CA1256887A

CA1256887A - 7-oxabicycloheptane substituted prostaglandin analogs

Info

Publication number: CA1256887A
Application number: CA000448662A
Authority: CA
Inventors: Steven E. Hall; Martin F. Haslanger
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1983-03-14
Filing date: 1984-03-01
Publication date: 1989-07-04
Also published as: PL246663A1; DE3409124A1; GB8406100D0; IE840525L; CH658247A5; LU85249A1; ATA83484A; FI841008A0; ES8506270A1; GB2136428A; FI841008A; DD216932A5; AU567919B2; NL8400797A; IL71184A0; GR79881B; DK155584A; KR840009085A; AU2523584A; HUT34179A

Abstract

HA290/280 ABSTRACT 7-OXABICYCLOHEPTANE SUBSTITUTED PROSTANGLANDIN ANALOGS 7-Oxabicycloheptane substituted prostaglandin andlogs are provided having the structural formula wherein B is oxygen (-O-) or wherein n' is 0 to 2, R is hydrogen, lower alky, alkali metal or trihydroxymethylaminomethane, R1 is alkyl, alkenyl, alkynyl, aryl, aralkyl; aralkenyl, aralkynyl, cycloalkylalkyl, cycloalkylalkenyl or cycloalkynyl. A is -CH=CH- or -(CH2)2-, n is 1 to 4, and m is 1 to 8, and including all stereoisomers thereof. The compounds are cardiovascular aqents useful, for example, in the treatment of thrombolytic disease.

Description

~25~887 - _~A290/280 _ ; . 7-O~ABICYCLOHEPTA~E SUBSTITUTED
PROSTAGLANDIN ~NALOGS
, ., .
; 5 The present invention relates to 7-oxabicycloheptane prostaqlandin analogs which are cardiovascular agents us~eul, ~or example, in the treat~ent o~ thrombolytic disease. These compounds have the structura1 formula I ~ CH2-A-(CH2)m-cOOR
< ~ I

(C~2)n-B-R

wherein B is oxygen (-O-) or -~- w,herein n' is 0 to 2, R is hydrogen, lower alky~, alkali metal or trihydroxymethylaminomethane, Rl is alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkylalkyl, cycloaLkylalkenyl or cycloalkynyl.
~ A is -CH=CH- or -(C~2)2-, n is l to 4, and m is l to ; 8, and including all stereoisomers thereof.
The term "lo~er alkyl" or "alkyl" as employed herein includes both st~aight and beanched chain : 25 radicals of-up to 12 carbons, preferably l to 8 , .

.ar ~25~
i HA2~0/2~0

-2~

. carbons, such as methyl, ethyl, propyl, isopcopyl, - butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the ~arious branched chain isomers thereo~, and ~he like as well as such srouPs ; incl~ding a halo-sub~tituent, such as F, Br, Cl o~
I OL CF3, an alkoxy substituent, a haloaryl substituent, a cycloalkyl substituent (that is, cycloalkylalkyl3 or an alkylcycloalXyl substituent.
The terms "alkenyl" and "alkynyl" as used herein contemplate simllar hydrocarbon groups bearing therein a carbon-carbon double or triple hond such as for example, 2-propenyl, 2-hexenyl, 3-hexenyl, 3-hexynyl and in the case of an aryl substituent or cycloalkyl substituent as defined below, 3-phenyl-2-propenyl, 3-phenyl-2-propynyl, 3-cyclohexyl-2-propenyl and 3-cyclo-hexyl 2-propynyl.
The ter~ "cycloalkyl" includes saturated cyclic hydrocarbon groues containing 3 to 12 carbans, pre~erably 3 to 8 carbons, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl ~nd cyclododecyl, any of which groups may be substituted with l or 2 halogen, l or 2 lower alkyl groups and/or lower alkoxy groups.
The term ~aryl~ or ~Ar~' as employed herein refers to monocyclic or bicyclic aro~atic groups containing ~rom 6 to lO carbons in the ring portion, such a~ phenyl, naphthyl, substituted phenyl or substituted naph~hyl wherein the substituent on either the phenyl or naphthyl may be lower alXyl, halogen (Cl, 8r or F~, or lower alkoxy.

~25~ HA2 5 0 / 2 8 0 . 3 .~ .
. .
The term ~aralkyl~ aryl-alkyl~ or "aryl-lower alkyl~ as used herein Lefers to lower alkyl groups as discussed above having an acyl substitu~nt, such as benzyl.
The terms "(CH2)n~" and "(CH2~n" includes a straight or branched chain radic:al having from 1 to 8 carbons in the normal chain i.n th~ cas~ of " (CH2),1," and 1 to 4 carbons i~ th~ rlormal chain in ~he cas~ of " (CH2)n" and may contain one or more lower alkyl substituents. E~ca~npl~s of (CH;~)m and (CEI2)n groups include CH2.
CH2CEI~, ( CH2 ) 3, ( CE~2 ) 4 ~ ( CH2 ) 5 ' ( 2 6 10 ( CEI2 ) 7 - ( CEI2 ) 2 -Cl H- . -CH2 -Cl E~-, -CH2 - ICEI--~H-CEI2 -, C~I3 C~3 CE~3 CH3 -CH2- IH-CH2-ClEI-, and ~he likQ.
CH3 , CE~3 . .

~8~ ~

_4_ The compounds of Formula I (wherein R is alkyl) are prepared by etherifying or thioether-ifying a compound of the Form~la II:

~ 2-A-(C~)m 2 (C~2)n_} 2 q with the desired Rl-oH or R~SH groups or thelr equivalents according to conventional methods.
TXe synthesis of ethers an-d thioethers is based on the Williamson Synthesis (J. Chem. Soc.
4, 229 (1852)) wherein ethers (and later thio-ethers) were synthesized by alkylation ofalkoxides with alkyl halides:

R'(O or S)Na ~ R"X-~ R'(O or S)R" + NaX
.
The modern version of this synthesis envisions use of other leaving groups in addition to halides.
Thus with respect to Formula II above, the ether-ification or thioetherification reaction comprehends reaction of a Formula IIa compound of the formula ~H 2-A-(ca2)m-co2alkyl IIa ~ (CH2) n-~ ca2X

wherein X in addition to hydroxy can also be -SH or their sodium or potassi~um salts, chloro, bromo, iodo and alkyl, aryl- and aralkyl-sulfonyloxy groups with a complementary RlX compound to form the following type compounds of Formula I:

_5 _ .

(C~ ) -A- ~C~ ) -CO alkyl ~/ ~f 2 2 in 2 ~ j CH2 -A- (CH2 ) CO alkyl ~ C~2) n~~R \~~~ (CH2 ) -S-R
III IV
The thioethers of Formula IV can then be oxidized to the sulfinyl and sulfonyl derivatives ~n'=l or 2 in Formula I~ having the formulae~

10 ~C82-A~(c~2)mco2alkyl CH2~A~(C~i2)m~C2 (CH2) n~~~R \~;~ (C~2) n O R

V VI ., 15 ' ' ' The compounds o Formula I wherein R ls an alkali metal or hydrogen (free acid) can then be prepared from the above products where R is alkyl by conventional basic hydrolysis with sodium or potassium hydroxide to form the sodium and potassium ; salts followed by acidification to the free acid.
Etherification is usually accomplished by reacting the Formula II compound with a compound of the formula RlX wherein X is chloro, bromo, or iodo or methylsulfonyloxy or toluenesulfonyloxy, in the presence of a strong base such as sodium or potassium hydroxide in an appropriate solvent. In carrying out the reaction a molar excess of the RlX reactant varying from .25 mole excess to a 5 mole excess is used employing a solvent such as xylene, tetrahydrofuran, dimethylsulfoxlde or dimethylformamide. In the case where X is bromo or chloro, a phase transfer etherification can be - employed in which case tetrahydrofuran is used as the solvent and a phase transfer reagent such as .

~:256~7 ~ ---H~290/2~0 Bu4NHS04 or (C6H5CH2)~CH3)3NHS04 is employ~d- In the case wherein Rl is aryl it is convenient to first react the alcohol group of the Formula II
compound with triphenylphosphine and diethylazo-dicarboxylate in solution with an inert solventsuch as tetrahydrofuran and then with an Rl(aryl) alcohol such as phenol. As is generally known in the art, the sequence of reacting the Formula II
alcohol with the RlX compound to achieve ether-ification can be reversed by converting the FormulaII alcohol into a Formula II compound wherein the alcohol group has been replaced with another radical from the group X and then reacting with an Rl-alcohol or al~oxide to form the Formula I product.
Thioetherification is usually accomplished by flrst converting the Formula II alcohol to another Formula II-X derivative as indicated above and thioetherifying with an RlS~ mercaptan in the presence of a base or with an alkali metal sal~
thereof.
Oxidation of the sulfide product where n'=O
to the sulfinyl and sulfonyl analogs where n' is 1 or 2 is readily accomplished by reacting with sodium periodate in the presence of methanol and tetrahydrofuran to form the sulfinyl and sulfonyl derivatives which may then be separated by chromatography or other conventional separation procedures.
The starting materials of Formula II wherein n is 1 (hydroxymethyl group) are known from U.S.
; Patent 4,143l054 and can be prepared as described therein. These compounds can be used to prepare starting materials of Formula II wherein n is 2 to 4 by oxidation of the hydroxymethyl group to an aldehyde by way of a Collins oxidation, for example, by reacting Compound II with chromium trioxide in pyridine, to form a intermediate of the formula ~CH2 A- (CH2) mC02~11kyl C~O
VII
The Formula VII aldehyde is subjected to a homologation sequence by way of a Wittig reaction using (C6H5)3P=CHOCH3 folIowed by hydrolysis 5n-1) times followed by reduction of the aldehyda to the alcohol employing a reducing agent such as sodium borohydride or sodium cyanoborohydride in a solvent such as methanol to fbrm the Formula II
starting material:
.

~25~7 - ` HA290/280 .

. , .

a) I r~

_I
o ,., /1`. ~, ~o~

o~ ~;o ~) o ~ ~

3~
~0 ~7 O
~!
_~
. ,~
3 C~ I .
. , .

, - ~ ~ HA290/280 _g _ .

Th.e tris(hydroxymethyl)aminomethane salt of any of the acids of focmula I of the present invention i~ formed by reacting a solution of such acid in an inert solvent such as methanol with tristhydroxymethyl)aminomethane and thereafter ~he solvent is re~oved by evaporation to leave the desired salt.
The compounds o~ this invention have ~our centers o~ asymmetry as indicated by the asterisks i~ ~ormula I. However, i~ ~ill be apparent that.
each of the formulae set out above which do not include asterisks still represent all of the possible stereoisomers thereof. All of the YariOUs stereoisomeric forms are within the scope of the in~ention.
The ~arious stereoisomeric forms of the compounds of the invention. namely, cis-exo, : cis-endo and all trans forms and stereoisomeriF

.~

- ~256~7 HA2so/280 , pairs may be prepared as shown in the working Examples which follow and by employing starting materials and following the procedures as ouelined in U. S. Patent No. 4.143.054. Examples of such stereoiso~e~s are set out below.

CH2-A-~CH2)m-C02R

CH2)n-~-R

O E~

~cis endo) . ..

I~ . ~ ~ _-C~2-A-(c~2~m O (CH;~)n-B-R

(cis-exo) ' I g \~¦ ~ ~ C~2 -A- ( CHz ) m-C2 <~1~ ( C~2 ) n~ B -R
O ~1 (trans) I ~I2-A-tC~2)m-cO2 Ih \ ~H

O (CE[ ) B

ttrans) The nucleus in each of the comp~unds of the invention is depicted as /~

O

. HA290/280 for matter of convenience: it will also beappreciated that the nucleus in the c:ompounds of the invention may be depicted as ~b The eomp~unds of this invention are cardio~ascular agents useful as platelet ag~regation inhibitors, e.g., for treatment of t~ro~bolytic disease, such as coronary or cerebral thrombo~es. They are also selective thromboxane A2 receptor antagonists and syn~hetase inhibitors, e.g., having a vasodilatory effec~ for treatment o~ myocardial ischemic disease, such as ~ angina pectoris. The compounds of the invention ; 20 are also arachidonic acid cyclooxygenase inhibitors. ~hey can be administered orally or parenterally to various mammalian species known to be subject to such maladies, e.g., cats, dogs, and the like in an effective amount ~ithin the dosage 25 range of about 1 to 100 mg/ky, preerably about 1 to 50 mg/kg a~d especially about 2 to 25 ~g/kg on a regimen in single or 2 to 4 divided daily doses.
The active substance can be u~ilized in a composition such as tablet, capsule, solution or suspension containing about 5 to about 500 mg per .

~i@5~

. 13-unit of dosage of a compound oc mix~ure ofcompounds o~ ~ormula I. They ~ay be compounded in conventional matter with a physiologically acceptable vahicle or carrier, excipient, binder, preservative, stabilizer. ~lavor, etc. as called for by ac~epted pharmaceutical p actice. Also as indicated in the discussion above, certain members additionally ser~e as intermediates ~or other ~embers of the group.

HA2so/280 .
The following Examples represent preferred embodimen~s of the invention.
Exampl e LlB.2~5Z),3~ 4~1-?- r~3- L(HexYlox~lme-thyll=7-oxabicyclor2._.llhePt-2-vl~5-he~tenoic acid. hexyl ester A. ~ 2~(5Z).3~.4BL-7-L3-(HY~roxYmethYl)-7-oxab_yclo~2.2.11he~t-2-yll-5-heptenoic acid, methyl_ester (a) A mixture of N-acetylpyridinium chloride was pcepared by adding 9.6 ml (136 mmole) of acetyl chlo ide dropwise to 56 ml of pyridine. To thls was added 5.0 g (27 mmole) of ~qxo)-3-(2-methoxy-ethenyl)-7-oxabicyclot2.2.1]heptanq-2-methanol dl~solved in 5 ml af py~idlne. The resulting mixture was stirred at room temperature ~or 1.5 hours and poured into brine. The product was extrac~ed into ether (3 x 200 ml); the ether extracts were washed with S~ hydrochloric acid (2 x 20 400 ml) and brine (1 x 200 ml) and dried over sodium sulfate. Concentration yielded a yellow oil which was purified by passage through a short column of silica gel (150 ml) with dichloromethane: yield

4.42 g of an oil.

(b) To a solution of 4.42 g (19.6 mmole) of the oil in 500 ml of tetrahydrofuran containing 50 ml of water was added 31.1 g (97.8 mmole) of mercuric acetate. T~e yellow suspension which formed was stirred for 10 minutes and then the -HA~90/280-15-entire mixture was poured into a solution containing200 g of potassium iodide in 2 l. of water. Upon shaking, the yello~ color disappeared and the mixture was extracted with benzene (~ x 500 ml).
S The combined benzene extracts were washed with potassium iodide solution and brine and dried over sodium sulfate. Concentration yielded 3.7 g of ~aterial which crystallized on standing in an ice box, (c) A Wittig reagent was prepared in dimethyl sulfoxide (dried over calciu~ hydride) by adding a solution of sodiu~ methylsulfinylmethide (prepared by heating 300 mg of sodium hydride in 60 ml of dimethyi sulfoxide at ~5 until hydrogen evolution itopa) dropwise to a solution of 5~32 g (12 mmole~
of 4-carboxybutyl triphenylphosphonium bromide in 100 ~1 o~ dimethyl sulfoxide. After the first orange color lasting more than 10 seconds formed, an equivalent amount o~ base was added to ~orm the ylide. To this deep orange solution was added a solution of the product of part (b) in 20 ml of dime~hyl sulfoxide and the resulting mixture stirred at room temperature for 45 minutes. The reaction was quenched by addition of 24 mmole of acetic acid a~d the mixture poured into brine (300 ml) and extracted with ether (3 x 200 ml). Concentration of these extracts gives an oil which was stirred with saturated sodium bicarbonate solution until crystalline triphenylphosphine oxide formed in the HA29~/280 - . mixture. This mixture was washed with benzene and acidified with 10% hydrochloric acid. The aqueous layer was saturated with salt and extrac~ed with ether which on drying (sodiu~ sulfate) and ~oncentration ga~e 2.43 g o~ crude product. The mixture was stirred 24 hours with 10'~ aqueous sodiu~
hydroxide and reisolated by acidification and ether extraction. The produet was purified on 500 q o silica gel with 50/50 ethyl acetate-hexane as the eluant ~hich ga~e 600 mg of acid ~hich crystallized on standing. This was recrystallized twice fsom ethyl acetate-cyclohexane to yield 320 mg of tl~.2~(5Z),3~,4R~-7-~3-(hydroxymethyl)-7-oxabi-cyclot2.2.~lhept-2-yl]-5-heptenoic acid,m.p. 59-63C.
Anal. Calc'd ~or C14H2204: C,66~ H,8-72 Found: C,66.06i H,8.79 The acid is then converted to the correspondiny methyl ester by treating with diazomethane.

B. Ll~ ~2~t5Z),3~,4~1-7-~3-~HexYloxy)-~ethyll-7-oxabicYclo~2.2.llhe~t-2-Yll-5-he~tenoic acid, hexYl ester A suspension of 0.56 g of powdered KOH in 15 ml of dry xylene was heated to reflux and 7 ml of xylene was distilled ofE. To this mixture was added a solution of 300 mg (1.12 mmol) of alcohol ester from part A in 10 ml of dry xylene. The resulting mixture was heated to reflux and 9 ml of xylene was distilled off. To this mixture was added 1.0 g .

.

. -6~3~7 - -' 'HA290/280 (5.6 mmol) of n-hexylmethanesulf,onate and the resulting mixture was heated at reflux for 1-1/2 hours. The reaction mixture was cooled to ambient temperature and diluted with CH2C12 (~0 ml).
The resulting solution was poured into 50 ml satura~ed NaHC03. The layers were separated and the aqueous phase was extracted (2 x 60 ml) with CH2C12. The combined CH2C12 extracts were dried over MgSO4, then concentrated in vacuo to yield 0.9 g of crude prod,uct. The crude product was chromatogr~phed on 33.4 g of silica gel 60 with hexane:~ther (5:1) to yield 390 mg ~83~) of the title hexyl ester.

