NZ207361A

NZ207361A - 7-oxabicycloheptane derivatives and pharmaceutical compositions

Info

Publication number: NZ207361A
Application number: NZ207361A
Authority: NZ
Inventors: S E Hall; M F Haslanger
Original assignee: Squibb & Sons Inc
Priority date: 1983-03-14
Filing date: 1984-03-02
Publication date: 1986-12-05
Also published as: PL246663A1; DE3409124A1; GB8406100D0; IE840525L; CH658247A5; CA1256887A; LU85249A1; ATA83484A; FI841008A0; ES8506270A1; GB2136428A; FI841008A; DD216932A5; AU567919B2; NL8400797A; IL71184A0; GR79881B; DK155584A; KR840009085A; AU2523584A

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £07361 : i riority Date(s): /f/.?.;?? Complete Specification Filed: Class: CftV. ...... £<?."} .9/."7 7)... Publication Date: £ £ R§P. ]v86... P.O. Journal, No: .. NEW ZEALAND § MAMES PATENTS ACT, ]953 No.: Date: COMPLETE SPECIFICATION ' '7-OXABICYCLCHGPTANE SUBSTITUTED PROSTAGLANDIN ANALOGS" X/We, E. R. SQUIBB § SONS, INC., a corporation of Delaware, United States of America, of Lawrenceville-Princeton Road, Princeton, New Jersey, United States of America, hereby declare the invention for which &/ we pray that a patent may be granted to ga©c/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - - 1 - (followed by page la) ■\ ~ ' I ■■■'}■ ' '■ k ■ ;"'v\ J 207361 -ir 10 15 7-OXABICYCLOHEPTANE SUBSTITUTED PROSTAGLANDIN ANALOGS The present invention relates to 7-oxabicycloheptane prostaglandin analogs which are cardiovascular agents useful, for example, in the treatment of thrombolytic disease. These compounds have the structural formula ch_-a-(ch_) -coor 2 z in (CH2)n-B-aL wherein B is oxygen (-0-) or -S- wherein n' is 0 (o) n' to 2, R is hydrogen, lower alkyl, alkali metal or1 tris(hydroxymethy1 )aminomethane, r-*- is alkyl, alkenyl, alkynyl, aryl,' aralkyl, aralkenyl, aralkynyl, 20 cycloalkylalkyl. cycloalkylalkenyl or cycloalky lal kynyl. A is -CH=CH- or n is 1 to 4, and m is 1 to 8, and including all stereoisomers thereof. The terra "lower alkyl" oc "alkyl" as employed herein refers to both straight and branched chaia 25 radicals of up to 12 carbons; preferably 1 to 8 >l.o carbons, such as methyl, ethyl, propyl, isopropyl. butyl, t-butyl, isobutyl. pentyl, hexyl, isohexyl. heptyl, 4,4-dimethylpentyl, octyl. 2.2,4-tcimethylpentyl. nonyl, decyl. undecyl. dodecyl, the various branched chain isomers thereof, and the like as well as such groups including a halo-substituent, such as F, Br. CI or I or CF3, an alkoxy substituent, a haloaryl substituent, a cycloalkyl substituent (that is, cycloalkylalkyl) or an alkylcycloalkyl substituent. The terms "alkenyl" and "alkynyl" as used herein contemplate similar hydrocarbon groups bearing therein a carbon-carbon double or triple bond 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 term "cycloalkyl" includes saturated cyclic hydrocarbon groups containing 3 to 12 carbons, preferably 3 to 8 carbons, which include cyclopropyl, cyclobutyl. cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, any of which groups may be substituted with 1 or 2 halogen, 1 or 2 lower alkyl groups and/or lower alkoxy groups. The term "aryl" or "Ar" as employed herein refers to monocyclic or bicyclic aromatic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl wherein the substituent on either the phenyl or naphthyl may be lower alkyl, halogen (CI, Br or F), or lower alkoxy. -3- Ji&2£ 0/200 The term "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" as used herein refers to lower alkyl groups as discussed above having an aryl substituent, such as benzyl. The terras "(CH2)m" and includes a straight or branched chain radical having from 1 Co 8 carbons in the normal chain in the case of "(CH-) " and 1 to 4 carbons in the normal chain 2 ra in the case of "(CH,) " and may contain one or « It more lower alkyl substituents. Examples of (CH2)m and (CH2)n groups include CH2, CH2CH2. (CH2)3. <CH2)4. (CH2)5. (CH2)6. ?H3 10 cch2)7. -(ch2)2-ch-. -ch2-ch-. -ch2-ch—<jh-ch2-. CH3 CH3 GH3 CH3 -CH2-CH-CH2. and the like. ch3 ch3 fitfjr ''■* • IIA2 9 0/280 - -4- The compounds of Formula I (wherein R is alkyl) are prepared by etherifying or thioether-ifying a compound of the Formula II: 1Q with the desired Rl-OH or R-^-SH groups or their equivalents according