
H O
'OH
O OEt TFA
(t)-(2R 3S 5R 1'S 2'RS)-2~1-Acetamido-2-hydroxy-3-ethoxycarbon~prop cis-proaen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO) b 7.75 (m, 1 H), 5.60 (m, 1 H), 5.29 (m, 1 H), 4.55-4.25 (m, 3H),4.15-4.0 (m, 3H), 3.9-3.6 (m, 3H), 3.15 (m, 1 H), 2.45-2.3 {m 2H), 1.9 (s, 3H), 1.8-1.5 (m, 5H), 1.2 (m, 3H).

MS: (M+H)+= 343 Examele 244 /_ :.

AcHN , .,, OH
H ~IO~
'OCH3 TFA
(t)-(2R,3S,5R.1'R,2'S)-2 ~1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(cis-proeen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (DMSO-ds) d 7.91 (d, J=8.05Hz, 1 H), 5.50(m, 2H), 5.30(m, 3H), 4.27(m, 1 H), 4.23(m, 1 H), 3.75(m, 1 H), 3.48(m, 1 H), 3.23(m, 1 H), 3.15(s, 3H), 2.40(rn, 1 H), 1.80(s, 3H), 1.68(m, 1 H), 1.64(dd, J=1.83, 7.32Hz, 3H) MS: (M+H)+= 297, (M-H)-= 295 Example 245 /_ ...

AcHN N~.,,, OH
H H ~I
O O
TFA
(t)-(2R,3S.5R.1'R.2'S~-2-(1-Acetamido-2-ethoxy-2-vinyl)eth I-y 3-(cis-preen-1_yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR(DMSO-ds) d 7.90(d, J=7.85Hz, 1 H), 5.57(m, 2H), 5.48(m, 3H), 4.27(m, 1 H), 4.22(m, 1 H), 3.77(m, 1 H), 3.60(m, 1 H), 3.46(m, 1 H), 3.23(rn, 2H), 2.39(m, 1 H), 1.80(s, 3H), 1.70(m, 1 H), 1.64(dd, J=1.47, 6.73Hz, 3H), 1.12(t, J=6.83 Hz, 3H) MS: (M+H)+= 311, (M-H)- = 309 Example 246 AcHN N,.,,, OH
~ H ~I~
OH O
TFA
fit)-(2R~3S 5R 1'R 2'S)-2-(1-Acetamido-2-hydroxy~propeny-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrofidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR(DMSO-ds) 8 7.69(d, J=9.75Hz, 1H), 5.47(m, 1H), 5.28(m, 1H), 5.03(m, 1 H), 4.86(m, 1 H), 4.40(m, 1 H), 4.30(m,1 H), 4.18(m, 1 H), 3.97(m, 1 H), 3.68(m, 1 H), 3.21 (m, 1 H), 2.43(m, 1 H), 1.82(m, 1 H), 1.73(s, 3H), 1.64(s, 3H), 1.59(m, 3H) MS: (M+H)+= 297, (M-H)-= 295 Example 247 H C
Acl1 N OH
H N/ r~~I~
H O
~OH
TFA
(t)-(,2R.3S,5R,1'R,2'R)-2-f 1-Acetamido-2-hydroxy~propen~yl)ethyl-3-(cis-propen-1-yl)pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds) 8 7.65(d, J=9.80 HZ, 1 H), 5.48(m, 1 H), 5.23(m, 1 H), 4.99(s, 1 H), 4.88(s, 1 H), 4.46(m, 1 H), 4.30(m, 1 H), 4.19(m, 1 H), 3.55(m, 1 H), 3.22(m, 1 H), 2.44(m, 1 H), 1.78(s, 3H), 1.75(m, 1 H), 1.65(s, 3H), 1.58(dd, J=1.23, 6.70HZ, 3H) MS: (M+H)+= 297, (M-H)-=295 Example 248 AcHN, OH

TFA
(t)-(2R,3S,5R.1'R,2'S)-2-(1-Acetamido-2-methoxy-2-(propeny-2-yl))ethyl-3- cis-propen-1-yl)-pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt 1 H NMR (DMSO-d6) d 7.77(d, J=9.8 Hz, 1 H), 5.49 (m, 1 H), 5.25(m ,1 H), 5.07(m, 1 H), 4.94(m, 1 H}, 4.32(m, 1 H), 4.25(m, 1 H), 3.75(m, 1 ), 3.48(m, 1 H), 3.25(m, 1 H), 3.08(s, 3H), 2.40(m, 1 H), 1.77(s, 3H), 1.68(m, 1 H), 1.fi4(dd, J=1.22, 6.71 Hz, 3H), 1.56(s, 3H) MS: (M+H)+=311, (M-H)~=309 Example 249 /_ :.
H C
Ac~-IN OH
H O
TFA
(tl~2R.3S,5R.1'R -~1-Acetamido-2-ethyl)buty~cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds) 8 7.62(d, J=9.21 Hz, 1 H), 5.58(m, 1 H), 5.28(m, 1 H), 4.37(m, 1 H), 3.98(m, 1 H), 3.57(m, 1 H), 3.10(m, 1 H), 2.45(m, 1 H), 1.92(s, 3H), 1.76(m, 1 H), 1.62(dd, J=1.83, 6.72Hz, 3H), 1.24(m, 5H), 0.84(t, J=7.61 Hz, 3H), 0.77(t, J=7.61 Hz, 3H) MS: (M+H)+=297, (M-H)-=295 Example 250 /_ ...

AcHN. OH
H ~>~~~~I~
O
TFA
St)~2 R.3S.5R,1'S,)-2-( 1-Acetamido-2-ethyl) butyl-3-(cis-propen-1-yl)-pyrrolid i ne-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds) b 7.76(d, J=9.2 Hz, 1 H), 5.46(m, 1 H), 5.29(m, 1 H), 4.23(m, 1 H), 3.63(m, 1 H), 3.15(m, 1 H), 3.01 (m, 1 H), 2.38(m, 1 H), 1.87(s, 3H), 1.71 (m, 1 H), 1.60(m, 3H), 1.36(m, 1 H), 1.20(m, 4H), 0.83 (t, J=7.3Hz, 6H) MS: (M+H)+=297, (M-H)-=295 Example 251 /= , H C H C
Ac~HN H N).,~ Et Ac~iN H N~OEt OH O ~OH
~-)-(2R.3S.5R 1'Sl-2~1-Acetamido-2-eth~rlLut~l-3-(cis-propen-1-yl)-pyrrolidine-carboxylic Acid Ethyl Ester and (+)-(2S,3S.5S.1'R)-2-(1-Acetamido-2-ethyl)but rLl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Ethyl Ester (t)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid ethyl ester (100 mg) was chromatographed in one injection on a chiral HPLC column of dimensions 5 x 30 cm. The column was packed with Chiralpak AD chiral stationary phase packing from Chiral Technologies. The mobile phase consisted of 1:9 ethanol:hexanes at a flow rate of 117 mUmin. Two peaks were observed at (24-36) minutes (-)-(2R,3S,5R,1'S) (yield: 45 mg) and at (66-96) min (+)-(2S,3S,5S,1'R) (yield: 45 mg).
(-)-(2R,3S,5R,1'S) [ajo = -26° (c=0.78, dichloromethane) Example 252 ~(2R, 3S.5R.1'S)-2-( 1-Acetamido-2-ethyl)butyl-3-f cis-propen-1-yl)-pyrrolidine-5-carboxylate Ammonium Salt ...
AcHN O NN4 O
OH
(-)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid ethyl ester (4.9 mg, 0.0157 mmoie) prepared according to the procedure of Example 251 was reacted with lithium hydroxide (0.75 mg, 0.0314 mmole) in a mixture of methanol (0.75 mL) and water (0.25 mL) at 0°C for 7 hours. Then 0.1 N aqueous Hydrochloric acid (1 mL) was added, the reaction was concentrated in vacuo and the resulting residue purified by ion exchange chromatography on Aldrich Dowex 50WX8-400 strongly acidic resin. The residue was placed on the column and washed with water (5 mL) followed by elution using 0.5 N aqueous Ammonium hydroxide to provide the title compound as a colorless solid (yield: 3.9 mg, 83%). [a)o = - 40° , c=0.08 (water).
1 H NMR (DMSO-d6) s 7.71 (d, J= 9.2 Hz, '! H), 5.38 (m, 1 H), 5.29 (m, 1 H), 3.92 (m, 1 H), 3.65 (t, J= 8.5 Hz, 1 H), 3.43 (m, 1 H), 3.33 (m, 1 H), 2.98 (m, 1 H), 2.23 (m, 1 H), 1.76 (s, 3H), 1.54 (dd, J= 6.7, 1.8 Hz, 3H), 1.46 (m, 2H), 1.23 (m, 1 H), 0.84 (t, J= 7.3 Hz, 3H).
MS: (M+H)= 285, (M+Na)+= 307, (M-H)- = 283.
[a]o = - 40° , (c=0.08, water).
Example 253 AcHN N~.,,~ H
H H I IO
~OCH3 TFA
~tL,2R 3S 5R 1'R 2'S)-2-(1-Acetamido-2.3-dimethoxy)propel-3-(cis-propen-1-yl~
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (MeOD-d3) s.7.8(d, J=9.3Hz, 1 H), 5.49-5.43(m, 1 H), 5.25(dd, J=1.95, 9.3Hz, 1 H), 4.38-4.31 (m, 2H), 3.57-3.50(m, 1 H), 3.46(dd, J=4.9, 10.3Hz, 1 H), 3.42(s, 3H), 3.35-3.32(m, 2H), 3.27(s, 3H), 3.16-3.09 (m, 1 H), 2.46-2.40(m, 1 H), 1.80(s, 3H), 1.72-1.65(m, 1 H), 1.55(d, J=6.8Hz, 3H).
MS: (M+H)+=315, (M+Na)+=337, (M-H)-=313, (M+CI}-=349, (2M-H)-=627.
Example 254 AcHN N~.,~ H
H H