ExamPl~ 2 ~1~,2~t$Z~,3~,4~1-7-~3-t~HexYloxy)methvll-7-oxabicYclot2.2.llhept-2-~ll-s-heptenoi-c--acid To a st~red solu~ion of'115 mg (0.27 mmol) of the Example 1 hexyl ester in 12.0 ml of dis~illed THF and 1.60 ml f ~2 under argon was added 2.40 ~1 of lN aqueous lithium hydroxide solution. This mixture was purged with argon for 40 minutes and stirred at room temperature for 24 hours. At this time, TLC analysis showed that the reaction was not co~plete so an additional 1 ml of methanol and 1 ml of lN aqueous lithium hydroxide was added. The reaction mixture was kept stirring for another 4 hours and then was acidified to pH 4 by the addition of lN aqueous HCl solution. The resulting solution was poured into 25 ml of saturated NaCl solution and was saturated wth s~lid NaCl. The aqueous layer was extracted with EtOAc (4 x 40 ml). The combined EtOAc extracts ~ere dried over anhydLous MgS04, . .

~A290/230 filtered and concentrated in vacuo to gi~e 124 mg of crude oil. This was chromatographed on 20.6 g of silica gel 60 using hexane:ether (2:3) as eluant to giYe 102 mg Q~ desired product contaminated with a small a~ount of hexyl alcohol. The mixture was put in high ~acuum overnight at room temperature to giv~
77 mg (84%) of pure title acid. TLC: silica gel, a~
C~3~H~C~2C12. Rfl0.74. iodine-~nal. Calc d for C~oH3404 Found: C, ~70.60: H, 9.89 CNMR (CDC13, l5.0mHz)tau 33.4, 22.6, 24.6, 129.4, 130.1, 26.7, 46.4, 79.4, 29.5, - 80.1, 46.8, 71.3, 69.8, 31.7, 25.7, 29.7, 22.6, 14Ø
.
Example 3 ~lB.2~(5Z).3~,4~1-7-~3-~HexYloxY)methyll-7-oxa~icvclor2.2.11hePt-2-Yll-5-he~tenoic acid, hexYl ester 503 mg (1.83 mmol) o~ tlB,2~(5Z),3~,4~l-?-t3-(hydroxymethyl)-7-oxabicyclot2.2.1~hept-2-yl]-5-heptenoic acid, methyl ester (prepared as described in E~ample 1) ~as dissolved in 2.17 ml tetcahydro-uran. ThereaSter 2.17 ml (15.46 mmol) of n-hexyl bromide, 173.4 mg (0.51 mmol) te~rabutylammoniumbi-sulfate (Bu4NHS04), and 2.17 ml of a 50~ NaOH
solution were added and the mixture vigorously stirred at room temperature. A slightly yellowish-brown solution formed which upon stirring o~ernight for~ed a white precipitate.
The reaction mixture ~as poured into 25 ml of saturated NaHC03. The mixture was extracted with CH2C12 (4 x 25 ml). The combined CH2C12 , HA290/2~0 extracts were dried (MgS04), f~ltered and concenerated in va~uo to give tlfl,2l~(5Z),3~,4~-7-E3-~hexyloxy)methyl~-7-oxabicyclol2.2.1~hept-2-yl~-

5-heptenoic acid, hexyl .ester (1272 ~g). This ~as chroma~ogr~phed on 40 g ~llica gel using hexane:et~er (4:1) a~ eluant to give f~nal product.

ExamPle 4 ~lB,2~,3~4~)-7-~3-LtHexYl xy~meth~ll-7-oxa-bic~clot2~2~llhept-2-yl~heptanoic acid, hexyl ester A. ~lB,2~.3~.4~) 7-~3~ ydr~xxlmethyll-7 oxabicYclo~2.2.11he~t-2-YllhePtanoiC acid methYl ester To 800 mg ~3.0 m~ole) o~ the El~.2~(5Z).-3~,4~]-7-t3-thydroxy~ethyl)-7-oxabicyclot2.Z.l]-hept-2-yl]-5-heptenoic acid, met~yl ester as prepared in Example L, dissolved i~ 120 ml of ethyl aceCate wa~ added, und~r a3 argo~ at~os~here, 160 mg of 5% Pd on carbon. The arqon atmosphere was exchanged for a slight ~osit~ve pressure of hydrogen and the reaction was stirred for 8 hours at 25 , ~iltered through a Celite plug and evaporated to provide 730 mg (90~) o~ the title ~ compound.

B. ~1~;2~,3~,4~L~L Ll L~_exYloxylmethyll-7-oxabicy~lo~2.2.11hePt-2-Yll-S-hePtano~c aeid, hexYl ester Following the procedure of Exa~ple 1 except subs~ituting ~he Part A alcohol-ester for the Examp~e lA alcohol ester. the title product is obtained.

* Trade Mark _ -20-Example 5 (1~,2a,3a,4~)-7-[3-~(Hexyloxy)methyl~-7-oxabi-cyclo~2.2.1]hept-2-yl]heptanoic acid Following the procedure of Example 2 except substituting the Example 4 hexyl ester for the Example 1 hexyl ester, the title acid is obtained as an oil [a~25= -3.1(c=1.37, CHC13); TLC(silica gel, 8% CH30H)CH2C12 , Rf=0.74.
Anal. Calcd. for C2oH36O4: C,70.55; H,10.66 Found: C,70.30; H,10.70 CNMR (CDC13, 15-0MHz)tau 179.1, 33.9, 24.6, 27.6, 29.2, 29.3, 29.0, 47.0, 79.1, 29.7, 29.6, 80.1, 46.4, 71.2, 69.8, 29.3, 25.a, 31.6, 22.6, 1~.0 .. ~ .
[1~,2a(5Z),3~,4~]-7-[3-[(Hexyloxy)methyl]-7-oxabicyclo[2.2.11hept-2-yll-5-heptenoic acid Following the procedure of Examples 3 and 2 20 except substituting [1~,2a(5Z), 3~,4~]-7-[3-(hydroxymethyl)-.7-oxabicyclo[2.2.1l-hept-2-yl]-S-heptenoic acid, methyl ester for ~1~,2(5Z), 3a,4~]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid,. methyl ester, the title compound is obtained as an oil.
Anal. Calcd. for C20H34O4 Found: C, 70.93; H, 10.33 3C NMR (C3C13, 15.0MHz)tau 178.7, 33.4, 24.6, 26.6, 128.7, 129.9, 32.6, 47.9, 79.1, 29.5, 23.8, 80.5, 49.1, 71.7, 71.2, 31.6, 25.8, ~9.9, 22.6, 13.9 :`

' ` HA290/280 - -21~
Example 7 [1-~,2a(5Z),3a,4~]-7-[3-Methyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 1 and 2 except substituting methyl methanesulfonate for n-hexyl methanesulfonate, the title compound - is obtained as an oil, [a]25= ~10.4 (C=2.21, CHC13~.
Anal. Calcd. for.C~5X24O4: C, 67.14; H, 9.01 Found: C, 67.03; H, 9.14 3C NMR ~CDC13, 15 0MHz) tau 178.3, 33.2, 24.4, 25.5, 129.5, 129.8, 26.5, 46.5, 79.:L, 29.3, 29.3, 79.g, 46.2, 71.7, 58.6.

~ HA~90/280 Example 8 Ll~._a(5Zl.3~.4Rl-7-[3-~tProPYloxY)m~hy~
oxabicycloL2.2.11hePt-2-v~ 5-heptenoic acid Follo~ing the procedure of Example 6, excep~
subs~ituting n-propylbromide for n-hexylbromide, the title c~mpound is obtained.

~ xample 9 (lR.2~.3~4~)-7-~(3utyloxy)methY11-7-10. oxabicYclol2.2.llhe~t-2-~llheptano-ic acid Following the procedure of Examples 4 and S
eXcept subatituting n-butyl methanesulConate for n-hexyl m~thanesul~onate. the title compound is obtal~d.

ExamPle 10 ~lB.2~5Z),3~.4~1-7-t3-1(OctYloxY)methvll-7-oxabicvclot2.2.Llhe~t-2-yll-S-heptenoic_acid Pollowing the procedure of Examples 1 and 2 e~cept sub6tituting n-octyl methanesulfonate for n-hexyl methanesulfonate, the title compound is obtained.

ExamP-le 11 ~,2~5Z),3~,~81-7-~3-~(PhenYloxy)methyll-7 oxabicYclot2.2.1lhePt-2-vll-s-he~tenoic acid (a) Phenol (1 mmol) is added to a solution of triphenylphosphine (1 m~ol), diethylazodicarboxy}ate (1 mmol) and title A alcohol from Example 1 ~1 mmol) in 25 ml THF and is stirred under an argon .

. -23~

atmosphere for 48 hours at 23C. The reaction mix~ure is concentrated in vacuo. The residue is triturated with ether and the solids are removed.
The filtrate i5 concentrated in vacuo and ~j chromatographed OEl silic3 gel to give tlB,2~(5Z),3~.4B~-7-t3-t(phenyloxy)~ethyl]-7-oxabicyclol2.2.1]hept-2-yl3-5-heptenoic acid, methyl ester.

(b) Pollowing the procedure as set ou~ in Example 2. the ester ~ro~ part (a) is convereed to the title compound.

Exa~Ple 12 15 J~ g(SZ) ~3~.4Rl-7~ t (PhenYlox~r)meth~
7-oxab~cYcloL2.2~11he~-2-Yll-5-he~tenoic acid (a) Phenol (1 mmol~ i5 added to a so}ution of . triphenylphosphine (1 mmol~, diisopropylazodi-carboxylate (1 mmol) and title A alcohol fro~
Example 1 (1 mmol) in 25 ml THP and is stirred under an argon atmosphere for 48 hours at 23C. The reaction mixture is concentrated in vacuo. The resiaue is triturated with ether and the solids are removed. The ~iltrate is concentrated in vacuo and chromatogra~hed on si}ica qe} to give tl~2~(5z)~3B~4A]-7-t3-t(phenyloxy)methyli-7-oxabicyclot2.2.1]hept-2-y}]-5-heptenoic acid, methy}
ester.

~;æs6ss~

. -24-tb) Following the Procedure as set out inExample 2, the ester from part (a) is converted to the title compound.

S Exampls L3 llB,2~(5Z)~3~,4~1-7-t3 t(Ethvlox~lmethY11-7-ox~bic~clot?.2.11heue-2-Yll-s-heQtenoic acid Following the procedure of Examples 3 and 2 except substituting ethylbromide ~or n-hexylbromide, the title compound is obtained..

Exa.mPle 14 Ll~.2~ AL-7-t3-L~phenyloxylmQthyll-7-oxabicvcloL2.~ ept-2-~llheptanoic acid Following the, procedure o~ Example 11 exc~pt substituting (1~,23.3~.4~)-7-~3-~(hydeoxy)-methyl]-7-oxabicyclo~2.2.1~hep~-2-yl~heptanoic.a.cid, methyl ester ~or the alcohol o~ part (a) of Exam~le 11, the title compound is obtained.
Example 15 tlR.2~(5Z~.3~.4~1-7- r 3 r (~enzyloxYlmethyll-7=
oxabic~clor2.2.Llhept-2-vll-5-heptenoic acid Following the peocedure o~ 2xample 6 except ~ub~tituting benzylbromide ~o~ n-hex~ylbeomide, the title compound is ob~ained.

.~.. i .

5~
_ HA290/280 _ .
-25- - .

Example 16 (1~,2l,3~L~)-7:[3-[(~enzYloxyimethyll-7-oxabicvclo~2.2.11he~t-2-vllhePtanoic acid Following the procedure of ~xamples 4 and 5 S except substitu~ing benzyl methanesulfonate fo~
n-hexyl methanesulfonate, the ~itle compound is obtained.

~xam~le L7 t~ 25~s2~3~4Rl-7-~3-L~clohexylox~r)methyll-7 oxabicYclo~2.2.~1hePC-2-Y11-5-hePtenoic acid Following the procedure of Examples 1 and 2 except subætituting cyclohexyl methanesulfonate for n-hexyl methanesulfonate, the title compound is obtained.

Exam~le la tl~.2~(5Z) I~.4~1-7-13-L(CvcloPentyloxy)methyll-7 oxabicyclo~2.2.11he~t-2-~11-5-heptenoic acid Following the procedure of Examples 1 and 2 except substituting cyclopentyl methanesulfonate for n-hexyl methanesulfonate, and substituting tl~ (5Z).3~.4~]-7-~3-(hydroxymethyl)-7 oxabicyclot2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester (prepared as described in U. S. Patent No.
4,143,054) for tl~.2~(5Z),3~.4~]-7-t3-(hydroxymethyl)-7-oxabicyclotZ.2.1]hept-2-yl]-5-heptenoic acid. methyl ester, the title compaund is obtained.

~2~7 HA290~280 `

Example l9 (1~,2c~3~,4~1-7-L3-~(CYclohexyloxylmethYl]-7-oxabic~cloL2,2.llhe~-2-~llhe~tanoic acid Pollowing the procedure of Examples 4 and 5 except substituting cyclohexyl methanesulfonate for ~-~exyL ~e~hanesu~nate. the tit~e com~o~nd is oh ta ined .

~1~,2~Z~.3~,4~1-7-~3-12-~HexYloxY-ethYll-7-oxabicyclc~Z.2~L1hept-2-Yll-5-heQtenoic- acid A. LlB .2~(5Z).3~,4RI-7-~3-(2-Oxo) ethYIl-7-oxabi~Yalo t 2 . 2 . 11 hQPt-2-Yl 1 -S-hePteno~c ~n~o a dry 100 ml round bot~om 3-n~cked containing a stir bar was added dried 12.9 g t37.7 mmoles) methoxymethyltriphenylphosphonium chloride (~ 6~5)3P -CB20~3Cl ) and Z35 ml distilled toluene (stored over molecular sie~es).
The resulting suspension ~as stirred in an ice-bath, under argon. until cold and then a L.SS ~ solution of 18.3 ml t28.3 mmol) of potassium t-amylate in toluene was added dropwise. A bright red solution formed Which was stirred at 0C for an additional 35 minutes. Thereafter, a solution of 4.97 g (18.8 m~ol) ~,2~t5Z),3~,48]-7-t3-formyl-7-oxabi-; cyclot2.2.l]hept-2-yl~-5-heptenoic acid, methyl ester in 60 ml toluene was added by means o~ a dropping ~unnel over a 35 minute period with the ice-bath still in place. The reaction was then quenched by addieion of 2.3 g t39 mmol) acetic acid HA2so/280 ln 5 ~1 ethe~. The reaction ~ixture immed~ately tu~ned pale yellow and was immediat~aly pou~ed into 200 ml satura~ed NH~Cl. and ext~acted ~lth e~he~
(4 x 200 ml). ~he oo~bined ether plases ~ere washed with NaCl saturated solution, and dried (MgSO4) and concentra~ed to yiela a yellow oil in a white crystalline solid 5phosphine oxide). The white ~olid wa6 triturated with ~tOAo and the mo~her liquo~ wa~ purifiea by chromatography on an LPS-l sillca colu~n. ~he fractions obtained were (A) tlB,2~(5Z).3~.4B]-7-t3-t2-oxo)ethyl-7-oxabi-cyelot2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, (B) tlB,2~5Z),3~.4~]-7-t3-(2-methoxy~-ethendiyl~~7-oxabicyclo~2.2.1~hept-2-yl]-5-hepterloic acid,. methyl eaterj and (C)' tlH.2~$Z).3~.4~]~
7-t3-(2,2-di~ethoxy)ethyl-7-oxabicyclot2.2.1~hept-2-yl]-S-heptenoic aci~, methyl ester.
Compounds (~) and (C) a~e each trea~ed with trifluoroacetic acid to convert each to oompound (A).

B. tl~.2~5Z-.3~.4~1-7-r3-(2-~Ydr~xvethYll-7-oxabic~clor2.2.11hept-2-Yll-5-hePtenoi acid, methYl ester The aldehyde (1.4 g, 5 ~ol) ~rom part A in 25 methanol (50 ml) was treated with Na~Hg (0.19 ~, 5 mmol) in an argon at~osphere at 0C. After st~ring at 0 ~o~ 1 hour. the ~eaction was quenched by addition of 2N HCl (to p~ 2). The methanol was ~e~oved in vacuo and the reaction - 30 mixture was taken up in ether. The ethe~ solutlon * Trade Mark _ -28-.
was washed with saturated KHC03, saturated NaCl and d~ied (~gS04). The ether was e~aporated to yield the title B compound.

C. ~LB,2~5Z)L3n~4~ 3-t2-tHex~loxY~-sth~rll-7-oxabicYelor2.2011hePt-2-Yll-S-he~tenoic acid Following the procedure of Examples 1 and 2 - excep~ substituting ~he above part B alcohol for Che alcohol us~d in Example 1, the titl.e compound is obtained.

tl~.20t~5Z)..3~9..4~1-7-t3-L~-(H~xYlox~,r)ethYl1-7-oxabicvclot2.2.11hePt-2--Yll-$-hePtenoiC acid Following the procedure of Example 20, except ; substituting tl~,2~(5Z),3R,4~]-7-t3-formyl-7-oxabicyclo[2.2.1]hept-2-yll-5-heptenoic acid, methyl es~er for tl~2~(5z)~3~4B~-7-E3-formyl-7-oxabicyclo~2.2.1~-hept-2-yl]-5-heptenoic acid, methyl ester, the ~itle compound is obtained.

~xam~le 22 2~L3c~ 4B) -7- r 3- r z- ~Hexyloxy~ ethyl l -7 -oxabicvclot2.2.1~ePt-2-Yll-5-hepta-oic acid Following ~he procedure o~ Example 21 except substituting (l~,Z~,3a,4~)-7-t3-formyl-7-oxabicyclot2.2.1]hept-2-yl]heptanoic acid, methyl ester ~or tlB,2~(5Z),3~,4~]-7-t3-formyl-7-oxabicyclot2.2.1lhept-2-yl]~-5-heptenoic acid, methyl ester, the title compound is obtained.

, .

5~37 Example 23 rL~2(sz)~3R~4~l-7-l3-~2-~phen~lox~ethvll-7 oxabicyclor2.2.11hept-2~yll-5-he~tenoic acid Follo~ing the procedure of Example 11 except substituting tl~,2c(52),3~,4~-7-t3-[2-(hydroxy)ethyl]-7-oxabicyclot2.2.1~hept-2-yl]-5-heptenoic acid, methyl ester for tlB,2~(5Z),-3~,4B]-7-[3-(hydroxymethyl)-7-oxabicyclo~2.2.1]hept-2-yl~-S-heptenoic acid, methyl ester, the title compound i~ obtained.

