TETRAHEDRON:

ASYMMETRY
Pergamon Tetrahedron: Asymmetry 13 (2002) 173–190

Experimental and theoretical study of the 1,3-dipolar

cycloaddition between D-glyceraldehyde nitrones and acrylates.
Diastereoselective approach to 4-hydroxy pyroglutamic acid
derivatives
Pedro Merino,a,* Juan A. Mates,a Julia Revuelta,a Tomas Tejero,a Ugo Chiacchio,b
Giovanni Romeo,c,* Daniela Iannazzoc and Roberto Romeoc
a
Departamento de Quı́mica Orgánica, ICMA, Facultad de Ciencias, Universidad de Zaragoza, E-50009 Aragon, Spain
b
Dipartimento di Scienze Chimiche, Università di Catania, Viale Andrea Doria 6, Catania 95125, Italy
c
Dipartimento Farmaco-Chimico, Università di Messina, Via SS. Annunziata, Messina 98168, Italy
Received 21 January 2002; accepted 20 February 2002

Abstract—The 1,3-dipolar cycloaddition reactions of five D-glyceraldehyde nitrones with alkyl acrylates and Oppolzer’s sultam
acrylamide have been studied in detail, the study including double chiral induction experiments. A complete theoretical study of
the reaction has also been carried out using density functional methods (B3LYP/6-31G*) in which both ortho and meta channels
leading to 3,5- and 3,4-disubstituted isoxazolidines, respectively, were considered. The adducts obtained from the cycloaddition
reactions have been further used for the stereoselective synthesis of protected 4-hydroxy pyroglutamic acids, particularly the
(2S,4S)-isomer, which is prepared from the major adducts of the cycloaddition reactions. © 2002 Elsevier Science Ltd. All rights
reserved.

1. Introduction homochiral form. Among them, Nozoe et al.8 described

the oxidation of the enolate derived from L-pyroglu-
Enantiomerically pure functionalized derivatives of tamic acid; however, this procedure has been reported
pyroglutamic acid have stirred up great interest among to give low chemical yields due to side reactions.9 While
synthetic chemists since they can be used both for the preparing this work, Zhang et al.10 reported the oxida-
construction of peptide-based drugs1 and as building tion of trans-4-hydroxy-L-proline to give 1a in excellent
blocks in asymmetric synthesis.2 Pyroglutamic acid yield. However, these oxidative processes are limited to
derivatives can also be considered as conformationally the availability of starting materials (chiral pool). Alter-
constrained glutamate analogues of biological interest.3 natively, it is possible to construct the pyrrolidine ring
In spite of the growing interest in highly functionalized in a stereoselective way. We11 and others12 have been
pyrrolidines related to pyroglutamic acid,4 the synthesis exploring the utility of nitrones as starting materials for
of 4-hydroxy-pyroglutamic acids 1 has received little the preparation of 5-substituted-3-hydroxy-2-pyrrolidi-
attention. nones according to the general route depicted in
Scheme 1.
These compounds, in addition to their potential as
synthetic intermediates, constitute an entry to g-substi-
tuted glutamic acid analogues. Thus, g-hydroxyglu-
tamic acids (the open-chain form of 1) have been
reported to be amenable to conventional resolution
using alkaloids5 and the (4S)-isomer has been prepared
using chiral auxiliary methodology.6 There is only one
reported synthesis of racemic 4-hydroxypyroglutamic
acids7 and three reports on their preparation in
* Corresponding authors. Tel.: +34 976 762 075; fax: +34 976 762
075; e-mail: pmerino@posta.unizar.es

0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S 0 9 5 7 - 4 1 6 6 ( 0 2 ) 0 0 0 8 8 - 5
174 P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

idene-D-glyceraldehyde nitrone 2a and methyl acrylate

3a was reported by White et al. in 1986,15 the stereo-
chemistry of the adducts not being assigned unequivo-
cally. Subsequent studies by the same authors16 clarified
the absolute configuration of the major adduct. How-
ever, only two products were reported to be obtained
from the reaction.

A detailed inspection of the crude mixture of the reac-

tion revealed to us the formation of at least four
isomers consisting of one major product (ca. 63% of the
total isomeric amount) besides the other minor prod-
ucts (Table 1, entry 1). HPLC allowed high accuracy in
measuring isomeric ratios. Moreover, when the reaction
Scheme 1. was carried out on a multigram scale (ca. 10 g) traces of
a minor 3,4-regioisomer could be detected. All isomers
were separated and fully characterized (see Section 4).
In this vein, we have reported the first enantioselective
synthesis of the cis-isomer ent-1b formally derived from
D-pyroglutamic acid, by using Oppolzer’s sultam as a
The relative cis/trans configuration of the isoxazolidine
chiral auxiliary and the furan ring as an effective car- ring substituents has been assigned on the basis of NOE
boxyl group equivalent.13 Herein, we report the synthe- experiments (Fig. 1). Thus, for trans compounds 4a and
sis of enantiomerically pure protected derivatives of 1b 4d, irradiation of H-3 produced a strong enhancement
by using a diastereoselective version of the approach of only H-4a (15–17%) and irradiation of H-5 produced
illustrated in Scheme 1. We use as starting materials enhancement of only H-4b (11–13%). In addition, irra-
D-glyceraldehyde derived nitrones 2 and acrylates 3. diation of H-4a and H-4b in the same experiment
The choice of the starting materials was made upon produced enhancements of H-3 (9–11%) and H-5 (8–
three criteria: (i) the oxygen atom of the nitrone should 12%). For compound 4e, irradiation of H-4 produced
allow the installation of the hydroxyl group at the an enhancement of only H-5a and no NOE was
3-position of the pyrrolidine ring; (ii) the nitrogen atom observed between H-3 and H-4 upon irradiation of
of the cycloadduct should carry an easily removable H-3. For cis compounds 4b and 4c, irradiation of H-4a
substituent to facilitate the construction of unprotected produced strong enhancements of both H-3 (14–16%)
derivatives and (iii) the 1,3-dioxolane moiety should be and H-5 (9–12%). Irradiation of H-5 produced
used as both a chiral inductor and as a surrogate of the enhancement of H-4a (14–17%) and a much smaller
carboxyl group.14 The methodology is amenable to enhancement of H-4b (2–3%, not indicated in Fig. 1).
large scale synthesis. The preparation of other 4- Irradiation of H-3 only produced enhancement of H-4a
hydroxy pyroglutamates 1 is described and a DFT (12–14%).
study of the key reaction, i.e. the 1,3-dipolar cycloaddi-
tion between 2 and 3 is also presented.
The relative configuration between isoxazolidine and
1,3-dioxolane rings could not be determined by spectro-
2. Results and discussion scopic means but the major isomer crystallized and was
shown by X-ray crystallography17 to be the (3S,5S,1%S)
2.1. 1,3-Dipolar cycloadditions isomer 4a (Fig. 2).18 This assignment also served to
confirm the absolute configuration of the other trans-
The 1,3-dipolar cycloaddition between 2,3-O-isopropyl- isomer 4d. The absolute configuration of cis adducts 4b

Table 1. 1,3-Dipolar cycloaddition of nitrones 2 with dipolarophiles 3a

Entry Nitrone Acrylateb a:b:c:dc,d Adduct Yield (%)e

1 2a 3a 63:23:11:3 4 95
2 2a 3b 53:20:16:11 5 66
3 2b 3a 35:25:20:20 6 88
4 2c 3a 75:15:8:2 7 94
5 2d 3a 25:25.25:25 8 93
6 2a 3c 60:20:20:0 9 94
7 2e 3a 52:18:15:15 10 93

a
All reactions were carried out neat except for entry 6 which was carried out in toluene as a solvent.
b
20 equiv. of dipolarophile were used except for 3c (10 equiv.).
c
a:b:c:d ratio corresponds to anti–trans/anti–cis/syn–cis/syn–trans.
d
Ratios of products were determined by HPLC chromatography.
e
All yields are based on mixtures of adducts isolated by radial chromatography.
 P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190 175

A survey of reported stereoselective nitrone cycloaddi-

tion reactions with a-alkoxy nitrones indicates that
substituents at both the nitrone nitrogen and the dipo-
larophile influence the steric course of the reaction.19
Armed with this observation we studied differentially
substituted nitrones and acrylates (Scheme 2). The
results are collected in Table 1.

When tert-butyl acrylate was employed as dipolar-

ophile (entry 2), the reaction showed similar
diastereoselectivity as was observed with 3a. In addi-
tion, lower chemical yields were obtained for this reac-
tion due to considerable thermally induced
polymerization of the dipolarophile.20 Increasing the
bulk of the nitrogen substituent of the nitrone led to a
considerable lack of selectivity (entry 3). No substantial
changes were observed with nitrone 2e (entry 7). Dou-
ble chiral induction experiments were also carried out
(entries 4–6) and in the case of cycloaddition between
nitrone 2c and methyl acrylate 3a, an increasing
amount of the major adduct 8a was obtained (entry 4),
the reaction showing good diastereofacial selectivity
(anti/syn, 90:10). No selectivity was observed with
nitrone 2d (entry 5). With nitrone 2a, a better diastereo-
facial selectivity was obtained by using the chiral acryl-
ate 3c (entry 6).
Figure 1. Selected NOE observed for 4 (hobs given as percent
of hmax). Not all the isomeric cycloadducts corresponding to
entries 2–7 in Table 1 could be separated, and the yields
reported in Table 1 refer to the yield of the mixture of
and 4c was determined by chemical correlation as dis- isomers after purification of the crude product by
cussed below. For the 3,4-regioisomer 4e, although the column chromatography. The isomeric ratio was mea-
cis/trans stereochemistry has been confirmed by NOE sured by NMR spectroscopy or HPLC, when possible.
experiments, the assignment of the absolute configura- Compounds 5a, 5d, 6a, 7a–d, 8a–c, 9a and 10a–d were
tion is only tentative. separated and fully characterized (see Section 4).

Figure 2. Perspective view (ORTEP) of 4a. Non-hydrogen atoms are drawn as 50% thermal ellipsoids while hydrogens are drawn
at an arbitrary size. Only the atoms refined with anisotropic thermal parameters are drawn with the principal axes indicated; the
isotropic atoms are represented as simple circles.
176 P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

Scheme 2.

The stereochemical assignments of compounds 5–9 sistent with the relative cis/trans assignments made for
were made by their further conversion into the corre- C(3) and C(5) substituents of the pyrrolidinone ring.
sponding 3-hydroxy-2-pyrrolidinones 11, which can
also be obtained in pure form from compounds 4a–d 2.2. Synthesis of 4-hydroxy pyroglutamic acid
(Scheme 3). Both isolated compounds and mixtures of derivatives
adducts were cyclized into 11. In all instances the
observed ratio of isomers determined by HPLC was Our initial target was the isoxazolidine 16, from which
maintained after the cyclization process. In the case of pyroglutamic acid 1b can be obtained by
cyclization of mixtures of isomers, compounds 11 were hydrogenolytic NO bond cleavage and subsequent
more easily separated by chromatographic methods cyclization.21 In a first attempt, the conversion of the
than the precursor isoxazolidines. In the case of com- major adduct of the cycloaddition 4a to 14 was accom-
pounds 10a–d, the configurational assignment was plished in two steps by using catalytic p-toluenesulfonic
made by transformation of pure compounds into the
corresponding isopropylidene derivatives 4a–d (Scheme
4).

The absolute configuration of the cis-isomers 11a and

11d was known since the isoxazolidine precursors (4a
and 4d, respectively) had been unequivocally identified
by NMR spectroscopy and X-ray analysis, as indicated
above. The stereoconfiguration of trans-isomers 11b
and 11c was determined by transformation of 11b into
the corresponding p-nitrobenzoyl derivative 12 (Scheme
5). This compound proved to be identical to that
obtained from 11a by Mitsunobu reaction with p-
nitrobenzoic acid.

Since the absolute configuration of 11a was known, the

reactions shown in Scheme 5 demonstrated the anti
relative configuration between the dioxolane ring and
the isoxazolidine ring in 11b. Thus, the absolute
configurations of 11b and, by extension, that of 11c
were also confirmed. Complementary NOE experiments
performed on compounds 11a–d and 12 are fully con- Scheme 3. (i) H2/Pd(OH)2–C/MeOH/150 bar/24 h.
 P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190 177

carbonyl derivative 20.22 The failure of 11a to undergo

N-protection can be rationalized by the presence of an
intramolecular hydrogen bond interaction which com-
promises the lone pair of the lactam nitrogen.

Scheme 4. (i) (1) HCl/MeOH; (2) acetone/p-TosOH/MgSO4.