to conventional methods. The synthesis of -ethers and thioethers is based on the Williamson Synthesis (J. Chem. Soc 4, 229 (1852)) wherein ethers (and later thio-15 ethers) were synthesized by alkylation of alkoxides with alkyl halides: R' (0 or S) Na + R"X^3« R' (0 or S)R" + NaX 20 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 thioethexification reaction comprehends reaction of a Formula Ila compound of the formula 25 Ila (CH^-CV 30 wherein X in addition to hydroxy can also be -SH or their sodium or potassium salts, chloro, bromo, iodo and alkyl, aryl- and aralkyl-sulfonyloxy groups with a complementary R^X compound to form the following type compounds of Formula I: 35 I 10 15 IIA2 90/20 0 -5- (CH2)-A-(CH2)m-C02alkyl V Ich2)„-O-H \T"iCH,) -s-R1 0 ^ n 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: V VI The compounds of Formula I wherein R is 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 20 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 R^-X wherein X is chloro, bromo, or 25 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 rIx reactant varying from .25 mole excess to a 5 30 mole excess is used employing a solvent such as xylene, tetrahydrofuran, dimethylsulfoxide or dimethylformamide. In the case where X is bromo or chl-oro, a phase transfer etherif ication can be employed in which case tetrahydrofuran is used as 3 5 the solvent and a phase transfer reagent such as N " I HA2 90/28TI -6 - Bu4NHS04 or (CgH5CH2)(CH3)3NHS04 is employed. In the case wherein is aryl it is convenient to first react the alcohol group of the Formula II compound with triphenylphosphine and diethylazo-5 dicarboxylate in solution with an inert solvent such as tetrahydrofuran and then with an R^(aryl) alcohol such as phenol. As is generally known in the art, the sequence of reacting the Formula II alcohol with the R^X compound to achieve ether-10 ification can be reversed by converting the Formula II 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 R "'"-alcohol or alkoxide to form the Formula I product. 15 Thioetherification is usually accomplished by first converting the Formula' II alcohol to another Formula II-X derivative as indicated above and thioetherifying with an R^SH mercaptan in the presence of a base or with an alkali metal salt 20 thereof. Oxidation of the sulfide product where n'=0 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 25 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 30 n is 1 (hydroxymethyl group) are known from U.S. Patent 4,14 3,054 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 35 aldehyde by way of a Collins oxidation, for example, I ■J HA290/280" • -7- by reacting Compound II with chromium trioxide in pyridine, to form a intermediate of the formula 10 The Formula VII aldehyde is subjected to a homologation sequence by way of a Wittig reaction using (CgH5)3P=CHOCH3 followed'by hydrolysis (n-1) times followed by reduction of the aldehyde to the alcohol employing a reducing agent such as 15 sodium borohydride or sodium cyanoborohydride in a solvent such as methanol to form the Formula I-I starting material: 20 V Wittig |<c6»5) 3P=CliOCll3 CH -A-(CH-) -CO alkyl ^ A m 2 OCH. h3° ■CH -A- (CH ) CO alkyl ^ 2 m 2 (CVn-l (repeat n-1 times) Reduction NaBH. H -A-(CH ) -CO„alkyl 2 2 m 2 V (CH ) —CH_OH \ 2 n-1 2 I oo s I ~ilA2 00/200 -9- ' The tris (hydroxymethyl )aminoinethane salt of any of the acids of formula I of the present invention i^ formed by reacting a solution of such acid in an inert solvent such as methanol with tris(hydroxymethyl)aminomethane and thereafter the 5 solvent is removed by evaporation to leave the desired salt. The compounds of this invention have four centers of asymmetry as indicated by the asterisks 10 ■ in. formula I. However, it will be apparent that . each of the formulae set out above which do not include asterisks still represent all of the possible stereoisomers thereof. A.11 of the various stereoisomeric forms are within the scope of the 15 invention. * The various stereoisomeric forms of the •compounds of the invention, namely, cis-exo, cis-endo and all trans forms and stereoisomeric pairs may be prepared as shown in the working Examples which follow and by employing starting materials and following