ExamPle 24 5~,2~(5Z~,3B,4Bl-7-~3-L2-~PhenYlox~ethY}]--7 oxabicYalo~2.2~1~he~t-2-Yll-5-hep-tenoic-acid ' Followinq the ~cocedure of Example 12 except ~ubs~i~uting tl~.2~(5Z).3~.4~-7-~3-t2-(hydroxy)-ethyl~-7-oxabicyclo~2.2.1]hept-2-yl]-S-heptenoic acid, methyl ester ~or t1~,2~5Z),3~,4~]-1-~3-(hydroxy~ethyl)-7-oxabicyclo~Z.2.1~hept-2-yl)-S-heptenoic acid, methyl ester, the titl~ compound is obtained.

Exam~le 25 (1~L2~.3~-4B)-7- r 3-~2-~PhenvloxY)eth~11-7-oxabic~clo~2.2.11hept-2-~Llhe~tanoic acid Following the procedure of Example 11 exGept substituting (1~,2~,3~,4~)-7-t3-t2-(hydroxy)-ethyl~-7-oxabicyclot2.2.1]hept-2-yl]heptanoic acid, me~hyl e6ter for tl~2~tsz)~3~J4~]-7-t3-(hydroxymathyl)-7-oxabicyclot2.2.1]hep~-Z-yl~-S-heptenoic acid, ~ethyl ester, the title compound is obtained.

.

_ - HA290/280 Exam~le 26 rlB~2~(5z2~3~4Rl-7-~3-~2-(Benzyloxy)ethyll-7 oxabicyclo~2.2.11he~t-2-~11-5-heptenoic acid Following the ~rocedure of Exan~ple 20 except substituting benzyl methanesulfonate for n-hexyl methanesulfonate, the title comp~und is obtained.

ExamPle 27 r L~,2~(5Z),3~,4~1-7-~3- r 2-~enzYloxY)ethyll-7 oxabicYclot2.2.11hePt-2-Y11-5-hePtenoic acid Followin~ the p~ocedure of Example 21 except aubstltuting benzyl methanesul~onat3 for n~hexyl ~ethanesul~onate, the title com~ound is obtained.

ExamPle 2 rl~.2~tsz) ,3e~4~l-7~L3-~2-(~cloPe-ntvloxy)eth 7-oxabicyclor2.2.11hePt-2-~11-5-heP_enoic acid Following the procedure of Example 20 except substitutinq cyclopentyl ~ethanesulfonate for n-hexyl methanesulfonate, the title compound is o~tained.

Example 29 SlB,2~(5ZI,3~,4131-7-~3-L2-tC~clohe~loxY)ethYl'1-7-oxabicYclo~2.2 11hePt-2~ 5-hePtenoic aci~
Following the procedure of Example 20 except substituting cyclohexyl methanesulfonate for n-hexyl methanesulfonate, the title compound is obtained.

~25~
. HA290/280 .
Example 30 r 1~ . 2~(5Z).3~,4~1-7-t3-t4-(HexyloxYlbutY11-7-oxabicYclot2.2.11he~t-2-Yll-S-hePterloic acid ~ ,2~(5Z~,3~,4~1-7-~3-(3-Oxo)pro~Yl-7-S oxabicyclor2.2.11he~t-2-yll-5-hePtenoic acid, ~ethvl_ester Following the procedure o~ Example 20, part A except substituting tl~,2~(5Z),3~,4A]-7-13-(2-oxo)-ethyl-7-oxabicyclot2.2.1~hept-2-yl~-S-hep~enoic acid, methyl ester for tl~,2~(5Z),3~,-4R]-7-~3-~ormyl-7-oxabicyclot2:2.1~hept-2-yl]-5-heptenoic acid. methyl ester, the title A compound ~ ~bta~ne~l.

B . ~ 2~ (5 Z l . 3~ . q~ 1~7 - ~ 3 - ( 4 -~xo l~u tY1~7 ~
oxablc~lot2~2-llhept-2-vll-5-heptelloi~
ac d~th~l ester .
: ~oll~wing the p~o~edure of~~xa~ple zo ~ part A, except substiCuting the aldehyde from part A a~o~e, ~or tl~,2Q~5Z).3~,4B~-7-t3-for~yl-7-oxabicyclo-2.2.1~hept-2-yl~-$-heptenolc acid, methyl ester, the title B aldehyde is obtained.

c . r lB 2~t SZ~ . 3~. 4R~ 3- (~-HYdroxYbutYl) -7-oxabicYclor2~2~11hept-2-Yll-S-heptenoic acid, m~thYl ester Following the procedure of E~ample 20, part B, exc~pt substiCuting the title B aldehyde ~o~
~1~,,2~(5Z) ,3~"4~1-7-~3-(2-oxo)ethyl-7-oxabi-cyclo[2.2.1]hept-2-yll-S-heptenoic acid, methyl ester, the title C alcohol is obtained.

' ''~ A2 gO/ 2 8 0 ~ -32-I)-. r 1~, 2~ ( 5Z ) . 3~, 4~1-7 13 - ~ 4- ( Hex~loxY ) -but~ll-7-oxabic~clot2.2.1lhe~t-2-Yl]-5-hePtenoic acid Following the procedure of Examples l and 2.
except substituting the above part C alcohol for the alcohol used in Example l, the title compound is obtained.
.
Example 31 o .r 1~, 2~(5Z)~3~,4~l-7-r3- r 4=tCYclohexYloxv)butYl~-7-oxabicvclol2.2.11he~t-2-Yll-S-heptenoic,acid Following the procedure oS Example 30 except substituting cyclohexyl methanesul~onate ~or n-hexyl ~ methaneaul~onat~, the ti~l~ com~ound is obtained.
ExamPle 32 .
~lB,2c~(5Z~.3~.,4Rl-7-r3-r4-(PhenYloxyLbutyll-7- .
oxabicYclor2.2 llhe~t-2-Yll-5-he~enoic acid Following the procedure of Example 11 except subatituting ~lB,2~(5Z),3~,4~]-7-t3-(9-hydroxybutyl)-7-oxabicyclot2.2.1]hept-2-yl]-5-heptenoic acid, ~eChyl ester for ~lR,2(5Z),-3~4~]-7-t3-(hydroxymethyl)-7-oxabicycloE2.2~l]hept 2-yl]-S-heptenoic acid, methyl ester, the title compound is obtained.
.
Example 33 ~}B,2~(5Z~,3~,4~1-7-~3-~4-(BenzvloxY~butY11-7-oxabicYclot2.2.1lhept-2-Yll-s--heptenoic acid ~ollowing the procedure of Example 30 except substituting benzyl methanesulfonat for n-hexyl ~ethanesulfonate, the title compound is obtained.
.

~ 35 .
, ~ , , ' Example 34 Tris~h~dromethYl~aminomethane salt of 2Q(SZ~.3~.4~l-7-r3~ exYloxY)methY1~-7-oxabicvclo[2.2.11hePt-~-ylt-5-heptenoic acid A solution of the compound formed in Example 2 in methanol is treated with an equivalent amount of tris(hydromethyl)a~inomethane. The solvent is removed by eva~oratio~ to yield the title compound as a solid, m.~. 68.5-70C. TLC (silica ~el, 10 8~ CH30H/CH2C12)Rf=0,74, Anal. Calcd. for C24H4507N: C,62.72; H,9.87; N,3.04 Found: C,62.71; H,3.80; M,3.10 Exam~le 35 15 ~lA.2~5Z)L3~.4~1-7-~3-L2~(PentYloxY)ethYll-7 oxabicycloL2.2.11hept-2-Yll-5-heptenoic acid A. ~1~,2~(5Z),3~,4~L-7-t3-~2-(PentYlox~) ethYl1-7-oxabicYclo~2.2~1lhePt-2-yll-5 he~tenoic acid,_~_nt~l ester A mixture of powdered KOH (0.36 g) in 15 ml of dry xylene was heated to re~}ux under argon atmosphere and 6 ml of xylene was removed by distillation. To this mixture was added a solution of 200 mg (0.71 mmol) of Example 20, part B, alcohol methyl ester in 17 ml of dry xylene. The volume of the reaction mixture was reduced 15 ml by distillative removal of xylene. To the reaction mixture ~as then added a solution of 0.5 g (3.55 mmol) pentylmesylate in 10 ml of dry xylene. This 30 ~ixture ~as refluxed for 2 hours and 30 minutes.
The cooled reaction mixture was diluted ~ith 50 ml of saturated Na~C03 solution and extracted with CH2C12 (3 x 60 ml). The combined C~2C12 extracts were dried (MgSO4), filte~ed and concentrated ln vacuo. Purification was ~ffected by fla h chromatography on 33 g of silica gel 60 usin~ hexane:ether ~5:1) as eluant. This gave 238 ~g of title pentyl ester (83~) a~; a colorless oil. TLC: silica gel, hexane:ether (1:1).

B. ~ 2~5Z~.3~4~1-7-L3-12-(Pent~lox~-ethY11-7-oxabic~cloL2.2.LlhePt-2-~11-5-hePtenoic acid To a stirred solution of 238 mg (0.58 mmol)of pentyl ester from Part A, 26 ml of distilled THF, 2.1 ~1 of CH3OH and 3.4 ml of H2O under argon was added 6.4 ml o~ lN aqueous lithium lS hyd~oxid~ solution. This mixturo was purg~d ~ith a~gon vigorously ~o~ 30 mlnutes and stirred at coom temperatur~ ~oc 7 hou~. The reaction mixture was ~cidified to pH 3 b~ the addition of lN aqueous HCl solution. The ~esulting solution was poured into 50 ml of saturated NaCl solution and was saturated with solid NaCl. The aqueous layer was extracted w~th EtOAc (4 x 60 ~1). The combined E~OAc extracts were dried (MgSO4), filtered and concentrated in vacuo. This was chromato~raphed on 24 g of silica gel 60 using 3% CH30H in CH2C12 as eluant to give 181 m~ (92~) of title pur~e acid, T~C: silica gel, 4% CH3OH/CH2C12, R~0.30, vanillin.
Anal. Calcd. for C20 34 4 C20H34O4 0.22 H2O: C, 70.16; H, 10-14 - Found: C, 70.16; H, 9.87 CNMR ~CDC13, 15.0MHz)tau 173.5, 33.8, 24.7, 26.7, ; 129.5, 130.1, 28.0, 43.8, 79.8, 29.5, 29.5, 30.3, 47.3, 29.7, 71.0, 70.3, 28.7, 22.4, 28.3, 13.9, 64.3, 28.3, 22.2, 28.3, 13.9 HA290/`280 _ -- ~xamPle 36 LlB~2~(sz)~3~4Bl-7-~ u~o~)-ethY11-7-oxabicyclo~2.2,.1lhePt-2-~l1-S-he~tenolc acid A. r 1~ .2~5Z~.3~4~l-7- U3-Phen~lpro~oxy)-meth~ 7-o~abicYclor2.2.;1he~t-2-yl]-5-hepte~oic acid, Phenylpro~ ester A mixture of powdered KOH (~.59 g) in 16 ml of d~y xyle~e was heated tG reflux under argon atmosphere and 9 ~l of xylese was removed by distillation. To this m~xture was added a solu~ion o~ 410 mg (1.53 mmol) oS Exa~ple l. part A, alcohol ~ethyl est~r in 10 ml o~ dry xylene. The volume of the reaction ~i~ture was ~educed 6 ml by di~tillati~e removal o~ xylene. To the reacton mixture was then added a solution of 1.66 g (7.58 ~mol) of 3-phenylpropylmesylate in 36 ml of dry ~ylene. Thi~ mixture was refluXed for 1 hour. The cooled reaction mixture was diluted with 50 ml of ~atu~ated NaHC03 solution and extracted with C~2C12 (3 x 50 ~l). The combined CH2C12 extracts were dried (MgS0~), filtered. and concentrated ln vacuo. P~rification was effected by flaah chromatography on 40 g of silica gel 60 using hexane:ether ~3:1) as eluant. This gave 0.61 q of ~itle phenylpropyl ester (al~) as a colorles~ oil. TLC: silica gel, 2 C~3OH/C~2Cl2, Rf: .60, iodine.

HA290/.
~36-B. LL~2~ L~3~.4~l-7-~(3-PhenYlpro~oxY)-me~hYl1-7-oxabicyclo~2.2.11hePt heptenoic acid : To a sti~red solution of 610 mg (1.24 mmole) S o~ title A phenyl~ropyl efiter, 55 ml o~' distilled . T~F, 4.40 ml of C~30~ and 7.30 ml of H20 under a~gon was added 13.7 ml o' lN aqueous lithium hydroxide solution. This ~ixture was purged with argon vigo~ously for 30 minutes and stirred at room te~pe~atu~e foE 14 hours. The rea~tion mixture was dlluted with 100 ml o~' 0.1 N aqueous lithium hyd~oxide solution and ~ashed once with lOO ml of hexane. The eeactio~ mixture was acidi'ied ~o pH 3 by the a~dition of lN aqueoua HCl ~olution and was pour~d into 100 ml o' saturated NaCl solution. rrhe resulting mixtu~e was satu~ated with solid NaC1 and ext~acted with EtOAc (4 x 150 ml). The combined .
EtOAc extracts were d~ied (~gS04), filtered and concentrated in va~uo. This was ch~oma~ographed on 44 g o' silica gel 60 using 4~ C~30H in C~2C12 as eluant to give 3ao mg (a2%) of pu~e title acid. TLC: silica gel, 4 CH30H/CHzCl2, Rf30.30. iodine.

Anal Calcd fo~ C23H3204 23~324 0 35 K20: C, 72.94; H, 8.70 Found: C, 72.94; H, a . 49 3C NMR (C~C13, 15.0MHz)tau 17~.7, 33.4, 24.5, 25.7, 129.5, 130.1, 26.6, 46.3, 7q.3, 29.5, 30.1, 46.8, 70.2, 69.9, 31.2, 32.3, 141.9, 128.4, 128.4.

, ExamPle 37 ~lfl,Z~SZl,3~.4~1-7-[3-t(Octyloxy)methyll-7-o~abicyGlot2.2.11hept-2-yll-S-heptlnoi _acid A. ~l~,2~tSZ),3~,4fll-7- r 3- ~ ~OC tYlox~- `
methyll-7-oxabicYclO~2.2.11hePt-2-Y11-5-To a sti~red solution o~ 50~ mg (1.89 mmol) of Examele 1, Part A, ester alcohol in 2.69 ml THF
was added in order 2.69 ~1 (L5.6 m~ol) of n-octyl bromide, 642 mg ~L.89 mmol) o~ te~rabutylammonium hydrogen sulfate and 2.69 ml of 50~ aqueous sodium hydroxide solutio~. This mixture was stirred aC
roo~ temperature in dar~naas for l9 hours. The reaction mixture was poured lnto 25 ml of saturatQd lS sodiu~ bicarbonate solution and extracted with fo~r 25 ml portions of C~2Cl2. The co~bined C~2C12 extracts were dried (MgSO4), filtered, and concen~rated ln vacuo. Purlication was effected by flash chromatography on 39.6 g of silica gel 60 using hexane:ether (3:1) as eluant to gi~e 333 m~ ~37~) of octyl ester and 250 mg of a ~ixed band of octyl ester and corresponding methyl ester. TLC: silica gel, 3~ C~3OH/C~2Cl2, Rf:octyl este~, 0. a5; me~hyl ester, 0.80, iodine.
B~ ,2~(5Z),3~ 7~ (OctYlox~l-met~ -7-oxablcYclo~2.2.llhePt-2-vll-5-he~tenoic acid To a stirred solution of 333 mg (0.70 mmol) of Part A octyl eseec in 31 ml of distilled THF, ~ HA290/280 2.50 ml of CH30H and 4.1 ~1 o~ H20 under argonwas added 7.70 ml of lN aqueous lith;.um hydroxide solu~ion. This mixture was purged with argon vigorously for 20 minutes and stirred at room temperatu~e for 16 hours and 30 minutes. The ~ixture of octyl ester a~d corresponding methyl es~er was hydrolyzed in the exact sa~e manner. To a stirred solution of this mixture (250 mq) in 29 ~1 of distilled THF, 2.40 ml of C~30R and 3.9 ml of H20, ~as added 7.30 ml of lN aqueous lithium hydroxide. This mixture was purgsd with argon vigorously ~or 20 minutes and stirred at room tempe ature for 16 hours and 30 minutes.
These 2 reaction mixtures were com~ined and dlluted with a solutlon of 120 ~l of 0.1 N aqU~ous lithium hydroxide solution and 50 ~1 of H20. The resulting mixture was extracted once with 220 ml of hexane. The aqueous layer was acidified to pH 3 by the addition of lN aqueous HCl solution ~aturated with solld NaCl, and extracted with EtOAc (4 x 150 ml). The hexane extract and EtOAc ex~racts (hexane extract contained the desired - acid) were combined, dried (~gS04), filtered and concen~rated in vacuo to give 0.53 g of c~ude product. This was chromatographed on 4~ g of silica gel 60 using 3~ CH30H in CH2C12 to gi~e 222 mg (45%) of desired ti~le acid. TLC:
silica gel, 4~ CH30H/CH2C12, Rf=0.40.
vanillin ~nal CalCd for C22H3804: C. 72-09; H- LO-45 C22H3804 0.24 H20: C. 7L.25: H, 10.45 ; Found: C, 7L.25: H, 10.20 .

3C NMR ~CDCl , 15.0mHz)tau 178.7, 33.8, 24.9, 26.2, 129.6, 130.0, 26.8, ~6.5, 79.3, 29.5, 29.5, 80.1, 46.9, 71.2,~69.9, 31.7, 29.7, 29.2, 28.7, 25.9, 22.6, 14.0, 64.4, 31.7, 29.7, 29.2, 28.2, 25.8, 22.6, 14Ø

. ~

- methvll-7-oxabic~clo~2.2.11hept-2-yl~-5- heQtepoic acid A. LlB,2~1sZ),3~,4Bl-7-L3-~yclohexYl-meehoxY~meth~ Z~ xabicYclo~2.2.11he2t-2-YlL-5- heptenoic acid, cYclohexylmeth estQr A mixture o~ powde~ed KO~ (0.56 g) in 15 ml o~ dry xylene was heated to reflu~ unde~ argon atmosphere and 7 ml of xyle~e was removed by distillation. To this mixture was added a solution of 300 mg (1.12 mmol) of Example 1, Part A, alcohol methyl ester in 10 ml of dry xylene. The volume of the reaction ~ixture was reduced to 11 ml by distillative removal of xylene. To the reacton mixture was then added a solution of 2.47 g (12.9 mmol) cyclohexylmethylmesylate in 10 ml of dry xylene. This mixture was refluxed for 5 hours.
The cooled reaction mixture was diluted with 50 ml of saturated NaHCQ~ solution and extcacted with CH2C12 (3x50 ml). The combined CH2C12 extracts were dried (~gSO4), filtered a~d concentrated in vacuo. Purification was affected by flash chro~atography on 35 g of silica ge} 60 using 1~ CH30H in C~2Cl2 aa eluant. This gave 0.46 g o~ title hexyl es~er (93%) as a colorless oil. TLC: silica gel, 2 ; 35 C~3OH/C82C12, Rf , 0.80, iodine.