TFA
(t~(2R.3S 5R31'R 2'R)-2-(1-Acetamido-2,3-dimethox~prop~3-(cis-propen-1-~rl)-pyrrolidine-5-carbox~ Acid Trifluoroacetic Acid Salt 'H NMR (MeOD-d3) 8.8.04(d, J=8.5Hz, 1 H), 5.52-5.48(m, 1 H), 5.27-5.22(m, 1 H), 4.32-4..25(m, 2H), 3.74-3.71 (m, 1 H), 3.53(dd, J=2.4, 10.1 Hz, 1 H), 3.33-3.25(m, 2H), 3.31 (s, 3H), 3.25(s, 3H), 3.21-3.17(m, 1 H), 2.42-2.36(m, 1 H), 1.86(s, 3H), 1.71-1.63(m, 1 H), 1.62(d, J=7.3Hz, 3H).
MS: (M+H)+=315, (M+Na)+=337, (M-H)-=313, (M+CI)-=349, (2M-H)-=627 WO 99!54299 PCT/US99/07945 Example 255 AcHN. N~.,~OH
H H
OH O
OH TFA
(t~ ~2 R.3S, 5R.1' R,2' Rl-2-( 1-Acetamido-2-)~droxyethyl-2-hyd roxy~ pentyl-3-(cis-propen-1- I~yrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds): 8 7.60 (m, 1 H), 5.46 (m, 1 H), 5.30 (m, 1 H), 4.54 (m, 1 H), 4.35 (m, 1 H), 4.03 (m, 1 H), 3.96 (m, 1 H), 3.69 (m, 1 H), 3.15 (m, 1 H), 2.40 (m, 1 H), 1.98 (m, 2H), 1.80 (s, 3H), 1.70-1.50 (m, 5H), 1.38 (m, 3H), 0.83 (m, 3H).
MS: (M+H)+=343, (M-H)-=341 Example 256 /_', AcHN, N~.,~OH
H H
O
TFA
(t)-(2R.3S,5R,1'R~-2-(1-Acetamido-2-(3-pentyloxy))ethyl-3-(cis-propen-1_yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (MeOD-d3) 8 5.69-5.59 (m, 1 H), 5.33-5.25 (m, 1 H), 4.39 (m, 1 H), 4.34 (dd, J=7.8, 10.2Hz, 1 H), 3.73 (dd, J=4.8, 10.2Hz, 1 H), 3.58-3.47 (m, 2H), 3.38-3.24 (m, 1 H), 3.27-3.20 (m, 1 H), 2.61-2.52 (m, 1 H), 2.02 (s, 3H), 1.90-1.78 (m, 1 H), 1.70 (dd, J=1.7, 6.8Hz, 3H), 1.60-1.50 (m, 4H), 0.92 (t, J=7.5Hz, 6H) (M+H)+= 327, (M+Na)+= 349 Example 257 /= , AcH N N ~. , ~ H
H H
O
TFA
(t)-(2R.3S,5R.1'S)-2-(1-Acetamido-2-(3-pentyloxy))ethyl-3-(cis-propen-1-yl)-pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (MeOD-d3) S 5.73-5.66 (m, 1 H), 5.32-5.25 (m, 1 H), 4.36 (dd, J=7.8, 10.2Hz, 1 H), 4.09 (m, 1 H), 3.68 (dd, J=6.1, 10.2Hz, 1 H), 3.61 (d, J=4.4Hz, 2H), 3.35-3.23 (m, 1 H), 3.24-3.16 (m, 1 H), 2.65-2.55 (m, 1 H), 2.03 (s, 3H), 1.92-1.80 (m, 1 H), 1.70 (dd, J=2.0, 7.1 Hz, 3H), 1.59-1.47 (m, 4H), 0.94-0.88 (m, 6H) (M+H)+ = 327, (M+Na)+ = 349 Exami~le 258 /=.:.
H C
Ac~iN OH
~ N / .,'~~
HH O
'O
~~ TFA
(~~~2R 3S 5R 1'R 2'S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(cis-propen-1-yl~pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds) s 8.01 (d, J= 8.6Hz, 1 H), 5.76 (m, 1 H), 5.49 (m, 1 H), 5.25 (m, 1 H), 5.05 (m, 2H), 4.28 (m, 1 H), 4.02 (m, 1 H), 3.77 (m, 1 H), 3.62 (m, 1 H), 3.36 (m, 1 H), 3.29 (m, 1 H), 3.18 (m, 1 H), 2.43 (m, 1 H), 2.38 (m, 1 H), 2.16 (m, 1 H), 1.87 (s, 3H), 1.69 (m, 1 H), 1.63 (dd, J=6.7, 1.2 Hz, 3H), 1.12 (t, J=6.7 Hz, 3H).
MS: {M+H)= 325, (M-H)- = 323 Example 259 ...
H C
Ac~i N OH
N~ .°I~
H H
O O
TFA
ft)-(2R,3S.5R.1'R)-2-{1-Acetamido-2-allyloxy)ethLrl,-3-(cis-propen-1-yl)-evrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt H NMR {DMSO-ds) 8 9.16 (m,2H), 8.13(d,J=7.5Hz,1 H), 5.88(m,1 H), 5.50 (m,1 H), 5.15-5.32(m, 3H), 4.35(m,2H), 3.95(m,2H), 3.61 (m,1 H), 3.40(m,2H), 3.20(m, 1 H), 2.40(m,1 H), 1.87(s,3H), 1.72(m,1 H), 1.62(d, J=6.2,3H) MS: (M+1 )=297, (M+23)=319, (2M+23)=615 Example 260 /_', AcHN N~., ~ H
H H
OH O
~O
OEt TFA
(t)-(2R 3S 5R 1'R 2'RS)-2-(1-Acetamido-2-hydroxy-2-(2-ethoxycarbonyl))pentrl-3-(cis-propen-1-yl)-pyrrolidine-5-carbox Iy IC Acid Trifluoroacetic Acid Salt ' H NMR (DMSO-ds): 8 7.57 (d, J=1 OHz, 1 H), 5.45 {m, 1 H), 5.29 (m, 1 H), 4.35 (rn, 1 H), 4.09 (m, 1 H), 3.68 (m, 1 H), 3.44 (m, 1 H), 3.17 (m, 1 H), 2.87 (m, 1 H), 2.64 (m, 1 H), 2.39 (m, 1 H), 1.80 (s, 3H), 1.65-1.56 (m, 2H), 1.53 (m, 3H), 1.50-1.30 (m, 3H), 1.21 (t, J=7.5Hz, 3H), 0.80 (t, J=7.5Hz, 3H).
MS: (M+H)+=385, (M-H)-=383 Example 261 !_', AcHN N~.,~ H
HO, H H
O
TFA
HO

,~t~-~2R 3S 5R 1'S 3'R)-2-(1-Acetamido-3,4-dihydrox~butyl-3-(cis-propen-1-yl~
pyrrolidine-5-carboxylic Acid Trifluoraacetic Acid Salt H NMR (CD30D) 8 5.58-5.70 (m, 1 H), 5.24-5.38 (m, 1 H), 4.34-4.50 (m, 2H), 3.58-3.72 (m, 2H), 3.42-3.48 {d, 2H), 2.50-2.63 (m, 1 H), 2.04 (s, 3H), 1.77-1.95 (m, 1 H), 1.65-1.76 (m, 4H), 1.50-1.63 (m, 1 H).
MS: (M+H)+= 301 Example 262 /_', AcHN. N~,~ H
HO H H O
TFA
HO
(t)-(2R 3S 5R.1'S 3'S)-2 ~1-Acetamido-3,4-dihydroxy)butyl-3-(cis-proc~en-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt 'H NMR (CD~OD) 8 5.58-5.72 (m, 1 H), 5.25-5.37 (m, 1 H), 4.30-4.45 (m, 2H), 3.63-3.77 (m, 2H), 3.44-3.49 (d, 2H), 2.50-2.63 (m, 1 H), 2.03 (s, 3H), 1.76-1.95 (m, 2H), 1.65-1.75 (m, 4H).
MS: (M+H)+= 301 Example 263 (t)-(2R 3S 5R 1'R)-2-(1-Acetamido-2-methox )ythyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.

AcHN_ N)., OiBu H Boc 263A (t)-(2R 3S 5R.1'R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-methoxy)ethyl-3-(cis-proyen-1-yl)-pyrrolidine-5-carboxylic Acid f-Bu I Ester.
The title compound was prepared according to the method described in Example 84A, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester for (t)-(2 R, 3S, 5R,1'R,2'S)-1-t-butoxycarbonyl-2-( 1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 4.2 mg, 20%).
MS: (M+H)+=427, (M+Na)+=449, (M-H)-=425.

AcHN_ N~.,~ H
HH O

TFA
2638 (t)-(2R.3S.5R.1'R)-2-(1-Acetamido-2-methoxy)ethyl-3-(cis-propen-1-yIL
pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.0031 g, 100%).
'H NMR (DMSO-ds) b 8.12 (d, J=7.9Hz, 1 H), 5.50 (m, 1 H), 5.23 (m, 1 H), 4.33 (m 1 H), 3.56 (dd, J=9.7,8.OHz, 1 H), 3.4-3.3 (m, 2H), 3.26 (s, 3H), 3.19 {m, 1 H), 2.39 (dt, J=12.8,7.3Hz, 1 H), 1.86 {s, 3H), 1.71 (m, 1 H), 1.61 (dd, J=6.7,1.8Hz, 3H).
MS: (M+H)+=271, (M+Na)+=293.
Example 264 fit)-{2R.3S.5R 1'R 2'S)-2-(1-Acetamido-2-h day-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .

AcHN_ N,., OtBu H Boc -OH
264A ~t)-(2R,3S,5R,1'R,2'Sl-1-t-Butoxvcarbonyl-2-(1-acetamido-2-hydrox~3-dimethyl)butyl-3-(cis-t~ropen-1-yl)-pyrroiidine-5-carboxylic Acid t-Butyl Ester.
The title compounds were prepared according to the method described in Example 41 B, substituting t butyl lithium for ethyl magnesium bromide to provide (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbony!-2-(1-acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrroiidine-5-carboxylic acid t-butyl ester (yield:
2.5 mg, 11 %) (t)-(2R,3S,5R,1'R,2'S) MS: (M+H)+ = 469; (M-H)- = 467.

/_', AcHN. N~.,~OH
H'H
O
OH
TFA
264B (t)-(2R 3S 5R.1'R.2'S)-2~1-Acetamido-2-hy"droxy-4-vinyl)butyl-3~cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt The title compound was prepared according to the method described in Example 41C, substituting (t)-(2R,3S,5R,1'R,2'S)-1-t butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (t)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 2.3 mg, 100%).
'H NMR (DZO) 8 5.40 (m, 1 H), 5.10 (t, J=5.5Hz, 1 H), 4.13 (t, J=9.2Hz, 1 H), 3.46 (m, 1 H), 3.22 (d, J=7.3Hz, 1 H), 3.00 (m, 1 H), 2.41 (m, 1 H), 1.70 (s, 3H), 1.45 (m, 1 H), 1.39 (d, J=4.9Hz, 3H), 1.07 (t, J=5.5Hz, 1 H), 0.70 (s, 9H) MS: (M+H)'' = 313.
Using the methods described above and the general knowledge of one skilled in the art, compounds of the invention can be prepared which are represented by taking one core from Table 1 (wherein Ac is acetyl), one Y
substituent from Table 2, one R substituent from Table 3 and one R3 substituent from Table 4a, 4b, 4c, 4d, 4e, 4f or 4g.

Table 1 Y, Y, AcHN, 3 H N~ ~OR AcHN 3 H Nil ~OR
R H IOI R ~ H IIO

Y~ Y, CH3S02tiN, >. OR CH3S02i-IN ~. OR
N ~ N
R3H H O RsN H O

O Y, O Y, II II
CF3C-HN, 3 H N~.. ~OR CF3C-HN 3 H N~ ~OR
R H IOI R ~ H IIO

Table 2 H3 ~ ~ HN
H3C ~~~~- H ~~~~ CI

H3 ~ H3C
"- ""~". H3C ,~~~ ~ "",~

F~
H ,~~~~ , F ~~-HN~N ~N ~O F3C F

HN~ N~ CI~

Ha ~ Hs ~ ~ F3 F ~~- CI ~~ F3C ~~~~ H

H3 ~ HN =~ N~ N=
N

H 3C ...,.", , , F3 ~ F~ F3 ~ N~S

F ~~~- F3C ~~~, CI ,~~~---I H F
Et Et Et F3 ~ I F~CI Et, H3C ,,O
,N
H
C

F r,~~~, F3C ~~~~ H ."...... .,.",.

H\ CH3 F\ HN~ CI, Hj~.,~..".C i ~ ~~..~~H

HO O
=~ N-N

N

HN~~ > N\N~ ~NO
~

N -N N-N

N.N HN~N' HN~N" N HN~N~ N
N N=( ~ ' N
~( N , , , / ~N
N

HN , , N-N

S ~ , S'.=( SN=( g=

~ O, N, S~ N

S

F~ H
H F F

F\ F F' .F ~ H3 H3 ~ H3 H/~(\ F~ H
C

H3 ~ H ~ I CI, CI CI' CI
H ~~~~~~ H~)--.(~ CI/~~(\~~~~
C

CI~ ~ I ~ F3 F3 ~ F3 CI/ \ CI

F3C ..:,.... F3C~ H3C~ CI~

1 ~ H3 F3 ~ F3 H3 ~ i H3C .~.~. CI F3C H3C

CI~ H3C

F~ F~ ~ H3 H3 ~ I
F ~ H3C F ~ CI

H3C .,.:.... F~ H3C ' H3C

H3 ~ F\ ,CH3 H3 ~ F~F
""."", ~(\ F .,.,.,.". H3C~~-."",r, H3 ~ F3 ~ H3 ~ F3 H3 ~ H3 F3C ~ H3C ~ H3C F3C

C/ \ F
C

H3 H3 ~ F3 F3 ~ F3 CI'-\
F F H F
. C C
C

~..."", 3 3 116 F\ .CI F' ,CI CI~ ~ I
F~~--(~ F

CI, .F CI, C1 F' _F
CI CI~)--.(~~ F~~--(~ C ~~---(~I

CI"F CI, CI CI~ CI, CF3 F~)---(~ C~~.-(~~ C/
F F

125 ~ 3 128 F3 ~ 1 F3 ~ I F3 ~ i F3 ~ F3 F CI ~~-w ...""~, CI
C

C1~' F CI~ F3C
C~

F' ,CF3 F\ ,CF3 F' .CF3 F' ,F
~ C~~.(~ ~~--(~C
F F

Fs ~ Fs ~ ~ Fs F3 F .,."..", ~""..., F .,...",~. F3C .",.""