the procedures as outlined in IT. S. Patent No. 4,143.054, Examples of such stereoisomers are set out below. ch_-a-(ch,) -co-r 2 2 in 2 le — H CCH2VB'"r1 0 h (cis-endo) h If —ch--a-(ch_)-co_r 2 2 m 2 ■H 0 (CH2)n-B-R 1 (cis-exo) 1 00/^8=6- -11- ig --CH2-A-(CH2)m-C02R (CH2)n-S-RJ O H (trans) Ih CH2-A-(CHa)m-C02H - -H 10 <ch2Vb-r (trans) The nucleus in each of the compounds of the invention is depicted as -HA343t^6-0-. -12- for matter of convenience; it will also be appreciated that the nucleus in the compounds of the invention may be depicted as The compounds of this'invention are cardiovascular agents useful as platelet aggregation inhibitors, e.g.. for treatment of thrombolytic disease, such as coronary or cerebral thromboses. They are also selective thromboxane A2 receptor antagonists and synthetase inhibitors, e.g.. having a vasodilatory effect for treatment of myocardial ischemic disease. s.uch as angina pectoris. The compounds of the invention are also arachidonic acid cyclooxygenase inhibitors. They can be administered orally or parenterally to various raamraalian species known to be subject to such maladies, e.g.. cats, dogs, and the like in an effective amount within the dosage range of about 1 to 100 mg/kg.. preferably about 1 to 50 rag/kg and especially about 2 to 25 mg/kg on a regimen in single or 2 to 4 divided daily doses. The active substance can be utilized in a composition such as tablet, capsule, solution or suspension containing about 5 to about 500 mg per -13- ~msZ3X&2&Q- unit of dosage of a compound or mixture of compounds of formula I. They may be compounded in conventional matter with a physiologically acceptable vehicle or carrier, excipient, binder, 5 preservative, stabilizer, flavor, etc. as called for by accepted pharmaceutical practice. Also as indicated in the discussion above, certain members additionally serve as intermediates for other members of the group. 10 7 ?"■ ^HA2 90/2'8tT -14- The following Examples represent preferred embodiments of the invention. Example 1 r lfl.2a(5Zl.3a.4fl1-7-r3~r(Hexvloxv)methyl 1-7-5 oxabicvclof2.2.nhept-2-vn-S-heptenoic acid, hexvl ester A. f IB . 2a(5Z1. 3<*. 4fl 1-7-T 3-(Hvdroxvmethvn-7-oxabicvclor 2.2.nhept-2-yll -5-heptenoic acid, methyl ester 10 (a) A mixture of N-acetylpyridiniuro chloride was prepared by adding 9.6 ml (136 mmole) of acetyl chloride dropwise to 56 ml of pyridine. To this was added 5.0 g (27 ramole) of (exo)-3-(2-methoxy-ethenyl)-7-oxabicyclo[2.2.l]heptane-2-methanol 15 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 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. 25 (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 30 formed was stirred for 10 minutes and then the 35 -15- entire mixture was poured into a solution containing 200 g of potassium iodide in 2 1. of water. Upon shaking, the yellow color disappeared and the mixture was extracted with benzene (3 x 500 ml). The combined benzene extracts were washed with potassium iodide solution and brine and dried over sodium sulfate. Concentration yielded 3.7 g of material which crystallized on standing in an ice box. (c) A Wittig reagent was prepared in dimethyl sulfoxide (dried over calcium hydride) by adding a solution of sodium methylsulfinylmethide (prepared by heating 300 rag of sodium hydride in 60 ml of dimethyl sulfoxide at 75° until 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 formed, an equivalent amount of base was added to form 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 mixture poured into brine (300 ml) and extracted with 6ther (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 ; r\ — 1 •• ** -16- mixture. This mixture was washed with benzene and acidified with 10% hydrochloric acid. The aqueous layer was saturated with salt and extracted with echer which on drying (sodium sulfate) and 5 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 10 eluant which gave 500 rag of acid which crystallized on standing. This was recrystallized twice from ethyl acetate-cyclohexane to yield 320 nig of [IB,2a(5Z),3a.4fl]-7-[ 3-(hydroxymethyl)-7-oxabi-cyclo[2.2.1]hept-2-yl]-5-heptenoic acid,m.p. 59-63°C. 15 Anal. Calc'd for C]_4H22^4: C,66.11; H,8.72 Found: C,66.06; H,8.79 The acid is then converted to the corresponding methyl ester by treating with diazomethane. 