~2~

B. r~,2n(5Z~,3~,4~l-7-r3-tCYclohexYl-me~hoxy~methyll-7-oxabicyclo[2.2.1lhePt-2-yll-5- heptenoic acid To a stirred solution of 460 mg ~1.03 mmol) of Part A cyclohexylme~hyl ester, 45 ml of distilled THF, 3.80 ml of CH30H and 6.10 ml of H20 under argon was added 11.~ ml of lN aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for 20 minutes and stirred at room temperature for 16 hours. The reaction mixture was diluted with 83 ml of 0.1 N
aqueous lithium hydroxide solution and washed once with 83 ml of hexane. The aqueous layer was acidi~ied to pH 3 by the addition of l~ aqueous EICl solution and saturated with solid NaCl. The resulting aqueous layer was extracted with EtOAc (4x120 ml). The combined EtOAc extracts were dried (MgS04~. filtered and concentrated in vacuo to give 0.32 g of crude product. This was chromatographed on 34.6 g of silica gel 60 usiny 3%
CH30H in CH2Cl2 as eluant to give 278 mg ~77%) of pure title acid. TLC=silica gel, 4%
CH30HtCH2Cl2, Rf=O. 2a ~ iodine.

~nal. Calcd for C2lH3404: C. 71.g6; H. 9-78 C2lH3404 0.31 H20: C, 70.84, H, 9.80 Found: C, 70.B4: H, 9.68 C NMR (CDC13, 15.0MHz)tau 173.5, 33.7, 24.9, 25.3, 129.5, 129.9, 26.0, 46.4, 79.2, 29.6, 29.6, 79.~, 46.8, 70.0, 77.~, 37.9, 30.0, 2607, ~5.8, 26.7, 30.0, 69.3, 37.1, 29.1, 26.3, 25.6, 26.3, 29.1 ..~

~5~ HA290/280 Example 39 l[a,2~(Z),3~,4al-7-[3-[[(l-methylhexyl)oxy]-methyl]-7-oxobicyclo[2.2.lJhept-2-yl]-5-heptenoic acid By following the procedures of Examples 1 and 2 except substituting l-methylhexyl methane sulfonate for n-hexylmethanesulfonate, the titled compound is obtained, TLC (selica gel, 4% CH3OH/CH2C12) Rf = 0-47- .
Anal. Calc 21 36 4 ~ Found: C, 71.73; H, 10.21 3C NMR tCDCl , l5.0MHz)tau 178.8, 33.4, 24.6, 25.7, 129.4, 130.2, 26.7, 46.4, 79.5, 29.5, 80.1, 47.1, 67.5, 75.9, 36.7, 25.3, lS 31.g, 22.6, 1~.0, 19.7 Example 40 {la,2~(Z),3~,4]-7-[3-[(3-hexynyloxy)methyl-7-oxabicvclo[2.2.1]hept-2-vl]-5-heptenoic acid By followlng the procedures of Examples 1 and 2 except substituting 3-hexynylmethane-sulfonate, the titled compound is obtained as an oil, TLC (silica gel, 4~ CH3OH/CH2C12) Rf 0-32 Anal. calcd for C20H30O4: C, Found: C, 71.66; H,9.21 C NMR (CDC13, 15.0MHz)tau 178.9, 33.4, 22.0, 24.5, 129.5, 130.0, 26.7, 46.4, 79.4, ~9.4, 29.5; ~0.0, 46.7, 69.0, 58.8, 76.1, 86.8, 22.0, 25.8, 13.4 ~ ` HA290/280 Example 41 [1~,2a(Z),3(Z),4~]-7~[3 [(3-hexenyloxy)methyl~--- . _ 7-oxabicyclo[2.2.1]hept-2-yl]-S-heptenoic acid By following the procedure of Examples 1 and 2 except substituting cis-3-hexen-1-mesylatè for the n-hexylmethanesulfonate, the titled compound is obtained as an oil. TLC ~silica gel, 4~ CH3OH/CH2C12) Rf = 0-3-Anal. calcd. for C20H32O4: C, Found: C, 71.10; H, 9.59 C ~MR ~DC13, 15.0~IHz)tau 178.9, 33.4, 24.5, 25.6, 129.5, 130.1, 27.7, 46.3, 79.3, 29.4, 80.1, 46.7, 70.7, 69.8, 26.6, 133.6, 124.8, 20.6, 14.2 Example 42 [1~,2~(Z),3a(Z),4~]-7-[3-[(2-hexenyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid By following the procedure of Examples l and 2 and substituting 2-1-hex-2-enyl-mesylate for n-hexylmethanesulfonate, the ~itled compound is prepared as an oil, TLC (silica gel, 2~ CH3OH/CH2C12~ Rf = 0.22, vanlllin.
Anal. calcd. for C20H32O4 Found: C, 70.97; H, 9.64 13C NMR (CDC13, 15.0MHz)tau 178.8, 33.4, 24.5, 25.8, 129.5, 130.1, 26.7, 46.4, 79.5, 29.5, 29.5, 80.1, 46.9, 69.3, 66.6, 133.5, 126.2, 29.5, 22.6, 13.6 -Example 43 [1~,2a(Z),3a,4a]-7-[3-[2-propenyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, and methyl ester To a stirred solution of 310 mg (1.16 mmol) of [ 1 ~ , 2a ( 5 Z ) , 3a,4~]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1~hept-2-yl]-5-heptenoic acid, methyl ester in 1.34 ml of tetrahydrofuran was added in order, 1.34 ml of allyl bromide, 107 mq of tetrabutylammonium hydrogen sulfate and 1.34 ml of 50~ aqueous sodiu~ hydroxide solution. The mixture was stirred at room tempera~ure in darkness for 23 hours and then poured into 30 ml of saturated lS sodium bicarbonate solution and extracted twice with 30 ml portions of methylene chloride. The combined extracts were dried over magnesium sulfate, filtered and concentrated to dryness in vacuo.
Purification was effected by flash chromatography on 35 g of silica gel 60 using hexane-ether (2:1) as eluant to give 220 mg of the methyl ester product, ~LC (sillca gel, hexane-ether ~l:l) Rf = 0.4, iodine.
The ester was dissolved in 36 ml of tetra-hydrofuran along with a small amount of hydroquinone,

6 ml of water and 7 ml of lN aqueous lithlum hydroxide solution and stirred at room temperat~ure for 5.5 hours whereupon the reaction mixture was poured into 80 ml of saturated aqueous sodium chloride solution and was saturated with additicnal solid sodium chloride. The aqueous layer was extracted with 4 portions of ethyl acetate (125 ml each), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromato-gxaphed on 30 g of silica gel using 4~ CH3OH/CH2C12 as eluant to give l90 mg of the acid product, TLC
(silica gel, hexane-ether (1:1)) Rf = 0.15.

r HA290/280 ~44~
Anal. Calcd for Cl7 264 Found: C, 69.72; H, 9.05 C NMR (CDCl3, 15.0MHz)tau 178.9, 33.4, 24.5, 25.7, 129~5~ 130.0, 26~6~ 46~3~ 79.3, 29.4, gO.l, 46~7~ 69~3~ 72~0~ 134.7, 117.0 E~ample 44 [lB ,2a(5Z), 3a,4~] -7- ~3- ~ (Hexylthio)methyll -7 oxabicyclo [2.2. l~hept-2-yl]-5-heptenoic acid, methyl ester A. [1~,2~tSZ), 3a, 4~ ] -7- ~3- ~Hydro~ymethyl) -

7 oxabicyclo[2.2.11hept-2-yl]-5-heptenoic acid (a) A mixture of N-acetylpyridinium chloride was prepared by addin~ 9.6 ml (136 mmole) of acetyl chl~ride dropwise to 56 ml o~ pyridine. To thi~
was added S.0 g (27 mmole) of (exo)-3-~2-methoxy-ethenyl)-7-axabi.cyclo[2.2.1]heptane-2-methanol dissolved in 5 ml of pyridine. The resulting mixture was stirred at room temperature for 1.5 hours and poured into brine. The product was extracted into ether (3 x 200 ml), the ether extracts were washed with 5~ hydrochloric acid ~2 x 400 ml) and brine (1 x 200 ml) and dried over sodium sulfate.
Concentration yielded a yellow oil whic~ was purified by passage through a short column of ~ilica gel (150 ml) with dichloromethane, yield 4.42 g of an oil.

(b) To a solution of 4.42 g (19.6 mmole) of the oil in 500 ml of tetrahydrofuran containing 50 ml of water was added 31.1 g (97.8 mmole) of mercuric acetate. The yellow suspension which formed was stirred for 10 minutes and then the entire mixture was poured into a solution containing 200 g of potassium iodide in 2 1. of water. Upon , , HA290/2~0 shaking, the yellow color disappeared and themixture was extracted with benzene (3 x 500 ml).
The combined benzene extracts were washed wi-th potassium iodide solution and brine and dried over sodium sulfate. Concentration yielded 3.7 g of material which crystallized on ~tanding in an ice box.

(c) A Wittig reagent was prepared in lG dimethyl sulfoxide (dried over calcium hydride) by adding a solution of sodium methylsulfinylmethide ~prepared by heating 300 mg of sodium hydride in 60 ml of dimethyl sulfoxide at 75 untll hydrogen evolution stops) dropwise to a solution of 5.32 g (12 mmole) of 4-carboxybutyl triphenylphosphonium bromide in 100 ml of dimethyl sulfoxide. After the first orange color lasting more than 10 seconds forme~jan equivalent amount of base was added to orm the ylide. To this deep orange solution was added a solution of the product of part (b) in 20 ml of dimethyl sulfoxide and the resulting mixture stirred at room temperature for 45 minutes. The reaction was quenched by addition of 24 mmole of acetic acid and the ~ixture poured into brine (300 ml) and extra~ted with ether (3 x 200 ml).
Concentration of these extracts gives an oil which was stirred with saturated sodium bicarbonate solution until crystalline triphenylphosphine oxide formed in the mixture. This mixture was washed with benzene and acidified with 10% hydrochloric acid.

.

~25~
` HA2 9 n /~
-46- . , .
The aqueous layer was saturated with salt and extracted with ether which on drying (sodium sulfate) and concentration gave 2.43 g of crude product.
The mixture was stirred 24 hours with 10~ aqueous sodium hydroxide and reisolated by acidification and ether extraction. The product was purified on - 500 g of silica gel with 50/50 ethyl acetate-hexane as the eluant which gave 600 mg of acid which crystallized on standing. This was recrystallized twice from ethyl acetate-cyclohexana to yield 320 mg of [1~,2a(5Z),3a,4~]-7-[3-~'hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid.

~. [1~,2a(5Z),3a,4S]-7-[3-(~-ToluenesulfonYI-oxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl e5ter To a solution of 300 mg (1.12 mmol) of alcohol ester from Part A in 4 ml of dry pyridine was added 427 mg ~2.24 mmolj of tosyl chloride.
The mlxture was stirred at room temperature under an argon atmosphere for 10hours. The reaction mixture was diluted with 300 ml of ether, washed with lN aqueous HCl solution (3 x 100 ml), and 0.5 N aqueous NaOH solution (3 x 100 ml). The ether layer was dried over anhydrous magnesium sulfate and concentrated ln vacuo. Purification 3~ was effected by flash chromatography on 30 g of . H.-~2so/2~a -47- .
.
silica gel 60 using 50~ hexane in ether as eluant to give 450 mg of title compound (95~). TLC~silica gel, 4~ C~30H in C~2C12, Rf=0.80, iodine.

S C. [1~,2a(5Z),3a,4~]-7-[3-[~exylthio)methyl]-?-oxabicy~o~[2_______Pt-2-yl]-5 heptenoic acid, me~hyl ester To a solution of 132 mg (1.17 ~mol) of potassium t-butoxide in 10 ml of dry THF under argon was added 378 mg (3.21 mmol) of l-hexanethiol. To . this.mixture was added a solution of 450 mg (1.07 mmol) of Part B tosylate in 5 ml of THF. The reaction mixture was stirred at room temperature under argon ror 2.5 hours and then heated to reflux lS for 5.5 houxs. The cooled reaction was diluted with 300 ml of ether and poured into lO0 ml of saturated NaHC03 solution. The aqueous layer was extracted with ether ~2 x 100 ml). The combined ether extracts (S00 ml) were washed with O.SN
aqueous sodium hydroxl~e ~2 x 100 ml), brine (lO0 ml), and then dried (MgS04), filtered and concentrated ln vacuo to give 0.55 g of crude oil. Purification was ef~ected by chromatography on 25.2 g of silica gel 60 using 5:1 pet ether:ether as eluant to give 328 mg of title product as an oil (84~). TLC=silica gel, petroleum ether:ether 3;2, Rf=0.55, iodine.

Example 45 ,2a(5Z),3a,4~]-7-[3-[(Hexvlthio)methyl]-7-o~abicy-c13 ~2.2 l]hept-2-vl]-5-he~tenoic acid 3 0 ~
To a stirred solution of 328 mg (0.89 mmol) . . .

.

HA290/2~0 of the Example 1 methyl ester in 43.8 ml of THF
~nd 6.67 ml of H2O under argon was added 8.40 ml of lN aqueous lithium hydroxide solution. Thi-~. mixture was purged with argon vigorously for 20 minutes and ~tirred at room temperaturA for 12.5 hours. The reaction mixture was acidi~ied to pH 4 by the addition of lN aqueous HCl solution and poured into 50 ml of saturated NaCl solution.
The resulting solution wa3 saturated with solid NaCl and extracted with Et~Ac (4 x 50 ml). The combined EtOAc extracts were dried (MgSO4~, ~iltered and concentrated in vacuo to give 295 mg of crude acid. Purification was effected by flash chromatogr~phy on 25 g of SiliCAR CC-7 using 2:3 petroleum ether:ether as eluant to give title product (250 mg, 79%) as an oil. TLC:9ilica yel, 2:3 petroleum ether:ether, Rf~ 0.25, iodine.
Anal Calc'd for C20H3403S: C, 67.80; H, 9.61;
S, g.04 Found: C, 67.80; H, 9.85;
S, ~.14 3C NMR (CDCl3, lS.0MHz)tau 173.5, 33.1, 24.5, 25.6, 129.~, 128.8, 26.5, 45.9, 79.9, ~9.2, 28.8, 78.3, 45.9, 69.5, 144.5, i29.7, 127.6, 132.1, 127.6, I29~7, 21.3,. Sl.l Ex mple 46 (1~,2a,3a,4~)-7-t3-~(Hexylthio)meth~1]-7-oxabicyclo-t2.2Ol]hep~-2-yl]-S-heptenoic acid, methyl ester A.

acid, meth~l ester : . To 800 mg (3.0 mmole~ of the tl~,2a(52) ,-3a,4~]-7-13-(hydroxymethyl) -7-oxabicyc~o[2.2.1~-* Trade Mark l;~S~!3'7 H~29n~280 hept-2-yl]-5-heptenoic acid, methyl ester as prepared in Example 1, dissolved in 120 ml of ethyl acetate W~5 added, un~er a~l argon atmosphere, 160 mg of 5% Pd on carbon. ~he zlrgon atmosphere was exchanged fsr a slight posit;~ve pressure of hydrogen and the reaction was stirred for 8 hours at 25, filtered through a Celite plug and evaporated to provide 730 mg (90%) of the title A compound B. (1~ ,2a, 3a,43) -7- t3-t(~ex~lthio)methyl~-7 oxabicyclot2.2.1]hept-2-yl~ hept~noic acid, methyl ester Following the procedure of Example 1 except substituting the Part A alcohol-ester for the Example lA alcohol ester, the title product is obtained.

Exam~le 47 ~lB,2,3a,4~) -?- [3-[(Hexylthio)meth~1]-7-oxabicyclo-[2.2.1]he~t-2-yl]-heptanoic acid_ Following the procedure of Example45 except substituting the Example 46methyl ester ~or the Example 45methyl ester, the title acid is obtained~

Exam~le 48 [lB,2~(5Z),3B,4~]-7-[3-[(PeIItylthio)methyl]-7-oxabicvclo~2 2.1]he~t-2-Y1~-5-heptenoîc acid, methyl ester tl~ , 2a t 5 Z ) , 3~ , 4B 1 -7- [ 3- hydroxy-_ 3 methyl)-7-oxabicyclo[2.2.1]hept-2-vl}-o 5-heptenoic acid, methvl ester _ * Trade Mark :,;`1, HA2~0/280 To a solution of 2.6S g of [1~,2~(5Z),3,4~]-7-[3-(hydroxymethyl~-7-oxabicyclo-[2.2.1]hept-2-yl]-S-heptenoic acid in 175 ml of dimethylformamide was added 13.16 g of pyridinium di.chromate. This mixture was stirred at room temperature for ~9 hours at which time an additional 8 g of pyridinium dichromate was added. This mixture was allowed to : stir an additional 24 hours. The reaction mixture was diluted with 500 ml of ether a~d the xesultant black gummy precipitate was removed by filtration through a pad of Celite. The filtrate was concentrated in vacuo. The resulting dark brown oil was passed through 60 g of silica gel 60 and eluted with 5% MeOH/CH2C12 to give 1.86 g of brown oil.
This was purified by chromat~graphy on 150 g of silica gel 60 using 1:1:0.01 pentane-ether-acetic acid as eluant. This gave 0.63 g of ~1~,2,-(SZ) ,3a,4~]-7-13- (carboxy)-7-oxabicyclo12.2.1~ hept-2-yl]-5-heptenoic acid methyl ester and 0.31 ~ of [1~,2,(5Z~,3~,4~-7-t3-tcarboxy~-7-oxabicyclo-~ [2.2.1lhept-2-yll-$-heptenoic acid methyl ester.
3C NMR (CDC13 ,15 . OMHz) tau 177 . O, 174 . O, 130 . 6, 127.7, 8}.5, 77.9, 54.7, 51.3, 46.2, 33.4, 32.3, 29.2, 26.6, 25.~, 24.7.
A salution of 350 mg of tlB~2a~sz) ,3~,4~1-7-[3-(carboxy)-7-oxabicyclo[2.2.1]hept-2-yl~-S, heptenoic acid methyl ester and 0. 35 ml of triethyl-amine in 3.0 ml of dry THF under argon was cooled to 0C. To this stirred solution was added dropwise 0.24 ml of ethylchloroformate. The resulting mixture was stirred at ~C for 50 minutes and then diluted with 20 ml of anhydrous ether. The mixture was filtered through a pad of MgSO4 and concentrated in vacuo. The rPsidue was dissolved in 2~ml of * Trade Mark ~2~6~37 H~2 9 0/2 8 o absolute EtOH and 3.3 ml of dry THF. This solutlon was cooled in an ice bath and then 80 mg of NaBH4 was added. The mixture was stirred for 30 min. at 0C and then the ice bath was removed. After 15 minutes, the reaction mixture was poured into 25 ml of ice-cold lN HCl.
The aqueous layer was extracte~ with three 25 ml portions of ether. The ether layers were combined dried over MgS04, filtered, and concentrated ln vacuo to afford the crude product. Purification was effected by flash chromatography of 22 g o~
silica gel using 2~ MeOH/CH2C12 as eluant. This gave 250 mg of [1~,2a~5Z),3~,4~]-7-[3-(hydroxy-methyl)-7-oxabicyclo[2.2.1~hept-2-yl]-5-heptenoic acid methyl ester;
15 13C NMR ~CDC13, 15.OMHz)tau 174.1, 130.0, 128.5, 80.6, 78.7, 63.4, 51;7; 51.4, 47.8, 33.4, 32.7, 29.8, 26.6, 24.7, 23.7 B. [1~,2a(5Z),3~,4~]-7-[3-(p-Toluenesulfonyl-oxymethyl)-7-oxobicyclo[2.~.1]hept-2-yl-5-heotenoic acid, methYl ester ~25~

To a solution of 300 mg (1.12 mmol) of [1~,2~(5Z),3~,4~]-7-[3-(hydroxymet:hyl)-7-oxa-bicyclo[2~2.11hept-2-yl]-S-heptenoic acid, methyl ester from part A in 4 ml of dry pyridine is added 427 mg (2.24 mmol) of tosyl chloride.
The mixture is stirred at room temperature under argon atmosphere for 10 hours. The reaction mixture is diluted with 300 ml of ether, washed with lN aqueous HCl solution (3 x 100 ml), and 0.5 N aqueous NaOH solution (3 x 100 ml). The ether layer is dried over anhydrous magnesium sulfate and concentrated ln vacuo; Purification is effected by flash chromatography on 30 g of silica gel 60 using 50% hexane in ether as eluant to give 450 mg Of title B compound.