Scheme 6. (i) MeOH, p-TosOH; (ii) NaIO4; (iii) NaBH4.

Exposure of 18a to the acidic conditions needed for the

transformation of the dioxolane ring into the carboxyl
group (the first step should be deacetalyzation) led to
loss of the TBS group. On the other hand, release of the
carboxylic function could be made by treatment of 18b
with periodic acid and subsequent in situ oxidation of
the resulting aldehyde with sodium chlorite, according
Scheme 5. (i) 4-Nitrobenzoyl chloride/Py/CH2Cl2; (ii) 4- to a protocol previously described by us.14b After ester-
nitrobenzoic acid/DIAD. Ar: p-nitrobenzoyl. ification with diazomethane the protected (2S,4S)-4-
hydroxy pyroglutamic acid 19 was obtained.

acid in MeOH and subsequent treatment of the result-

ing 1,2-diol 13 with NaIO4 (Scheme 6).

Unfortunately, attempted oxidation of formyl isoxazo-

lidine 14 with KMnO4, NaClO2 or TEMPO/BAIB led
to extensive decomposition. Alternatively, we explored
the oxidation of the completely reduced diol 15,
obtained by reduction of 14 with sodium borohydride.
Also in this case, all the oxidation conditions examined
failed. These unsuccessful results are probably due to
the presence of a basic nitrogen, which may suffer
collateral oxidations. Therefore, we decided to change
the strategy and to form the pyrrolidine ring before
oxidizing the dioxolane moiety.

The pyrrolidinone derivative 11a was protected with

both tert-butyldimethylsilyl and benzoyl groups to give
compounds 17a and 17b, respectively. These products
were treated with di-tert-butyldicarbonate to afford the
completely protected pyrrolidinones 18a and 18b
(Scheme 7).
Scheme 7. (i) TBSCl, DMF; (ii) PhCOCl, CH2Cl2; (iii)
Attempts to introduce the Boc group at the nitrogen Boc2O, DMAP; (iv) H5IO6, then NaClO2, NaH2PO4, then
atom prior to O-protection only led to O-tert-butoxy- CH2N2.
178 P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

Nevertheless, the protecting groups present in 19 can- protocol was repeated for all adducts obtained from the
not be considered to be orthogonal, since two ester cycloaddition reaction (Scheme 8). Also, for the reduc-
functionalities are present in the molecule. As a conse- tion of adducts 4b and 4c minor amounts of deaceta-
quence, competitive reactions might be found in further lyzed isoxazolidines 22b and 22c were obtained,
synthetic transformations. In order to avoid these trou- respectively. Only reduction of 4d afforded pure pyrro-
bles a different protecting group system was studied. lidinone 21d. In all cases, the products were isolated
and fully characterized as the corresponding acetylated
As an alternative, it is also possible to reduce the NO derivatives 23b–d.
bond in adducts 4 without debenzylating the nitrogen
atom. Thus, treatment of the major adduct 4a with zinc Finally, all of the possible isomers of 4-hydroxy pyro-
in acidic media provided a mixture of pyrrolidinone 21a glutamic acid were prepared by unmasking the carboxyl
and deprotected isoxazolidine 13 (Scheme 8). Because group. Conversion of the dioxolane moiety into the
of the nature of this reduction reaction, we were unable carboxylic functionality was achieved by treatment of
to find conditions that avoided concomitant deprotec- compounds 23a–d with periodic acid and sodium chlor-
tion of the acetonide moiety, although in any case the ite, as described above for compound 18b. Both 25a
yield of 13 was higher than 10%, the total chemical and 25b, and their antipodes were prepared. Com-
yield of the reaction being 86%. pounds 25b and ent-25a had been prepared previously
in our laboratories.13 Thus, this also served to confirm
Due to difficult chromatographic separation, purifica- previous configurational assignments. The orthogonal
tion of compounds 21a and 13 was made as the corre- protection of compounds 25 should allow their further
sponding acetylated derivatives 23a and 24a. This use as building blocks in organic synthesis.

Scheme 8. (i) Zn, AcOH; (ii) Ac2O, Py; (iii) H5IO6, then NaClO2, NaH2PO4, then CH2N2.
 P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190 179

2.3. Theoretical study ring has been chosen. We considered two reaction
channels, ortho and meta, corresponding to the forma-
In order to rationalize the above 1,3-dipolar cycloaddi- tion of 3,5- and 3,4-disubstituted isoxazolidines, respec-
tions we have also performed a computational study of tively. Endo and exo approaches by Re and Si faces
the reaction between 2a and 3a using transition state completed the study. The nomenclature used for defin-
(TS) modelling. Several studies concerning 1,3-dipolar ing stationary points is given in Scheme 9. Starting
cycloadditions of nitrones with electron-rich23 and elec- from TS1–TS8, the minima associated with the final
tron-poor24 dipolarophiles have recently been carried cycloadducts, P1–P8 have also been located. The opti-
out.25 From these and other26–28 related work, we found mized geometries of transition states TS1–TS4, leading
B3LYP/6-31G(d) level of theory to be quite promising to the formation of the 3,5-cycloadducts, are
in this respect. Therefore, stationery points (reactants, displayed31 in Fig. 3 (the geometries of TS5–TS8, P1–
transition structures and products) were fully P8 and the reagents are available from the authors
characterized29 as minima or first-order saddle points upon request). The values of total and relative energies
by diagonalizing the Hessian matrices of the optimized for the different stationery points as well as selected
structures at that level.30 All transition structures were geometrical parameters are given in Table 2. In all cases
found to have only one negative eigenvalue with the the cycloaddition reactions are exothermic in the range
corresponding eigenvector involving the formation of of −17 to −20 kcal/mol, the most stable product being
the newly created CC and CO bonds. Vibrational the (3R,5S)-isomer. Slightly higher energy differences
frequencies were calculated (1 atm, 298.15 K) for all are observed for 3,5-cycloadducts (ortho channel) with
B3LYP/6-31G(d) optimized structures and used, respect to the reagents, than for 3,4-cycloadducts (meta
unscaled, to compute both ZPVE and activation ener- channel). Clearly, the most favoured reaction channel
gies. The only simplification of the calculations con- corresponds to the ortho one, through an endo
sisted of replacement of the benzyl group by a methyl approach by the Si face of the nitrone. The energy
group. activation value for the corresponding transition state
TS1 is 11.7 kcal/mol. From the analysis of the other
We studied all types of selectivity, i.e. regio- and activation energies, in several cases not different
diastereoselectivity, the latter including both endo/exo enough for the calculation errors, a mixture of products
and p-facial selectivity. Consequently, a total of eight can be expected. Thus, although TS6 and TS8 can be
transition states leading to the eight corresponding discarded, very close energy barriers are observed for
cycloadducts, have been located. For each transition TS2, TS3, TS4, TS5 and TS7 (0.4 kcal/mol maximum
state the most stable conformation of the dioxolane difference).

Scheme 9.
180 P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

Figure 3. Optimized (B3LYP/6-31G(d) transition structures (bond lengths in A, ) for cycloaddition of nitrone 2a and methyl
acrylate 3a. Only transition structures, TS1, TS2, TS3 and TS4, leading to 3,5-regiosiomers are shown.

Table 2. Total energies (au), relative energies (kcal/mol) and selected geometrical parameters for the reactants, transition
structures and products of the cycloaddition between NI and MA

Total energy Relative energya O1–N2 N2–C3 C4–C5 O1–C5 O1–C4 C3–C4 C3–C5 w imag

NI −554.696533 1.280 1.306 – – – – – –

MA −306.365295 – – 1.335 – – – – –
TS1 −861.043148 11.7 1.285 1.352 1.390 2.337 – 2.053 – −395.1
TS2 −861.041232 12.9 1.288 1.350 1.389 2.320 – 2.081 – −397.0
TS3 −861.040746 13.2 1.281 1.352 1.390 2.291 – 2.086 – −378.8
TS4 −861.040979 13.1 1.282 1.353 1.389 2.295 – 2.102 – −378.7
TS5 −861.041129 13.0 1.311 1.337 1.400 – 1.961 – 2.288 −418.5
TS6 −861.038162 14.9 1.315 1.335 1.400 – 1.948 – 2.340 −416.6
TS7 −861.041445 12.8 1.313 1.332 1.404 – 1.883 – 2.369 −388.7
TS8 −861.034063 17.4 1.313 1.333 1.406 – 1.882 – 2.404 −378.7
P1 −861.091394 −18.6 1.479 1.476 1.535 1.414 – 1.533 – –
P2 −861.088992 −17.0 1.476 1.492 1.530 1.416 – 1.549 – –
P3 −861.091521 −18.6 1.485 1.473 1.538 1.411 – 1.533 – –
P4 −861.093299 −19.7 1.470 1.480 1.544 1.413 – 1.549 – –
P5 −861.090914 −18.3 1.440 1.476 1.546 – 1.435 – 1.566 –
P6 −861.090124 −17.8 1.438 1.467 1.544 – 1.445 – 1.569 –
P7 −861.090188 −17.8 1.464 1.485 1.536 – 1.418 – 1.545 –
P8 −861.087840 −16.3 1.464 1.478 1.556 – 1.414 – 1.569 –

a
Relative to NI+MA.

These results are in agreement with the experimental 31G(d) calculations. Nevertheless, DFT calculations are
observations, since the energy of TS1 is only 1.2 kcal/ the only ones that correctly predicted the preferential
mol higher than that of TS2, thus justifying the prefer- formation of P1. Hartree–Fock calculations or DFT
ential, but not only, formation of P1. However, the single point calculations using the same basis set (6-
proximity of energy values mentioned above means that 31G(d)) suggest the formation of other cycloadducts
the experimentally observed 3,5-regioselectivity cannot (data corresponding to lower level calculations are
be said to be completely predictable by B3LYP/6- available from the authors upon request). This strong
 P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190 181