20 B. nfl.2a(5Z1.3o.4B1-7-r3-r(HexvloxV)- methvl1-7-oxabicvclor2.2.11hept-2-yl1-5-heptenoic acid, hexyl ester A suspension of 0.56 g of powdered KOH in 25 15 ml of dry xylene was heated to reflux and 7 ml of xylene was distilled off. To this mixture was added a solution of 300 rag (1.12 mraol) 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 30 distilled off. To this mixture was added 1.0 g i Ham *"iiA29Q/2 0.0- -17- (5.6 mmol) of n-hexylmethanesulfonate 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 (60 ml). 5 The resulting solution was poured into 50 ml saturated NaHCO^. The layers were separated and the aqueous phase was extracted (2 x 60 ml) with CH2C12. The combined CH2C12 extracts were dried over MgS04. then concentrated in vacuo to 10 yield 0.9 g of crude product. The crude product was chroraatographed on 33.4 g of silica gel 60 with hexaneiether (5:1) to yield 390 rag (33%) of the title hexyl ester. 15 ■ Example 2 rifl.2o(5Z).3a.4fl1-7-T 3-f(Hexvloxy)methyll-7-oxabicvclo r 2 ■ 2-. llhept-2-yl 1-5-heptenoic acid To a stirre-d solution of 115 rag (0.27 mmol) of the Example 1 hexyl ester in 12.0 ml of distilled 20 THF and 1.60 ml of HjO under argon was added 2.40 ml of IN 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 25 complete so an additional 1 ml of methanol and 1 ml of IN 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 IN aqueous HC1 solution. The resulting solution 30 was poured into 25 ml of saturated NaCl solution and was saturated wth solid NaCl. The aqueous layer" was extracted with EtOAc (4 x 40 ml). The combined EtOAc extracts were dried over anhydrous MgS04. 15 •fT&gqn/33Q--18- . • filtered and concentrated in vacuo to give 124 mg of crude oil. This was chromatographed on 20.6 g of silica gel 60 using hexane:ether (2:3) as eluant to give 102 mg of desired product contaminated with a 5 small amount of hexyl alcohol. The mixture was put in high vacuum overnight at room temperature to give 77 mg (84%) of pure title acid. TLC: silica gel, 8% CH30H/CH2C12. Rf=0.74, iodine. 10 Anal. Calc'd foe C2QH3404: C. 70.97: H. 10.12 Found: C. 70.60: H. 9.99 13CNMR (CDC13, 15.OmHz)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, 14.0. Example 3 rifl.2a(SZl .3a.4J31-7-r3-r (HexvloxV) methyl1-7-oxabicyclo[2.2■11hept-2-yl1-5-heptenoic acid, hexyl ester 503 mg (1.88 mmol) of [ IB. 2<*(5Z). 3<*. 4fl] -7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester (prepared as described in Example 1) was dissolved in 2.17 ml tetrahydrofuran. Thereafter 2.17 ml (15.46 mmol) of n-hexyl bromide, 173.4 mg (0.51 mmol) tetrabutylammoniumbi-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 overnight formed a white precipitate. The reaction mixture was poured into 25 ml of saturated NaHC03. The mixture was extracted with CH2C12 (4 x 25 ml). The combined CH2C12 20 25 30 35 -19- -HA2 90/200 extracts were dried (MgS04). filtered and concentrated in vacuo to give [IB.2a(5Z),3a. 4B ] -7-[3-[(hexyloxy)methyl]-7-oxabicyclo[2.2.l]hept-2-yl]-S-heptenoic acid, hexyl .ester (1272 mg). This was 5 chromatographed on 40 g silica gel using hexane:ether (4:1) as eluant to give final product. Example 4 (IB. 2a. 3a.4fl~)-7-r 3-f (Hexvloxv")methyl 1 -7-oxa-10 bicvclor2.2 . nhept-2-vllheptanoic acid, hexvl ester A. (lfl.2a.3a.4fl->-7-r 3-f (Hydroxv)methvn-7- oxabicvclof2.2.llhept-2-yllheptanoic acid, methyl ester To 800 mg (3.0 mmole) of the [IB,2a(5Z) 15 3a.4B]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid, metljyl ester as prepared in Example 1. dissolved in 120 ml of ethyl acetate was added, under an argon atmosphere. 160 mg of 5% Pd on carbon. The argon atmosphere was 20 exchanged for a slight positive pressure of hydrogen and the reaction was stirred for a hours at 25°, filtered through a celite plug and evaporated to provide 730 mg (90%) of the title A compound. 25 B. (IB ;2a.3a. 4fl)-7~r3~r(Hexvloxv)methyl1-7- oxabicyclof 2.2.nhept-2-yl1-5-heptanoic acid, hexvl ester Following the procedure of Example 1 except substituting the Part A alcohol-ester for the 30 Example 1A alcohol ester, the title product is obtained. 