C. [l~2a(5z)r3~l4a]-7-~3~(pentylthio)methyl]
7-oxabicyclo~2.2.1]hept-2-yl]-S eptenoic acid, methyl ester To a soLution of 132 mg (1.17 mmol) of potassium t-butoxide in 10 ml of dry THF under argon is added 318 mg (3.21 mmol) of l-pentanethiol.
To this mixture is added a solution of 4S0 mg (1.07 mmol) of Part B tosylate in 5 ml of THF. The reaction mixture is stirred at room temperature under argon for 2. 5 hours and then heated to reflux for 5.5 hours. The cooled reaction is diluted with ~2568~7 H~290/280 300 ml of ether and poured into 100 ml of saturated NaHCO3 solution. The aqueous layer is extracted with e~her (2 x 100 ml). The co~bined ether extracts (500 ml) are washed with 0.5 N aqueous sodium hydroxide (2 x 100 ml), brine ~100 ml~, and then driad (MgSO4~, filtered and concentrated in vacuo to give 0.55 g of crude oil. Purification was effected by chromatography on 25.2 g of sllica gel 60 using 5:1 pet. ether:ether as eluant to givc 328 mg of ti le compoundO
Exam~le 4g [lB, 2a (5Z), 3~, 4B 1-7- ~3-[(Pentylthio)me~hyl]-7 oxabicvclot2.2.1]he~t-2~Yl]-S-hePten~ic acid To a stirred solution of 328 mg ~0.89 mmol) of Example 4~methyl ester in 43.8 ml of THF and 6~67 ml of H20 under argon is added 8.40 ml of lN
aqueou~ lithium hydroxide solution. This mixture ~g purged with argon vigorously fox 20 minutes and stirred at room temperature for 12.5 hours. The reaction mixture is acidified to pH 4 by the addition of l~ aqueous HCl solution and poured into 50 ml of saturated NaCl solution. The resulting solution is saturated with solid NaCl and extracted 2S with EtOAc ~4 x 50 ml). The co~bined EtOAc extracts are dried (~gSO4), filtered a~d concentrated in vacuo to give 295 mg of crude acid. Purification *is effected by flash chromatography on 25 g of Sili~A~ CC-7 using 2:3 petroleum ether:ether as eluan~ to give the acid.
Example50 a~5Zl,3a,4B]-7-[3-[~Methylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-~1]-5-heptenoic acid Following the procedure of Examples~4 and 45 except substituting methyl mercap~an for l-hexane-thiol the title compound is obtained.

* Trade Mark ~æs~7 -Example 51 [1~,2a(5Z),3~,4~]-7-[3~ropylthio)methyl]-7-oxabicvclo[2.2.1]hept-2-yl]-5-heptenoic acid ~ _ Following the procedure of Examples 48 and 49 except substituting propylmercaptan for l-pentanethiol, the title compou~d is obtained.

~ ple52 (1~,2a,3a,4~-7-~3-(Bu~lthio)methyl]-7-oxabicyclo-- 10 [2.2.1]hept-2-yl]he~tanoic acid Following t~e procedure of ~xamples 46 and 47 except substituting butylmercaptan for l-hexanethiol, the title compound is obtained.

E~ ele_53 ~1~,2a(5Z)~3a,4~]-7-[3-~(Octylthio)methyl}-7-oxabicyclo~2.2.1]hept-2-yl]-S-heptenoic acld Following the procedure of Examples 44 and 45 except substituting l-octanethiol for l-hexanethiol, the title compound is obtained.
Anal. Calcd. for C22H38O3S: C, 69.0~; H,10.01; S, 8.38 Found: C, 69.08; H, 9.75;S,8.20 C NMR (CDCl , 15.0MHz)tau 178.7, 32.6, 29.1, 29.4, 129.8, 129.8, 29.4, 46.9, 80.6, 29.7, 31.7, 80.4, 47.5, 33.4, 32.1, 29.1, 28.8, 26.7, 26.2, 24.5, 22.5, 13.9 . , .
Example 54 [1~,2a(5Z),3a,43]-7-~3-~Phenylthio)methyl]-?-oxabicyclo~2.2.1]he~t-2-yl]-5-heptenolc acid Following the procedure of Examples 44 and 45 except substituting phenylmercaptan for l-hexanethiol, the title compound is obtained.

' . HA290/28~ ~
_ O Example 55 (1~,2a, 3a, 4~) -7-~3-[(Phenylthio)methyl]-7-oxabicyclo-[2 2 l]he t-2- l]he~tanoic acid P Y ._ _ ~
Following the procedure of Examples 46 and47 except substituting phenylmércaptan for l-hexanethiol, the title compound is obtained.

Example 56 [1~,2a~5Z~,3a,4~]-7-[3-~(Ethylthio)meth~1]-7-oxabicyclo[2.2.1~hept-2-yl}-5-heptanoic acid Follow mg the procedure of Examples 44 and 45 except substituting ethylmercaptan for l-hexanethiol, the title compound is obtained.

Example 57 ~1~,2a(5Z),3~,4~]-7-[3~(Phenylthio)methyl]-7-oxabicvclo [2~2~1]heDt-2-Yl~-5-he~tenoic acid Following the procedure of ExampLes 48 and 49 except substituting phenylmercaptan for l-pentane-thiol, the title product is obtained.
Exa~le 58 [1~,2a(5Z),3~,4~]-7-[3-[(Benzylthio)methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acld Following the procedure of Examples 48 and 49 except substituting.benzylmercaptan for l-pentanethiol, the title product is obtained.

Example 59 3 ~1~,2a 3a 43)-7-[3-[(Benzvlthio)methyl]-O
7-oxabicyclo[2.2.1]he~t-2-yl]heptanoic acid Following the procedure of Examples 46 and 47 except substituting benzylmercap~an for l-hb~anethiol, the title product is obtained '' " ' .

HA290/2~30 .
Example 60 [1~,2a(5Z),3a,4~]-7-[3-[(Cyclohexylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-S-heptenoic acid Following the procedure of Examples 44 and 45 except subs~ituting cyclohexylmercaptan for l-hexane-thiol, the title product is obtained.

Example 61 - ~
[1~,2a(5Z),3~,4~]-7-[3-[(Cyclopentylthio)me_hyl]-7-oxabicyclo~2.2.1]he~t-2-yl~-5-heptenoic acid Following the procedure of ExampI~s 48 and 49 except substituting cyclopentylmercaptan for l-pentanethiol, the title product is obtained.

Example 62 (1~,2a,3a,4~)-7-[3-~(Cyclohex~ o)methyl]-7-oxabic~clo[2.2.1]hept-2-yl]heptanoic acid Following the procedure of Examples 46 and 47 except substituting cyclohexylmercaptan for l-hexanethiol, the title product is obtained.
.
Example ~3 [1~,2a(5Z),3a,4~]-7-[3-E2-(Hexylthio)ethyl]-7-oxabicyclo[2 2.1]hept-2-yl]-S-heptenoic acid A. [1~,2a(5Z),3a,43]-7-~3-(2-Oxo)ethyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, meth~l ester Into a dry 100 ml round bottom 3-necked flask containing a stir bar was added dried 12.9 g (37.7 mmoles) methoxymethyltriphenylphosphonium chloride ((C6H5)3P+-CHzOCH3Cl ) and 235 ml distilled ~2~ HA290/280 toluene (stored over molecular sieves~O The resulting suspension was stirred in an ice-bath, under argon, until cold and then a 1.55 M solution of 18.3 ml (28.3 mmol) of potassium t-amylate in ~oluene was added dropwise. A bright re,d solutio~ formed which was stirred at 0C ~or an additional 35 minute~.
Thereafter, a solution of 4.97 g (18. 8 m~ol) [1~,2a(5Z),3a,4~]-7-[3-formyl 7-oxabicyclo[2.2.1~-hept-2-yl~-5 heptenoic acid, methyl ester in 60 ml toluene was added by maans of a dropping funnel ovar a 35 minute period with the ice-bath still in placeO The reaction was then quenched by additio~ of 2.3 g ~39 mmol) acatic acid in 5 ml ether. The reaction mixture immediately turned lS pale yellow and was immediately poured into 200 ml saturated NH4Ci, and extracted with ether (4 x 200 ml).
The combined ether phases were washed with NaCl, saturated solution, and dried ~MgSOi) and concen~
tra~ed to yield a yellow oil in a white crystalline solid (ph~ne cxide). The white solid wa~ triturated with EtCAc and the m~er liquor was p~ied by ch3~hx~aphy on an LPS-l silica column. The fractions obtained were (~) [1~,2a(5Z),3a,4~]-7-[3-(2-oxo)ethyl-7-oxabicyclol2.2.1]hept-2-yl]-5-heptenoic acid, 25 methyl ester, (B) [1~,2a(5Z),3a,4~]-7-[3-(2-methoxy)-ethendiyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, and (C) [1~, 2a(5z),3a,4~J-7-E3~
(2,2-dimethoxy)ethyl-7-oxabicyclo[2.2.1]hept-2-yl]-S-heptenoic acid, methyl ester.
Compounds (B) and (C) are each treated with trifluoroacetic acid to convert each to compound (A).

* Trade Mark ~, .

` ~256~7 - HA290/280 B. ~1~,2a(5Z),3a,4~]-7-[3-(2-Hydroxyethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester The aldehyde (1.4 g, 5 mmol~ from part A
in methanol (50 ml) is treated with ~aBH4 (0.19 g, 5 mmol) in an argon atmosphere at 0 C. After stirring at 0 for 1 hour, the reac~ion is quenched by addition of 2N HCl (to pH 2). The methanol is removed in vacuo and the reaction mixture is taken up in ether. ~he ether solution is washed with satu~ated KHC03, saturated NaCl and dried (MgS04~.
The ether LS evaporated to yield the title B compound.

C. ~1~,2a~5Z),3a,4~]-7-~3-E2-~exylthio)-ethyl]-7-oxabic~clo[2.2 1 ~ t-2-yl]-5-heE~noic acid -Following the procedure of Examples 44 and 45 except substitu~Lng the above part B alcohol for the alcohol used in Example 44,the title compaund is obtained.

Example 64 [1~,2a(SZ),3~,4~]-7-[3-[2~Hexylthio)ethyl~-7-oxabicyclo~2.2.1]hept-2-yl]-5-heptenoic acid 2~ Following the procedure of Example 63, except substituting [1~,2a(5Z) ,3~,4~]-7-[3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester for [1~,2a(52~,3a,4~]-7-~3-formyl-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, the title compound is obtained.

- ~% ~ ~ ~ HA290/280 Example 65 (1~,2a,3~,4~)-7-[3-[2-(Hexylthio)ethyl]-7-oxabicyclo-[2.2.1]hept-2-yl]heptanolc acid Following the procedure of Example 64 except substituting (1~,2a,3a,4~)-7-[3-formyl-7-oxabicyclo-[2.2.1]hept-2-yl]heptanoic acid, ~ethyl ester for [1~,2a(52),3a,4~]-7-[3-formyl-7-oxabicyclo[2.2.1]-hept~2-yl]-5-heptenoic acid, methyl ester, the title compound is obtained.

Æxam~ le 6 6 [1~, 2a ~ 5Z ), 3a,4~]-7-E3-[2-(Phenylthlo)ethyl]-7-oxablcyclo[2.2.1]hept-2-yl]-5-heptenoic acid ; Following the procedure of Example 63 lS except substituting phenyl~ercaptan for l-hexanethiol, the title compound i9 obtained.

Example 67 [1~,2a(5Z),3~,43]-7-[3-[2-(Phenylthio)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Example 64 except substituting phenylmercaptan for l-hexanethiol, the title compound is obtained.

Example h8 (1~,2a,3a,4~)-7-[3-[2-~Phenvlthio)ethYl]-7-oxabic~clo-.
~2.2.1]hept-2-yl]heptanoic_acld Following the procedure of Example 65 except substituting phenylmercaptan for l-hexanethlol, the title compound is obtained.

.
:~ .
~:

.

- ~2~ HA290/280 , Example 69 [1~,2a(5Z),3,4~}7-[3-[2-(-Benzylthio)ethyl~-7-oxabicycl_[2.2.1]hept-2-yl]-5-heptenoic acld Following the procedure of Example 63 except substituting benzylmercaptan for l-hexanethiol, the title compound is obtained.

Example 70 [1~,2a(5Z),3~,4~-7-[3-t2-(Benzylthio)ethyl]-7-oxabicycloE2.2.11hept-2-yl]-5-heptenoic aci_ Following the procedure of Example 64 except substituting benzylmercaptan for l-hexanethiol, the title compound is obtained.

Exam~le 71 [1~,2(5Z),3a,4~}7-~3-[2-( Cyclopentyl)thio) e~hyl]-7-oxabic~vclo~2.2.1]hept-2-yl]heptenoic acid Following the procedure of Example 63 except substituting cyclopentylmercaptan for l-hexanethiol, the title compound is obtained.
Example 72 [1~,2a(5Z),3a,4~}7 [3-[2-(Cyclohexylthio)ethyl]-7-oxabicvclo[2.2.l]hept-2-Yl]-5-hePtenoic acid Following the procedure of Example 63 except substituting cyclohexylmercaptan for l~hexanethiol, the title product is obtained.

Example 73 [ 1~ , 2a ( 52 ) , 3a,4~}7-[3-[4-(Hexylthio)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid A. [1~,2a(5Z),3a,4~]-?-[3-(3-Oxo)~ropyl-7-oxabicvclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester ~ ~ ~ HA290/280 Following the procedure of Example 63, part A
except substituti~g [1~,2a(5Z),3a,4~] 7 ~3-(2-oxo)-ethyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester for [1~, 2(5Z), 3a, 43 ] -7 [3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]-S-heptenoic acid, methyl ester, the title A compound is obtained.

B. [1~,2a(5Z),3a,4~]-7-[3-(4-Oxo)butyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-hep~enoic acid, methyl ester Following the procedure o~ Example 63, par~ A, except substituting the aldehyde from part A above, ~or ~1~,2a(5Z) ,3a,4~ 7- [3-formyl-7-oxabicyclo[2.2.1]-hspt-2-yl]-5-heptenoic acid, methyl ester, the title B
15 aldehyde is obtained.

C. [1~,2(5Z),3a,4a]-7-~3-(4-Hydroxybutyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester Following the procedure of Example 63, part B, except substituting the title ~ aldehyde for [1~,2a~5Z),3a,4~]-7-[3-(2-oxo)ethyl]-7-oxabicyclo-[2.2.1]hept-2-yll-5-heptenoic acid, methyl ester, the title C alcohol is obtained.

D. [1~,2a(5Z),3~,4~}7-[3-[4-(Hexylthio)-butyll-7-oxabi yclo[2 2 l]hept 2 yl]-5-heptenoic acid Following the procedure of Examples 44 and 4~, 30 except substituting the above part C alcohol for the alcohol used in Example 44, the title compound is obtained.

, ; 35 .
, . .

~ HA290/2~0 Example 74 [1~,2a(5 ~ [3-[4-(Cyclohe~ylthio)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Followins the procedure of Example 73 except substituting cyclohexylmercaptan for l-hexanethiol, the title compound is obtained.

Example 75 [1~,2a(5Z),3a,4~]-7 [3-[4-(Phenylthio)buty~l-?-oxabicyclo[2.2.l]hept-2-yl]-s-heptenoic acid -Following the procedure of Example 73 except substituting phenylmercaptan for l-hexanethiol, the title compound is obtained.

ExamD~le 76 ~1~,2a(5Z),3a,4~]-7-[3-~4-(Benzylthio)butyl]-7-oxabicycloE2.2.1]hept-2-yl]heptenolc acid Following the procedure of Example 73 except substituting benzylmercaptan fox l-hexanethiol, the title compound is obtained.
Examples 77 78 and 79 [13,2a(5Z),3a,4~]-7-[3-[(He~ylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester (~ast movin~Lisomer), [13,2a(5Z),3a,4~]-7-_ ~3-[(Hexylsulflnyl)methyl]-7-oxabicyclo[2.2.1]he~t-2-yl]-5-he~tenoic acid, _ethyl ester (slow movlng isomer) and ~1~,2a(5Z),3a,4~]-7-[3-[(Hexylsulfonyl)-methyl]-7-oxabicyclo[2.2.1lhept-2-yI]-5-heptenoic ~ acid, methyl ester To a solution of 634 mg (1.72 mmol) of .