dependence on the method for predicting regioselectiv- (10–15 microns) as stationary phase, and the eluting
ity in 1,3-dipolar cycloadditions of nitrones has previ- solvents were delivered by the pump at a flow rate of
ously been described and discussed by Marco and 16–20 mL min−1. Preparative centrifugally accelerated
Domingo,25 and Cossio.28 radial thin-layer chromatography (PCAR-TLC) was
performed with a Chromatotron® Model 7924 T (Har-
The geometry of the transition structures is consistent rison Research, Palo Alto, CA, USA); the rotors (1 or
with a rather asynchronous process. For TS1–TS4 2 mm layer thickness) were coated with silica gel Merck
(ortho channel), the CO forming bond is longer than grade type 7749, TLC grade, with binder and fluores-
the CC forming bond. On the other hand, for TS5– cence indicator (Aldrich 34,644-6) and the eluting sol-
TS8 (meta channel), the CC bond is longer than the vents were delivered by the pump at a flow rate of
CO bond. Although differences of values of forming 0.5–1.5 mL min−1. All solvents used for preparative
bonds are not comparable for measuring asynchronicity chromatography were distilled prior to use. HPLC
since CO bonds are shorter than CC bonds, what is analyses were carried out using a Waters 2695 Alliance
clear is that the cycloaddition reaction has a high System, peaks being detected with a 2996 photodiode
character of Michael addition of the nitrone to the array detector. Melting points are uncorrected. 1H and
dipolarophile.32 In all cases the shorter forming bond 13
C NMR spectra were recorded on a Varian Unity or
corresponds to that in which C(3) of methyl acrylate is on a Bruker 300 instrument in CDCl3 at 55°C. Chemi-
involved. Marco and Domingo25 have described this cal shifts are reported in ppm (l) relative to CHCl3
observation previously for other electron-poor (l=7.26) in CDCl3. Optical rotations were obtained at
dipolarophiles. 25°C on a Perkin–Elmer 241 polarimeter. Elemental
analyses were performed on a Perkin Elmer 240B
The imaginary frequencies for the transition states are microanalyzer.
in the range of −378.7 to −418.5, indicating that the
processes are associated with displacement of heavy 4.1. 1,3-Dipolar cycloaddition of nitrones 2 with acryl-
atoms. Those values corresponding to the ortho channel ates 3. General procedure
(−378.7 to −397.0) are slightly lower than those corre-
sponding to the meta channel (−388.7 to −418.45). The corresponding nitrone (20 mmol) was dissolved in
acrylate (20 equiv.) and the resulting solution was
stirred under reflux until no more nitrone was observed
3. Conclusions (TLC). (In the case of cycloaddition with acrylamide
3c, the reaction was conducted in toluene (600 mL) at
We have studied in detail the stereoselective 1,3-dipolar reflux.) The reaction mixture was evaporated to dryness
cycloadditions of D-glyceraldehyde-derived nitrones and the residue purified by MPLC to give the adducts
with methyl acrylate and other dipolarophiles. This (eluent is given in brackets). In the case of nitrone 2a
study has allowed us to assign unequivocally the abso- the reaction was repeated with 10.6 g (45 mmol) of
lute configuration of the obtained adducts. The starting material and the same results were obtained.
observed regio- and stereochemical results can be
explained by means of computational methods using 4.1.1. (3S,5S)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox-
density functional theory. In addition, the present olan-4-yl]-isoxazolidine-5-carboxylic acid methyl ester
method offers a facile route for the stereoselective 4a. (hexane/EtOAc, 90:10); 3.856 g (60%); mp 72–74°C;
D +20 (c 0.17, CHCl3); H NMR (CDCl3) l 1.31 (s,
[h]25 1
preparation of protected (2S,4S)-4-hydroxy pyroglu-
tamic acids. Since the (2R,4R)- and (2S,4R)-isomers 3H), 1.37 (s, 3H), 2.62 (ddd, 1H, J=2.2, 7.7, 15.5 Hz),
can be readily prepared as described before by us13 and 2.75 (ddd, 1H, J=7.3, 8.4, 15.5 Hz), 3.23 (ddd, 1H,
others,10 respectively, the present strategy provides a J=2.2, 7.3, 8.6 Hz), 3.50 (dd, 1H, J=5.1, 8.3 Hz), 3.74
complementary method for constructing advanced syn- (s, 3H), 3.76 (d, 1H, J=12.9 Hz), 3.91 (ddd, 1H,
thetic intermediates such as polyfunctionalized J=5.1, 6.2, 8.6 Hz), 4.00 (dd, 1H, J=6.2, 8.3 Hz), 4.21
pyrrolidines. (d, 1H, J=12.9 Hz), 4.58 (dd, 1H, J=7.7, 8.4 Hz),
7.30–7.50 (m, 5H). 13C NMR (CDCl3) l 25.2, 26.9,
34.2, 52.6, 62.7, 67.4, 68.2, 75.5, 77.3, 109.6, 127.8,
4. Experimental 128.6, 129.4, 137.0, 173.2. Anal. calcd for C17H23NO5:
C, 63.54; H, 7.21; N, 4.36. Found: C, 63.48; H, 7.11; N,
The reaction flasks and other glass equipment were 4.49%.
heated in an oven at 130°C overnight and assembled in
a stream of Ar. All reactions were monitored by TLC 4.1.2. (3S,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox-
on silica gel 60 F254; the position of the spots was olan-4-yl]-isoxazolidine-5-carboxylic acid methyl ester
detected with 254 nm UV light or by spraying with one 4b. (hexane/EtOAc, 90:10); 1.414 g (22%); oil; [h]25
D −12
of the following staining systems: 50% methanolic sul- (c 0.18, CHCl3); 1H NMR (CDCl3) l 1.32 (s, 3H), 1.38
furic acid, 5% ethanolic phosphomolybdic acid and (s, 3H), 2.56 (ddd, 1H, J=2.7, 5.6, 13.3 Hz), 2.79 (ddd,
iodine. Preparative flash column chromatography was 1H, J=8.0, 9.9, 13.3 Hz), 3.16 (ddd, 1H, J=2.7, 8.0,
performed on silica gel (40–60 microns) columns. 8.3 Hz), 3.51 (dd, 1H, J=5.3, 8.2 Hz), 3.77 (s, 3H), 3.82
Preparative medium pressure liquid chromatography (d, 1H, J=12.9 Hz), 4.00 (dd, 1H, J=5.3, 8.2 Hz), 4.04
(MPLC) was performed on a Buchi B-680 chromatog- (d, 1H, J=12.9 Hz), 4.05 (ddd, 1H, J=5.3, 6.2, 8.3
raphy system using dry-filled columns with silica gel Hz), 4.79 (dd, 1H, J=5.6, 9.9 Hz), 7.30–7.50 (m, 5H).
182 P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

C NMR (CDCl3) l 25.2, 26.8, 34.7, 52.4, 61.3, 66.4,

13
137.1, 171.8. Anal. calcd for C20H29NO5: C, 66.09; H,
67.9, 75.5, 76.3, 109.2, 127.8, 128.5, 129.1, 136.2, 171.5. 8.04; N, 3.85. Found: C, 65.96; H, 8.11; N, 3.69%.
Anal. calcd for C17H23NO5: C, 63.54; H, 7.21; N, 4.36.
Found: C, 63.46; H, 7.38; N, 4.25%. 4.1.7. (3S,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox-
olan-4-yl)]-isoxazolidine-5-carboxylic acid tert-butyl
4.1.3. (3R,5S)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox- ester 5b and (3R,5S)-2-benzyl-3-[(4S)-2,2-dimethyl-1,3-
olan-4-yl]-isoxazolidine-5-carboxylic acid methyl ester dioxolan-4-yl)]-isoxazolidine-5-carboxylic acid tert-butyl
4c. (hexane/EtOAc, 90:10); 0.643 g (10%); mp 40–42°C; ester 5c. (hexane/EtOAc, 85:15); 1.743 g (24%) of a
D +61 (c 0.10, CHCl3); H NMR (CDCl3) l 1.31 (s,
[h]25 1
mixture of 5b and 5c was obtained: 5b (selected signals):
3H), 1.38 (s, 3H), 2.25 (ddd, 1H, J=5.5, 6.5, 13.2 Hz), 1
H NMR (CDCl3) l 1.28 (s, 3H), 1.39 (s, 3H), 1.48 (s,
2.58 (ddd, 1H, J=8.5, 9.1, 13.2 Hz), 3.08 (dd, 1H, 9H), 2.26 (ddd, 1H, J=4.8, 7.2, 12.7 Hz); 2.74 (ddd,
J=6.5, 8.5 Hz), 3.71 (dd, 1H, J=6.8, 8.0 Hz), 3.75 (s, 1H, J=8.0, 9.5, 12.7 Hz), 3.16 (q, 1H, J=7.6 Hz), 3.50
3H), 4.00 (d, 1H, J=14.5 Hz), 4.00 (dd, 1H, J=6.4, 8.0 (dd, 1H, J=5.1, 8.1 Hz), 3.95 (d, 1H, J=13.8 Hz),
Hz), 4.10 (ddd, 1H, J=6.4, 6.8, 8.0 Hz), 4.36 (d, 1H, 4.10–4.28 (m, 2H), 4.29 (d, 1H, J=13.8 Hz), 4.49 (dd,
J=14.5 Hz), 4.57 (dd, 1H, J=5.5, 9.1 Hz), 7.19–7.44 1H, J=4.2, 8.1 Hz), 7.20–7.50 (m, 5H).
(m, 5H). 13C NMR (CDCl3) l 25.1, 26.6, 34.8, 52.1,
60.8, 66.6, 66.9, 74.2, 76.8, 109.8, 127.1, 128.1, 129.3, 5c (selected signals): 1H NMR (CDCl3) l 1.32 (s, 6H),
136.9, 172.2. Anal. calcd for C17H23NO5: C, 63.54; H, 1.47 (s, 9H), 2.49–2.61 (m, 2H), 3.19 (dt, 1H, J=2.4,
7.21; N, 4.36. Found: C, 63.65; H, 7.44; N, 4.28%. 7.2 Hz), 3.74 (dd, 1H, J=6.4, 8.3 Hz), 3.84 (d, 1H,
J=13.3 Hz), 4.10–4.30 (m, 2H), 4.32 (d, 1H, J=13.3
4.1.4. (3R,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox- Hz), 4.64 (dd, 1H, J=4.8, 9.5 Hz), 7.20–7.50 (m, 5H).
olan-4-yl]-isoxazolidine-5-carboxylic acid methyl ester
4d. (hexane/EtOAc, 90:10); 0.193 g (3%); oil; [h]25D +57 4.1.8. (3R,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox-
(c 0.18, CHCl3); 1H NMR (CDCl3) l 1.33 (s, 3H), 1.39 olan-4-yl)]-isoxazolidine-5-carboxylic acid tert-butyl
(s, 3H), 2.35 (ddd, 1H, J=7.0, 9.1, 15.9 Hz), 2.50 (ddd, ester 5d. (hexane/EtOAc, 85:15); 0.508 g (7%); oil; [h]25D
1H, J=5.5, 7.6, 15.9 Hz), 3.25 (q, 1H, J=7.3 Hz), 3.73 +44 (c 0.28, CHCl3); 1H NMR (CDCl3) l 1.33 (s, 3H),
(dd, 1H, J=6.5, 8.3 Hz), 3.76 (s, 3H), 3.98 (dd, 1H, 1.39 (s, 3H), 1.49 (s, 9H), 2.36 (ddd, 1H, J=7.1, 8.8,
J=6.5, 8.3 Hz), 4.08 (q, 1H, J=6.8 Hz), 4.14 (d, 1H, 12.7 Hz); 2.45 (ddd, 1H, J=5.6, 7.6, 12.7 Hz), 3.24 (q,
J=13.6 Hz), 4.20 (d, 1H, J=13.6 Hz), 4.51 (dd, 1H, 1H, J=7.4 Hz), 3.71 (dd, 1H, J=6.9, 8.0 Hz), 4.00 (t,
J=5.5, 9.1 Hz), 7.29–7.39 (m, 5H). 13C NMR (CDCl3) 1H, J=8.1 Hz), 4.18 (q, 1H, J=6.6 Hz), 4.20 (s, 2H),
l 25.2, 26.8, 33.9, 53.0, 62.4, 66.5, 67.8, 75.4, 75.9, 4.42 (dd, 1H, J=5.6, 8.8 Hz), 7.29–7.40 (m, 5H). 13C
109.9, 127.4, 128.3, 129.2, 137.1, 172.0. Anal. calcd for NMR (CDCl3) l 25.3, 26.5, 28.0, 35.2, 62.7, 66.3, 66.6,
C17H23NO5: C, 63.54; H, 7.21; N, 4.36. Found: C, 76.5, 76.8, 81.9, 109.7, 127.3, 128.3, 129.2, 137.6, 171.2.
63.32; H, 7.32; N, 4.50%. Anal. calcd for C20H29NO5: C, 66.09; H, 8.04; N, 3.85.
Found: C, 66.13; H, 8.25; N, 3.96%.
4.1.5. (3S,4R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox-
olan-4-yl]-isoxazolidine-4-carboxylic acid methyl ester 4.1.9. (3S,5S)-2-[Bis-(4-methoxyphenyl)-methyl]-3-(2,2-
4e. (hexane/EtOAc, 90:10); traces (when the reaction dimethyl-[1,3]dioxolan-4-yl)-isoxazolidine-5-carboxylic
was conducted with 10 g of 2a, ca. 80 mg (about 0.6%) acid methyl ester 6a. (hexane/EtOAc, 80:20); 2.834 g
of 4e could be isolated); white foam; [h]D +18 (c 0.15, (31%); oil; [h]25 1
D +28 (c 0.56, CHCl3); H NMR (CDCl3)
CHCl3); 1H NMR (CDCl3) l 1.28 (s, 3H), 1.35 (s, 3H), l 1.24 (s, 3H), 1.30 (s, 3H), 2.70–2.80 (m, 2H), 3.35
3.24 (ddd, 1H, J=4.8, 6.0, 8.8 Hz), 3.56 (dd, 1H, (ddd, 1H, J=2.9, 4.8, 8.6 Hz), 3.51 (dd, 1H, J=5.7, 8.1
J=4.8, 6.2 Hz), 3.74 (s, 3H), 3.80 (dd, 1H, J=6.0, 8.8 Hz), 3.62 (s, 3H), 3.74 (s, 6H), 3.99 (dt, 1H, J=6.2, 8.6
Hz), 3.99 (dd, 1H, J=6.0, 8.8 Hz), 4.10 (q, 1H, J=6.0 Hz), 4.10 (dd, 1H, J=6.4, 8.1 Hz), 4.54 (t, 1H, J=8.1
Hz), 4.12 (d, 2H, J=14.8 Hz), 4.13 (t, 1H, J=8.8 Hz), Hz), 4.94 (s, 1H), 6.76–6.84 (m, 4H), 7.22–7.26 (m, 2H),
4.25 (dd, 1H, J=7.0, 8.8 Hz), 7.24–7.39 (m, 5H). 13C 7.38–7.42 (m, 2H). 13C NMR (CDCl3) l 25.4, 26.7,
NMR (CDCl3) l 24.6, 26.2, 49.9, 52.4, 53.7, 60.7, 65.9, 33.3, 52.4, 55.2 (2C), 65.7, 68.5, 72.7, 75.7, 77.8, 109.4,
68.9, 69.6, 109.5, 127.5, 128.3, 129.3, 136.7, 173.2. Anal. 113.7, 114.3, 128.2, 129.0, 133.9, 135.1, 158.3, 159.2,
calcd for C17H23NO5: C, 63.54; H, 7.21; N, 4.36. 173.2. Anal. calcd for C25H31NO7: C, 65.63; H, 6.83; N,
Found: C, 63.39; H, 7.41; N, 4.58%. 3.06. Found: C, 63.70; H, 7.00; N, 3.29%.