35 \ / SO Sj -TIA2 00/200- -20- Example 5 (l|3,2a,3a,4g)-7-[3-[ (Hexyloxy)methyl] -7-oxabicyclo [2.2,1]hept-2-yl]heptanoic acid Following the procedure of Example 2 except 5 substituting the Example 4 hexyl ester for the Example 1 hexyl ester, the title acid is obtained as an oil [a]^= -3.1(c=1.37, CHCl^) ; TLC (silica gel, 8% CH30H)CH2C12 ,.Rf=0.74, Anal. Calcd. for C20H36°4: C,70.55; H,10.66 10 Found: C,70.30; H,10.70 13CNMR (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, 25.8, 31.6, 22.6, 14.0 15 Example 6 [lp,2g(5Z),3g,43]-7-[3-[(Hexyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 3 and 2 20 except substituting [10,2a(5Z), 33,4(3] —7 — [3 — (hydroxymethyl)-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid, methyl ester for [l3,2a(5Z), . 3a,4p]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1] -hept-2-yl]-5-heptenoic acid, methyl ester, the 25 title compound is obtained as an oil. Anal. Calcd. for ^0.97; H, 10.12 Found: C, 70.93; H, 10.33 13C NMR (CDC13, 15.0MHz)tau 178.7, 33.4, 24.6, 26.6, 128.7, 129.9, 32.6, 47.9, 79.1, 30 29.5, 23.8, 80.5, 49.1, 71.7, 71.2, 31.6, 25.8, 29.9, 22.6, 13.9 '.-Hftasva-M- -21-Example 7 • [1-3, 2ct (5Z), 3a,43]-7-[3-Methyloxy)methyl]-7- oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 1 and 5 2 except substituting methyl methanesulfonate for n-hexyl methanesulfonate, the title compound 25 is obtained as an oil, [alD = +10.4 (C=2.21, CHC13). Anal. Calcd. for. C^5EJ2404: C, 67.14; H, 9.01 10 Found: C, 67.03; H, 9.14 13C NMR (CDC13, 15*OMHz) tau 178.3, 33.2, 24.4, 25.5, 129.5, 129.8, 26.5, 46.5, 79.1, 29.3, 29.3, 79.9, 46.2, 71.7, 58.6. 15 Example 8 rifl.2«»(5ZK3fl.4fl1-7-r3-r CPropyloxv^methyll-7-oxabicvclor2.2.11hept-2-vll-5-heptenoic acid Following the procedure of Example 6. except substituting n-propylbcomide Cor n-hexylbromide. the title compound is obtained. Example 9 (lfl. 2a. 3a.4fl)-7-T3-(Butyloxvlmethvll-7-oxabicvclo T 2.2. nhept-2-yllheptanoic acid Following the procedure of Examples 4 and 5 except substituting n-butyl methanesulfonate foe n-hexyl methanesulfonate, the title compound is obtained. Example 10 f lfl . 2a( 5Z) . 3a. 4Q1 -7- f 3-1" (Octyloxv)methyl 1 -7-oxabicvclor 2.2.11hept-2-vl1-5-heptenoic acid Following the procedure of Examples 1 and 2 except substituting n-octyl methanesulfonate for n-hexyl methanesulfonate, the title compound is obtained. Example 11 r^lfl. 2a(5Z~) , 3a, 4fl 1 -7- r 3- r ( Phenyloxy )methvl 1 -7-oxabicvclor2.2.11hept-2-yl1-5-heptenoic acid (a) Phenol (1 mmol) is added to a solution of triphenylphosphine (1 mmol), diethylazodicarboxylate (1 mmol) and title A alcohol from Example 1 (1 mmol) in 25 ml THF and is stirred under an argon -23- atmosphere for 43 hours at 23°C. The reaction mixture is concentrated in vacuo. The residue is triturated with ether and the solids are removed. The filtrate is concentrated in vacuo and 5 chromatographed on silica gel to give [ IB,2a(5Z). 3a. 4J3]-7-[ 3 - [ (phenyloxy)methyl ] -7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid, methyl ester. 10 (b) Following the procedure as set out in Example 2. the-ester from part (a) is converted to the title compound. Example 12 L5 nfl.2a(5Z),3fl.4fl1-7-r3-rfPhenvloxv)methyl 1- 7-oxabicvclor2.2.11hept-2-vll-5-heptenoic acid (a) Phenol (L mmol) is added to a solution of t'riphenylphosphine (1 mmol). diisopropylazodi-carboxylate (1 mmol) and title A alcohol from 20 Example 1 (1 mmol) in 25 ml THF and is stirred under an argon atmosphere for 48 hours at 23°C. The reaction mixture is concentrated in vacuo. The residue is triturated with ether and the solids are removed. The filtrate is concentrated in vacuo and 25 chromatographed on silica gel to give Clfl.2a(5Z) .3fl.4fi]-7-[3-[(phenyloxy)raethyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid, methyl ester. 30 (■ ... : - HAaOO/2-8^- -24- (b) Following the procedure as set out in Example 2, the ester from part (a) is converted to the title compound. 5 Example 13 f lfl.2a(5Z^.3«.4B1-7-r3-r(EthvloxvImethvll-7-oxabicvclor2.2.11hept-2-yl1-5-heptenoic acid Following the procedure of Examples 3 and 2 except substituting ethylbroraide for n-hexylbromide, 10 the title compound is obtained. . Example 14 (lfl < 2a.3a.4fl1—7—r 3 — f(Phenyloxy)methyl1-7-oxabicvclo r 2.2.11hept-2-vllheptanoic acid 15 Following the procedure of Example 11 except substituting (lfl.2a.3a,4B)-7-[3-[(hydroxy)-methyl]-7-oxabicyclo[2.2.1]hept-2-yl]heptanoic.acid, methyl ester for the alcohol of part (a) of Example 11, the title compound is obtained. 