~ HA290/280 -~3-[13,2a(5Z),3,4~]-7-[3-[(hexylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester (prepared as describ~ed in ~xam~le 4,~) in 6.78 ml of methanol at 0C was added dropwise over 4 minutes 8.37 ml of 0.5M aqueous sodlum periodate solution. Tetrahydrofuran t2 ml) was then added and the resulting reaction mixture was stirred at room temperature for 15 hours. A
white precipitate was removed by filtration and washed with ether (3 x 50 ml)~ The filtrate was washed with 60 ml of saturated aqueous NaHC03 solution and dried over anhydrous magnesium sulfate.
Concentration in vacuo afforded 648 mg of an oily crude produc~. This was chromatographed on lS 54.16 g of silica gel 60 using O.S-l. a~ CH30H
in CH2C12 as eluent. This gave FMI ~East moving isomer) sulfoxide (Example 77) (211 mg, 32~), SMI
(slow moving isomer) sulfoxide (Example 78) ~142 mg, 21~) and sulfone (Example 79) (165 mg, 24%). These products were oils which so~idified on storage in the freezer. TLC = silica gel, 2%
(CX3O~CH2C12, Rf: Example 77 sulfoxide, 0.28;
Example 78 sulfoxide, 0.21; Example 79 ;ulfone, 0.74; iodine.

Example 80 [1~,2a(5Z),3a,43]-7-~3-[~Hexylsulfonyl)methyl]-7-oxablcyclo[2.2.1]hept-2-yll-5-heptenoic acid To a stirred solution of 165 mg ~0.41 ~mol) of [1~,2a(5Z),3a,4~]-7-[3-[(hexylsulfonyl~methyl]-7-oxabicyclo[2.2.1]hep~-2-yl]-5-heptenoic acid, .~

.

-64- _ me~hyl ester (Example 79 in 20.3 ml of THF and 3.09 ml of H20 under argon ~as added 3.90 ml of lN
aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for 10 minutes and stirred at room temperature for 6 hours. The reaction mixture was acidi~ied to pH 4 by addition of lN a~ueous HCl solution and pollred into 30 ml of saturated NaCl solution. The resulting solution was saturated with solid NaCl and extracted with EtOAc (4 x 50 ml). The combined EtOAc extracts ~ were dried (MgS04), filtered and concentrated ; in vacuo to give 165 mg of crude acid. Purification was effected by flash chromatography on 2Q g of silica gel 60 using 3~ C~30H in C~2C12 as eluant.
This aorded title acid (145 mg, 91%) which solidified on storage in the free7er. TLC~silica gel, 4~ CH30H/CH2C12, Rf 0.32, iodine.
Anal. Calcd for C20H3405S: C, 62.18; H, 8-31; S, 8-29 Found: C, 61.99; H, 9.01; S, 8.33 13C NMR (CDC13, 15.OMHz)tau 178.4, 33.1, 24.3, 26.7, 12a.9, 130.3, 28.0, 39.9, 79.8, 31.1, 28.8, 80.9, 47.0, 54.1, 51.7, ~9.4, 27.1, 22.2, 21.9, 13.7 Example 81 ~1~,2a (5Z?,3a,4~]-7-E3-E(Hexylsulfinyl)methyl]-7-oxabicycloE2.2.1]hept-2-yl]-5-heptenoic acid (fast movin~ isomer) To a stirred solution of 211 mg (0.55 mmol) of [1~,2a(5Z),3a,4~]-7-[3-[(hexylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yll-5-heptenoic acid, methyl ester (fast moving isomer) prepared in Example 77 in 27.0 ml of T~F and 4.11 ml of H20 under argon was added 5.19 ml of lN aqueous lithium .

z~

hydroxide solution. This mixture was purged with argon vigorously for ten mlnutes and stirred at room temperature for 6 hours. The reaction mixture was acidified to pH 4 ~y addition of lN aqueous HCl solution and poured into 50 ml of saturated NaCl solution. The resulting solution was saturated with solid NaCl and extracted with EtOAc (4 x 100 ml).
The combined EtOAc extracts were dried (MgSO4), filtered and concentrated ln vacuo.to give 216 mg of crude acid. ,Purification was effected by flash chromatography ~n 20.2 g of silica gel 60 using 3% CH30H in CH2C12 as eluant to give the title acid (17~ mg, 85~) as a white solid. TLC = silica gel, 4% CH3OEI/CH2C12, R~ 0!10, iodine.
Anal. Calcd for C20H3404S: C, 64-83; H~ 9.25t, ~, 8-65 Found: C, 64.7~; H, 9.17; S, 3.55 C NMR (CDC13, 15,0MHz)tau 176.8, 33,3, 24,5, 26.9, 129.0, 130.2, 28.4, 41.1, 80.1, 31.2, 28.3, 80.4, 47.1, 52.7, 52.7, 29.6, ; 20 26.7, 22.6, 22.3, L3.8 Example 82 [lB,2alSZ),3a,4~]-7-[3-[(Hexylsulfinyl)methyl]-7-oxa~icyclo[2.2.1]hept-2-yl]-5-heptenoic acid (slow moving.isomer) To a stirred solution of 142 mg (0,37 mmol) of [1~,2a(5z),3a,4~]-7-[3-[(hexyl-sulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester (slow moving isomer) prepared as described in Example 78 in 18.2 ml of THF and 2.77 ml of H2O under argon was added 3.50 ml of lN aqueous lithium hydroxide solution, This mixture was purged with argon vigorously for 15 minutes and stirred at room temperature for ~; 35 HA29Q/~80 4 hours and 40 minutes. The reaction mixture was acidified to pH 4 by addition of lN aqueous HCl solution and poured into 30 ml of saturated NaCl solution. The resulting solution was saturated with S solid NaCl and extracted with EtOAc (3 x 70 ml).
The combined ~tOAc extracts were dried (MgSO4), filtered and concentrated ln vacuo to give 152 mg of crude acid. Purification was effected by flash chromatography on 20.8 g of silica gel 60 using 4% CH30H in CH2C12 as eluant to give title acid (116 mg, 85~). TLC: silica gel, 4~ CH3OH/CH2C12, Rf 0.6, iodine.
Anal. Calcd for C20H34O4S: C, 64.83; H, 9.25; S, 3-65 Found: C, 64~44; H, 9.1S; S; 8.58 13C NMR (CDCl , 15.0MHz)tau 33.4, 24.6, 26.7, 129.0, 130.3, 27.1, 41.8, 80.0, 31.3, 28.4, 81.7, 47.3, 52.8, 52.8j 29.4, 27.1, 22.4, 22.4, 13.8 Example 83 [1~,2a(5Z),3,4~]-7-[3-[(Methylsulfinyl)methyl]-7-oxablcyclo[2.2.1]h_pt-2-yl]-5-heptenoic acid (fast moving isomer) Following the procedure of Examples 44, 77 and 81 except substituting methyl mercaptan for l-hexanethiol, the title compound is obtained.

Example 84 2a(5Z),3a,4~]-?-~3-[(Oct}~ulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic_acid (slow movlng isomer) - Following the procedure of Examples 44 77 and 82 except substituting l-octanethiol for l-hexanethiol, the title compound is obtained.

. . HA290/280 Example 85 [1~,2a(5g),3~,43]-7-[3-[(Phenylsulfinyl)methyl]-?-oxabicyclo[2.2.11hept-2-yl~ ~-heptenoic acid (fast moving isomer) Follow mg the procedure of Examples 48, 77 and 81 except substituting phenylmercaptan for l-pentanethiol,-the title compound is obtained.

Example 86 [1~ ! 2a (SZ), 3,4~]-7-[3-~(Ethylsulfinyl)methyl]-7-oxabi~yclo[2.2.1]hept-2-yl]-5-heptenoic acid (slow movin~ isomer) ~ollowing the procedure of Example 48, 77and 82 except substituting ethylmercaptan for l-pentane-thiol, the ~itle compound is obtained.

Example 87 (13, 2a, 3a, 4~) -7- [3- [ (Heptylsulfinyl~methyl] -7-oxabicyclo[2.2.1]hept-2-yll-5-heptanoic acid (fast moving isomer) Following the procedure of Examples 46, 77 and 81 except substituting l-heptanethiol for l-hexanethiol, the tltle compound is obtained.

Example 88 [l~,~a(5Z) ,3a,4~l-7-~-[(Benzylsulfinyl)methyl]-7-oxabicyclo [2 . 2.11hept-2-yl]-5-heptenoic acid Following the procedure of Examples 44, 77 and 81 excep~ substituting benzylmercaptan for l-hexanethlol, the title compound is obtained.

:, , .

r . ~ HA290/2~.0 Example 89 [lB,2a(5Z),3~,4~]-7-[3~[(Benzylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2~yl]-5-heF)tenoic acid (slow moving isomer) Following the procedure of Examples 48, 77 and 82 except substituting benzy].mercaptan for l-pen~anethiol, the title compound is obtained.

Example 90 ~1~,2a(5Z),3a,4~]-7-[3-~(Cyclohexylsulfinyl)methyl]-7-o~abicyclo[2.2.1]hept-2-yl]-5-heptenoic acid ~fast moving isomer) Following the procedure of Examples 44, 77 and 81 except substituting cyclohexylmercaptan for l-hexanethiol, the title compound is obtained.
Example 91 [1~,2a(5Z),3a,4~]-7-[3-[(Cyclopentylsulfi ~ )-methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (fast movin~ isomer) Following the procedure of Examples 44, 77 and 81except substituting cyclopentylmercaptan for l-hexanethiol, the title compound is obtained.

Example 92 [1~,2a(5Z),3a,4~]-7-[3-[(Octylsulfonyl)methyl]-7-oxabicyclo~2.2.1]hept-2-yl]-5~heptenoic acid Following the procedure of Examples 44, 77 and 80except substituting octylmercaptan for l-hexanethiol, the title compo nd is obtained.

, ~25~3~ HA2 9 o / ~ 8 o _ -69-O Example 93 [1~,2a(5Z),3a,4~]-7-[3-[(Propylsulf~nyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 44, 77 and 80 excep~ substituting propylmercaptan for l-hexanethiol, the title compound is obtained.

Example 94 [1~,2a(5Z),3a,4~]-7-[3-[(Phenylsulfonyl)methyl]-7-19 oxabicyclo~2.2.1~hept-2-yl]-5-heptenoic acid Foll~wing the procedure of Examples 44, 77 and 80 except substituting phenylmercaptan for l-hexanethiol, the title compound is obtained.

Exam~le 95 [1~,2a(5Z),3a,4~]-7-[3-[(Benzyl~ul~onyl)methyl]-7-oxabicyclot2.2.1]hept-2-yl]-S-heptenoic acid Following the procedure of Examples 44, 77 and 80 except substituting benzylmercaptan for l-hexanethiol, the title compound is obtained.
Example 96 [1~,2~(5Z),3a,4B]-7-[3-[(Cyclohexylsu~fonyl)methyl]-7-oxabicyclo[2.2.1]hep~-2-yl]-5-heptenoic acid Following the-procedure of Examples 44, 77 and 80 except substituting cyclohexylmercaptan for l-hexanethiol, the title compound is obtained.

Example 97 [1~,2~(5Z),3~,4~]-7-[3-[(Heptylsulfonyl?methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 48, 77 and 80 except substituting l-heptanethiol for l-pentanethiol, the title compound is obtained.

:~2~
. HA290~280 .-70-Example 98 Cl3,2a(5z) ,3~,4~]-7-[3-[(Benz~lsulfonyl)methyl]-7-oxabicyclo [2 . 2 .1 ] hept-2-yl]-5-hep _noic acid Foll~wing the procedure of Examples 48, 77 and 80 except substituting benzylmercaptan for l-pentanethiol, the title compound is obtained.
.
~9 [1~,2a(5Z?,3~,4~]-7-~3-[(Cyclopentylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl].-S heptenoic acid Following the procedure of Examples 48, 77 and 80 except substituting cyclopentylmercaptan for l-pentanethiol, th.e title compound is obtained.

Example lon [1~,2a(5Z),3~,4B]-7-[3-[(Phenylsulfonyl)methy~-7-oxabicyclo~2.2.1]hept-2-yl]-5_heptenoic acid . Following the procedure of Examples 48, 77 and 80 except substituting phenylmercaptan for ; 20 l-pentanethiol, the title compound is obtained.
.
Example 101 (1~,2,3a,4~)-7-[3-[(Cyclopropylsulfinyl)methyl]-7-oxabicyclo[2.2 l]hept-2-yl]-5-heptanoic acid Following the procedure of Examples 46, 77 and 80 except substituting cyclopropylmercaptan for l-hexanethiol, the title compound is obtained.
~' - ~2:;6~187 . HA290/280 .
Example 102 (1~,2a,3a,4~)-7-[3-[(Benzylsulfirlyl?methyl]-7-oxabicyclo[2.2.1]hept 2-yl]-5-heptanoic acid Following the procedure of Examples 47, 77 and 81 S except substituting benzylmercaptan for l-hexanethiol, the title compound is obtained.

Example 103 .

[i~2~sæ) ,3a,4~}7-[3-[2-(Pentylsulfinyl)ethyl]-7-oxabicyclo~2.2.1]hept~2-yl]-5-heptenoic acid Following the procedure of Examples 63, 44, ~ 77 and 81 except sub~tituting l-pentanethiol for l-hexanethiol, the title compound is obtained.

Exam~le 104 ~1~,2a(5Z),3~,4~}1-~3-~2-(Phenylsulfonyl)ethyl] 7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic aci.d Following the procedure of Examples 63, 44, 77 and 80 except substituting phenylmercaptan for 2~ l-hexanethiol, the title compound is obtained.
.
Example 105 [la, 2a(5Z),3a,4~}7-[3-[2-(Cyclohexylsulfonyl)ethyl]-7-oxabicyclo[2 2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 63, 44, 77 and 80 except substituting cyclohexylmercaptan for l-hexanethiol, the title compound is obtained.

ExamDle 106 [1~,2a(5Z),3a,43~7-[3-[2 (Be~ lsulfinyl)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 63, 44, 77 and 81 except substituting benzylmercaptan for l-hexanethol, the title compound is obtained ., .

' HA2~0/280 OExample 107 [13,2~5Z), 3a, 4~]-7-~3-[2-(Bu ylsulfonyl)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 63, 48, 77 and 80 except substituting butylmercaptan for l-pentanethiol, the title compound is obtained.

Exam~ 8 [1~!2a(sZ),3~,4~7-E3-E2-(Phenylsulfinyl)ethyl]-7-oxabicycloE2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 63, 48, 77 and 81 except substituting phenylmercaptan for l-pentanethiol, the title compound is obtained.

Example 109 [1~,2a(5Z) ,3~,4~}7-E3-[2-(Benzylsulflnyl)ethyl]-7-oxabicycloE2.2.1]~hept-2-yl]-5-heptenoic acid Following the procedure of Examples 63, 48, 77 and 81 except substituting benzylmercaptan for l~pentanethiol, the title compound is obtained.
Example llD
[1~,2a(5Z),3~,4B}7-[3-[2-(Cycloheptylsulfonyl)-ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 63, ~8 77 and 80 except substituting cycloheptylmercaptan for l-pentanethiol, the title compound is obtained.

Example 11~
(1~,2a,3a,4~)-7-E3-E2-(Pentylsulfonyl)ethyl]-7-oxabicyclo[2.2._1]hept-2-yl]-5-heptanolc acid Following the procedure of Examples 63, ~ 77 and 80 except subs~ituting l-pentanethiol for l-hexanethiol, the title compound is obtained.

:3.2~i;~3~7 290~280 ~ 73-Example 112 (1~,2a,3a,4~7-[3-[2-(Phenylsulfinyl)ethyl] ?_ oxabicyclo~2.2.1]hept-2-yl]-5-heptanoic acid Following the procedure of Examples 63, 46, 77 S and 81 except subs~ituting phenylmercaptan for l-hexanethiol, the title compo~nd is obtained.

Example 113 , 2a, 3a, 4 ~ ~7- [3- ~2-(Benz~lsulfinyl)ethyl]-7~
oxablcyclo~2.2.1]hept-2-yl]-5-heptanoic acid Following the procedure of Examples 63, 46 77 and 81 except substituting benzylmercaptan for l-hexanethiol, the title compound is obtained.

~ 4 , 2a, 3a, 4~ ~7-~3-~2-(Cyclohexylsulfonyl)ethyl]-7-oxabicyclo[2.2.1]he~t-2-yl]-5-hepta~oic acid Following the procedure of Examples 6 3, 4 8 77 and 8n except substituting cyclohexylmercaptan for l-hexanethiol, the title compound is obtained.
'; ' .
Example_115 _~,2a~5Z),3a,4~}7-[3-[4-(Pentylsulfonyl)butyl~-7-oxabicyclo[2.2.1]hept-2-yl]~S-h~ptenoic acid Following the procedure of E~ples 73, 63, 44 77 and 80 except substituting pentylmercaptan for l-hexanethiol, the title compound is obtained.

Example 116 [1~,2a(5Z),3a,4~}7-[3-[4-(Cyclohexylsulfinvl)butyl]--oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 73, 63 44, 77 and 81eXcePt substituting cyclohexylmercaptan for l-hexanthiol, the title compound is obtained.

~ ~ HA290/280 _ -74-Example 117 [13,2a(5Z),3a,4~]-7-[3-[4-lPhenylsulfin~but~1]-7-oxabicyclo[2.2.1]hept-2-yll-5-heptenoic acid Following the procedure of Examples 73, 63, 44, 77 an~ 81except substituting phenylmercaptan : for l-hexanethiol, the title compound i5 obtained.

. Example 1.1~
[1~,2~(5Z),3a,4~7-[3-~4-(Benzylsulfonyl~butyl]-7-oxabicvclo[2.2.1~hept-2-vl]-5-heptenoic acid ~ . . . _ _ .
Following the procedure of Examples 73, 63 44, 77 and 80eXcept substituting benzylmercaptan for l-hexanethiol, the title compound is obtained.