4.1.6. (3S,5S)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox- 4.1.10. (3S,5S)-3-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-2-

olan-4-yl)]-isoxazolidine-5-carboxylic acid tert-butyl [(1R)-1-phenylethyl]-isoxazolidine-5-carboxylic acid
ester 5a. (hexane/EtOAc, 85:15); 2.542 g (35%); oil; methyl ester 7a. (hexane/EtOAc, 90:10); 4.763 g (71%);
D +33 (c 0.56, CHCl3); H NMR (CDCl3) l 1.29 (s,
[h]25 D +79 (c 0.28, CHCl3); H NMR (CDCl3) l 1.17
1
oil; [h]25 1

3H), 1.32 (s, 3H), 1.49 (s, 9H), 2.62 (dt, 1H, J=7.6, (s, 3H), 1.24 (s, 3H), 1.51 (d, 3H, J=6.3 Hz), 2.55 (ddd,
12.9, 12.7 Hz); 2.73 (ddd, 1H, J=2.0, 8.5, 12.9 Hz), 1H, J=7.5, 8.8, 12.9 Hz), 2.70 (ddd, 1H, J=0.8, 9.6,
3.22 (dt, 1H, J=2.0, 7.4 Hz), 3.50 (dd, 1H, J=5.2, 8.3 12.9 Hz), 3.14 (td, 1H, J=0.8, 8.5 Hz), 3.26 (dd, 1H,
Hz), 3.79 (d, 1H, J=13.3 Hz), 3.93 (ddd, 1H, J=5.2, J=5.8, 8.5 Hz), 3.79 (s, 3H), 3.83 (ddd, 1H, J=5.8, 6.3,
6.1, 7.4 Hz), 4.01 (dd, 1H, J=6.1, 8.3 Hz), 4.26 (d, 1H, 8.3 Hz), 3.85 (q, 1H, J=6.3 Hz), 3.95 (dd, 1H, J=6.3,
J=13.3 Hz), 4.50 (t, 1H, J=7.3 Hz), 7.26–7.40 (m, 8.5 Hz), 4.60 (dd, 1H, J=7.5, 8.5 Hz), 7.20–7.40 (m,
5H). 13C NMR (CDCl3) l 25.2, 26.8, 28.0, 34.1, 62.7, 5H). 13C NMR (CDCl3) l 21.3, 25.2, 26.5, 33.3, 52.1,
67.2, 68.1, 75.4, 78.0, 81.9, 109.4, 127.6, 128.4, 129.3, 65.6, 66.2, 68.2, 75.6, 76.5, 109.1, 127.7, 127.8, 128.6,
 P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190 183

142.9, 173.1. Anal. calcd for C18H25NO5: C, 64.46; H, NMR (CDCl3) l 19.1, 19.9, 25.3, 26.3, 26.5, 26.7, 26.9,
7.51; N, 4.18. Found: C, 64.38; H, 7.49; N, 4.02%. 36.5, 44.6, 47.8, 48.9, 53.0, 53.8, 61.4, 62.9, 66.5, 68.8,
75.4, 109.4, 127.5, 128.9, 129.3, 136.8, 171.0. Anal.
4.1.11. (3S,5R)-3-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-2- calcd for C26H36N2SO6: C, 61.88; H, 7.19; N, 5.55.
[(1R)-1-phenylethyl]-isoxazolidine-5-carboxylic acid Found: C, 61.74; H, 7.32; N, 5.40%.
methyl ester 7b. (hexane/EtOAc, 90:10); 0.939 g (14%);
D +36 (c 0.21, CHCl3); H NMR (CDCl3) l 1.15
oil; [h]25 1
4.1.15. (3S,5S)-2-Benzyl-3-(1,4-dioxa-spiro[4.5]dec-2-yl)-
(s, 3H), 1.22 (s, 3H), 1.45 (d, 3H, J=6.3 Hz), 2.53 (ddd, isoxazolidine-5-carboxylic acid methyl ester 10a. (hex-
1H, J=1.8, 5.5, 13.2 Hz), 2.66 (ddd, 1H, J=7.7, 9.9, ane/EtOAc, 85:15); 3.470 g (48%); oil; [h]25 D −1 (c 0.22,
13.2 Hz), 3.06 (ddd, 1H, J=1.8, 7.7, 8.8 Hz), 3.23 (dd, CHCl3); 1H NMR (CDCl3) l 1.28–1.63 (m, 10H), 2.68
1H, J=5.8, 9.1 Hz), 3.73 (q, 1H, J=6.3 Hz), 3.76 (s, (dt, 1H, J=7.8, 12.7 Hz), 2.76 (ddd, 1H, J=2.0, 8.3,
3H), 3.95 (dd, 1H, J=6.3, 9.1 Hz), 3.99 (ddd, 1H, 12.7 Hz), 3.25 (dt, 1H, J=2.0, 7.8 Hz), 3.50 (dd, 1H,
J=5.8, 6.3, 8.8 Hz), 4.60 (dd, 1H, J=5.5, 9.9 Hz), J=5.4, 8.3 Hz), 3.76 (s, 3H), 3.78 (d, 1H, J=13.2 Hz),
7.24–7.39 (m, 5H). 13C NMR (CDCl3) l 21.1, 25.4, 3.92 (ddd, 1H, J=5.4, 6.3, 7.8 Hz), 4.00 (dd, 1H,
26.8, 34.5, 52.3, 64.2, 65.6, 68.4, 75.7, 76.6, 109.0, 127.9, J=6.3, 8.3 Hz), 4.22 (d, 1H, J=13.2 Hz), 4.58 (t, 1H,
128.2, 128.8, 142.4, 171.3. Anal. calcd for C18H25NO5: J=8.1), 7.23–7.36 (m, 5H). 13C NMR (CDCl3) l 23.7,
C, 64.46; H, 7.51; N, 4.18. Found: C, 64.48; H, 7.77; N, 23.9, 25.1, 34.3, 34.8, 36.6, 52.1, 53.8, 62.7, 67.6, 67.7,
4.26%. 75.2, 110.0, 127.5, 128.3, 129.2, 137.1, 172.9. Anal.
calcd for C20H27NO5: C, 66.46; H, 7.53; N, 3.88.
4.1.12. (3R,5S)-3-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-2- Found: C, 66.39; H, 7.50; N, 3.71%.
[(1R)-1-phenylethyl]-isoxazolidine-5-carboxylic acid
methyl ester 7c. (hexane/EtOAc, 90:10); 0.537 g (8%); 4.1.16. (3S,5R)-2-Benzyl-3-(1,4-dioxa-spiro[4.5]dec-2-
oil. This compound was impurified with 10% of 7d yl)-isoxazolidine-5-carboxylic acid methyl ester 10b.
which could not be separated. 1H NMR (CDCl3) l 1.36 (hexane/EtOAc, 85:15); 1.229 g (17%); oil; [h]25D +16 (c
(s, 3H), 1.43 (s, 3H), 1.57 (d, 3H, J=6.8 Hz), 2.29 (ddd, 0.35, CHCl3); 1H NMR (CDCl3) l 1.10–1.61 (m, 10H),
1H, J=5.5, 8.8, 12.9 Hz), 2.44 (ddd, 1H, J=6.3, 8.1, 2.58 (ddd, 1H, J=2.9, 5.5, 13.2 Hz), 2.78 (ddd, 1H,
12.9 Hz), 3.40 (dt, 1H, J=5.9, 8.5 Hz), 3.59 (dd, 1H, J=8.3, 9.8, 13.2 Hz), 3.17 (dt, 1H, J=2.9, 8.1 Hz), 3.50
J=7.0, 8.4 Hz), 3.71 (q, 1H, J=6.8 Hz), 3.74 (s, 3H), (dd, 1H, J=4.9, 8.1 Hz), 3.74 (s, 3H), 3.82 (d, 1H,
3.99 (dd, 1H, J=6.5, 8.4 Hz), 4.11 (q, 1H, J=6.6 Hz), J=13.2 Hz), 3.98 (d, 1H, J=13.2 Hz), 4.02 (dd, 1H,
4.40 (dd, 1H, J=6.3, 8.4 Hz), 7.23–7.40 (m, 5H). 13C J=5.1, 8.1 Hz), 4.10 (dt, 1H, J=5.0, 8.1 Hz), 4.74 (dd,
NMR (CDCl3) l 21.6, 25.4, 26.5, 34.5, 52.0, 62.9, 64.2, 1H, J=5.5, 9.8 Hz), 7.19–7.37 (m, 5H). 13C NMR
66.5, 74.3, 75.6, 109.7, 127.1, 127.9, 128.6, 142.1, 171.7. (CDCl3) l 23.7, 24.0, 25.1, 34.6, 34.8, 36.6, 52.4, 61.4,
66.6, 67.6, 75.4, 75.9, 109.8, 127.7, 128.5, 129.1, 136.3,
4.1.13. (3R,5R)-3-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-2- 171.5. Anal. calcd for C20H27NO5: C, 66.46; H, 7.53; N,
[(1R)-1-phenylethyl]-isoxazolidine-5-carboxylic acid 3.88. Found: C, 66.32; H, 7.68; N, 3.75%.
methyl ester 7d. (hexane/EtOAc, 90:10); 0.134 g (2%);
D +46 (c 0.14, CHCl3); H NMR (CDCl3) l 1.35
oil; [h]25 1
4.1.17. (3R,5S)-2-Benzyl-3-(1,4-dioxa-spiro[4.5]dec-2-
(s, 3H), 1.42 (s, 3H), 1.56 (d, 3H, J=6.4 Hz), 2.15 (dt, yl)-isoxazolidine-5-carboxylic acid methyl ester 10c.
1H, J=6.6, 12.8 Hz), 2.31 (dt, 1H, J=8.1, 12.8 Hz), (hexane/EtOAc, 85:15); 1.012 g (14%); oil; [h]25 D +2 (c
3.18 (dt, 1H, J=6.8, 7.8 Hz), 3.63 (dd, 1H, J=6.6, 8.5 0.31, CHCl3); 1H NMR (CDCl3) l 1.15–1.63 (m, 10H),
Hz), 3.70 (q, 1H, J=6.4 Hz), 3.75 (s, 3H), 3.98 (dd, 1H, 2.25 (ddd, 1H, J=5.4, 7.3, 12.7 Hz), 2.56 (dt, 1H,
J=6.6, 8.5 Hz), 4.15 (q, 1H, J=6.8 Hz), 4.33 (dd, 1H, J=8.8, 12.7 Hz), 3.06 (q, 1H, J=7.3 Hz), 3.68 (dd, 1H,
J=6.6, 8.5 Hz), 7.26–7.41 (m, 5H). 13C NMR (CDCl3) J=6.8, 8.3 Hz), 3.73 (s, 3H), 4.00 (dd, 1H, J=6.8, 8.3
l 20.8, 25.3, 26.7, 35.1, 52.2, 63.5, 63.6, 66.7, 74.3, 75.4, Hz), 4.01 (d, 1H, J=14.3 Hz), 4.11 (q, 1H, J=6.8 Hz),
109.8, 127.4, 128.0, 129.2, 140.7, 171.8. Anal. calcd for 4.38 (d, 1H, J=14.3 Hz), 4.54 (dd, 1H, J=5.4, 8.8 Hz),
C18H25NO5: C, 64.46; H, 7.51; N, 4.18. Found: C, 7.22–7.45 (m, 5H). 13C NMR (CDCl3) l 23.7, 24.0,
64.42; H, 7.41; N, 4.29%. 25.1, 34.8, 34.9, 36.4, 52.0, 60.9 (2C), 66.4, 66.9, 74.3,
109.9, 127.3, 128.3, 129.1, 137.3, 173.6. Anal. calcd for
4.1.14. (3S,5S)-{2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox- C20H27NO5: C, 66.46; H, 7.53; N, 3.88. Found: C,
olan-4-yl]-isoxazolidin-5-yl}-(10,10-dimethyl-3,3-dioxo- 66.56; H, 7.59; N, 3.93%.
3l6-thia-4-azatricyclo[5.2.1.01,5]dec-4-yl)-methanone 9a.
(hexane/EtOAc, 80:20); 5.652 g (56%); oil; [h]25 D −8 (c 4.1.18. (3R,5R)-2-Benzyl-3-(1,4-dioxa-spiro[4.5]dec-2-
0.33, CHCl3); 1H NMR (CDCl3) l 0.93 (s, 3h), 1.10 (s, yl)-isoxazolidine-5-carboxylic acid methyl ester 10d.
3H), 1.31 (s, 3H), 1.34 (s, 3H), 1.50–1.60 (m, 2H), (hexane/EtOAc, 85:15); 1.012 g (14%); oil; [h]25 D −5 (c
1.80–1.90 (m, 2H), 2.03 (dd, 1H, J=8.0, 13.6 Hz), 0.11, CHCl3); 1H NMR (CDCl3) l 1.29–1.60 (m, 10H),
2.08–2.12 (m, 1H), 2.38 (ddd, 1H, J=6.3, 8.5, 12.9 Hz), 2.48 (ddd, 1H, J=4.4, 7.8, 12.7 Hz), 2.54 (ddd, 1H,
2.70 (ddd, 1H, J=5.5, 7.7, 12.9 Hz), 3.32 (t, 1H, J=7.0 J=8.3, 9.2, 12.7 Hz), 3.35 (q, 1H, J=7.8 Hz), 3.65 (dd,
Hz), 3.35 (d, 1H, J=13.6 Hz), 3.46 (d, 1H, J=13.6 Hz), 1H, J=6.4, 8.3 Hz), 3.79 (s, 3H), 4.04 (dd, 1H, J=6.3,
3.68 (dd, 1H, J=7.0, 8.2 Hz), 3.85 (dd, 1H, J=5.2, 7.7 8.3 Hz), 4.29 (d, 1H, J=14.1 Hz), 4.50 (d, 1H, J=14.1
Hz), 4.00 (dd, 1H, J=6.6, 8.2 Hz), 4.10 (q, 1H, J=7.0 Hz), 4.71 (dd, 1H, J=4.4, 8.3), 7.25–7.40 (m, 5H). 13C
Hz), 4.17 (d, 1H, J=14.3 Hz), 4.23 (d, 1H, J=14.3 Hz), NMR (CDCl3) l 23.5, 24.1, 24.8, 33.8, 34.5, 37.2, 52.9,
4.97 (dd, 1H, J=5.2, 8.5 Hz), 7.20–7.38 (m, 5H). 13C 55.1, 64.6, 67.5, 69.3, 74.9, 110.1, 127.2, 128.1, 129.3,
184 P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