F3t ~ F3 H3 ~ H3 ~ I
F3C .""..., F .~...r". CI ~~~~~~ F

CI"F F~CI F' ,CH3 CI' CH3 C~~.~(~~ C~~--~(~~~~~ CI/~\ /u\F
H H

H3 ~ F3 H3 ~ I CI~ F3 F3 ~ I
C ~ HsC ~' H3C .~.
F

CI .~,~."~ 3 155 156 F3 ~ H3 Cli \ H3 H3 ~ F3 H3 CI ~~~ F F F
C C

157 3 i59 3 F\ .CF3 F~CF3 F3 ~ F3 ~ H3 C/~\ C~~--(~ H F
H H C

F~CH3 CI, CF3 CI"F F~CF3 C~~-(~ F~~-(~ C~---~ C ~~-(~I
F F

NH H2N~ H2N
N
HZN-~/ N ~ , H ~ ~

H2N, NH
~'" H2N-l/
~NH

Table 3 -H
CH3 ~ CH3 ~~CH3 / CH3 ~~CH3 l~./ 4 6 CH3 CH3 ~,,~' _ ~~CH3 ~ . \
CH3 ~ CH3 ,r,,.~~CH3 \.-~-CH3 ,CH3 ~~ CH3 ~~ ~--CH3 ~ N N
'-CH3 13 CH3 14 ~CH3 15 Table 4a CH3 ~ CH3 H C~ ~ HsC~OH

3 ~' HsC OH HsC l -OH ~OH
OH H C
CH CHs s CH3 CHs /\ OH OH OH OH
H3C CHs CHs HsC CH3,~"' ~ \

OH -OH OH OH
H3C CHs HsC CHs CHs CHs \ \
~OCH H3C~OCH ~ H3C~OCH
CHs 3 3 OCHs 3 CHs HsC~OCH OCHs H3C~OCH3 OCHs CH CHs HsC CHs ~OCH3 OCH3 OCH3 OCH3 H3C CH3~ ~ \

OH ~~~~ OH
~ H C H C
OCH 3 ~ H 3 ~OCH3 i\ 'OH ~ s H C O HsC H

H3C _ H3C\~ ~~
H3C~OH - 'OH H3C - -OH
OH

OH ~ OH
OH -OH

H3C\~ ~, ~
HsC~OCH3 - 'OCH3 H3C~OCH3 OCH3 ~OCH3 OCH3 ~OCH3 Table 4b i 'OH ~OCH3 ~O~CH3 ~O~

"OH ~ "OCH3 ~ "O~CH3 ~ "O~

HO~~OH HO~OCH3 HO'~O CH3 HO~'O
OH OH off OH CH3 HO~OH HO~OCH3 Ho' Y 'o CH3 HO~O

HO~~ "OH HO~ "OCH3 HO~ ~O~CH3 HO~ "O~
OH OH ~H OH CH3 HO~ "OH HO~ "OCH3 HO~ O cH3 HO~ "O~

~O~ ~~ "O HO~O HO~O
OH II OH ~ OH ~ OH

HO~~'O HO~'O ~OCH3 ~~OCH3 OH ~ OH ~ OCH3 OCH3 CH30~~OCH3 CH30~OCH3 CH30~'OCH3 CH30~'OCH3 HC
H3C~OH H3C~OCH3 H3C~0~CH3 H3C~0 CH~",~".
HsC OH HsC~OCH3 H3C~0~CH3 H3C~~
IOH O OH
H C OH H3C Hs OH CH3 H3C~OH H3C~OCH3 H3C~O~CH3 H3C~OH HsC'~OCH3 H3C'~O~OH3 H3C~0 ~~ ~ ~~ HC~~
H3C "r 'OH H3CY 'OCH3 H3C Y 'O~CH3 3 ~O~

I ~ l H3C~;~OH H~C~~OCH3 H3C''~O~CH3 H3C~0 HC ~, H3C~ ~OH H3C~'OCH3 H3C~ ~O~CH3 H3 CHI.."",.
H3C~ ~OH H iC~'OCH3 H3C~ 'O~~H3 H3C

H3C s OH CH3 H3C~OH H3C~OH H3C~OCH3 H3C~OCH3 OOH CH3 OOH ~~CH3 OH CH3 jOH ~'CH3 H3C~OH H3C~~/~'OH H3C~OCH3 H3C--~OCH3 OH CH3 OH ~CH3 OH CH3 OH ~CH3 H3C ~OH H3C~OH H3C~OCH3 H3C~OCH3 H3C O CH3 H3C~OH '-CH3 H3C~OH CH3 H3C~OH ''-CH3 CH~~- CH3~~~~~ H3C
H C~,~ OH OH ~OCH3 H3C~OCHg ~f"i3 '-CH H3C~ ,CH '-CH

Table 4c H3C''-CH3 HsC~-CH3 ~-CH3 ~CH
OH OH pH s \. ' I
-CHs ~CH3 CHs ~'~'CH3 CHs CHs CH3 ICHs CHs ~ CHs ~~~-.CH H3C \ ~CH3 \ ~CH H3C~ ~CH3 3 ~ 3 CHs CHs CHs ,~~~- CHs .~~~- \
CHs H3C~ ~CH HsC \ ~CH
3 ~ 3 ~CH3 HsC CHs H3C CHs H3C~.CH3 H3C~.CH3 _CH3 .CHs CHs HsC CHs CHs '~"" CHs ""~' CHs 'CHs ~CH3 ~ ~CH3 ~CH3 H3C CHs CHs CHs H3C CHs CHs '~"' HsC \
HsC~.CHs ~~.CH3 .,..",.CHs .CHs OH OH OH OH

CH CH HsC
1' 'CHs ~ ~CH3 CH
~CH3 ~ 3 OH OH ~H OH

OH OH OH
:CHs ,~,.GH3 .~.GH3 HsC CH3 CH3 CH3 "CH3 \~ _ 'CH3 ~'CH3 CH3 ~ CH3 ~CH HsC \ CHs \ CH HsC~CHa 3 ~ 3 ' CH3 GH3 ,~.~- \
CH3 H3C CH3 H3C~CH3 ~CH3 HsC CHs HsC CHs H3C~CH3 H3C CH3 CH3 CH3 CH3 ~ CH3 """' CH3 GH3 [ CH3 Y 'CH3 ~GH3 CH3 ','." H3C \, H3C~CH3 ~~CH3 ~CH3 CH3 OH OH OH OH

CH CH HsC
Y 'CH3 Y 'CH3 CH
~CH3 ~ 3 OH OH ~H OH

OH '~"' OH
Y 'CH3 CH3 ~CH3 CH3 H3C\
H3C~.~C1"lg HsC~CH3 ~.~CH3 l~~I.~CH3 ~~~CH3 ~.~CH3 ~~'~CH3 ~~~iCH3 CH3 CH3 ~~~-~~./CH3 HgC~'.~CH3 ~ ..~CH3 H3C~'.~CH3 CIH3 I CH3 ~ \
~. ~CH3 H3C~. ~CH3 H C ~ . ~CH3 CH
3 ~ ~~ 3 H C CH3 H3C CHa H3C ~. ~CH3 H3C ~. ~CH3 ~. ~CH3 ~. ~CH3 CH3 .",."' CH3 '""" CH3 . ~CH3 ~ . CHs ~. ~CH3 ~. ~CH3 I CH3 ....'.' H3C \
H3C~.~CH3 ~~,~CH3 , CH ,~CH3 iOH OH OH OH

CH CH Hs0 \
~../CH3 ~\~'../CH3 ~~./~H3 ~../CH3 OH OH OH OH

OH i OIH OIH
\ .NCH ~'1~~L~..iCH3 ~'.iCH3 ~'.iCH3 CH H3~
H3C~CH3 HsC~CH3 ~CH3 ~~H3 C

,...,... .~,~., C~ ~"". HsC~CHs ' \C~H ~3 C ~3 CH3 CH3 ~ \
CH3 H3C;~CH3 H C \ CH3 CH
3 ~ 3 HsC CHs HsC CHs H3C ~CH3 H3C CH3 CH3 CH3 CH3 H3(., CH3 CH3 "."" CH3 '~"' CHs CH
CH3 CH ~ 3 CH3 ' 3 129 130 i31 132 I CIH3 .""" H3C \
H3C~CH3 ~CH3 \~CH3 CH3 i j O
' _ ~' OH OH OH OH

CH3 H3C, ~ \~ I
H3C~'~CH3 ~CH3 ~CH3 ~CH3 OH OH OOH ~' ~~O'' ~~''H

i OH OH OH
\ ~ ~ CH3 ~CH3 CH3 CH3 CHs CHs CH3 ; CHs H3C~ ~ J H3C~. . J . ~ H3 CHs w CH CHs CHs J. J ~. J 3 J.J .....~. J
J
CHs CHs CHs CHs CHs ~ CHs ~ Hs J.. J ~3C-~J. ~-~ ~ . J H3~-~ J..
CHs i51 152 153 1~4 CHs CHs CHs CHs ~.~~,~ Hs ~ .""..~ Hs ~ . J H C-~-J . J J~

CHs HsC CH
HsC 3 H3C .,.",.~ Hs HsC ."..".~ Hs .,..",.~ Hs .~.", J Hs CHs HsC CHs CHs ""~'~ CHs ',.."'~ CH. 3 j 'J ~ ".~'~
Hs Hs Hs Hs H3C CHs CHs CH3 H3C CHs "..",.J CHs ...."'~ H30 ~~ Hs ~ '~"'~
Hs Hs Hs OH OH OH OH

CH, 3 j 'J Hs CH3 j 'J Hs H3C~'~ H3 ~ '~ Hs OH OH OH OH
171 l72 173 174 .~.... J H pH ; ' CHs OH '"""'~ Hs OH """'~ Hs /I\
OH OH HsC CHs HsC i CHs ; CHs CH~CH3 HsC
J HsC 1 j ,CHs 179 180 181 I8 '\~2 CHs \ CHs I CHs \ i 'CHs \~C'H ~3 CH~CH3 CHs CHs ~ CHs CHs [\\ Ej3C~\-~J \ HgC

CHs CHs CHs CHs CH3 CHs \ CHs H3C' v v H3C

HsC HsC CHs CHs CHs CHs CHs H3C 1 H3C' I
CHs HsC CHs CHs .'~' CHs CHs ""~' CH3 j ,CHs ~ CHs CHs H3C CHs CHs CHs H3C CHs I CIHs CHs """' HsC CHs \ CHs H3C CHs i ' O OH OH OH
H

CH3 j ,CHs CH3 j ,CHs f"13C~~CH3 \ CH3 J '~.~~~J

OH OH OH OH

~CH OH j ,CHs OH CHs OH CHs J ~

H
OH OH 3 CHs H3C~'~ H3C~'~ CH. 3 ; 'J HsC
~.J

. J ~.~: . J ~. . J

CHs C~i . J H3C-,-~ . C~ ~ J H3C \ ~J
J

CHs CHs CH CH
~.J H~C-~.J H3C ; .~~ ~.J
CH3 HsC CH
H3C s H3C .~J H3C ~.J .~J ~.J

CH3 ~ '~ CH3 '~"'~ CH3 j ' J y. J

H C ~: . .J ~ 3 ~: J H3c ~: ~ ~ ~: J

OH OH OH OH

°H~, J ~~,~ "3° ~:J ~~J
OH OH ~H OH

~"~. J °" ~ J °H ~:J
H C' ' OH OH 3 CHg H3C~ H3C

\
CHs CH3 ; " /~ CH3 HsC \ \w~I H3C/
I
CHs CHs CHs ~ CHs ~~~-H3C~ HsC w HsC CHs HsC ~CH3 HsC ~ HsC
i CHs HsG CHs CH3 """' I CHs """" I CH
H3C CHs CHs CHs H3C CHs CHs ~ ~ HsC \