Example~
[1~,2a(5Z),3~,4~}7-~3-[4-(Cyclopentylsulfinyl)butyl]-7-oxabicyclo~2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 73, 53 48, 77 and 8] except substituting cyclopentylmercaptan for l-pentanethiol, the title compound is obtained.
Example 120 [1~,2a(5Z),3~,4~}7-[3-[4-(Benzylsulfinyl)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-he~tenoic acid ~ollowing the procedure of Examples 73, 63 48, 77 and 80 except substituting benzylmercaptan for l-pentanethiol, the title com~ound is obtained.
.
Example 121 ~; 30 [1~,2a(5Z),33,4~}7-[3-[4-(Propylsulfinyl)butvl]-7-o abicyclo[2.2.1]hept-2-yl]-5-he~tenoic acid Followi~g the procedure of Examples 73, 63, 48, 77 and 81 except substituting propyl~ercaptan for l-pentanethiol, the title compound is obtained.

, ~A290/280 '' V
-7~

Example 122 [1~,2a(5Z?,3~,4B}7-[3-[4-t~henylsulfonyl?butyl]-?-oxabic clo[2.2.l]hept-2-yl]-5-he~tenoic acid Following the procedure of Examples 73, 63 48, 78 and 80 except substituting phenylmercaptan for l-pentanethiol, the title comDound is obtained.

Examp le 12 3 , 2a, 3a, 4B)-7-~3-[4-(Nonylsulfinyl)butyl]-7-oxabicyclo~2.2.1]hept-2-y~-5-heptanoic acid Following the procedure of Examples 73, 63 46, 77 and 8lexcept substituting l-nonanethiol for l~hexanethiol, the title compound is obtained.

Example 124 (13,2a, 3a, 4~)-7- ~3-[4-(Pentylsulfonyl)butyl]-7-oxabicyclo~'2.2.1]he~t-2-yl]-5-heptanoic acid ; Following the procedure of Examples 73, 63, 46 7i and 80 except substituting l-pentanethiol for l-hexanethiol, the title compound is obtained.
Example 125 (1~,2a,3a,4~)-7-~3-[4-(Phenvlsulfinyl)butyl]-7-.
oxabicyclo[2.2.1]hept-2-yl}-5-heptenoic acid Following the procedure of Examples 77, 63 46, 77 and 81except substituting phenylmercaptan for l-hexane~hiol, the title compound is obtained.

Example 126 ,2a,3a,4~)-7-[3-[4-(CYclohexylsulfonyl)butyl]-7-- -oxablcvclo[2.2.1]hept-2-yl]-5-heptanoic acld Following the procedure of Examples 73, 63, 46 77 and 8C except substituting cyclohexylmercaptan for l-hexanethiol, the title compound is obtained.

~ ~5~
- ~ HA290/280 xample 127 [1~,2a(5Z),3a,4~]-7-[_-[[(Cyclohexylmethyl)thio]-methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid A. [1~,2~(5Z),3a,4~]-7-[3-[[(Cyclohexyl-me~h~l)thio]methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid, methyl ester To a solution of 88 mg (0.78 mmol) of potassium t-butoxIde in S ml of dry THF under argon was added 277 mg (2.13 mmol) of cyclohexylmethane-thiol (prepared from cyclohexylmethanol by the method of Volante: Tetrahedron Letters 1981, 22, 3119). To this m~xture was added a solution of 300 mg (0.71 mmol) of ~1~,2~sZ),3,4~]-7-E3-(p-toluenesulfonyloxymethyl)-7-oxabicyclo[2.2.1~-hept-2-yl]-S-heptenoic acid, methyl ester,prepared as described in ExampLe 44B, in S.5 ml of dry THF.
The reaction mixture was heated to reflux for 7 hours.
The cooled reaction mixture was dilu~ed with 250 ml of ether and poured into 100 ml of saturated NaHCO3 solution. The a~ueous layer was extracted with ether ~2 x 100 ml). The combined ether extracts ~450 ml) were washed with 0.5 N aqueous sodium hydroxide solution (2 x 100 ml) and brine (100 ml). The ether extxacts were dried over anhydrous MgSO4 and corlcentrated ln vacuo to give an oily product. Purification was effected by chromatography on 20.2 g of silica gel 60 using hexane:ether (3:1) as eluant to give 253 mg of tit}e ~ methyl ester as an oil (94~). TLC:silica gel, petroleum ether:ether (3:2), Rf=0.70; iodine.

. - ~ HA290/28 _ _77_ ~ Bo [1~,2(5Z),3a,4~]-7-[3 [[(Cyclohexyl-, methyl)thio]methyl]-7-oxabicyclo[2.2.1]-hept-2-yl ~ acid ~; To a stirred solution of 243 mg (0.64 mmol) S of Part A methyl ester in 31.4 ml of THF and 4.80 ml of H20 under argon was added 6.00 ml of lN aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for 2S minutes and stirred at room temperature for 16 hours. The react~on mixture was acidified to pH 5 by addition o lN aqueous HCl solution and poured into 40 m~l of saturated NaCl solution. The resulting solution was saturated with solid NaCl and extracted with EtOAc (4 x 50 ml). The combined EtOAc extracts lS were dried (MgSO4), filtered and concentrated ln vacuo to give 253 mg of crude acid. Purification was effected by flash chromatography on 20.6 g of silica gel 60 using ~etroLeum-ether:ether (2:3) as eluant to give pure title product (117 mg, 50~) along with 108 mg (46~) of mixed fractions of which title product was the major component. TLC:silica gel, Pet-ether:ether (2:3), Rf = 0.32, iodine.
Anal. Calcd for C~lH34O3S: C, 68.85; H, 9-29; S, 3-74 Found: C, 68.90; H, 9.43; S, 8.66 3C NM~ (CDC13, 15.0MHz)tau 178.7, 32.9, 24.6, 26.1, 129.7, 129.9, 29.5, 47.1, 80.4, 25.7, 26.3, 80.7, 47.6, 33.4, 40.4, 38.0, 32 . a, 29.5, 26.1, 29.5, 32.9 290/2~0 .
Example 128 ~1~, 2a (5Z), 3a, 43] -7- ~3- ~ [ (2-Phenylethyl)thlo]methyl]-7-oxabicyclo[2.2.1]hept-2 vl]-5-h~ptenoic acid A. [ 1~, 2a ( 5 Z ~, 3a, 4~ ] -7-~3-[[~2-Phenylethyl)-thio]methyl]-7-oxablcyclo[2.2.1]hept-~ 2-ylJ-5-heptenoic acid, methyl ester To a solution of 55.7 mg (0 50 mmol) of potassium t-butoxide in 5 ml of dry THF under argon was added 185 mg (1.35 mmol) of phenylethanethiol.
1~ To this mixture was added a solution of 189 mg (0.45 mmol) of [1~,2~(5Z),3a,4~-7-~3-~p toLuene-sulfonyloxymethyl)l-7-oxabicyclo[2.2.1}hept-2-yl~-5-heptenoic acid, methyl ester,prepared as described in Example 44B, in 6 ml of dry THF. The reacti~n 15 mixture was heated to reflux for 4 hours and 30 minutes. The cooled reaction mixture was diluted with 160 ml of ether and poured into Ç0 ml of~
saturated ~aHCO3 solution. The aqueous layer ~as extracted with ether (2 x 60 ml). ~he combined 20 ether extracts (280 ml) were washed with 0.5 N
aqueous sodium hydroxide solution (2 x 60 ~1) and brine ( 75 ml). The ether extracts were dried over MgSO4 and concentrated ln vacuo to give an oily product. Purification ~as effected by chromatography 25 on 21.6 g of silic gel 60 using petroleum ether:ether (5:1) as eluant to give 157 mg of title A compound as an oil (90%). TLC:silica gel, petroleum ether:ether ; (2:1), Rf = 0.60, iodine.

~ % S ~ ~ HA290/280 -79~
B. [1~, 2a ( 5z ?, 3a,43]~7- E 3~[[(2-Phenylethyl)-thio]methyl~-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenolc acid -To a stirred solution of lS0 mg ~0.39 mmol) of Part A methyl ester in 19 ml of freshly distilled THF and 2.91 ml of H20 under argc,n was added 3.64 ml of lN aqueous lithi~m hyc~oxide solution.
This mixture was purged with argon vigorously Eor 25 minutes and stirred at room temperature for 6 hours. The reaction mixture was acidified to pH 5 ~y additio~ of lN aqueous HCl solution and.
poured into 40 ml of saturated NaCl solution.
The resulting solution was saturated with ~solid NaCl and extracted with EtO~c (4 x 60 ml). The combined EtOAc extracts were dried (MgSO~), filtered and concentrated in ~acuo to give 147 mq o -crude acid. Purification was effected by flash chromatography on 20 g of silica gel 60 using 2~ CH30H in CH2C12 as eluant to give title product (122 mg, 84~) as an oil. TLC:silica gel, 6 CH3OH in CH2C12, Rf = 0.32, iodine.
A~al. Calcd for C22H3003S: C, 70.55; ~, 8.07; S, 8-56 Found: C, 70.54; H, 8.08; S, 8.48 13C NMR (CDC13, 15.0MHz)tau 179.0, 33.4, 24.5, 26.2, 129.9, 129.7, 26.7, 46.9, 80.4~
29.5, 80.6, 47.5, 32.3, 34.1, 36.4, 140.5, 128.4, 126.3, 128.4, 12~.4 Example 129 [lB,2a($Z),3,43]-7-[3-[[(3-Phenylpropyl)thio]-met yll-7 oxabicyclo[2.2.1]hept-2-yl]-S-heptenolc acid A. [lB,2~(5Z),3a,4B]-7-[3-[~(3-Phenvl~ro~Yl)-,, ~ ~
thlo]methyl~-7-oxabicyclo[2.2.1]hept-2-~tl]-S-heptenoic acid, methyl ester To a solution of 88 mg (0.78 mmol) of 3~ potassium t-butoxide in 5 ml of dry THF under argon : . .

.
was added 324 mg (2.13 mmol) of 3--phenylpropyl-mercaptan. To this mixture was added a solution of 300 mg (0 71 mmol) of [1~,2a(5Z),3a,4~]-7-~3-(p-toluenesulfonyloxymethyl)-7-oxabicyclo[2.2.1]-S hept-2-yl]-5-heptenoic acid, methyl ester in 7 ml of dry THF. The reaction mixture was heated to - - raflux for 6 hours and 30 minutes. The cooled reaction mixture was diluted with 25C ml of ether and poured into 100 ml of saturated NaHC03 solution.
The aqueous layer was extracted with ether (2 x 100 ml). The combined ether extracts (4;0 ml) was washed with 0~5 N a~ueous sodium hydroxide solution (2 x 100 ml) and brine (100 ml)~ The ether extracts were dried over MgS04 and concentrated ln vacuo to give a~ 4ily product. Purification was efected by chromatography on 25 g of silica gel 60 using hexane:ether (3:1) as eluant to give 280 mg of title A compound as an oil (98%).
TLC:silica gel, petroleum ether:ether t2:1), Rf 0.60, io*ine.

B. [1~,2a(5Z),3a,4~]-7-[3-~[(3-Phen~lpro~yl)-thiolmethyl]-7-oxabicyclo~2.2.1]hept-2-yl]-5-heptenoic acid To a stirred solution of 280 my (0.70 mmol) of Part A methyl ester in 34.4 ml oP freshly dlstiiled THF and 5.30 ml of H20 under argon was added 6.60 ml of lN aqueous lithium hydroxide solution. This mixture was purged with argon for an hour and stirred 3~ at room temperature for 3 hours. The reaction mixture was acidified to p~ 5 by addition of lN
aqueous HCl solution and poured into 50 ml of saturated NaCl solution. The resulting solution was saturated with solid NaCl and extracted with EtOAc (4 x 60 ml). The combined EtOAc extracts `
.

~ ~ HA290/280 were dried (MgSO4), filtered and concentrated n vacuo to give 280 mg of crude acid. Purification was effected by flash chromatography on 29 g of silica gel 60 using 2~ CH3OH in CH2Cl2 eluant to give title product (205 mg, 76~). TLC:silica gel, 6% CH3OH/CH2C12, Rf=0.34, iodine.
Anal. Calcd for C23~32Q3S: C, ~1.09; H, 8-30; S, 8.25 Found: C, 70.81; H, 8.36; S, 8.14 13C NMR (CDC13, 15.0MHz)tau 179.0, 33.4, 24.7, 26.7, 129.7, 129.8~ 29.5, ~6.9, 80.4, 29.5, 80.6, 47.5, 32.1, 31.9, 26.2, 34.7, 141.4, 128.4, 128.4, 125.8, 128.4, 128.4 Example 130 ~1~,2a~5Z),3~,4~]-7-~3-~(C~clohexylmethyl)_ thio]methyl]-7-oxabicyclo~2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of ExampIes 48 and 49 except suhstituting cyclohexylmethanethiol for l-pentanethiol, the title compou~d is obtained.

Example 131 [1~,2a(5Z),3~,43]-7-[3-~[~3-Cyclohexylpropyl)thio]-methyl]-7-oxabicyclo[2.2.1Jhept-2-yl]-5-heptenoic acid Following the procedure of Exa~ples 48 and 49 except substituting 3-cyclohexylpropanethiol for l-pentanethiol, the title compound is obtained.

Example ]~2 (13,2a,3a,4~)-7-[3-[[(2-Cyclohexylethyl)~hio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl~-5-heptanoLc acid Following the procedure of Examples 46 and 47 except substituting 2-Cyclohexylethanethiol for l-hexanethiol, the title compound is obtained.

82- ~ _ Example 133 [lB,2a(5Z),3~,4B]-7-[3~[[(2-Phenylethy~thio~ methyl]-7-oxabic ~1 _2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 48 and 49 except substituting 2-phenylethanethiol for l-pentane-thiol, the title compou~d is obtained.

~ 4 [1~,2a(5Z),3~,4~-7-~3-[[(3-Phenylpropyl)thio]methyl]-7-oxabicyclo~2.2.1]hept-2-yl]-S-heptenoic acid Followiny the procedure of Examples 48 and 49 except substituting 3-phenylpropanethiol for l-pentane-thiol, the title compound is obtained.

Example 135 (l~,Zd,3a,4~)-7-~3-~(2-Phenylethyl)thio]meth~1]-7-oxabicyclo~2.2.1]hept-2-yl]-5 heptanoic acid Following the procedure of Examples 46 and 47 except substituting 2-phenylethanethiol for l hexane-thiol, the title compound is obtained.
; Example 1~
(1~,2a,3a,43)-7-~3-[~(3-Phenylpropyl)th~,Q]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-S-heptenoic a~id Following the procedure of Examples 46 and ~5 except substit~i~g 3-phenylpnopanethiol for l-hexane~iol, the title compound is obtained.

Example 137 [1~,2a(5Z),3a,43]-7-[3-[~(Cyclohe~ylmethyl)sulfinyl]-methyl]-7-oxabicyclo[2.2 l]hept-2-yl]-S-heptenoic acid (slow moving isomer) Following the procedure of Examples 44, 77 and 81except substituting cyclohexylmethanethiol for l-hexanethiol, the title compound is obtained.

' . HA2gO/280 Example 138 [1~,2a(5Z),3~,4~]-7-[3-[[(_yclohexylmethyl)sulfinyl]-meth~]-7-oxa~icyclo[2.2.1~hept-Z-yl]-5-heptenoic acid (fast moving isomer) Following the procedure of Examples 48, 77 and 81 except substituting cyclohexylmethanethiol for l-pentanethiol, the title compound is obtained.

Example 139 [1~,2a(5Z),3~,4~]-7-[3-~[(2-Phenylethyl)sulfinyl]-methyl]-7 oxabic~clo~2.2.1]hept-2-yl~-5-heptenoic acid (fast moving isomer~
Following the procedure of Examples '44, 77 and 81 except substituting 2~henylethanethiol for l-pentanethiol, the title compound ls obtained.
Exam~le 1~0 ~1~,2a(5Z),3a,4~]-7-[3-[1(3-Phenylpropyl)sulfinyl]-methyl~-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenolc 2~ acid (slow moving isomer?
Following the procedure of Examples 48, 77 and 82 ~xcept substituting 3-~henyl~ropanethiol for l-pentanethiol, the title compound is obtained.
.
Example 141 (1~,2a,3a!4~)-7-~3-[[(2-Phenylethyl)sulfinyl]methyl]-7-oxablcyclo[2.2.1]hept-2-yl]-5-heptano~c acid (fast movin~ isomer) Following the procedure of Examples 46, 77 and 81 except substituting 2-phenylethanethiol for l-hexanethiol, the title compound is obtained.

. HA290/280 Example 142 [13~ 5~ 3a~43]_7_[3-[[~Cyclohe ylmet_yl)sulfonyl]-meth~l]-7-oxabicyclo[2.2_.1 h_p -_-yl]-5-heptenoic acid Following the procedure of Examples 44,.77 and 80 except substituting cyclohexylmethane~hiol for l-hexanethiol, the title compound is obtained.

Example _43 [1~,2a~5Z),3a,4~]-7-~3-~[(2-Phenylethyl)sulfonyl]-methyl]-7 oxabicyclo~2.2.1]hept-2-yl~-5-heptenoic acid Following the procedure of Examples 44, 77 and 80 except substitutiny 2-~henyle~ethiol for l-hexanethiol, the title compound is obtained.

lS Example 144 [1~,2~5Z),3~,43]-7-~3-~(3-Phenylpropyl)sulEonyl]-meth ~]-7-oxabicyclo~2.2.1]hept-2-yl]-S-heptenoic acid Following the procedure of Examples 44, 77 and 80 except substituting 3-phenylpropanethiol for l-hexanethiol, the title compound i5 obtained.

ExampIe 145 [1~,2a(5Z),3a,4~]-7-[3-[2-[(Cyclohexylmethyl)thio]-ethyl~-7-oxabicyclo[2.2.1]hept-2-yl~-5-heptenoic acid Following the procedure of Examples 63 and 44 except substituting cyclohexylmethanethiol for l-hexanethiol, the title compound is obtained.

Example 146 [1~,2a(5Z),3a,43]-7-~3-[2-[(Cyclohexylmethyl)sulfinyl]-ethyl]-7-oxablcyclo[2.2.1]hept-2-yl~-5-heptenolc acid Following the procedure of ~xamples 63, 44 77 and 81 except substituting cyclohexylmethanethiol for l-hexanethiol, the title compo~nd ls obtàined.

' `HA290/280 ~ -Example 14~7 [1~,2a(5Z),3a,4~]-7-~3-[2_1(Cyclohexylmethyl) sulfonyl ethyl~-7-oxabicyclo[2.2.
heptenoic acid Following the procedure of Examples 63, 44, 77 and 80 except subs~ituting cyclohexylmethanethiol for l-hexanethiol, the title compound is obtained.