137.0, 173.1. Anal. calcd for C20H27NO5: C, 66.46; H, J=7.7, 12.9 Hz), 2.38 (ddd, 1H, J=1.5, 8.1, 12.9 Hz),
7.53; N, 3.88. Found: C, 66.68; H, 7.43; N, 3.80%. 3.53 (m, 1H), 3.74 (dd, 1H, J=5.3, 8.2 Hz), 4.00, 4.11
(m, 2H), 4.40 (t, 1H, J=8.0 Hz), 6.20 (bs, 1H), 7.02 (bs,
4.2. Synthesis of pyrrolidin-2-ones 1H). 13C NMR (CDCl3) l 25.0, 26.5, 32.4, 53.6, 65.7,
68.6, 78.9, 109.8, 177.9. Anal. calcd for C9H15NO4: C,
4.2.1. (3S,5S)-5-((4S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3- 53.72; H, 7.51; N, 6.96. Found: C, 53.76; H, 7.42; N,
hydroxy-pyrrolidin-2-one 11a. A solution of 4a (1.0 g, 7.25%.
3.11 mmol) in methanol (50 mL) was treated with
Pearlman’s catalyst, Pd(OH)2–C (120 mg), and stirred The same procedure was applied to 7c (0.5 g, 1.49
under hydrogen at room temperature and 2000 psi. mmol) and pure 11c (0.276 g, 92%) was obtained, the
After 24 h the reaction mixture was filtered through a physical and spectroscopic properties being identical to
pad of Celite, which was washed with methanol. The those obtained for the compound prepared from 4c.
filtrate was evaporated and the residue was purified by
flash chromatography on silica gel (EtOAc/MeOH, 5:1) 4.2.4. (3R,5R)-5-((4S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-
to afford pure 11a (0.576 g, 92%) as a white solid; mp 3-hydroxypyrrolidin-2-one 11d. The same procedure
148–149°C; [h]D −5 (c 0.92, CHCl3); 1H NMR (CDCl3) described above for the conversion of 4a to 11a was
l 1.33 (s, 3H), 1.43 (s, 3H), 1.68 (dt, 1H, J=8.0, 16.0 applied to 4d (0.150 g, 0.47 mmol). After flash chro-
Hz), 2.56 (ddd, 1H, J=6.8, 8.3, 16.0 Hz), 3.10 (bs, 1H, matography (EtOAc/MeOH, 5:1) of the crude product,
ex. D2O), 3.74 (dddd, 1H, J=1.8, 4.4, 6.8, 8.0 Hz), 3.79 pure 11d (87 mg, 92%) was obtained as a white solid;
(dd, 1H, J=6.3, 8.5 Hz), 4.02 (dd, 1H, J=6.5, 8.5 Hz), mp 133–135°C; [h]25 1
D −19 (c 0.99, CHCl3); H NMR
4.14 (dt, 1H, J=4.4, 6.4 Hz), 4.32 (t, 1H, J=8.2 Hz), (CDCl3) l 1.32 (s, 3H), 1.40 (s, 3H), 1.64 (dt, 1H,
6.69 (bs, 1H). 13C NMR (CDCl3) l 24.7, 26.3, 32.3, J=8.0, 15.8 Hz), 2.46 (ddd, 1H, J=6.7, 8.3, 15.8 Hz),
52.1, 64.9, 69.1, 77.3, 109.7, 177.8. Anal. calcd for 3.52 (m, 1H), 3.70 (dd, 1H, J=4.9, 8.3 Hz), 3.97 (q, 1H,
C9H15NO4: C, 53.72; H, 7.51; N, 6.96. Found: C, 53.60; J=6.7 Hz), 4.05 (dd, 1H, J=6.4, 8.3 Hz), 4.31 (t, 1H,
H, 7.58; N, 7.13%. J=8.3 Hz), 4.40 (bs, 1H, ex. D2O), 6.70 (bs, 1H). 13C
NMR (CDCl3) l 25.1, 26.7, 32.3, 53.8, 65.9, 69.0, 79.1,
The same procedure was applied to 5a (1.0 g, 2.75 110.1, 177.4. Anal. calcd for C9H15NO4: C, 53.72; H,
mmol), 6a (1.0 g, 2.19 mmol), 7a (1.0 g, 2.98 mmol) and 7.51; N, 6.96. Found: C, 53.91; H, 7.46; N, 6.84%.
9a (1.0 g, 1.98 mmol), and pure 11a (0.498 g, 90%;
0.405 g, 92%; 0.540 g, 90% and 0.351 g, 88%, respec- The same procedure was applied to 7d (0.12 g, 0.36
tively) was obtained in all cases, the physical and mmol) and pure 11d (62 mg, 86%) was obtained, the
spectroscopic properties being identical to those physical and spectroscopic properties being identical to
obtained for the compound prepared from 4a. those obtained for the compound prepared from 4d.

4.2.2. (3S,5R)-5-((4S)-2,2-Dimethyl-1,3-dioxolan-4-yl)- 4.3. Transketalization of isoxazolidines 10a–d

3-hydroxy-pyrrolidin-2-one 11b. The same procedure
described above for the conversion of 4a to 11a was A solution of the corresponding isoxazolidine 10 (0.5 g,
applied to 4b (1.0 g, 3.11 mmol). After flash chromatog- 1.38 mmol) in dry acetone (50 mL) was treated with
raphy (EtOAc/MeOH, 5:1) of the crude product, pure p-toluensulfonic acid (30 mg, 0.174 mmol) and the
11b (0.563, 90%) was obtained as a white solid; mp resulting solution was stirred at ambient temperature
118–120°C; [h]25 D −30 (c 0.43, CHCl3); 1H NMR for 8 h, at which time saturated aqueous sodium bicar-
(CDCl3) l 1.31 (s, 3H), 1.40 (s, 3H), 2.12 (ddd, 1H, bonate (10 mL) was added. The reaction mixture was
J=7.6, 8.6, 16.3 Hz), 2.42 (ddd, 1H, J=2.6, 8.4, 16.3 evaporated under reduced pressure and the residue was
Hz), 3..80 (bs, 1H, ex. D2O), 3.63 (m, 1H), 3.75 (m, partitioned between EtOAc (100 mL) and brine (100
1H), 4.03 (m, 2H), 4.36 (t, 1H, J=8.2 Hz), 7.07 (bs, mL). The organic layer was separated, dried over mag-
1H). 13C NMR (CDCl3) l 24.9, 26.4, 31.4, 53.3, 65.9, nesium sulphate and evaporated. The crude product
68.3, 77.4, 109.9, 178.7. Anal. calcd for C9H15NO4: C, was purified by flash chromatography (hexane/EtOAc,
53.72; H, 7.51; N, 6.96. Found: C, 53.81; H, 7.60; N, 4:1) to give the corresponding isoxazolidines 4. Starting
7.08%. from 10a, 10b, 10c and 10d, compounds 4a (0.390 g,
88%), 4b (0.381 g, 86%), 4c (0.392 g, 88%) and 4d (0.373
The same procedure was applied to 7b (0.9 g, 2.68 g, 84%) were obtained, respectively. In all cases, the
mmol) and pure 11b (0.491 g, 91%) was obtained, the physical and spectroscopic properties of these com-
physical and spectroscopic properties being identical to pounds were identical to those obtained for the corre-
those obtained for the compound prepared from 4b. sponding compounds prepared from nitrone 2a.

4.2.3. (3R,5S)-5-((4S)-2,2-Dimethyl-1,3-dioxolan-4-yl)- 4.4. 4-Nitrobenzoic acid (3R,5S)-5-[(4R)-2,2-dimethyl-

3-hydroxy-pyrrolidin-2-one 11c. The same procedure 1,3-dioxolan-4-yl]-2-oxo-pyrrolidin-3-yl ester 12
described above for the conversion of 4a to 11a was
applied to 4c (0.5 g, 1.56 mmol). After flash chromatog- From 11a: To a stirred solution of 11a (0.2 g, 1 mmol),
raphy (EtOAc/MeOH, 5:1) of the crude product, pure triphenylphosphine (1.28 g, 4.92 mmol) and p-nitroben-
11c (0.292 g, 93%) was obtained as a white solid; mp zoic acid (0.730 g, 4.38 mmol) in dry toluene (30 mL) at
112–114°C; [h]25 D −22 (c 0.21, CHCl3); 1H NMR ambient temperature was added slowly diisopropyl-
(CDCl3) l 1.40 (s, 3H), 1.31 (s, 3H), 1.62 (dt, 1H, azodicarboxylate (1.30 g, 6.4 mmol). After 6 h, the
 P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190 185