20 Example 15 rifi.2a(5Z).3fl.4fl1-7-r3-r(Benzyloxylmethyl 1-7-oxabicyclof2.2.11 hept-2-yl 1 - 5-he-ptenoic acid Following the procedure of Example 6 except 25 substituting benzylbromide for n-hexylbromide, the title compound is obtained. 30 -25- Example L6 ( LJ3. 2a. 3a.4fl)-7-f 3-f (Benzyloxy)methyl 1 -7-oxabicycloT 2.2.11hept-2-yllheptanoic acid Following the procedure of Examples 4 and 5 5 except substituting benzyl methanesulfonate for n-hexyl methanesulfonate. the title compound is obtained. Example 17 10 flfi.2a(SZ).3a.4fl1-7-f 3-f(Cvclohexyloxv)methyl!-7-oxabicyclof 2.2.11 hept-2-yII-5-heptenoic acid Following the procedure of Examples 1 and 2 except substituting cyclohexyl methanesulfonate for n-hexyl methanesulfonate. the title compound is 15 obtained. . . Example 13 rlfl.2a(5Z1,38,4fll-7-r3-r CCvclopentyloxy)methyl1-7-oxabicyclo(2.2.1lhept-2-yl1-5-heptenoic acid 20 Following the procedure of Examples 1 and 2 except substituting cyclopentyl methanesulfonate for n-hexyl methanesulfonate. and substituting [lfl,2a(5Z) .3fl,4fl]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl 25 ester (prepared as described in U. S. Patent No. 4,143.054) for [lfl,2a(5Z) . 3a. 413 ]-7-[ 3-(hydroxymethyl)-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid, methyl ester, the title compound is obtained. 30 I \ -26-Example 19 (Ifl ■ 2a. 3a. 4fl1-7-[ 3 - f (Cvclohexvloxv)niethvn-7-oxabicvclof2.2. llhept-2-vnheptanoic acid Following the procedure of Examples 4 and 5 5 except substituting cyclohexyl methanesulfonate for n-hexyl methanesulfonate, the title compound is obtained. Example 20 10 rifl.2a(5Z1.3a.4fll-7-f3-T2-(HOXVlOXV)ethYl1-7-oxabicvclor2.2.llhept-2-vll-5-heptenoic acid A. r IB . 2a( 5Z~> . 3a ■ 4131 -7-I 3 - (2-QXO) ethvl 1 -7 -oxabicyclor2. 2. nhept-2-vl1-5-heptenoic acid, methyl ester 15 Into a dry 100 ml round bottom 3-necked flask containing a stir bar was added dried 12.9 g (37.7 ramoles) methoxymethyltriphenylphosphonium chloride ((CgHs )3P+-CH'20CH3C1") and 235 ml distilled toluene (stored over molecular sieves). 20 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-araylate in toluene was added dropwise. A. bright red solution formed which was stirred at 0°C for an additional 25 35 minutes. Thereafter, a solution of 4.97 g (18.8 mmol) [lfl,2a(5Z).3a.4fl]-7-[3-formyl-7-oxabi-cyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester in 60 ml toluene was added by means of a dropping funnel over a 35 minute period with the 30 ice-bath still in place. The reaction was then quenched by addition of 2.3 g <39 mmol) acetic acid \ -HA29Q/20-9- -27- in 5 ml ether. The reaction mixture immediately turned pale yellow and was immediately poured into 200 ml saturated NH.Cl, and extracted with ether (4 x 200 ml). The combined ether phases were washed 5 with NaCl saturated solution, and dried (MgS04) and concentrated to yield a yellow oil in a white crystalline solid (phosphine oxide). The white solid was triturated with EtOAc and the mother •liquor was purified by chromatography on an LPS-1 10 silica column. The fractions obtained were (A) [lfl.2a(5Z) . 3a.4J3]-7-[3 -(2-oxo)ethy 1-7-oxabicyclo [2.2. l]hept-2-yl]-5-heptenoic acid, methyl ester, (B) [lfl,2a(5Z),3a, 4fl]-7-[3-(2-methoxy)-ethendiyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic 15 acid,, methyl estec, and- (C) [lfl, 2a(5Z). 3a, 4fl]- 7-[3-(2,2-dimethoxy)ethyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid. methyl ester. Compounds (B) and (C) are each treated with trifluoroacetic acid to convert each to compound (A). 20 B. riB.2a(5Z)■3a.4fl1-7-\3-(2-Hvdroxvethvl)-7-oxabicvclof 2.2.11hept-2-vl1-5-heptenoic acid, methyl ester The aldehyde (1.4 g, 5 mmol) from part A in 25 methanol (50 ml) was treated with NaBH^ (0.19 g, 5 mmol) in an argon atmosphere at 0°C. After stirring at 0° for 1 hour, the reaction was quenched by addition of 2N HC1 (to pH 2). The methanol was removed in vacuo and the reaction 30 mixture was taken up in ether. The ether solution 4ms -- imp-* HterZOfig&Q. -28- was washed with saturated KHC03, saturated NaCl and dried (MgS04). The ether was evaporated to yield the title B compound. C. rifl.2a(5Z) . 