Exam~le 143 [1~,2a(5Z),3a,4~]-7-~3-[2-~(2-Phen~lethyl)thio]-ethyl]-7-oxabicyclo[2.2.1~hept-2-yl]-5-heptenoic acid Following the procedure o~ Examples 63 and 44 except substituting 2-phenylethanethiol for l-hexane-thiol, the title compound is obtained.
lS
Example 143 [1~,2(5Z),3~,4~]-7-[3-~2-[(2-Phenylethyl)sulfinyl]-ethyl]-7-oxabicycl_[2 2.1]hept-2-yl]-5- ~enoic a~id Following the procedure of Examples 63, 44, 77 and 81 except substitutins 2-phenylethanethiol for l-hexanethiol, the title compound is obtained.

Example 150 [13 ,2a(5Z), 3a,43]-7-[2-~(3-Phenylpropvl)thio]ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 63 and 44 except substituting 3-phenylpropanethiol for l-hexane-thiol, the title compound is obtained.

Example 151 [1~,2a(5Z),3a,4~]-7-[3- ~-r(3-Phenylpropyl)sulfinyl~-ethyl]-7-oxabicvclo[2. 2 .1 ] he~t-2-y]l-5-he~tenoic acid Following the procedure of Examples 63, 44 77 and 81 except substituting 3-phenylpropanethiol fer l-hexanethiol, the title compound is obtained.

3iL~Sf i~7 ~ , HA290~230 Example 152[1~,2a(sZ),3a,43]-7-E3-[2-~(2-Phenylethyl)sulfonyl]-ethyl] 7-oxabicycloE2.2.1}hept-2-yl]-5-heptenoic acid -Following the procedure of Examples 63, 44 77 and 80 except substituting 2-phenyleth~nethiol for l-hexanethiol,'the title compound is obtained.

Example 15'3 [1~2a(5Z)~3a,4~]-7-[3-[2-[(3-Phenylpropyl)sulfonyl]-ethylj-7-oxabicyclo[2.2.1]hept-2-~1]-5-heptenoic acid ' Following the procedure of Examples 63, 44, 77 and 80 except substituting 3-phenylpropanethiol for l-hexanethiol, the title compound'is obtained.

Example 154 ~13,2a(SZ),3a,4~]-7-~3-[4-~(Cyclohexylmethyl)thio]-butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Eollowing'the proce'dure of Examples 73, 63 and 44 except substituting cyclohexylmethanethiol for l-hexanethiol, the title compound is obtained.
Example 15~
[13,2a(5Z),3,4~]-7-[3-[4-[(Cyclohexylmethvl)-sulinyl tyl]-7-oxabic~ycloE2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 73, 63, 44,77 and 81except s~stituting cyclohexylmethanethiol for l-hexanethiol, the title compound is obtained.

Example 156 [1~, 2 (5S), 3a, 4~ ] -7-[3-[4-[(Cyclohexylmethyl)-sulfonyl]butyl]-7-oxabicyclo~2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 73,63 '~A290/?80 44, 77and 80 except substituting cyclohexylmethane~ol for l-hexanethiol, the title compound is obtained.

Example 157 [1~,2(5Z),3a,4~]-7-[3-[4-[(2-Phenylethyl)thio]-butyl]-7-oxabicyclo[2.2.1lhept-2-yl]-5-heptenoic acid Followins the procedure of Examples 73, 63.
and 44except substituting 2-phenyleth~nethiol for l-hexanethiol, the title compound is obtained.

E mple 158 [1~,2a(5Z),3a,43]-7-[3-[4-~2~Phenylethyl)sulfinyl]-buty~1]-7-oxabicyclo[2.2 llhept-2-yl]-5-heptenoic acid Following the procedure of Examples 73, 63, 44,77 and 81 except substitutinq 2-PhenY1et~ethiol for 1-hexanethiol, the title compound is obtained.

Example lS9 [1~,2a(5Z),3a,4~] 7-[3-[4-~(2-Pheny~ethyl)sulfonyl]-butyl] 7-oxabicyclo~2.2.1]hept-2-yl]-S-he~tenoic acid Following the procedure of Examples 73, 63, 44, 77and 80 except substituting 2-2henvlet~nethiol for 1-hexanethlol, the title compound is obtained.

~56~ -HA290/280 Example 160 [1~,2a(5Z?,3a,4~)-7-[3-[2-(hepty:Lthio)eth~1]-7-oxabicyclo[2.2.11hept~2-yl~-5-heptenoic acid and me hyl_ester By reacting [1~,2a(5Z),3a,4~]-7-[3-(2-hydroxyethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester (sec example 20B~
with tosyl chloride as per Example 44B and with heptanethiol according to the procedure of 44C, the titled product is obtained as the methyl ester as a colorless oil, TLC(silica gel,-hexane:ether~2:1) Rf - 0.45. Hydrolysis according to the procedure of example 45 affords the free acid as an oil, TLC(silica gel, 3 lS CH3OH/CH2cl2) Rf - 23-Anal. calcd. for C22H38O3S: C,69-06; H,10-01; S,8-38 Found: C,68.80; H, 9.99; S,8.24 3C NMR (CDC13, 15.0MH~)tau 178.8, 33.4, 22.5, 24.5, 129.5, 130.1, 26.6, 46;1, ~30.1, 29.7, 29.7, 80.1, 47.3, ~2.3, 31.7, 31.7, 29.5, 28.8, 32.3, 28.8, 26.6, 13.9 Example 161 [1~,2~(5Z),3a(E),4~]-7-[3-[~(3-phenyl-2-propenyl)-thiolmethyl]oxabicycloj2.2.1]hept-2-yl]-5-heptenoic acid and methyl ester By following the procedure of exam~le 44 and . substituting 3-phenyl-2-propenylthiol for the 1-; hexanethiol used in example 44(C), the titled methyl ester is obtained, TLC~silica gel, hexane:
30 ether(2:1)) Rf = 0.35; and continuing on with the hydrolysis procedure outlined in example 45 affords the titled free acid, TLC(silica gel, 3 CH3OH/CH2C12), Rf - 0.25 Anal. calcd. for C23H30O3S: C,71.46; H,7.82; S,8.30 Found: C,71.31; H,7.87; S,8.26

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound having the struc-tural formula:

I and including all stereoisomers thereof, wherein A is -CH=CH- or -(CH2)2-;
B is oxygen (-O-) or -?- ;

m is 1 to 8;
n is 1 to 4;
n' is 0 to 2;
R is hydrogen, C1-C12 alkyl, alkali metal or tris-(hydroxymethyl)aminomethane; and R1 is C1-C12 alkyl, C6-C10 aryl, C6-C10 aralkyl, C3-C12 cycloalkyl or C3-C12 cycloalkylalkyl;
characterized by etherifying or thioetherifying a compound of the formula:

II with the desired R1-OH or R1-SH group.

2. A process according to claim 1 wherein B is -O-.

3. A process according to claim 1 wherein B is -S-.

4. A process as defined in claim 1 wherein A is -CH=CH-.

5. A process as defined in claim 1 wherein R is H.

6. A process as defined in claim 1 wherein n is 1.

7. A process as defined in claim 1 wherein n is 2.

8. A process as defined in claim 1 wherein n is 3 or 4.

9. A process as defined in claim 1 wherein A is -CH=CH-, m is 2 to 4, n is 1 or 2, R is H and R1 is lower alkyl or cyc-loalkyl.

10. A process as defined in claim 1 wherein A is -CH=CH-, m is 3, n is 1, R is H, CH3 or C6H13 and R1 is lower alkyl.

11. A process as defined in claim 1 wherein the product is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(hexyloxy)methyl]-7-oxabicyclo[2.2.
1]hept-2-yl]-5-heptenoic acid or its hexyl ester.

12. A process as defined in claim 1 wherein the product is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(2-pentyloxy)ethyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid.

13. A process as defined in claim 1 wherein the product is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(phenylpropoxy)methyl]-7-oxabicyclo-[2.2.1]hept-2-yl}-5-heptenoic acid.

14. A process as defined in claim 1 wherein the product is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(octyloxy)methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid.

15. A process as defined in claim 1 wherein the product is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(cyclohexylmethoxy)methyl]-7-oxa-bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid.

16. A process as defined in claim 1 wherein A is -CH=CH-, m is 3, n is 1, n' is 1 and R1 is lower alkyl.

17. A process as defined in claim 1 wherein A is -CH=CH-, m is 3, n is 1, n' is 2 and R1 is lower alkyl.

18. A process as defined in claim 1 wherein the product is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(hexylthio)methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid or its methyl ester.

19. A process as defined in claim 1 wherein the product is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(hexylsulfinyl)methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid or its methyl ester.

20. A process as defined in claim 1 wherein the product is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.-7-[3-[(hexylsulfonyl)methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid or the methyl ester thereof.

21. A process as defined in claim 1 wherein the product is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[[(cyclohexylmethyl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or the methyl es-ter thereof.

22. A process as defined in claim 1 wherein the product is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[[(2-phenylethyl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or the methyl es-ter thereof.

23. A process as defined in claim 1 wherein the product is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[[(3-phenylpropyl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or the methyl es-ter thereof.

24. A compound having the structural formula:

I and including all stereoisomers thereof, wherein A is -CH=CH- or -(CH2)2-;
B is oxygen (-O-) or -?- ;

m is 1 to 8;
n is 1 to 4;
n' is 0 to 2;
R is hydrogen, C1-C12 alkyl, alkali metal or tris-(hydroxymethyl)aminomethane; and R1 is C1-C12 alkyl, C6-C10 aryl, C6-C10 aralkyl, C3-C12 cycloalkyl or C3-C12 cycloalkylalkyl;
whenever prepared by the process of claim 1.

25. A compound according to claim 24 wherein B is -O-, whenever prepared by the process of claim 2.

26. A compound according to claim 24 wherein B is -S-, whenever prepared by the process of claim 3.

27. The compound as defined in claim 24 wherein A is -CH=CH-, whenever prepared by the process of claim 4.

28. The compound as defined in claim 24 wherein R is H, whenever prepared by the process of claim 5.

29. The compound as defined in claim 24 wherein n is 1, whenever prepared by the process of claim 6.

30. The compound as defined in claim 24 wherein n is 2, whenever prepared by the process of claim 7.

31. The compound as defined in claim 24 wherein n is 3 or 4, whenever prepared by the process of claim 8.

32. The compound as defined in claim 24 wherein A is -CH=CH-, m is 2 to 4, n is 1 or 2, R is H and R1 is lower al-kyl or cycloalkyl, whenever prepared by the process of claim 9.

33. The compound as defined in claim 24 wherein A is -CH=CH-, m is 3, n is 1, R is H, CH3 or C6H13 and R1 is lower alkyl, whenever prepared by the process of claim 10.

34. The compound as defined in claim 24 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(hexyloxy)methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid or its hexyl ester, whenever pre-pared by the process of claim 11.

35. The compound as defined in claim 24 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(2-pentyloxy)ethyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid, whenever prepared by the process of claim 12.

36. The compound as defined in claim 24 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(phenylpropoxy)methyl]-7-oxabicycl-[2.2.1]hept-2-yl]-5-heptenoic acid, whenever prepared by the process of claim 13.

37. The compound as defined in claim 24 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(octyloxy)methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid, whenever prepared by the process of claim 14.

38. The compound as defined in claim 24 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.] 7-[3-[(cyclohexylmethoxy)methyl]-7-oxabicyc-lo[2.2.1]hept-2-yl]-5-heptenoic acid, whenever prepared by the process of claim 15.

39. The compound as defined in claim 24 wherein A is -CH=CH-, m is 3, n is 1, n' is 1 and R is lower alkyl, when-ever prepared by the process of claim 16.

40. The compound as defined in claim 24 wherein A is -CH=CH-, m is 3, n is 1, n' is 2 and R is lower alkyl, when-ever prepared by the process of claim 17.

41. The compound as defined in claim 24 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(hexylthio)methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid or its methyl ester, whenever pre-pared by the process of claim 18.

42. The compound as defined in claim 24 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.-7-[3-[(hexylsulfinyl)methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid or its methyl ester, when-ever prepared by the process of claim 19.

43. The compound as defined in claim 24 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3 [(hexylsulfonyl)methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid or the methyl ester thereof, whenever prepared by the process of claim 20.

44. The compound as defined in claim 24 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[[(cyclohexylmethyl)thio]methyl]-7-oxa-bicyclo[2.2.1]hept-2 yl}-5-heptenoic acid or the methyl ester thereof, whenever prepared by the process of claim 21.

45. The compound as defined in claim 24 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[[(2-phenylethyl)thio]methyl]-7-oxabi-cyclo[2.2.1]hept-2-yl]-5-heptenoic acid or the methyl ester thereof, whenever prepared by the process of claim 22.

46. The compound as defined in claim 24 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[[(3-phenylpropyl)thio]methyl]-7-oxa-bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or the methyl ester thereof, whenever prepared by the process of claim 23.

47. A compound having the structural formula:

and including all stereoisomers thereof, wherein A is -CH=CH- or -(CH2)2-;
B is oxygen (-O-) or ;
m is 1 to 8;
n is 1 to 4;
n' is 0 to 2;
R is hydrogen, C1-C12 alkyl, alkali metal or tris-(hydroxymethyl)aminomethane; and R1 is C1-C12 alkyl, C6-C10 aryl, C6-C10 aralkyl, C3-C12 cycloalkyl or C3-C12 cycloalkylalkyl.

48. A compound according to claim 47 wherein B is -O-.

49. A compound according to claim 47 wherein B is -S-.

50. The compound as defined in claim 47 wherein A is -CH=CH-.

51. The compound as defined in claim 47 wherein R is H.

52. The compound as defined in claim 47 wherein n is 1.

53. The compound as defined in claim 47 wherein n is 2.

54. The compound as defined in claim 47 wherein n is 3 or 4.

55. The compound as defined in claim 47 wherein A is -CH=CH-, m is 2 to 4, n is 1 or 2, R is H and R1 is lower al-kyl or cycloalkyl.

56. The compound as defined in claim 47 wherein A is -CH=CH-, m is 3, n is 1, R is H, CH3 or C6H13 and R1 is lower alkyl.

57. The compound as defined in claim 47 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(hexyloxy)methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid or its hexyl ester.

58. The compound as defined in claim 47 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(2-pentyloxy)ethyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid.

59. The compound as defined in claim 47 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(phenylpropoxy)methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid.

60. The compound as defined in claim 47 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(octyloxy)methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid.

61. The compound as defined in claim 47 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(cyclohexylmethoxy)methyl]-7-oxabicyc-lo[2.2.1]hept-2-yl]-5-heptenoic acid.

62. The compound as defined in claim 47 wherein A is -CH=CH-, m is 3, n is 1, n' is 1 and R1 is lower alkyl.

63. The compound as defined in claim 47 wherein A is -CH=CH-, m is 3, n is 1, n' is 2 and R1 is lower alkyl.

64. The compound as defined in claim 47 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(hexylthio)methyl]-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid or its methyl ester.

65. The compound as defined in claim 47 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(hexylsulfinyl)methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid or its methyl ester.

66. The compound as defined in claim 47 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(hexylsulfonyl)methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid or the methyl ester thereof.

67. The compound as defined in claim 47 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[[(cyclohexylmethyl)thio]methyl]-7-oxa-bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or the methyl ester thereof.

68. The compound as defined in claim 47 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[[(2-phenylethyl)thio]methyl]-7-oxabi-cyclo[2.2.1]hept-2-yl]-5-heptenoic acid or the methyl ester thereof.

69. The compound as defined in claim 47 having the name [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[[(3-phenylpropyl)thio]methyl]-7-oxabi-cyclo[2.2.1]hept-2-yl]-5-heptenoic acid or the methyl ester thereof.

70. A pharmaceutical composition comprising a compound having the structural formula:

I and including all stereoisomers thereof, wherein A is -CH=CH- or -(CH2)2-;
B is oxygen (-0-) or ;
m is 1 to 8;
n is 1 to 4;
n' is 0 to 2;
R is hydrogen, C1-C12 alkyl, alkali metal or tris-(hydroxymethyl)aminomethane; and R1 is C1-C12 alkyl, C6-C10 aryl, C6-C10 aralkyl, C3-C12 cycloalkyl or C3-C12 cycloalkylalkyl;
together with a pharmaceutically acceptable carrier therefor.

71. A composition as defined in claim 70 wherein B is -O-.

72. A composition as defined in claim 70 wherein B is -S-.

73. A composition as defined in claim 70 wherein A is -CH=CH-.

74. A composition as defined in claim 70 wherein R is H.

75. A composition as defined in claim 70 wherein n is 1.

76. A composition as defined in claim 70 wherein n is 2.

77. A composition as defined in claim 70 wherein n is 3 or 4.

78. A composition as defined in claim 70 wherein A is -CH=CH-, m is 2 to 4, n is 1 or 2, R is H and R1 is lower al-kyl or cycloalkyl.

79. A composition as defined in claim 70 wherein A is -CH=CH-, m is 3, n is 1, R is H, CH3 or C6H13 and R1 is lower alkyl.

80. A composition as defined in claim 70 wherein the compound is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(hexyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or its hexyl ester.

81. A composition as defined in claim 70 wherein the compound is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(2-pentyloxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid.

82. A composition as defined in claim 70 wherein the compound is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(phenylpropoxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid.

83. A composition as defined in claim 70 wherein the compound is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(octyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid.

84. A composition as defined in claim 70 wherein the compound is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(cyclohexylmethoxy)me-thyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid.

85. A composition as defined in claim 70 wherein A is -CH=CH-, m is 3, n is 1, n' is 1 and R1 is lower alkyl.

86. A composition as defined in claim 70 wherein A is -CH-CH , m is 3, n is 1, n' is 2 and R1 is lower alkyl.

87. A composition as defined in claim 70 wherein the compound is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(hexylthio)methyl]-7-oxabicyclol2.2.1]hept-2 yl]-5-heptenoic acid or its methyl ester.

88. A composition as defined in claim 70 wherein the compound is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(hexylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or its methyl ester.

89. A composition as defined in claim 70 wherein the compound is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[(hexylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or the methyl ester thereof.

90. A composition as defined in claim 70 wherein the compound is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[[(cyclohexylmethyl)thio]-methyl]-7 oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or the methyl ester thereof.

91. A composition as defined in claim 70 wherein the compound is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[[(2-phenylethyl)thio]-methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or the methyl ester thereof.

92. A composition as defined in claim 70 wherein the compound is [1.beta.,2.alpha.(5Z),3.alpha.,4.beta.]-7-[3-[[(3-phenylpropyl)thio)]-methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid or the methyl ester thereof.