reaction mixture was evaporated to dryness and the by column chromatography on silica gel to give pure 15
residue was purified by flash chromatography (hexane/ as a light yellow oil (188 mg, 80%). [h]25
D +8 (c 0.78,
EtOAc, 2:3) to give pure 12 (0.235 g, 67%) as a white CHCl3); 1H NMR (CDCl3+D2O) l 2.22 (ddd, 1H,
D −19 (c 0.40, CHCl3); H NMR (CDCl3) l
foam; [h]25 1
J=1.8, 7.3, 13.2 Hz), 2.36 (ddd, 1H, J=3.4, 8.8, 13.2
1.35 (s, 3H), 1.50 (s, 3H), 2.26 (dt, 1H, J=8.8, 13.9 Hz), Hz), 3.22 (m, 1H), 3.56 (dd, 1H, J=6.4, 14.8), 3.59 (dd,
2.65 (ddd, 1H, J=1.8, 8.5, 13.9 Hz), 3.67 (dd, 1H, 1H, J=6.2, 14.8), 3.62 (dd, 1H, J=6.8, 14.8 Hz), 3.81
J=5.9, 8.5 Hz), 3.84 (ddd, 1H, J=1.8, 3.7, 8.8 Hz), 4.10 (dd, 1H, J=6.5, 14.8), 4.03 (d, 1H, J=14.4), 4.12 (d,
(dd, 1H, J=7.0, 8.5 Hz), 4.19 (ddd, 1H, J=3.7, 5.9, 7.0 1H, J=14.4 Hz), 4.21 (m, 1H), 7.15–7.32 (m, 5H). 13C
Hz), 5.62 (t, 1H, J=8.6 Hz), 6.28 (s, 1H), 7.40–7.51 (m, NMR (CDCl3) l 30.0, 32.7, 62.7, 64.1, 66.6, 79.0, 127.8,
2H), 8.00–8.13 (m, 2H). 13C NMR (CDCl3) l 24.7, 26.4, 128.7, 129.3, 137.8. Anal. calcd for C12H17NO3: C,
30.2, 38.6, 53.0, 67.1, 69.5, 109.9, 125.6, 131.4, 138.3, 64.55; H, 7.67; N, 6.27. Found: C, 64.70; H, 7.80; N,
151.6, 165.7, 172.1. Anal. calcd for C16H18N2O7: C, 6.10%.
54.86; H, 5.18; N, 8.00. Found: C, 54.92; H, 5.33; N,
8.42%. 4.7. (3S,5S)-5-((4R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-
(tert-butyldimethylsiloxy)-pyrrolidin-2-one 17a
From 11b: A solution of 11b (0.2 g, 1 mmol) in dry
dichloromethane (20 mL) was treated with 4-nitroben- A solution of 11a (0.402 g, 2 mmol) in DMF (15 mL)
zoyl chloride (0.223 g, 1.2 mmol) and pyridine (0.158 g, was treated with imidazole (0.756 g) and tert-
2 mmol), and the resulting solution was stirred at butyldimethylsilyl chloride (0.452 g, 3 mmol). The
ambient temperature for 12 h. The reaction mixture was resulting solution was stirred at 70°C until no more
washed sequentially with 2N HCl and saturated starting material was observed by TLC (ca. 4 h).
aqueous sodium bicarbonate. The organic layer was Methanol (5 mL) and water (50 mL) were added and the
separated, dried over magnesium sulphate and concen- resulting mixture was extracted with EtOAc (3×40 mL).
trated to dryness. The residue was purified by radial The organic layers were combined, dried over magne-
chromatography (hexane/EtOAc, 2:3) to give pure 12 sium sulfate and evaporated under reduced pressure to
(0.287 g, 82%). The physical and spectroscopic proper- give crude 17a, which was purified by flash chromatog-
ties of this compound were identical to those obtained raphy (hexane/EtOAc, 2:3) to afford pure 17a (0.467 g,
for the compound prepared from 11a. 74%) as an oil; [h]25 D +9 (c 0.28, CHCl3);
1
H NMR
(CDCl3) l 0.12 (s, 3H), 0.14 (s, 3H), 0.89 (s, 9H), 1.33
4.5. (3S,5S)-2-Benzyl-3-formyl-isoxazolidine-5-carboxy- (s, 3H), 1.42 (s, 3H), 1.66 (dt, 1H, J=7.4, 13.1 Hz), 2.50
lic acid methyl ester 14 (ddd, 1H, J=7.1, 8.1, 13.1 Hz), 3.68 (dt, 1H, J=4.5, 7.3
Hz), 3.83 (dd, 1H, J=6.0, 8.2 Hz), 4.03 (dd, 1H, J=6.2,
To a solution of 4a (0.32 g, 1 mmol) in MeOH (60 mL) 8.2 Hz), 4.07 (q, 1H, J=6.1 Hz), 4.27 (t, 1H, J=7.8 Hz),
was added p-TsOH (43 mg, 0.25 mmol) and the result- 6.8 (bs, 1H). 13C NMR (CDCl3) l −5.2, −4.6, 18.2, 24.9,
ing solution was heated under reflux for 4 h. The 25.7, 26.5, 34.1, 51.8, 65.2, 70.1, 77.9, 109.4, 176.5. Anal.
reaction mixture was cooled at room temperature and calcd for C15H29NO4Si: C, 57.11; H, 9.27; N, 4.44.
neutralized with Amberlite IRA-400. The mixture was Found: C, 57.03; H, 9.42; N, 4.37%.
filtered and the filtrate was evaporated under reduced 4.8. Benzoic acid (3S,5S)-5-[(4R)-2,2-dimethyl-1,3-diox-
pressure. The crude diol 13 (1H NMR (CDCl3+D2O) l olan-4-yl]-2-oxo-pyrrolidin-3-yl ester 17b
2.58 (dt, 1H, J=7.3, 13.2 Hz), 2.81 (ddd, 1H, J=3.4,
8.8, 13.2 Hz), 3.29 (m, 1H), 3.51 (m, 2H), 3.74 (s, 3H), The same procedure described above for the conversion
3.85 (d, 1H, J=12.7 Hz), 4.16 (m, 1H), 4.23 (d, 1H, of 11b to 12 was applied to 11a (0.402 g, 2 mmol). After
J=12.7 Hz), 4.58 (dd, 1H, J=7.3, 8.8 Hz), 7.15–7.32 flash chromatography (hexane/EtOAc, 2:3) of the crude
(m, 5H) was taken up into a 1:1 mixture of MeOH:H2O product, pure 17b (0.519 g, 85%) was obtained as a
(30 mL), cooled at 0°C and treated with NaIO4 (0.214 white foam; [h]25 1
D +17 (c 0.20, CHCl3); H NMR
g, 1 mmol). The resulting suspension was stirred at 0°C (CDCl3) l 1.34 (s, 3H), 1.43 (s, 3H), 1.90 (dt, 1H,
for 1 h, filtered and rotatory evaporated to give 14 as a J=7.8, 13.7 Hz), 2.86 (ddd, 1H, J=6.8, 8.8, 13.7 Hz),
yellow oil (0.19 mg; 78%). 1H NMR (CDCl3) l 2.40 3.84 (dt, 1H, J=6.7, 8.0 Hz), 3.88 (dd, 1H, J=6.4, 8.3
(ddd, 1H, J=2.2, 4.4, 13.2 Hz), 2.60 ( ddd, 1H, J=6.4, Hz), 4.05 (dd, 1H, J=6.4, 8.3 Hz), 4.18 (q, 1H, J=6.4
8.8, 13.2), 3.54 (m, 1H), 3.74 (s, 3H), 3.78 (d, 1H, Hz), 5.54 (t, 1H, J=8.3 Hz), 7.40 (bs, 1H), 7.48–7.52
J=12.4 Hz), 3.82 (d, 1H, J=12.4), 4.42 (dd, 1H, J=4.4, (m, 3H), 7.59–7.63 (m, 2H). 13C NMR (CDCl3) l 24.8,
8.8 Hz), 7.15–7.45 (m, 5H), 9.42 (bs, 1H). The aldehyde 26.4, 30.5, 38.1, 52.2, 65.0, 70.6, 109.8, 128.4, 129.2,
was immediately used in the next step without further 129.9, 1233.4, 165.8, 173.2. Anal. calcd for C16H19NO5:
purification. C, 62.94; H, 6.27; N, 4.59. Found: C, 63.10; H, 6.11; N,
4.70%.
4.6. (3S,5S)-2-Benzyl-3,5-bis(hydroxymethyl-isoxazol-
idine 15 4.9. (3S,5S)-1-(tert-Butoxycarbonyl)-5-((4R)-2,2-
dimethyl-1,3-dioxolan-4-yl)-3-(tert-butyldimethylsiloxy)-
A solution of 14 (0.19 g, 0.76 mmol) in aqueous pyrrolidin-2-one 18a
methanol (10 mL) was cooled to 0°C and treated with
NaBH4 (0.117 g, 3 mmol). After stirring at the same A solution of 17a (0.4 g, 1.27 mmol) in CH2Cl2 (20 mL)
temperature for 2 h, the reaction mixture was concen- was treated with Boc2O (0.44 g, 2 mmol), Et3N (0.30
trated under reduced pressure. The residue was purified mL, 2 mmol) and DMAP (0.244 g, 2 mmol). The
186 P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

reaction mixture was stirred at ambient temperature for residue which was taken up in diethyl ether (20 mL)
12 h, at which time 1N KHSO4 (20 mL) was added. and treated with a freshly distilled ethereal solution of
The organic layer was separated, washed with water diazomethane at 0°C for 5 min. The solvent was
(1×15 mL) and brine (1×15 mL), dried over magnesium removed under reduced pressure and the residue was
sulfate and evaporated to give crude 8, which was subjected to purification by radial chromatography
purified by flash chromatography (hexane/EtOAc, 4:1) (hexane/EtOAc, 9:1) to give the pure 19 (0.218 g, 60%)
to afford pure 18a (0.464 g, 88%) as a solid which as a colorless oil; [h]25 1
D −10 (c 0.19, CHCl3); H NMR
solidified upon standing; mp 69–71°C; [h]25 D −44 (c 0.48, (CDCl3) l 1.49 (s, 9H), 2.40 (dt, 1H, J=6.8, 13.7 Hz),
CHCl3); 1H NMR (CDCl3) l 0.12 (s, 3H), 0.14 (s, 3H), 2.85 (dt, 1H, J=8.3, 13.7 Hz), 3.75 (s, 3H), 4.59 (dd,
0.89 (s, 9H), 1.31 (s, 3H), 1.40 (s, 3H), 1.52 (s, 9H), 2.11 1H, J=6.8, 7.8 Hz), 5.57 (dd, 1H, J=7.3, 8.3), 7.38–
(dt, 1H, J=4.9, 13.6 Hz), 2.24 (dt, 1H, J=7.9, 13.6 7.41 (m, 3H), 7.97–8.04 (m, 2H). 13C NMR (CDCl3) l
Hz), 3.75 (dd, 1H, J=7.2, 8.6 Hz), 4.01 (dd, 1H, 27.8, 27.9, 52.7, 55.8, 70.1, 84.5, 128.5, 130.0, 133.7,
J=6.2, 8.6 Hz), 4.05 (ddd, 1H, J=4.6, 6.2, 7.8 Hz), 149.0, 165.3, 168.1 (2C), 170.8. Anal. calcd for
4.23 (dd, 1H, J=5.1, 8.0 Hz), 4.40 (dt, 1H, J=6.2, 7.2 C18H21NO7: C, 59.50; H, 5.83; N, 3.85. Found: C,
Hz). 13C NMR (CDCl3) l −5.2, −4.5, 18.2, 25.5, 25.8, 59.37; H, 5.72; N, 4.75%.
26.4, 28.1, 29.4, 56.8, 67.7, 71.1, 79.4, 83.7, 109.1, 150.7,
172.5. Anal. calcd for C20H37NO6Si: C, 57.80; H, 8.97;
N, 3.37. Found: C, 57.96; H, 9.12; N, 3.12%. 4.12. Carbonic acid tert-butyl ester (3S,5S)-5-[(4S)-2,2-
dimethyl-1,3-dioxolan-4-yl]-2-oxo-pyrrolidin-3-yl ester
4.10. (3S,5S)-5-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-3- 20
(benzoyloxy)-2-oxo-pyrrolidine-1-carboxylic acid tert-
butyl ester 18b The same procedure described above for the conversion
of 17a to 18a was applied to 11a (0.2 g, 1 mmol). After
The same procedure described above for the conversion radial chromatography (hexane/EtOAc, 1:1) of the
of 17a to 18a was applied to 17b (0.410 g, 1.17 mmol). crude product, pure 20 (0.223 g, 74%) was obtained as
D −4 (c 0.14, CHCl3); H NMR (CDCl3) l
an oil; [h]25 1
After flash chromatography (hexane/EtOAc, 4:1) of the
crude product, pure 18b (0.403 g, 85%) was obtained as 1.28 (s, 3H), 1.36 (s, 3H), 1.43 (s, 9H), 1.67 (dt, 1H,
J=8.4, 16.7 Hz), 2.57 (ddd, 1H, J=6.7, 8.6, 16.7 Hz),
D −49 (c 0.57, CHCl3); H NMR (CDCl3) l
an oil; [h]25 1

1.29 (s, 3H), 1.34 (s, 3H), 1.57 (s, 9H), 2.24 (dt, 1H, 3.53 (ddd, 1H, J=6.7, 7.4, 8.4 Hz), 3.66 (dd, 1H,
J=4.9, 5.9, 14.2 Hz), 2.63 (ddd, 1H, J=8.3, 9.3, 14.2 J=4.6, 8.3 Hz), 3.93 (ddd, 1H, J=4.6, 6.4, 7.4 Hz),
Hz), 3.70 (dd, 1H, J=6.8, 8.8 Hz), 4.10 (dd, 1H, 4.00 (dd, 1H, J=6.4, 8.3 Hz), 5.11 (t, 1H, J=8.7 Hz),
J=6.8, 8.8 Hz), 4.24 (ddd, 1H, J=3.9, 4.9, 8.3 Hz), 6.70 (bs, 1H). 13C NMR (CDCl3) l 25.1, 26.7, 27.7,
4.60 (dt, 1H, J=3.9, 6.8 Hz), 5.55 (dd, 1H, J=5.9, 9.3 30.0, 53.4, 65.7, 72.1, 78.8, 83.2, 110.2, 152.7, 171.9.
Hz), 7.44–7.55 (m, 3H), 7.60–7.63 (m, 2H). 13C NMR Anal. calcd for C14H23NO6: C, 55.80; H, 7.69; N, 4.65.
(CDCl3) l 24.7, 26.0, 27.9, 36.6, 38.1, 56.5, 66.8, 70.6, Found: C, 55.62; H, 7.48; N, 4.45%.
84.2, 109.6, 128.4, 129.9 (2C), 133.4, 150.1, 165.6, 169.1.
Anal. calcd for C21H27NO7: C, 62.21; H, 6.71; N, 3.45. 4.13. Reduction of isoxazolidines 4
Found: C, 62.42; H, 6.61; N, 3.55%.