OH OH OH OH

CH~ ~~ HsC
OH OH ~H OH

i I I O~ OH I OH
~'Y~~

H CH3 ~ H3C J

Table 4d H3C CH3 H.~C CH3 H3C CH3 H3C' O H3C O
O HOC O

H3C ~ H3C ~ H3C
H;3C O ~ O O

H3C- ~O H3C ~O
~O H3C ~O

H3C ~ H3C ~ H3C
H3C ~O ~ ~O ~O

~O ~O ~O 'O
\ \

~O ~ 'O H3C ~O H3C 'O

Table 4e CH3 H3C _ H3C~.~OH HsC~OH ~,~OH ~.
OOH

~.'~OH ~'~OH ~.~OH ~.~OH

~,~OH H3C~.~OH \ ,OOH H3C~.~OH

CH3 CH3 ,~~~- \
~.~OH H3C~~~OH H3C \ ~~OH ~~OH
HsC CHs HsC CH3 H3C ~ . OOH H3C ~~OH ~. OOH ~~OH

CH3 "'~' CH3 """' CH3 . OOH , OOH ~ , OOH ~ ~~OH

WO 99154299 PCT/tlS99/07945 '""" CHs "."" HsC \
H3C~.~OH ~.~.~OH ~~OH .~pH
[OH TOH OH OH

CH CH HsC
~.~OH ~.~OH ~~OH .OOH
OH OH pH OH

i OH OH OH
\ I J- OH ~~..iOH ~. OOH ~. OOH
OH OH HsC CHs CHs H3C
H3C~OH HsC.,.~OH ~OH OH

~OH OH ~OH ~OH
lCH ~3 CHs CHs ~~~, H3C~OH \ OH H3C~OH
CH3 __ RICH ''''3 CHs CH3 -~~~- \
OH H~C~OH HsC \ OH OH
H C CHs HsC CHs H3C~OH H3C~OH OH OH
'~C'H3 ~ H3C~CH '3 CH3 ~ OH ~ 3 ~ OH CH~OH ~ OH

CH3 .,.",. H3C \
H3C ~OH ~ OH OH OH
OH OH OH OH

CH3 HsC \
H3C~OH ~~OH OH \~OH
OH OH ~H OH
s5 ss s7 s8 OH OH OH
\ I OH ~~OH OH OH

OH OH
HO~OH ~~ H3CO~OCH3 Table 4f H3C' '-CH3 H3C~-CH3 ~-CH3 OH OH OH ~CH3 -CH3 ~CH3 /~-~CH3 CH3 CH3 ~~~.
,,CH H3G~, H3 ~ -CH3 H3CyCH3 3 C~3 ~GH3 GH3 CH3 CH3 .,.",...
CHs H3C_ V 1-CH3 H3C ~ -CH3 ~GH3 CH3 CH ~GH3 CH

H3C~-CH3 H3G~-CH3 CH3 CH3 '~' ~CH3 H C~ -CH3 CH3 CH3 CH;j 3 GH3 CH3 '."" CH3 '~""' CH3 -CH3 -CH3 ~ CH3 ~ -CH3 ~CH3 ~CH3 , CH3 ~CH3 CHs "."" H3C
HsC -~ CH3 ~~./~ 'CH3 ~-CH3 'CHs CH I CH
OH s OH s OH CHs OH CHs CH CH ''~"' HsC
~CH 3 ~~'CH3 ~CH3 CHs 3 CHs , CHs OH OH ' CHs OH
OH

OH OH OH '~"' ~'CH ~~~CH3 'CHs CH s CH ~CH
CHs OH s OH s HsC CHs CHs H C CHs CHs ~~~- CHs HsC CH
H3C 3 ~ 3 CHs H3C CHs CHs CHs ~ ~ CHs ~~CH3 CHs ~ 11 11,,~~ CH
CHs CHs CHs s CHs 3 ~ J H3 .......,./ 3 Cw ~~CH3 H3C~.~CH C~ HsC ~ CH
~~--CH
s CH ~ CHs CHs CHs s CH3 CHs ~~~ CHs CHs .~..,- CHs ~CH3 H3C~J HsC~~ ~ ~CH3 H C ~CH3 ~CH3 ' 'C~H3 \CHs H3C CHs CHs 49 50 51 ~2 WO 99!54299 PCT/US99/07945 H C CHs H C CHs CHs CHs CHs CHs CHsCHs CHs CHs CHs i CHs 'Hs "..."'~ Hs CH~CH3 I ~~ Hs ~~.~J CHs ~-CH3 ~'' ~~~~./CHs ~ i'~CH3 H3C CHs CHs CHs H3C CHs H C
HsC _ CHs ~H3 ".""'~ Hs s ~ ~~CH3 ~ ~~CH3 ~CH 1 '-CHs 1 '--CH CHs OH s OH OH s OH

CHs ',.""~ Hs ~H~~CHs HsC~ CHs ~Cf"r3 ~Y~,~ ~ ~J
CHs , CHs ~CH3 ~ CHs OH OH OH OH

OH OH OH CHs ~~CH3 '~~CH3 ~~CH3 ~J
, CH ~CH ~~CHs CHs OH s OH s HsC CHs H3C ~V HsC H3C

HsC .~
HsC

HsC .~"" HsC H3C
H;jC

HsC HsC HsC H3C

HsC H3C HsC HsC
i CHs ~~ H3C
H C ~ ~CH3 HsC CHs CH3 CH

CHs CHs CHs CHs CHs W CH CHs CHs CHs CHs CH CH3 CHs CH3 -~ H3C
HsC \ \
H3C ~ w .,..,.,.
CHs il CHs HO~-CHs HO CHs HO HO
'~ NCH

CHs 109 110 IlI 112 CHs HO -CHs HO%~CHs HO HO
CH3 ~-CHs CHs l13 114 115 I16 OH OH CHs '~~' OH HsC
H3C~ HsC OH
OH HO
OH OH

OH CHs ~ OH HsC OH
HsC H3C ~OH
-OH OH OH OH

Table 4g ~~~, C H 3 ~~~.
H3C/' CHs H sC ~-CH s ~..~-CH s ~'CH3 OH OH pH OH

CHs CHs CHs CHs I CHs H3C~- _ / H3~~_ J ~_ J ~_ J
OH OH OH OH

H3C~-_ / CHs H C~_~CH3 CH~CH3 ~-~CH3 OH s OH 1~IOH O../H

H3C~' ._ ~ H3C~_ ~ CH~_ OH '~ 'OH V 'OH OH

CHs H3C~~CH3 H3C~-CH3 ~-CHs yCH3 OCHs OCHs OCHs OCHs CHs ' CHs CHs CHs ~ CHs H3C~_ _ l H3C~_ J ~_ _I _ .J
OCH3 '''''' ~'OCHs OCHs OCHs H3C~-_ ~CH3 H C~_~CH3 CH~CH3 ~-~CH3 / ~ J3 OCHs OCHs OCHs OCHs H3C~~ _ ~ H3C~_ ~ CH~_ OCH3 Y 'OCH3 v 'OCHs OCHs CHs H3C' ' OH HsC~-OH ~-OH ~-OH
CHs CHs CHs CHs H3C~H HsC~H f~3 ~-OH ~H
NCH _ NCH ~ CHs CHs ,."",.
i HsC -OH HsC -OH -OH -OH
CHs CHs CHs CHs CHs HsC -OH HsC -OH -OH -OH

CHs H3C~-OCHs HsC~-OCH3 ~-OCHs ~-OCHs CHs CHs CHs CHs ~ ~ CHs H3C~CH3 H3C~CH3 -OCHs ~CH3 ~CH3 CHs ~CH3 CHs CHs ~~~.
HsC -OCHs HsC -OCHs -OCHs -OCHs CHs CHs CHs CHs CHs HsC -OCHs HsC -OCHs -OCHs -OCHs CHs -CHs ~-CHs -CHs -CHs OH ~' \ OH OH
OH

WO 99/54299 PCTlUS99/07945 _ CH3 ~_ JCH3 CH3 ~~~ CH3 \ ~~~yCH3 _J
OH ~ OH OH OH

_ I CH3 ~~CH3 CH3 ~~~,~CH3 OH ~ OH ~ OH OH

_ ~ ~' CH3 ~~ \
OH OH OH OH

CH3 ~ \
CHs ~ CHs ~ CH3 ~-CH3 OCH %' \ OCH3 / \ OCH

_ CH3 ~""~ H3 CH3 ~~ H3 ~-~ Hs OCH3 OCH3 ~ OCH3 OCH3 _ ~CH3 ~~CH3 CH3 ~~CH3 \ ~ ~CH3 .l __ OCH3 OCH3 ~ OCH3 OCH3 _ ~ _ ~ CH3 ~ ~_ \ ."", OCH3 ~ OCH3 OCH3 OCH3 CH3 ~"" \
-OH -OH -OH -OH

CH3 ""~. \
-OH ~ -OH -OH ~-ON
CH3 CH3 ~-CH3 CH3 CH3 """,. \
-OH ~ -OH -OH -OH

CH3 "."", \
-OH ~ -OH -OH I-OH
,I

CH3 """ \

CH3 .,~", \
-OCH3 ~ -OCH3 -OCH3 -OCH3 CH3 ,...". \
-OCH3 ~ -OCH3 CH3 ,~"" \

CH3 -~~~ I \
HsC -OH ~ -OH -OH ~-OH
OH OH OH OH

CH3 ~~~, I \
HsC -OCH3 ~ -OCH3 -OCH3 ~-OCH3 OH OH OH OH

CH3 ~ I \
HsC -OCH3 -OCH3 -OCH3 ~-OCH3 ~ CH3 ~ I \
HsC~H ~..~ -OH ~H ~-OH
OOH '-OH OH
OH

~ - CH3 ~~~ I \
H3C~~CH3 ~.~ -OCH3 ~CH3 ~-OCH3 ~~..----OH ~OH OH
OH

CH3 ~ I \
HsC~CH3 ~-OCH3 ~CH3 ~-OCH
OCH3 ~OCH3 OCH3 3 -OH /~~H -OH -OH
'-OH ~ OOH OH OOH

-OCH3 ~~CH3 -OCH3 -OCH3 ' ~
~

'-OH ~ OH '-OH
-OH
~

HsC~~CH3 W~-OCH3 ~-OCH3 ~-OCH3 L ~

OCH ~ OCH3 CH3 s OCH OCH3 s CH3 ~I ~ \
HsC~~OH ~~OH ~OH ~

OH
O

OH H OH OH

CH3 ~ ~
H3C~OCH ~~ ~OCH

g OCH3 3 OCH

OH OH OH OH

CH3 ~ ~
H3C~OCH ~OCH ~OCH

H3C~OH ~..OH ~OH

OH
'-OH ~,--OH '--OH ~'-OH

CH3 II ! \
HsC~OCH3 ~OCH ~OCH3 ~

OH ~-OH OH

~-OH

CH3 I \
HsC~OCH3 ~OCH3 ~OCH3 '_ ~ ~OCH3 OCH3 'OCN3 OCH3 '-OCH

\
OH OH OH
'~-OH ~'-OH '~OH ' OH
~OH

".."' ...,." \

',r '~ ',- ~OCH3 OH ~ OH OH
'-OH

HsC~OCH3 OCH3 ~OCH3 ~OCH3 OCH ~ OCH3 '-OCH3 CH3 3 'OCH3 OH OCH3 O -O~
~-CH3 CH3 .~.,.. CHs .~.".. ~ , CHs ~---~
CH
O O CHs O ( ,O s 217 218 219 ~/ 220 -CHa -1 , CHs , The ability of the compounds of the invention to inhibit neuraminidase in vitro can be determined according to the method described below.
Neuraminidase Inhibition Assay:
Influenza virus A/N1/PR/8/34 was grown in the allantoic cavity of fertilized eggs and purified by sucrose density gradient centrifugation (Layer, W. G.
(1969) in "Fundamental Techniques in Virology" (K. Habel and N. P. Salzman, eds.) pp.
92-86, Academic Press, New York). Influenza virus A/N2lTokyo/3/67 was obtained from the tissue culture supernatents of virus grown on MDCK cells.
Neuraminidase from B/Memphis/3/89 virus was prepared by digestion of the virus with TPCK-trypsin followed by centrifugation and then purification of the neuraminidase catalytic fragment using sucrose density gradient centrifugation and dialysis as described previously (Air, G. M., Layer, W. G., Luo, M., Stray, S. J., Legrone, G., and Webster, R. G. (1990) Virolo4v 177, 578-587).