3a. 4J31 -7- T 3 - T 2 - (Hexvloxv) -ethvl1-7-oxabicvclo r2.2.llhept-2-vl1-5-heptenoic acid Following the procedure of Examples 1 and 2 except substituting the above part B alcohol for the alcohol used in Example 1. the title compound is obtained. Example 21 f lfl.2a(SZ1.3fl.4fl1-7-f 3-T 2-(Hexvloxvlethyl 1-7-15 ' oxabicyclor2.2.11hept-2-y11-5-heptenoic acid Following the procedure of Example 20. except substituting [1.3.2a(5Z). 3fl. 4fl]-7- [3-formyl-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid. methyl ester for [lfl.2a(5Z),3«.4B]-7-[3-20 forrayl-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid, methyl ester, the title compound is obtained. Example 22 (lfl . 2a. 3a. 431-7-f 3-T 2-(Hexvloxv') ethyl 1-7-25 oxabicyclor2.2.llhept-2-yl1-5-heptanoic acid Following the procedure of Example 21 except substituting (lJ3.2a, 3a. 4J3)-7-[3-formyl-7-oxabicyclo[2.2.l]hept-2-yl]heptanoic acid, methyl ester for [IB.2a(5Z),3fl,4fl]-7-[3-formyl-7-30 oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid, methyl ester, the title compound is obtained. 5 10 35 Y -29-Exampla 23 TIB.2a(5Z).3B.4B1-7-r3-r2-(Phenyloxy)ethyl 1-7-oxabicyclof 2.2.11hept-2-y11-5-heptenoic acid Following the procedure of Example 11 except 5 substituting tlfl,2<*(5Z),SaMfll-T-tS-^- diydroxyOethyll-T-oxabicyclo^^. l]hept-2-yl]-5-heptenoic acid, methyl ester for [ 1J3. 2a(5Z).-3a.4fl]-7-[3-(hydroxyroethyl)-7-oxabicyclo[2.2.l]hept 2-yl]-5-heptenoic acid, methyl ester, the title 10 compound is obtained. Example 24 rifl.2a(5Z1 .3B.4B1-7-T3-f2-(Phenyloxy)ethyl1-7-oxabicycloT2.2.11hent-2-v11-5-heptenoic acid 15 Following the procedure of Example 12 except substituting [lB,2a(5Z),3B,4B]-7-[3-[2-(hydroxy)-ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester for [ IB, 2«.( 5Z) , 3B, 4B]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.l]hept-2-yl]-5-20 heptenoic acid, methyl ester, the title compound is obtained. Example 25 (IB.2q.3a.4B)-7-f 3-f2-(Phenvloxv)ethvll-7-25 oxabicyclor2.2.11hept-2-yllheptanoic acid Following the procedure of Example 11 except, substituting (IB,2a ,3a,4fl)-7-[3 — [2-(hydroxy)-ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]heptanoic acid, methyl ester for [IB ,2a(5Z),3a,4B]-7-[3-30 (hydroxymethyl)-7-oxabicyclo[2.2.l]hept-2-yl]-5- heptenoic acid, methyl ester, the title compound is obtained. / ' '■ -8A290/200 ' ' . -30- Example 26 r lfl.2a(5Z).3a.4B1-7-T 3-f 2-(Benzyloxy1 ethyl1-7-oxabicvclor2.2.11hept-2-v11-5-heptenoic acid Following the procedure of Example 20 except substituting benzyl methanesulfonate for n-hexyl methanesulfonate, the title compound is obtained. Example 27 [IB.2a(5Z1. 3B.4fl1-7-f3-f2-(BenzvloxV) ethyl1-7-oxabicyclo[2.2.llhept-2-vl1-S-heptenoic acid Following the procedure of Example 21 except substituting benzyl methanesulfonate for n-hexyl methanesulfonate, the title compound is obtained. Example 28 f IB . 2a( 5Z"). 3a.4B1-7-r 3-f 2 - (Cvclopentyloxvlethvll -7-oxabicyclof 2.2.11hept-2-yl1-5-heptenoic acid Following the procedure of Example 20 except substituting cyclopentyl methanesulfonate for n-hexyl methanesulfonate, the title compound is obtained. Example 29 [lfl.2a(5Z1.3a. 4fl 1-7-[3-f2-(Cyclohexyloxy)ethy11-7-oxabicyclof 2.2.11hept-2-vl1-5-heptenoic acid Following the procedure of Example 20 except substituting cyclohexyl methanesulfonate for n-hexyl methanesulfonate, the title compound is obtained. > Example 30 fIB. 2a(5Z1.3a.4fll-7-r 3-T4-(Hexvloxv)butyl 1-7-oxabicyclof2.2.1]hept-2-vl1-5-heptenoic acid A. riB.2a(5Z1.3a.4fl1-7-f3-(3-Oxo)propvl-7-oxabicyclor 2.2.11 hept-2-y11-5-heptenoic acid, methyl ester Following the procedure of Example 20, part A except substituting [IB,2a(5Z).3a.4B]-7-[3-(2-oxo)-ethyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester for [lfl.2a(5Z),3a,-4fl]-7-C 3-formyl-7-oxabicyclo[2;2.l]hept-2-yl]-5-heptenoic acid, methyl ester, the title A compound is obtained. B. rifl.2a(5ZK3a.4Bl-7-r3-(4-OX0Tbutyl-7-oxabicyclof2.2.11hept-2-yll-5-heptenoic acid, methyl ester Following the procedure of Example 20, part A, except substituting the aldehyde from part A above, for [ IB. 2<a( 5Z). 