4.11. (2S,4S)-4-(Benzoyloxy)-5-oxo-pyrrolidine-1,2- 4.13.1. (3S,5S)-1-Benzyl-5-[(4S)-2,2-dimethyl-1,3-diox-

dicarboxylic acid 1-tert-butyl ester 2-methyl ester 19 olan-4-yl]-3-hydroxy-pyrrolidin-2-one 21a and (3S,5S)-2-
benzyl-3-[(1S)-1,2-dihydroxy-ethyl]-isoxazolidine-5-carb-
To a well-stirred suspension of periodic acid (0.536 g, oxylic acid methyl ester 13. A solution of 4a (0.82 g,
2.35 mmol) in dry diethyl ether (50 mL), compound 18b 2.55 mmol) in THF (25 mL) was treated with glacial
(0.450 g, 1 mmol) was added at ambient temperature acetic acid (40 mL) and Zn dust (0.196 g, 3 mmol); the
under an argon atmosphere in one portion. Stirring was resulting solution was heated at 60°C for 1 h. After
maintained for additional 4 h at which time the reac- cooling at ambient temperature, the reaction mixture
tion mixture was filtered. The filtrate was evaporated was treated with a saturated aqueous solution of
under reduced pressure and the residue was dissolved in sodium carbonate and the resulting mixture was
CH3CN (5 mL). To the resulting mixture, a solution of extracted with EtOAc (3×50 mL). The combined
NaClO2 (0.133 g, 1.53 mmol) in water (5 mL) was organic layers were washed with brine, dried over mag-
added dropwise. The resulting mixture was then treated nesium sulfate and evaporated to yield a residue which
with a solution of NaH2PO4 (29 mg, 0.25 mmol) in after a short flash chromatography (hexane/EtOAc, 1:4)
H2O (2 mL) and 35% H2O2 (82 mL, 0.88 mmol) keeping afforded a 90:10 mixture of compounds 21a and 13,
the temperature of the mixture below 10°C. After stir- which were used in the next acetylation step without
ring for 1 h, Na2SO3 (9 mg, 0.17 mmol) was added and further purification.
the resulting mixture was acidified (pH 2–3) with 10%
aqueous HCl. The resulting mixture was partitioned 21a: 1H NMR (CDCl3+D2O) l (selected signals) 1.30
between brine (30 mL) and EtOAc (30 mL), the layers (s, 3H), 1.46 (s, 3H), 1.88 (td, 1H, J=6.3, 12.7 Hz), 2.35
were separated and the aqueous layer was extracted (td, 1H, J=7.8, 12.7 Hz), 3.50 (m, 1H), 3.98 (dd,
with EtOAc (3×25 mL). The combined organic extracts 1H, J=6.5, 8.9 Hz), 4.14 (d, 1H, J=15.1 Hz), 4.30–
were washed with brine, dried over magnesium sulfate 4.40 (m, 3H), 5.05 (d, 1H, J=15.1 Hz), 7.15–7.32 (m,
and concentrated under reduced pressure to give a 5H).
 P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190 187

13: The 1H NMR spectra of this compound was identi- 13.7 Hz), 3.43 (q, 1H, J=7.3 Hz), 3.57 (1H, J=7.8 Hz),
cal to that observed for the same product obtained 3.91 (dd, 1H, J=6.8, 8.1 Hz), 4.12 (q, 1H, J=6.8 Hz),
from 4a as described above. 4.38 (t, 1H, J=7.8 Hz), 4.47 (d, 1H, J=14.6 Hz), 4.91
(d, 1H, J=14.6 Hz), 7.33–7.41 (m, 5H).
4.13.2. (3R,5S)-1-Benzyl-5-[(4S)-2,2-dimethyl-1,3-diox-
olan-4-yl]-3-hydroxy-pyrrolidin-2-one 21b and (3S,5R)-2- 4.14. Acetylation of pyrrolidin-2-ones 21 and diols 22
benzyl-3-[(1S)-1,2-dihydroxy-ethyl]-isoxazolidine-5-carb-
oxylic acid methyl ester 22b. The same procedure 4.14.1. Acetic acid (3S,5S)-1-benzyl-5-[(4S)-2,2-dime-
described above for the conversion of 4a to 21a and 13 thyl-1,3-dioxolan-4-yl]-2-oxo-pyrrolidin-3-yl ester 23a
was applied to 4b (0.68 g, 2.12 mmol). After a short and (3S,5S)-2-benzyl-3-[(1S)-1,2-diacetoxy-ethyl]-isoxa-
flash chromatography (hexane/EtOAc, 1:4) of the crude zolidine-5-carboxylic acid methyl ester. The above
product, a 93:7 mixture of 21b and 22b was obtained described mixture of compounds 21a and 13 was dis-
and used in the next acetylation step without further solved in dry dichloromethane (30 mL) and treated
purification. with acetic anhydride (2.44 g, 24 mmol) and pyridine
(3.20 g, 40 mmol), and the resulting solution was stirred
21b: 1H NMR (CDCl3+D2O) l (selected signals) 1.29 at ambient temperature for 12 h. The reaction mixture
(s, 3H), 1.42 (s, 3H), 1.87 (dt, 1H, J=8.8, 13.2 Hz), 2.40 was washed sequentially with 2N HCl and saturated
(ddd, 1H, J=1.9, 8.2, 13.2 Hz), 3.45 (dt, 1H, J=2.3, aqueous sodium bicarbonate. The organic layer was
8.6 Hz), 3.54 (dd, 1H, J=6.3, 8.5 Hz), 3.93 (dd, 1H, separated, dried over magnesium sulfate and concen-
J=7.3, 8.5 Hz), 4.09 (d, 1H, J=15.1 Hz), 4.27 (dt, 1H, trated to dryness. The residue was purified by MPLC
J=2.2, 7.0 Hz), 4.59 (t, 1H, J=8.5 Hz), 5.0 (sd, 1H, (hexane/EtOAc, 3:2) to give pure 23a and 24a.
J=15.1 Hz), 7.32–7.45 (m, 5H).
23a: 0.621 g (73%); oil; [h]25
D −45 (c 0.26, CHCl3); H
1

22b: H NMR (CDCl3+D2O) l (selected signals) 2.25–

1 NMR (CDCl3) l 1.25 (s, 3H), 1.47 (s, 3H), 1.85 (td,
2.65 (m, 2H), 3.19 (dt, 1H, J=5.1, 8.5 Hz), 3.56–3.63 1H, J=7.4, 13.2 Hz), 2.12 (s, 3H), 2.50 (ddd, 1H,
(m, 2H), 3.75 (s, 3H), 3.91 (d, 1H, J=12.8 Hz), 3.98 (m, J=7.3, 8.8, 13.2 Hz), 3.50 (dt, 1H, J=2.9, 7.0 Hz), 3.54
1H), 4.05 (d, 1H, J=12.8 Hz), 4.72 (dd, 1H, J=5.5, 8.8 (dd, 1H, J=6.6, 8.5 Hz), 3.96 (dd, 1H, J=7.0, 8.5 Hz),
Hz), 7.31–7.42 (m, 5H). 4.10 (d, 1H, J=15.4 Hz), 4.30 (dt, 1H, J=2.9, 6.6 Hz),
5.12 (d, 1H, J=15.4 Hz), 5.32 (dd, 1H, J=7.4, 8.8 Hz),
7.30–7.40 (m, 5H). 13C NMR (CDCl3) l 20.9, 24.6,
4.13.3. (3S,5R)-1-Benzyl-5-[(4S)-2,2-dimethyl-1,3-diox- 26.0, 26.5, 44.9, 54.9, 65.4, 70.1, 73.4, 109.8, 127.8,
olan-4-yl]-3-hydroxy-pyrrolidin-2-one 21c and (3R,5S)-2- 127.9, 128.8, 135.6, 170.4, 170.8. Anal. calcd for
benzyl-3-[(1S)-1,2-dihydroxy-ethyl]-isoxazolidine-5-carb- C18H23NO5: C, 64.85; H, 6.95; N, 4.20. Found: C,
oxylic acid methyl ester 22c. The same procedure 64.69; H, 6.80; N, 4.38%.
described above for the conversion of 4a to 21a and 13
was applied to 4c (0.44 g, 1.36 mmol). After a short 24a: 65 mg (7%); oil; [h]25 1
D −56 (c 0.51, CHCl3); H
flash chromatography (hexane/EtOAc, 1:4) of the crude NMR (CDCl3) l 1.82 (s, 3H), 2.03 (s, 3H), 2.50 (ddd,
product, a 90:10 mixture of 21c and 22c was obtained 1H, J=2.6, 8.8, 13.2 Hz), 2.66 (td, 1H, J=7.4, 13.2
and used in the next acetylation step without further Hz), 3.49 (dt, 1H, J=2.2, 7.7 Hz), 3.77 (s, 3H), 3.80 (d,
purification. 1H, J=12.9 Hz), 4.12 (dd, 1H, J=4.8, 12.1 Hz), 4.21
(d, 1H, J=12.9 Hz), 4.26 (dd, 1H, J=2.6, 12.1 Hz),
21c: 1H NMR (CDCl3+D2O) l (selected signals) 1.31 (s, 4.58 (t, 1H, J=8.5 Hz), 4.94 (ddd, 1H, J=2.9, 4.8, 7.9
3H), 1.37 (s, 3H), 1.85–2.10 (m, 2H), 3.30 (m, 1H), 3.56 Hz), 7.31–7.46 (m, 5H). 13C NMR (CDCl3) l 20.6, 20.9,
(dd, 1H, J=6.3, 8.6 Hz), 4.11 (dd, 1H, J=4.8, 8.6 Hz), 33.3, 52.5, 62.3, 62.8, 63.3, 70.4, 76.9, 127.7, 128.5,
4.30 (d, 1H, J=14.7 Hz), 4.31 (m, 1H), 4.50 (t, 1H, 129.4, 136.5, 170.3, 170.5, 172.7. Anal. calcd for
J=8.5 Hz), 5.13 (d, 1H, J=14.7 Hz), 7.28–7.39 (m, C18H23NO7: C, 59.17; H, 6.34; N, 3.83. Found: C,
5H). 59.28; H, 6.26; N, 3.91%.
22c: 1H NMR (CDCl3+D2O) l (selected signals) 2.34 4.14.2. Acetic acid (3R,5S)-1-benzyl-5-[(4S)-2,2-dime-
(ddd, 1H, J=2.2, 5.5 12.9 Hz), 2.76 (1H, J=8.1, 9.6, thyl-1,3-dioxolan-4-yl]-2-oxo-pyrrolidin-3-yl ester 23b
12.9 Hz), 3.43, 3.60 (m, 3H), 3.78 (s, 3H), 3.84 (d, 1H, and (3S,5R)-2-benzyl-3-[(1S)-1,2-diacetoxy-ethyl]-isoxa-
J=13.0 Hz), 4.08 (d, 1H, J=13.0 Hz), 4.11 (m, 1H), zolidine-5-carboxylic acid methyl ester 24b. The same
4.78 (dd, 1H, J=5.5, 9.6 Hz), 7.30–7.40 (m, 5H). procedure described above for the conversion of the
mixture of 21a and 13 to 23a and 24a was applied to
4.13.4. (3R,5R)-1-Benzyl-5-[(4S)-2,2-dimethyl-1,3-diox- the mixture of 21b and 22b. After MPLC (hexane/
olan-4-yl]-3-hydroxy-pyrrolidin-2-one 21d. The same EtOAc, 3:2) pure 24b and 24b were obtained.
procedure described above for the conversion of 4a to
21a and 13 was applied to 4d (0.3 g, 0.94 mmol). After 23b: 0.516 g (73%); oil; [h]25
D +18 (c 0.41, CHCl3); H
1

a short flash chromatography (hexane/EtOAc, 1:4) of NMR (CDCl3) l 1.26 (s, 3H), 1.48 (s, 3H), 1.83 (dt,
the crude product, only 21d was obtained and used in 1H, J=8.8, 12.9 Hz), 2.13 (s, 3H), 2.58 (dd, 1H, J=8.5,
the next acetylation step without further purification. 12.9 Hz), 3.43 (dt, 1H, J=1.8, 9.2 Hz), 3.51 (dd, 1H,
1
H NMR (CDCl3+D2O) l 1.30 (s, 3H), 1.34 (s, 3H), J=5.9, 8.5 Hz), 3.96 (dd, 1H, J=78.4, 8.5 Hz), 4.08 (d,
1.58 (dt, 1H, J=7.3, 13.7 Hz), 2.36 (dt, 1H, J=7.8, 1H, J=15.1 Hz), 4.30 (ddd, 1H, J=2.2, 5.9, 7.7 Hz),
188 P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