The neuraminidase inhibition assays used the neuraminidase enzymatic activity associated with the A/N1/PRIB/34 or A/N2/Tokyol3/67 whole virus, or the B/Memphis/3/89 catalytic head fragment. The whole virus or catalytic fragment was diluted appropriately with 20 rnM N-ethylmorpholine, 10 mM calcium choride, pH 7.5 buffer on the day of the experiment. Neuraminidase inhibition assays were conducted in 20 mM N-ethylmorpholine, 10 mM calcium choride, pH 7.5 buffer with 5% DMSO. Reaction mixtures included neuramfnidase, inhibitor (test compound) and 20-30,uM 4-methylumbelliferyl sialic acid substrate in a total volume of 200,uL and were contained in white 96-well U-shaped plates.
Typically, five to eight concentrations of inhibitor were used for each Ki value measurement.
The reactions were initiated by the addition of enzyme and allowed to proceed for 30-60 minutes at room temperature. The fluorescence for each well of the plate was measured once each minute during the reaction period by a Fluoroskan Il plate reader (1CN Biomedical) equipped with excitation and emission filters of +/- 35 nm and 460 +/- 25 nm, respectively. The plate reader was under the control of DeItaSoft II software (Biometallics) and a Macintosh computer. If the compound exhibited linear reaction velocities during the reaction period, then the reaction velocities for the dose-response study were fit to equation 1 using a nonlinear regression program (Kaleidagraph) to determine the overall Ki value (Segel, I. H. (1975) in Enzyme Kinetics, pp. 105-106, Wiley-Interscience, New York).
(1 - ViNo) _ [l]l {[I] + Ki(1 + [S]/Km)} eqn 1 In equation 1, Vi and Vo represent inhibited and uninhibited reaction velocities, respectively, and Km = 16 - 40 ~M depending on the neuraminidase strain tested. For those compounds exhibiting slow-binding inhibition (Morrison, J.
F.
(1982) Trends Biochem. Sci. 7, 102-105), a second experiment was performed in a manner identical to the first except that neuraminidase and inhibitor were preincubated in the absence of substrate for 2 hours at room temperature prior to initiating the reactions with substrate. Data analysis for the resulting linear velocities was conducted as described above.
Equation 2 was used to measure Ki values in the sub-nanomolar range (Morrison, J. F. And Stone, S. R. (1985) Comments Mol. Cell Biophys. 2, 347-368).
V = A{sqrt{(Ki' + It -Et)~2 + 4Ki'Et} - (Ki' + It - Et)] eqn. 2 In equation 2, V = velocity; A = akcat[S]/2(Km + [S]); a is a factor to convert fluorescence units to molar concentrations; Ki' = Ki(1 + [S]/Km); It = total inhibitor concentration and Et = total active concentration of neuraminidase.
The compounds of the invention inhibit influenza A neuraminidase and influenza B neuraminidase with Ki values between about 0.1 nanomolar and about 500 micromolar. Preferred compounds of the invention invention inhibit influenza A neuraminidase and influenza B neuraminidase with Ki values between about 0.1 nanomolar and about 3.5 micromolar.
The ability of the compounds of the invention to inhibit plaque formation in cell culture can be determined by the method described below.
Cell Culture Plague Formation Inhibition Assav Cell Cultures: MDCK cells obtained from the American Type Culture Collection were grown in Dulbecco's Modified Eagle Medium (DMEM) high glucose (GibcoBRL) supplemented with 10% fetal calf serum (JRH Biosciences), 40 mM
HEPES buffer (GibcoBRL) and antibiotics (GibcoBRL). Cells were routinely cultured in flasks or roller bottles at 37°C and 5% C02. At confluence cells were reduced to a density of 500,000 cells in a ml using trypsin/EDTA (GibcoBRL) treatment of the monolayer followed by cell centrifugation, resuspension, and dilution into growth media. Cells were planted at a volume to surface area ratio of 1 ml over 1 cm2 of growth surface.
Plaque Assay Protocol: On MDCK cell confluent 6 well plates growth media was removed and the cells were overlaid with 1.5 ml of assay media (DMEM with 1 % fetal calf serum, 40 mM HEPES buffer and antibiotics) containing pre-mixed virus (influenza AlTokyo/3/67 [H2N2]) (40 -100 plaque forming units) and 2x concentration test compound. The plates were placed on a rocker and incubated for 2 hours at room temperature. During the virus adsorption period agar overlay media was prepared. In a microwave oven 2X agarose (final concentration of 0.6% agarose) in overlay media (DMEM with 40 mM HEPES buffer) was melted and then placed in a 48°C water bath for temperature equilibration.
After the virus adsorption period was completed 1.5 ml agar over media was added and mixed with the 1.5 ml virus and test compound containing media per well.
Cultures were incubated at 35°C for the period required for plaque development, usually several days. Plaques were fixed with 3.7% formalin in PBS for 20 minutes followed by removal of the agar overlay and staining with 0.1 % crystal violet in distilled water for 15 minutes. Plaques were counted and EC 50 concentration determined from multiple concentrations of the tested compound using regression analysis.
Viral Stocks: Stocks were prepared in MDCK confluent roller bottles incubated at 37°C in DMEM supplemented with 1 % FCS, 40mM HEPES buffer, and antibiotics. Bottles were inoculated with a multiplicity of infection of approximately 0.1 plaque forming unit for each cell. Roller bottles were harvested after the cytopathic effect of the virus was observed to be complete. Stocks were prepared from the supernatant resulting from the low speed centrifugation of the media and cell lysate. Stocks were titered and stored at -80°C.

Compounds of the invention provided plaque formation inhibition for influenza virus A/N2lTokyo in MDCK cells with EC50 values between about 100 micromolar and about 1 nanomolar. Preferred compounds of the invention provided plaque formation inhibition for influenza virus A/N2/Tokyo in MDCK
cells with EC50 values between about 1 micromolar and about 1 nanomolar.
The compounds of the invention can be tested for in vivo antiviral activity using the method described below.
In Vivo Antiviral Efficacy Method Female BALB/c mice were placed under anesthesia (sevoflurane) and inoculated intranasally (IN) with 0.1 ml of influenza A VR-95 (Puerto Rico PR8-34) at 10-2 (diluted from frozen stock). This viral concentration consistently produced disease in mice within 5 days of inoculation. Animals were treated 4h.
pre-infection and 4h. post-infection, andperiodically thereafter, with one of the following therapies: no treatment; test compound (100, 25, 6.25, 1.39 mg/kglday BID, PO); or vehicle (sterile water BID, PO). A group of ten animals (designated as control) was inoculated with 0.9% saline. Percent survival was determined.
On day five, lungs were harvested, weighed and assigned scores of 0,1, 2, 3 or based on percentage consolidation (0; 10-20; 25-50; 50-75; 75-100%, respectively). In addition, each lung pair was image analyzed to determine objective lung consolidation percentages.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesuifonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesuifonate and undecanoate. Also, basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyi halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, malefic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, lithium, calcium or magnesium or with ammonium or N(R**)4+ salts (where R** is loweralkyl).
In addition, salts of the compounds of this invention with one of the naturally occurring amino acids are also contemplated.
Preferred salts of the compounds of the invention include hydrochloride, methanesulfonate, sulfonate, phosphonate and isethionate.
The compounds of the formula I, II and III of this invention can have a substituent which is an acid group (for example, -C02H, -S03H, -S02H, -P03H2, -P02H). Compounds of the formula I, II and 111 of this invention having a substituent which is an ester of such an acidic group are also encompassed by this invention. Such esters may serve as prodrugs. The prodrugs of this invention are metabolized in vivo to provide the above-mentioned acidic substituent of the parental compound of formula I, ll or III. Prodrugs may also serve to increase the solubility of these substances and/or absorption from the gastrointestinal tract. These prodrugs may also serve to increase solubility for intravenous administration of the compounds. Prodrugs may also serve to increase the hydrophobicity of the compounds. Prodrugs may also serve to increase the oral bioavailability of the compounds by increasing absorption and/or decreasing first-pass metabolism. Prodrugs may also serve to increase tissue penetration of the compounds, thereby leading to increased activity in infected tissues and/or reduced rate of clearance.
Such esters contemplated by this invention include:
alkyl esters, especially loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like;
alkoxyalkyl esters, especially, loweralkoxyloweralkyl esters, including, but not limited to, methoxymethyl, 1-ethoxyethyl, 2-methoxyethyl, isopropoxymethyl, t-butoxymethyl esters and the like;
alkoxyalkoxyalkyl esters, especially, alkoxyalkoxy-substituted loweralkyl esters, including, but not limited to, 2-methoxyethoxymethyl esters and the like;
aryloxyaikyl esters, especially, aryloxy-substituted loweralkyl esters, including, but not limited to, phenoxymethyl esters and the like, wherein the aryl group is unsubstituted or substituted as previously defined herein;
haloalkoxyalkyl esters, especially, haloalkoxy-substituted loweralkyl esters, including, but not limited to, 2,2,2-trichloroethoxymethyl esters and the like;
alkoxycarbonylalkyl esters, especially, loweralkoxycarbonyi-substituted loweralkyl esters, including, but not limited to, methoxycarbonylmethyl esters and the like;

cyanoafkyl esters, especially, cyano-substituted loweralkyl esters, including, but not limited to, cyanomethyl, 2-cyanoethyl esters and the like;
thioalkoxymethyl esters, especially, lowerthioalkoxy-substituted methyl esters, including, but not limited to, methylthiomethyl, ethylthiomethyl esters and the like;
alkylsulfonyialkyl esters, especially, loweralkylsulfonyl-substituted loweralkyl esters, including, but not limited to, 2-methanesulfonylethyl esters and the like;
arylsulfonylalkyl esters, especially, arylsulfonyl-substituted loweralkyl esters, including, but not limited to, 2-benzenesulfonylethyl and 2-toiuenesulfonylethyl esters and the like;
acyloxyalkyl esters, especially, loweralkylacyloxy-substituted loweralkyl esters, including, but not limited to, formyloxymethyl, acetoxymethyl, pivaloyloxymethyl, acetoxyethyi, pivaioyloxyethyl esters and the like;
cycloalkylcarbonyloxyalkyi esters including, but not limited to, cyclopentanecarbonyloxymethyl, cyclohexanecarbonyloxymethyl, cyclopentanecarbonyloxyethyl, cyclohexanecarbonyioxyethyl esters and the like;
arylcarbonyloxyalkyl esters including, but not limited to, benzoyloxymethyi esters and the like;
(alkoxycarbonyloxy)alkyl esters, especially, (loweralkoxycarbonyloxy)-substituted loweralkyl esters, including, but not limited to, methoxycarbonyloxymethyi, ethoxycarbonyioxymethyl, 1-(methoxycarbonyloxy)ethyl, 2-(ethoxycarbonyloxy)ethyl esters and the like;
(cycloalkyloxycarbonyioxy)alkyl esters, especially, (cycloalkyioxycarbonyloxy)-substituted loweralkyl esters, including, but not limited to, cyclohexyloxycarbonyloxymethyl, cyclopentyloxycarbonyloxyethyl, cyclohexyloxycarbonyloxypropyl esters and the like;
oxodioxolenytmethyl esters including, but not limited to, (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1,3-dioxoien-4-ylJmethyl, [5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5-(4-chlorophenyt)-2-oxo-1,3-dioxolen-4-yl)methyl, (2-oxo-1,3-dioxolen-4-yl)methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl, (5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl esters and the like;
phthatidyl esters wherein the phenyl ring of the phthalidyl group is unsubstituted or substituted as defined previously herein, including, but not limited to, phthalidyl, dimethylphthalidyl, dimethoxyphthalidyl esters and the like;
aryl esters including, but not limited to, phenyl, naphthyl, indanyl esters and the like;
arylalkyl esters, especially, aryl-substitued loweralky! esters, including, but not limited to, benzyl, phenethyl, 3-phenylpropyl, naphthylmethyl esters and the like, wherein the aryl part of the arylalkyf group is unsubstituted or substituted as previously defined herein;
dialkylaminoalkyl esters, especially dialkylamino-substituted loweralkyl esters, including, but not limited to, 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl ester and the like (heterocyclic)alkyl esters, especially, heterocyctic-substituted loweralkyl esters wherein the heterocycle is a nitrogen-containing heterocycle, including, but not limited to, (heterocyclic)methyl esters and the like, wherein the heterocyclic part of the (heterocyclic)alkyl group is unsubstituted or substituted as previously defined herein; and carboxyalkyl esters, especially, carboxy-substituted loweralkyl esters, including, but not limited to carboxymethy! esters and the like;
and the like.
Preferred prodrug esters of acid-containing compounds of the Formula t, II
or III are loweralkyl esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and benzyl esters wherein the phenyl ring is unsubstituted or substituted as previously defined herein.
Methods for the preparation of prodrug esters of compounds of the Formula I, II or III are well-known in the art and include:
reacting the acid with the corresponding halide (for example, chloride or acyl chloride) and a base (for example, triethylamine, DBU, N,N-dimethyiaminopyridine and the like) in an inert solvent (for example, DMF, acetonitrile, N-methyipyrrolidone and the tike);
reacting an activated derivative of the acid (for example, an acid chloride, sulfonyl chloride, monochlorophosphonate and the like) with the corresponding alcohol or aikoxide salt; and the like.
Other examples of prodrugs of the present invention include esters of hydroxyl-substituted compounds of formula I, tl or III which have been acylated with a blocked or unblocked amino acid residue, a phosphate function, a hemisuccinate residue, an acyl residue of the formula R'°°C(O)-or R'°°C(S)-wherein R'°° is hydrogen, lower alkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl or haloalkoxy, or an acyl residue of the formula Ra-C(Rb)(Rd)-C(O)- or Ra-C(Rb)(Rd)-C(S)- wherein Rb and Rd are independently selected from hydrogen or lower alkyl and Ra is -N{Re)(R~, -ORe or -SRe wherein Re and Rf are independently selected from hydrogen, lower alkyl and haloalkyl, or an amino-acyl residue having the formula R'°' NH(CH2)ZNHCHZC(O)- or R'°'NH(CH2)20CHZC(O)- wherein R'°' is hydrogen, lower alkyl, (aryl)alkyl, (cycloalkyl)aikyl, acyl, benzoyl or an a-amino acyl group. The amino acid esters of particular interest are of glycine and lysine; however, other amino acid residues can also be used, including any of the naturally occuring amino acids and also including those wherein the amino acyi group is -C(O)CH2NR'°ZR'°3 wherein R'°2 and R'°3 are independently selected from hydrogen and lower alkyl, or the group -NR'°2 R'°3, where R'°2 and R'°3, taken together, forms a nitrogen containing heterocyclic ring.
Other prodrugs include a hydroxyl-substituted compound of formula I, II or III wherein the hydroxyl group is functionalized with a substituent of the formula -CH(R'°4)OC(O)R'°$ or -CH(R'°4)OC(S)R'°5 wherein R'°5 is lower alkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy and R'°4 is hydrogen, lower alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl.
Such prodrugs can be prepared according to the procedure of Schreiber {Tetrahedron Left. 1983, 24, 2363) by ozonolysis of the corresponding methallyl ether in methanol followed by treatment with acetic anhydride.
The preparation of esters of hydroxyl-substituted compounds of formula formula I, II or III is carried out by reacting a hydroxyl-substituted compound of formula formula I, II or III, with an activated amino acyl, phosphoryl, hemisuccinyl or acyl derivative.
Prodrugs of hydroxyl-substituted-compounds of the invention can also be prepared by alkylation of the hydroxyl substituted compound of formula formula I, II or III, with (halo)alkyl esters, transacetalization with bis-(alkanoyl)acetals or condensation of the hydroxyl group with an activated aldehyde followed by acylation of the intermediate hemiacetal.
In preparing prodrugs it often is necessary to protect other reactive functional groups, in order to prevent unwanted side reactions. After protection of the reactive groups the desired group can be functionalized. The resulting functionalized product is then deprotected, to remove the protecting groups that were added to prevent unwanted side reactions. This will provide the desired prodrug. Suitable reaction conditions for preparing protecting groups are well known in the art. One source for reaction conditions is found in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 2nd edition, John Wiley &
Sons, New York (1991 ).
This invention also encompasses compounds of the Formula I, II or III
which are esters or prodrugs and which are also salts. For example, a compound of the invention can be an ester of a carboxylic acid and also an acid addition salt of an amine or nitrogen-containing substituent in the same compound.
The compounds of the present invention are useful for inhibiting neuraminidase from disease-causing microorganisms which comprise a neuraminidase. The compounds of the invention are useful (in humans, other mammals and fowl) for treating or preventing diseases caused by microorganisms which comprise a neuraminidase The compounds of the present invention are useful for inhibiting influenza A virus neuraminidase and influenza B virus neuraminidase, in vitro or in vivo (especially in mammals and, in particular, in humans). The compounds of the present invention are also useful for the inhibition of influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo, especially the inhibition of influenza A viruses and influenza B viruses in humans and other mammals. The compounds of the present invention are also useful for the treatment of infections caused by influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo, especially the human diseases caused by influenza A and influenza B viruses.
The compounds of the present invention are also useful for the prophylaxis of infections caused by influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo in humans and other mammals, especially the prophylaxis of influenza A

and influenza B viral infections; and, in particular, the prophylaxis of influenza A
and influenza B viral infections in human subjects who are at high risk of developing other respiratory diseases concurrent with or as a consequence of influenza virus infections, or who suffer from chronic respiratory illness, such as asthma, emphysema, or cystic fibrosis.
Total daily dose administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 10 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specifc compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
Administration of a compound of this invention will begin before or at the time of infection or after the appearance of established symptoms andlor the confirmation of infection.
The compounds of the present invention may be administered orally, parenterally, sublingually, intranasally, by intrapulmonary administration, by inhalation or insufflation as a solution, suspension or dry powder {for example, in a spray), or rectally, in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid fnd use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium.
Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biologv, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more anti-infective agents andlor other agents used to treat other acute or chronic respiratory ailments. Other agents to be administered in combination with a compound of the present invention include: an influenza vaccine; other influenza inhibitors such as, for example, amantadine, rimantadine, ribavirin, and the like; another influenza neuraminidase inhibitor, such as, for example, zanamivir or GS 4104 and the like; agents used to treat respiratory bacterial infections and bronchitis, such as, for example, erythromycin, ciarithromycin, azithromycin and the like; and agents used to treat asthma, such as, for example, zileuton, albuterol (salbutamol), salmeterol, formoterol, ipratropium bromide, inhaled steroids and the like, or anti-inflammatory agents for treating asthma such as, for example, beclomethasone dipropionate, fluticasone propionate, budesonide, triamcinolone acetonide, flunisolide, crornolyn, zafirlukast, montelukast used in combination with a compound of the present invention.
When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims.

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Claims (56)

What is claimed is:
1. A compound of the formula:

or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R1 is selected from the group consisting of (b) -CO2H, (b) -CH2CO2H, (c) -SO3H, (d) -CH2SO3H, (e) -SO2H, (g) -CH2SO2H, (g) -PO3H2, (h) -CH2PO3H2, (i) -PO2H, (j) -CH2PO2H, (l) tetrazolyl, (l) -CH2-tetrazolyl, (m) -C(=O)-NH-S(O)2-R11, (o) -CH2C(=O)-NH-S(O)2-R11, (o) -SO2N(T-R11)R12 and (p) -CH2SO2N(T-R11)R12 wherein T is selected from the group consisting of (i) a bond, (ii) -C(=O)-, (iii) -C(=O)O-, (iv) -C(=O)S-, (v) -C(=O)NR3, (vi) -C(=S)O-, (vii) -C(=S)S-, and (viii) -C(=S)NR36-, R11 is selected from the group consisting of (i) C1-C12 alkyl, (ii) C2-C12 alkenyl, (iii) cycloalkyl, (iv) (cycloalkyl)alkyl, (w) (cycloalkyl)alkenyl, (vi) cycloalkenyl, (vii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (ix) aryl, (x) (aryl)alkyl, (xi) (aryl)alkenyl, (xvii) heterocyclic, (xiii) (heterocyclic)alkyl and (xviii) (xiv) (heterocyclic)alkenyl; and R12 and R36 are independently selected from the group consisting of (i) hydrogen, (ii) C1-C12 alkyl, (iii) C2-C12 alkenyl, (iv) cycloalkyl, (v) (cycloalkyl)alkyl, (vi) (cycloalkyl)alkenyl, (vii) cycloalkenyl, (viii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (x) aryl, (xi) (aryl)alkyl, (xii) (aryl)alkenyl, (xiii) heterocyclic, (xiv) (heterocyclic)alkyl and (xv) (heterocyclic)alkenyl;
X is selected from the group consisting of (a) -C(=O)-N(R*)-, (b) -N(R*)-C(=O)-, (c) -C(=S)-N(R*)-, (d) -N(R*)-C(=S)-, (e) -N(R*)-SO2-, and (f) -SO2-N(R*)- wherein R* is hydrogen, C1-C3 loweralkyl or cyclopropyl;
R2 is selected from the group consisting of (a) hydrogen, (b) C1-C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl, (e) C5-C6 cycloalkenyl, (f) halo C1-C6 alkyl and (g) halo C2-C6 alkenyl;
or R2-X- is wherein Y1 is -CH2-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(R aa)(R bb)-wherein R aa and R bb are indepedently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
R3 and R4 are independently selected from the group consisting of (a) hydrogen, (b) cycloalkyl, (c) cycloalkenyl, (d) heterocyclic, (e) aryl and (f) -Z-R14 wherein Z is (ii) -C(R37a)(R37b)-, (ii) -C(R47)=C(R48)-, (iii) -C~C, (IV) -C(-O)-, (v) -C(=S)-, (vi) -C(=NR15)-, (vii) -C(R37a)(OR37c)-, (viii)-C(R37a)(SR37c)-(ix) -C(R37a)(N(R37b)(R37c))- (x) _C(R37a)(R37b)-O-, (xi) =C(R37a)(R37b)-N(R37c)- (XII) -C(R37a)(R37b)-N(O)(R37c)-(xiii) -C(R37a)(R37b)-N(OH)-, (xiv) -C(R37a)(R37b)-S-(xv) -C(R37a)(R37b)-S(O)-, (xvi) -C(R37a)(R37b)-S(O)2-, (xviii) -C(R37a)(R37b)-C(=O)-, (xviii) -C(R37a)(R37b)-C(=S)-(xxi) _C(R37a)(R37b)-C(=NR15)-, (xx) -C(R37a)(OR37c)-C(=O)-, (xxi) -C(R37a)(SR37c)-C(=O)-, (xxii) -C(R37a)(OR37c)-C(=S)-, (xxiii) -C(R37a)(SR37c)-C(=S)-, (xxiv) -C(=O)-C(R37a)(OR37c)-, (xxv) -C(=O)-C(R37a)(SR37c)-, (xxvi) -C(=S)-C(R37a)(OR37c)-, (xxvii) -C(=S)-C(R37a)(SR37c)-, (xxviii) -C(R37a)(OR37c)-C(R37a)(OR37c)-, (xxix) -C(R37a)(SR37c)-C(R37a)(OR37c)-, (xxx) -C(R37a)(OR37c)-C(R37a)(SR37c)-, (xxxi) -C(R37a)(SR37c)-C(R37a)(SR37c)-, (xxxii) -C(=O)-C(=O)-, (xxxiii) -C(=S)-C(=S)-, (xxxiv) -C(=O)-O-. (xxxv) -C(=O)-S-, (xxxvi) -C(=S)-O-, (xxxvii) -C(=S)-S-, (xxxviii) -C(=O)-N(R37a)-, (xxxix) -C(=S)-N(R37a)-, (x~) -C(R37a)(R37b)-C(=O)-N(R37a)-, (x~i) -C(R37a)(R37b)-C(=S)-N(R37a)-, (x~ii)-C(R37a)(R37b)-C(=O)-O-, (X~iii) -C(R37a)(R37b)-C(=O)-S-, (x~iv) -C(R37a)(R37b)-C(=S)-O-, (x~v) -C(R37a)(R37b)-C(=S)-S-, (x~vi) -C(R37a)(R37b)-N(R37b)-C(=O)-, (x~vii) -C(R37a)(R37b)-N(R37b)-C(=S)-, (x~viii) -C(R37a)(R37b)-O-C(=O)-, (x~iv) -C(R37a)(R37b)-S-C(=O)- (~) -C(R37a)(R37b)-O-C(=S)-, (~i) -C(R37a)(R37b)-S-C(=S)-, (~ii) -C(R37a)(R37b)-N(R37b)-C(=O)-N(R37a)-, (~iii) -C(R37a)(R37b)-N(R37b)-C(=S)-N(R37a)-, (~iv) -C(R37a)(R37b)-N(R37b)-C(=O)-O-, (~v) -C(R37a)(R37b)-N(R37b)-C(=O)-S-, (~vi) -C(R37a)(R37b)-N(R37b)-C(=S)-O-, (~vii) -C(R37a)(R37b)-N(R37b)-C(=S)-S-, (~viii) -C(R37a)(R37b)-O-C(=O)-N(R37a)-, (~ix) -C(R37a)(R37b)-S-C(=O)-N(R37a)-, (~x) -C(R37a)(R37b)-O-C(=S)-N(R37a)-, (~xi) -C(R37a)(R37b)-S-C(=S)-N(R37a)-, (~xii) -C(R37a)(R37b)-O-C(=(O)-O-, (~xiii) -C(R37a)(R37b)-S-C(=O)-S-, (~xiv) -C(R37a)(R37b)-O-C(=O)-S-, (~xv) -C(R37a)(R37b)-S-C(=O)-S-, (~xvi) -C(R37a)(R37b)-O-C(=S)-O-, (~xvii) -C(R37a)(R37b)-S-C(=S)-O-, (~xviii) -C(R37a)(R37b)-O-C(=S)-S-, (~xix) -C(R37a)(R37b)-S-C(=S)-S- or (~xx) -C(R37a)(R37b)-C(R37a)(OR37c)-, R14 is (i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) thiol-substituted alkyl, (vi) R37c O-substituted alkyl, (vii) R37c S-substituted alkyl, (viii) aminoalkyl, (ix) (R37c)NH-substituted alkyl, (x) (R37a)(R37c)N-susbstituted alkyl, (xi) R37a O-(O=)C-substituted alkyl, (xii) R37a S-(O=)C-substituted alkyl, (xiii) R37a O-(S=)C-substituted alkyl, (xix) R37a S-(S=)G-substituted alkyl, (xx) (R37a O)2-P(=O)-substituted alkyl, (xvi) cyanoalkyl, (xxi) C2-C12 alkenyl, (xviii) haloalkenyl, (xix) C2-C12 alkynyl, (xxii) cycloalkyl, (xxi) (cycloalkyl)alkyl, (xxii) (cycloalkyl)alkenyl, (xxiv) (cycloalkyl)alkynyl, (xxiv) cycloalkenyl, (xxv) (cycloalkenyl)alkyl, (xxvii) (cycloalkenyl)alkenyl, (xxvii) (cycloalkenyl)alkynyl, (xxviii) aryl, (xxx) (aryl)alkyl, (xxx) (aryl)alkenyl, (xxxi) (aryl)alkynyl, (xxxii) heterocyclic, (xxxiii) (heterocyclic)alkyl, (xxxiv) (heterocyclic)alkenyl or (xxxv) (heterocyclic)alkynyl, with the proviso that R14 is other than hydrogen when Z is -C(R37a)(R37b)-N(R37b)-G(=O)-O- -C(R37a)(R37b)-N(R37b)-C(=S)-O--C(R37a)(R37b)-N(R37b)-G(=O)-S- -C(R37a)(R37b)-N(R37b)-C(=S)-S--C(R37a)(R37b)-O-G(=O)-O- -C(R37a)(R37b)-O-C(=S)-O-_G(R37a)(R37b)-S-C(=O)-O- _C(R37a)(R37b)-S-G(=S)-O--C(R37a)(R37b)-O-C(=O)-S-, C(R37a)(R37b)-O-C(=S)-S--C(R37a)(R37b)-S-C(=O)-S- or -C(R37a)(R37b)-S-C(=S)-S-.
R37a R37b R47, and R48 at each occurrence are independently selected from the group consisting of (i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl, (v) alkoxyalkyl, (vi) C2-C12 alkenyl, (vii) haloalkenyl, (viii) C2-C12 alkynyl, (ix) cycloalkyl, (x) (cycloalkyl)alkyl, (xi) (cycloalkyl)alkenyl, (xii) (cycloalkyl)alkynyl, (xiii) cycloalkenyl, (xiv) (cycloalkenyl)alkyl, (xv) (cycloalkenyl)-alkenyl, (xvi) (cycloalkenyl)alkynyl, (xvii) aryl, (xviii) (aryl)alkyl, (xix) (aryl)alkenyl, (xx) (aryl)alkynyl, (xxi) heterocyclic, (xxii) (heterocyclic)alkyl, (xxiii) (heterocyclic)alkenyl and (xxiv) (heterocyclic)alkynyl;
R37c at each occurrence is independently selected from the group consisting of (i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) C2-C12 alkenyl, (v) haloalkenyl, (vi) C2-C12 alkynyl, (vii) cycloalkyl, (viii) (cycloalkyl)alkyl, (ix) (cycloalkyl)alkenyl, (x) (cycloalkyl)alkynyl, (xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) (cycloalkenyl)alkynyl, (xv) aryl, (xvi) (aryl)alkyl, (xvii) (aryl)alkenyl, (xviii) (aryl)alkynyl, (xix) heterocyclic, (xx) (heterocyclic)alkyl, (xxi) (heterocyclic)alkenyl, (xxiv) (heterocyclic)alkynyl, (xxiii) -C(=O)-R14, (xxiv) -C(=S)-R14, (xxv) -S(O)2-R14 and (xxvi) hydroxyalkyl;
or when Z is -C(R37a)(R37b)-N(R37c)-, then N(R37c) and R14 when taken together are an azido group;
or when Z is -C(R37a)(R37b)-N(O)(R37c)-, then N(O)(R37c) and R14 when taken together are an N-oxidized 3-7 membered heterocyclic ring having at least one N-oxidized ring nitrogen atom;
or when Z is -C(R37a)(OR37c)-, -C(R37a)(SR37c)- or -C(R37a)(N(R37b)(R37c))-, then R37a, R14 and the carbon atom to which they are bonded when taken together form a cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl ring;
R15 is selected from the group consisting of (i) hydrogen, (ii) hydroxy, (iii) amino, (iv) C1-C12 alkyl, (v) haloalkyl, (vi) C2-C12 alkenyl, (vii) haloalkenyl, (viii) cycloalkyl, (ix) (cycloalkyl)alkyl, (x) (cycloalkyl)alkenyl, (xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) aryl, (xv) (aryl)alkyl, (xvi) (aryl)alkenyl, (xvii) heterocyclic, (xviii) (heterocyclic)alkyl and (xix) (heterocyclic)alkenyl;

or R3 and R4 taken together, with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 8 ring atoms;
R5 is selected from the group consisting of (a) hydrogen, (b) -CH(R38)2, (c) -O-R40, (d) C2-C4 alkynyl, (e) cyclopropyl, (f) cyclobutyl, (g) -C(=Q1)-R17, and (h) -N(R19)2 wherein Q1 is O, S, or N(R18);
R17 and R18 are independently selected, at each occurrence, from the group consisting of hydrogen, methyl, and ethyl;
R19, R38, and R40 are independently selected, at each occurrence, from the group consisting of (i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) C2-C12 alkenyl, (v) haloalkenyl, (vi) cycloalkyl, (vii) (cycloalkyl)alkyl, (viii) (cycloalkyl)alkenyl, (ix) cycloalkenyl, (x) (cycloalkenyl)alkyl, (xi) (cycioalkenyl)alkenyl, (xii) aryl, (xiii) (aryl)alkyl, (xiv) (aryl)alkenyl, (xv) heterocyclic, (xvi) (heterocyclic)alkyl and (xvii) (heterocyclic)alkenyl;
Y is selected from the group consisting of (a) hydrogen, (b) C1-C5 alkyl, (c) C1-C5 haloalkyl, (d) C2-C5 alkenyl, (e) C2-C5 haloalkenyl, (f) C2-C5 alkynyl, (g) C3-C5 cycloalkyl, (h) C3-C5 cycloalkyl-C1-to-C3-alkyl, (i) C5 cycloalkenyl, (j) C5 cycloalkenyl-C1-to-C3-alkyl, (k) C5 cycloalkenyl-C2-to-C3-alkenyl, (I) -(CHR39)n OR20, (m) -CH(OR20)-CH2(OR20), (n) -(CHR39)n SR21, (o) -(CHR39)n CN, (p) -(CHR39)n N3, (q) phenyl, (r) halo-substituted phenyl, (s) -(CHR39)n C(=Q2)R22, (t) -(CHR39)n N(=Q3), (u) -N(O)=CHCH3, (v) -(CHR39)n NR23R24, (w) halo and (x) a heterocyclic ring having from 3 to 6 ring atoms;
wherein n is 0, 1, or 2; Q2 is O, S, NR25, or CHR26; and Q3 is NR41, or CHR42;
R20 at each occurrence is independently (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) C,-C3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x) allyl, (xi) C2-C3 haloalkenyl, (xii) amino, (xiii) -NHCH3, (xiv) -N(CH3)2, (xv) -NHCH2CH3, (xvi) -N(CH3)(CH2CH3), (xvii) -N(CH2CH3)2 or (xviii) -N(=CH2);
R21 is hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) C1-C3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x) allyl or (xi) C2-C3 haloalkenyl;
R22 is (i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi) hydroxy, (vii) thiol, (viii) methoxy, (ix) ethoxy, (x) n-propoxy, (xi) isopropoxy, (xii) cyclopropyloxy, (xiii) methylthio, (xiv) ethylthio, (xv) n-propylthio, (xvi) isopropylthio, (xvii) cyclopropylthio, (xviii) vinyl, (xix) propenyl, (xx) isopropenyl, (xxi) allyl, (xxii) -N(R28a)(R28b), (xxv) -CH2R29, (xxiv) aminomethyl, (xxv) hydroxymethyl, (xxvi) thioimethyl, (xxvii) -NHNH2, (xxviii) -N(CH3)NH2 or (xxix) -NHNH(CH3);
R23 and R39 are independently hydrogen or methyl;
R41 and R42 are independently hydrogen, methyl, or ethyl;
R24 is selected from the group consisting of (i) hydrogen, (ii) C1-C4 alkyl, (iii) C2-C4 alkenyl, (iv) C2-C4 alkynyl, (v) cyclopropyl, (vi) -C(=Q4)-R30, (v) -OR31, and (vi) -N(R32)2, wherein Q4 is O, S, or N(R33);
R25 is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -NO2;
R26 group is hydrogen, methyl or ethyl ;
R28a hydrogen, hydroxy, methyl, ethyl, amino, -NHCH3, -N(CH3)2, methoxy, ethoxy, or -CN;
R28b is hydrogen, methyl or ethyl;
or R28a, R28b and the nitrogen to which they are bonded taken together represent azetidinyl;
R29 group is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;
R30 group is hydrogen, methyl, ethyl, -OR34, -SR34, -N(R35)2, -NHOH, -NHNH2, -N(CH3)NH2, or -N(CH2CH3)NH2;
R31 and R32 substituents, at each occurrence, are independently hydrogen, methyl or ethyl;
R33 group is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -NO2;