5.08 (d, 1H, J=15.1 Hz), 5.47 (dd, 1H, J=8.5, 9.2 Hz), (s, 3H), 2.50 (ddd, 1H, J=7.3, 8.8, 13.7 Hz), 3.50 (q,
7.32–7.40 (m, 5H). 13C NMR (CDCl3) l 20.9, 24.3, 1H, J=7.3 Hz), 3.52 (dd, 1H, J=6.8, 8.3 Hz), 3.86 (dd,
25.9, 27.5, 44.7, 56.1, 65.7, 70.8, 72.9, 110.2, 127.8, 1H, J=6.8, 8.3 Hz), 4.10 (q, 1H, J=6.8 Hz), 4.46 (d,
127.9, 128.8, 135.5, 170.3, 170.9. Anal. calcd for 1H, J=14.6 Hz), 4.90 (d, 1H, J=14.6 Hz), 5.25 (dd,
C18H23NO5: C, 64.85; H, 6.95; N, 4.20. Found: C, 1H, J=7.0, 8.8 Hz), 7.32–7.41 (m, 5H). 13C NMR
64.69; H, 6.80; N, 4.38%. (CDCl3) l 20.9, 25.2, 26.3, 28.1, 45.8, 56.9, 65.8, 70.2,
78.8, 110.5, 127.6, 128.5, 128.7, 136.6, 170.3, 170.6.
24b: 46 mg (6%); oil; [h]25 1
D +3 (c 0.33, CHCl3); H NMR Anal. calcd for C18H23NO5: C, 64.85; H, 6.95; N, 4.20.
(CDCl3) l 1.82 (s, 3H), 1.99 (s, 3H), 2.43 (ddd, 1H, Found: C, 64.96; H, 6.88; N, 4.16%.
J=3.3, 4.7, 13.6 Hz), 2.73 (ddd, 1H, J=8.1, 9.9, 13.6
Hz), 3.38 (dt, 1H, J=2.9, 7.7 Hz), 3.75 (s, 3H), 3.85 (d, 4.15. Synthesis of N-benzyl pyroglutamates 25
1H, J=12.9 Hz), 4.12 (d, 1H, J=12.9 Hz), 4.15 (dd
1H, J=4.8, 12.1 Hz), 4.32 (dd, 1H, J=2.9, 12.1 Hz), 4.15.1. (2S,4S)-4-Acetoxy-1-benzyl-5-oxo-pyrrolidine-2-
4.75 (dd, 1H, J=4.7, 9.9 Hz), 4.99 (ddd, 1H, J=2.9, carboxylic acid methyl ester 25a. The same procedure
4.8, 7.7 Hz), 7.33–7.42 (m, 5H). 13C NMR (CDCl3) l described above for the conversion of 18b to 19 was
20.8, 21.2, 36.1, 51.4, 63.0, 63.5(2C), 69.7, 73.1, 127.6, applied to 23a (0.2 g, 0.6 mmol). After radial chro-
128.4, 129.5, 136.0, 170.1, 170.6, 173.0. Anal. calcd for matography (hexane/EtOAc, 4:1) pure 25a (0.115 g,
C18H23NO7: C, 59.17; H, 6.34; N, 3.83. Found: C, 66%) was obtained as an oil; [h]25D +17 (c 0.46, CHCl3);
59.08; H, 6.43; N, 3.69%. 1
H NMR (CDCl3) l 2.00 (dt, 1H, J=6.4, 13.9 Hz), 2.07
(s, 3H), 2.77 (dt, 1H, J=8.5, 13.9 Hz), 3.65 (s, 3H), 3.92
4.14.3. Acetic acid (3S,5R)-1-benzyl-5-[(4S)-2,2- (dd, 1H, J=6.4, 8.5 Hz), 4.13 and 5.13 (2d, 2H, J=14.9
dimethyl-1,3-dioxolan-4-yl]-2-oxo-pyrrolidin-3-yl ester Hz), 5.29 (dd, 1H, J=6.4, 8.5), 7.10–7.30 (m, 5H); 13C
21c and (3R,5S)-2-benzyl-3-[(1S)-1,2-diacetoxy-ethyl]- NMR (CDCl3) l 20.6, 29.9, 45.8, 52.5, 55.4, 69.5,
isoxazolidine-5-carboxylic acid methyl ester 22c. The 128.0, 128.4, 128.7, 134.8, 170.0, 170.1, 170.8. Anal.
same procedure described above for the conversion of calcd for C15H17NO5: C, 61.85; H, 5.88; N, 4.81.
the mixture of 21a and 13 to 23a and 24a was applied Found: C, 61.62; H, 5.99; N, 4.67%.
to the mixture of 21c and 22c. After MPLC (hexane/
EtOAc, 3:2) pure 23c and 24c were obtained. 4.15.2. (2S,4R)-4-Acetoxy-1-benzyl-5-oxo-pyrrolidine-2-
carboxylic acid methyl ester 25b. The same procedure
23c: 0.304 g (67%); oil; [h]25 D −49 (c 0.38, CHCl3); H
1
described above for the conversion of 18b to 19 was
NMR (CDCl3) l 1.32 (s, 3H), 1.38 (s, 3H), 1.95 (dt, applied to 23b (0.15 g, 0.45 mmol). After radial chro-
1H, J=8.8, 13.7 Hz), 2.13 (s, 3H), 2.18 (ddd, 1H, matography (hexane/EtOAc, 4:1) pure 25b (90 mg,
J=2.4, 9.3, 13.7 Hz), 3.46 (ddd, 1H, J=2.4, 7.3, 8.8 69%) was obtained as an oil; [h]25
D −7 (c 0.50, CHCl3);
Hz), 3.55 (dd, 1H, J=5.6, 8.3 Hz), 4.00 (dd, 1H, 1
H NMR (CDCl3) l 2.15 (dt, 1H, J=8.9, 13.4 Hz), 2.15
J=6.8, 8.3 Hz), 4.09 (q, 1H, J=6.4 Hz), 4.29 (d, 1H, (s, 3H), 2.64 (ddd, 1H, J=1.5, 8.9, 13.4 Hz), 3.67 (s,
J=15.1 Hz), 5.12 (d, 1H, J=15.1 Hz), 5.40 (t, 1H, 3H), 4.00 (dd, 1H, J=1.5, 8.9 Hz), 4.06 and 4.98 (2d,
J=8.3 Hz), 7.29–7.41 (m, 5H). 13C NMR (CDCl3) l 2H, J=14.8 Hz), 5.46 (t, 1H, J=8.9), 7.20–7.40 (m,
20.8, 25.0, 26.4, 29.7, 45.9, 56.4, 66.6, 70.2, 79.0, 110.58, 5H); 13C NMR (CDCl3) l 20.8, 30.6, 46.2, 52.7, 55.9,
127.7, 128.4, 128.7, 136.1, 170.4, 170.6. Anal. calcd for 69.7, 128.1, 128.7, 128.8, 134.7, 170.2, 170.5, 171.3.
C18H23NO5: C, 64.85; H, 6.95; N, 4.20. Found: C, Anal. calcd for C15H17NO5: C, 61.85; H, 5.88; N, 4.81.
64.73; H, 6.86; N, 4.15%. Found: C, 61.95; H, 6.02; N, 4.74%.

24c: 35 mg (7%); oil; [h]25 D +27 (c 0.27, CHCl3); H

1
4.15.3. (2R,4S)-4-Acetoxy-1-benzyl-5-oxo-pyrrolidine-2-
NMR (CDCl3) l 1.92 (s, 3H), 2.02 (s, 3H), 2.41 (ddd, carboxylic acid methyl ester ent-25b. The same proce-
1H, J=5.9, 10.3, 13.2 Hz), 2.73 (dt, 1H, J=9.2, 13.2 dure described above for the conversion of 18b to 19
Hz), 3.39 (ddd, 1H, J=5.5, 9.2, 10.3 Hz), 3.8 (s, 3H), was applied to 23c (0.12 g, 0.36 mmol). After radial
3.91 (d, 1H, J=13.2 Hz), 4.05 (d, 1H, J=13.2 Hz), 4.08 chromatography (hexane/EtOAc, 4:1) pure ent-25b (70
(dd, 1H, J=5.1, 12.1 Hz), 4.18 (dd, 1H, J=4.0, 12.1 mg, 67%) was obtained. The physical and spectroscopic
Hz), 4.70 (dd, 1H, J=5.9, 9.2 Hz), 5.04 (dt, 1H, J=4.0, properties of this compound were identical to those of
5.3 Hz), 7.30–7.40 (m, 5H). 13C NMR (CDCl3) l 20.6, 23b except for the sign of the optical rotation: [h]25
D +7
20.9, 34.1, 52.5, 61.5, 63.1, 63.2, 72.0, 75.3, 127.7, 128.5, (c 0.22, CHCl3). Anal. calcd for C15H17NO5: C, 61.85;
129.1, 136.2, 170.3, 170.4, 171.0. Anal. calcd for H, 5.88; N, 4.81. Found: C, 61.79; H, 6.00; N, 4.89%.
C18H23NO7: C, 59.17; H, 6.34; N, 3.83. Found: C,
59.04; H, 6.31; N, 3.95%. 4.15.4. (2R,4R)-4-Acetoxy-1-benzyl-5-oxo-pyrrolidine-2-
carboxylic acid methyl ester ent-25a. The same proce-
4.14.4. Acetic acid (3R,5R)-1-benzyl-5-[(4S)-2,2- dure described above for the conversion of 18b to 19
dimethyl-1,3-dioxolan-4-yl]-2-oxo-pyrrolidin-3-yl ester was applied to 23d (0.14 g, 0.42 mmol). After radial
23d. The same procedure described above for the con- chromatography (hexane/EtOAc, 4:1) pure ent-25a (86
version of the mixture of 21 and 13 to 23a and 24a was mg, 70%) was obtained. The physical and spectroscopic
applied to 21d. After flash chromatography (hexane/ properties of this compound were identical to those of
EtOAc, 3:2) pure 23d (0.235 g, 75%) was obtained as an 23a except for the sign of the optical rotation: [h]25
D −16
D −27 (c 0.32, CHCl3); H NMR (CDCl3) l 1.29
oil; [h]25 1
(c 0.40, CHCl3). Anal. calcd for C15H17NO5: C, 61.85;
(s, 3H), 1.33 (s, 3H), 1.46 (dt, 1H, J=7.0, 13.7 Hz), 2.14 H, 5.88; N, 4.81. Found: C, 61.83; H, 5.81; N, 4.90%.
 P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190 189

Acknowledgements 10. Zhang, X.; Schmitt, C.; Jiang, W. Tetrahedron Lett. 2001,
42, 5335–5338.
11. (a) Merino, P.; Anoro, S.; Merchan, F.; Tejero, T. Hete-
The authors gratefully acknowledge the financial sup- rocycles 2000, 53, 861–875; (b) Tejero, T.; Dondoni, A.;
port by the DGI (Project CASANDRA, MCYT, Rojo, I.; Merchan, F. L.; Merino, P. Tetrahedron 1997,
Madrid), DGA (Project P116-2001, Zaragoza), 53, 3301–3318; (c) Casuscelli, F.; Di Bella, M. R.;
MURST (Roma) and Italian CNR (Roma). Romeo, G.; Chiacchio, U.; Rescifina, A. Gazz. Chim.
Ital. 1977, 127, 367–371.
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W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; with electron-poor dipolarophiles.