R34 group is methyl or ethyl;
R35 group is independently hydrogen, methyl or ethyl;
with the proviso that when Q2 is CHR26 then R22 is selected from the group consisting of hydrogen, -CH3, -C2H5, -C3H7, -OCH3, -SCH3, -O-C2H5, and -S-C2H5, and with the proviso that when R3 and R4 are each hydrogen, then Y is other than hydrogen;
R6 and R7 are independently selected from the group consisting of (c) hydrogen, (b) C1-C12 alkyl, (c) C2-C12 alkenyl, (d) cycloalkyl, (e) (cycloalkyl)alkyl, (f) (cycloalkyl)alkenyl, (g) cycloalkenyl, (h) (cyclo-alkenyl)alkyl, (j) (cycloalkenyl)alkenyl, (j) aryl, (k) (aryl)alkyl, (l) (aryl)alkenyl, (m) heterocyclic, (o) (heterocyclic)alkyl and (o) (heterocyclic)alkenyl; and R8, R9, and R10 are independently selected from the group consisting of (a) hydrogen, (b) C1-C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl, (e) C3-C6 cycloalkenyl, and (f) fluorine, with the proviso that the total number of atoms, other than hydrogen, in each of R8, R9, and R10, is 6 atoms or less.
2. The compound according to Claim 1 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
3. The compound according to Claim 1 having the relative stereochemistry depicted by formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
4. The compound according to Claim 1 wherein -X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH-wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo alkenyl or -X-R2 is wherein Y1 is -CH2-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(Raa)(Rbb)-wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R14 wherein Z and R14 are as defined therein and wherein one of R3 and R4 is other than hydrogen;
R5 is hydrogen or loweralkyl;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen, fluoro or loweralkyl;
R10 is hydrogen, fluoro or loweralkyl; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl, -C(=Q2)R22, -N(=Q3), -N(O)=CHCH3, -NR23R24 or a heterocyclic ring having from 3 to 6 ring atoms, wherein R22, R23, R24, Q2 and Q3 are as defined therein.
5. The compound according to Claim 4 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
6. The compound according to Claim 4 having the relative stereochemistry depicted by formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
7. The compound according to Claim 1 wherein wherein -X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH-wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo alkenyl or -X-R2 is wherein Y1 is -CH2- and Y2 is -C(=O)- or -C(Raa)(Rbb)- wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R14 wherein Z and R14 are as defined therein and wherein one of R3 and R4 is other than hydrogen;
R5 is hydrogen or loweralkyl;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl, -C(=Q2)R22, -N(=Q3), -N(O)=CHCH3 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R22, Q2 and Q3 are as defined therein.
8. The compound according to Claim 7 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
9. The compound according to Claim 7 having the relative stereochemistry depicted by formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
10. A compound according to Claim 1 wherein -X-R2 is R2-C(=O}-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH-wherein R2 is C1-C3 loweralkyl, halo C1-C3 loweralkyl, C2-C3 alkenyl or halo alkenyl or -X-R2 is wherein Y1 is -CH2- and Y2 is -C(=O)- or -C(Raa)(Rbb)- wherein Raa and Rbb are independently selected from the group consisting of hydrogen, C1-C3 loweralkyl, hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R14 wherein Z and R14 are as defined therein and wherein one of R3 and R4 is other than hydrogen;
R5 is hydrogen or loweralkyl;
R6 and R7 are independently hydrogen or loweralkyl;
R8 and R9 are independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
11. The compound according to Claim 10 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
12. The compound according to Claim 10 having the relative stereochemistry depicted by formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
13. A compound according to Claim 1 wherein R1 is -CO2H;

-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH-wherein R2 is C1-C3 loweralkyl or halo-C1-C3 loweralkyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and -Z-R14 wherein Z and R14 are as defined therein and wherein one of R3 and R4 is other than hydrogen;
R5 is hydrogen or loweralkyl;
R6 and R7 are hydrogen independently hydrogen or loweralkyl;
R8 and R9 are hydrogen independently hydrogen or loweralkyl;
R10 is hydrogen or loweralkyl; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
14. The compound according to Claim 13 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
15. The compound according to Claim 13 having the relative stereochemistry depicted by formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
16. The compound according to Claim 1 wherein R1 is -CO2H;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH-wherein R2 is C1-C3 loweralkyl or halo-C1-C3 loweralkyl;
R4 is hydrogen or loweralkyl and R3 is heterocyclic or -Z-R14 wherein Z
and R14 are as defined therein;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
17. The compound according to Claim 16 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
18. The compound according to Claim 16 having the relative stereochemistry depicted by formula wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
19. The compound according to Claim 1 wherein R1 is -CO2H;

-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen or loweralkyl and R3 is (a) heterocyclic (b) alkyl, (d) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) -C(=O)-R14, (h) -C(R37a)(OR37c)-R14 or (i) -C(R37a)(R37b)-N(O)(R37c)R14 wherein R14 is (j) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37a O)-(O=)C-substituted alkyl or (xv) (R37a O)2-P(=O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and R37c is hydrogen, (ii) loweralkyl or (iii) loweralkenyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
20. The compound according to Claim 19 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
21. The compound according to Claim 19 having the relative stereochemistry depicted by formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
22. The compound according to Claim 1 wherein R1 is -CO2H;

-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R37a)(OR37c)-R14 wherein R14 is (ii) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl, (vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic, (x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii) cyanoalkyl, (xiv) (R37a O)-(O=)C-substituted alkyl or (xv) (R37a O)2-P(=O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of (i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and R37c is hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen ;
R10 is hydrogen; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
23. The compound according to Claim 22 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
24. The compound according to Claim 22 having the relative stereochemistry depicted by formula wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
25. The compound according to Claim 1 wherein R1 is -CO2H;

-X-R2 is R2-C(=O)-NH- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R37a)(OR37c)-wherein R14 is (i) loweralkyl, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyl or (iv) alkoxy-substituted loweralkyl;
R37a is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; and R37c is (i) hydrogen, (ii) C1-C3 loweralkyl or (iii) allyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
26. The compound according to Claim 25 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
27. The compound according to Claim 25 having the relative stereochemistry depicted by formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
28. The compound according to Claim 1 wherein R1 is -CO2H;

-X-R2 is R2-C(=O)-NH- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyl or halo C1-C3 loweralkyl;
R4 is hydrogen and R3 is -C(R37a)(OR37c)-R14 wherein R14 is loweralkyl or loweralkenyl;
R37a is loweralkyl or loweralkenyl; and R37c is hydrogen, C1-C3 loweralkyl or allyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
29. The compound according to Claim 28 having the relative stereochemistry depicted by the formula:

wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
30. The compound according to Claim 29 having the relative stereochemistry depicted by formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
31. A compound selected from the group consisting of:
(~)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R, 3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt;

(~)-(2R,3R,5R,1'R,2'R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(-)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylate Ammonium Salt;
(~)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2 R, 3S, 5 R,1'S,3'S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3R,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic Acid;

(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S,3'S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2 R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;

(~)-(2R,3S,5R,1'R.2'S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-(propeny-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R, 3S,5 R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxyethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;

(~)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-carboxylic Acid;
(~)-(2R,3S.5R,1'S,3'R)-2-(1-Acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(thiazol-4-yl)-pyrrolidine-carboxylic Acid;
(~)-(2R,3R,5R,1'S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(thiazol-2-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(2,2-difluoro-vin-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-carboxylic Acid;
(~)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-3-yl)-pyrrolidine-carboxylic Acid;
(~)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-5-yl)-pyrrolidine-carboxylic Acid;
(~)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-Carboxylic Acid;

(~)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-4-yl)-pyrrolidine-carboxylic Acid; and (~)-(2S,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-amino-pyrrolidine-5-carboxylic Acid; or a pharmaceutically acceptable salt, ester or prodrug thereof.
32. A compound selected from the group consisting of:
(~)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt;
(~)-(2R,3R,5R,1'R,2'R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis-propen-1-yl)-pyrroiidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(-)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylate Ammonium Salt;
(~)-(2R,3S,5R,1'R.2'R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;

(~)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3R,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S,3'S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid;

(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid (~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(~)-(2R, 3S, 5R, 1'R,2'S)-2-(1-Acetamido-2-ethoxy-3-vinyl) propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-(propeny-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid ; and (~)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
33. A pharmaceutical composition for inhibiting influenza neuraminidase comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
34. A pharmaceutical composition for treating an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
35. A pharmaceutical composition for preventing an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
36. A pharmaceutical composition for inhibiting influenza neuraminidase comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 31.
37. A pharmaceutical composition for treating an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 31.
38. A pharmaceutical composition for preventing an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 31.
39. A method for inhibiting neuraminidase from a disease-causing microorganism comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 1.
40. The method of Claim 39 wherein the disease-causing microorganism is a virus.
41. The method of Claim 40 wherein the virus is influenza virus.
42. A method for treating a disease caused by a microorganism which has a neuraminidase, comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 1.
43. The method of Claim 42 wherein the disease-causing microorganism is a virus.
44. The method of Claim 43 wherein the virus is influenza virus.
45. A method for preventing a disease caused by a microorganism which has a neuraminidase, comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 1.
46. The method of Claim 45 wherein the disease-causing microorganism is a virus.
47. The method of Claim 46 wherein the virus is influenza virus.
48. A method for inhibiting neuraminidase from a disease-causing microorganism comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 31.
49. The method of Claim 48 wherein the disease-causing microorganism is a virus.
50. The method of Claim 49 wherein the virus is influenza virus.
51. A method for treating a disease caused by a microorganism which has a neuraminidase, comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 31.
52. The method of Claim 51 wherein the disease-causing microorganism is a virus.
53. The method of Ciaim 52 wherein the virus is influenza virus.
54. A method for preventing a disease caused by a microorganism which has a neuraminidase, comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 31.
55. The method of Claim 54 wherein the disease-causing microorganism is a virus.
56. The method of Claim 55 wherein the virus is influenza virus.
CA002329422A 1998-04-23 1999-04-12 Pyrrolidines as inhibitors of neuraminidases Abandoned CA2329422A1 (en)

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WO1997047194A1 (en) 1996-06-14 1997-12-18 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane compounds useful as neuraminidase inhibitors
AU2200199A (en) 1997-12-17 1999-07-19 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane and cyclopentene compounds useful as neuraminidase inhibitors
US6455571B1 (en) * 1998-04-23 2002-09-24 Abbott Laboratories Inhibitors of neuraminidases
WO2000028328A1 (en) 1998-11-05 2000-05-18 Biocryst Pharmaceuticals, Inc. New cyclopentane and cyclopentene compounds and use for detecting influenza virus
AU2001252578A1 (en) * 2000-04-25 2001-11-07 Sankyo Company Limited Preventives for influenza
US6518299B1 (en) 2000-10-20 2003-02-11 Biocryst Pharmaceuticals, Inc. Substituted pyrrolidine compounds useful as neuraminidase inhibitors
WO2002081441A1 (en) * 2001-04-03 2002-10-17 Abbott Laboratories Process for the preparation of substituted pyrrolidine neuraminidase inhibitors
JP2005511573A (en) * 2001-11-02 2005-04-28 グラクソ　グループ　リミテッド 4- (5-membered) -heteroarylacylpyrrolidine derivatives as HCV inhibitors
WO2003037895A1 (en) * 2001-11-02 2003-05-08 Glaxo Group Limited 4-(6-membered)-heteroaryl acyl pyrrolidine derivatives as hcv inhibitors
KR20050057670A (en) * 2002-10-24 2005-06-16 글락소 그룹 리미티드 1-acyl-pyrrolidine derivatives for the treatment of viral infections
CN104402754B (en) * 2014-11-25 2016-03-02 广东东阳光药业有限公司 As the compound of neuraminidase inhibitor and the application in medicine thereof

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WO1997047194A1 (en) * 1996-06-14 1997-12-18 Biocryst Pharmaceuticals, Inc. Substituted cyclopentane compounds useful as neuraminidase inhibitors
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