3a. 4fl]-7-[ 3-formyl-7-oxabicyclo-[ 2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, the title B aldehyde is obtained. C. r lfl.2a(5Z),3a.4fl1-7-\3-C4-Hydroxybutyl)- 7-oxabicyclo f 2.2.11 hept-2-yl1-5-heptenoic acid, methyl ester Following the procedure of Example 20, part B, except substituting the title B aldehyde for [ IB ,.2<*( 5Z) ,3a;4B]-7-(;3-(2-oxo)ethyl-7-oxabi-cyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, the title C alcohol is obtained. j 2 n • HA290-/28 fr -32- D. f lfl.2a(5Z) ,3a. 4fl1 -"7 - T 3-f 4-(Hexyloxy)-butyl 1 -7-oxabicyclo f 2.2.11hept-2-yl1-5-heptenoic acid Following the procedure of Examples 1 and 2. 5 except substituting the above part C alcohol for the alcohol used in Example 1, the title compound is obtained. Example 31 10 rifl.2<*( 5Z~) . 3a. 4fl 1 -7-f 3-f 4-(Cvclohexvloxv) butvl 1 -7-oxabicvclor2.2.llhept-2-yl1-5-heptenoic acid Following the procedure of Example 30 except substituting cyclohexyl methanesulfonate for n-hexyl methanesulfonate, the title compound is obtained. 15 . Example 32 . rifl.2a(5Z-) ,3a. 4fll-7-f 3-r 4-(Phenyloxy^butyl 1-7-oxabicyclof 2 . 2*. 11 hept-2-yl 1 -5-heptenoic acid Following the procedure of Example 11 except 20 substituting [lS,2a(5Z),3a,4fl]-7-[3-(4- hydroxybutyl)-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid, methyl ester for [ 1J3, 2a(5Z),-3a,4fl]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, the title 25 compound is obtained. Example 3 3 rifl.2a( 5Z1 . 3a.4fl1-7-r3-r4-(Ben2VlOXV^bUtyn-7-oxabicyclor2.2.11 hept-2-yl1-5-heptenoic acid 30 Following the procedure of Example 30 except substituting benzyl methanesulfonate for n-hexyl. methanesulfonate, the title compound is obtained. J "1? •' in* .■-** -Hft290/28fr -33- Examole 34 Tris(hvdromethyl)aminomethane salt of I" IB . 2a( 5Z ) .3a.4B1-7-r3-r(Hexyloxy)methyl1-7-oxabicvcloT2.2.11 hept-2-yl1-5-heptenoic acid 5 A solution of the compound formed in Example 2 in methanol is treated with an equivalent amouat of tris(hydroraethyl)aminoraethane. The solvent is removed by evaporation to yield the title compound as a solid, m.p. 68.5-70°C. TLC (silica gel, 10 3% CH3CIH/CH2Cl2)Rf=0.74. Anal.-Calcd. for C24H450?N: C,62.72; H,9.87; N,3.04 Found: C,62.71; H,9.80; N,3.10 Example 35 15 rifl.2et(5Z-) .3a.4B1-7-r3-r2-(PentvloxvVethvl1-7-oxabicvclor2.2.11hept-2-yl1-5-heptenoic acid A. riB.2a(5Z1. 3a.4B1-7-f3-f2-(PentVlOXVT-ethyl1-7-oxabicyclo[2.2. nhept^-yll-s-heptenoic acid, pentyl ester 20 A mixture of powdered KOH (0.36 g) in 15 mL of dry xylene was heated to reflux under argon atmosphere and 8 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, 25 alcohol methyl ester in 17 ml of dry xylene. The volume of the reaction mixture was reduced 15 ml by diatillative removal of xylene. To the reaction mixture was then added a solution of 0.5 g (3.55 mmol) pentylmesylate in 10 ml of dry xylene. This 2Q mixture was refluxed for 2 hours and 30 minutes. The cooled reaction mixture was diluted with 50 ml of saturated NaHCO^ solution and extracted with CH2C12 (3 x 60 ml). The combined CH2C12 35 • HA290/283—- -34- extracts were dried (MgS04), filtered and concentrated in vacuo. Purification was effected by flash chromatography on 33 g of silica gel 60 using hexane:ether (5:1) as eluant. This gave 5 238 mg of title pentyl ester (83%) as a colorless oil. TLC: silica gel. hexane:ether (1:1). B. flfl.2a(5Z1.3a.4fl1-7-r3-r2-(Pentvloxv1-ethvlT-7-oxabicycloT 2 ■ 2 .11hept-2-vn~5-10 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 ml of CHLjOH and 3.4 ml of H20 under argon was added 6.4 ml of IN aqueous lithium 15 hydroxide solution. This mixture was purged with argon vigorously for 30 minutes and stirred at room temperature for 7 hours. The reaction mixture was acidified to pH 3 by the addition of IN aqueous HCl solution. The resulting solution was poured into 20 50 ml of saturated NaCl solution and was saturated with solid NaCl. The aqueous layer was extracted with EtOAc (4 x 60 ml). The combined EtOAc extracts were dried (MgSO^), filtered and concentrated in, vacuo. This was chromatographed on 25 24 g of silica gel 60 using 3% CH3OH in CH2C12 as eluant to give 181 rag (92%) of title pure acid, TLC: silica gel, 4% CH30H/CH2C12. Rf=0.30, vanillin. Anal. Calcd. for c2oH34°4: C' 7u*y7; H> 30 C2QH3404 0.2.2 H20: C, 70.16; H, 10.14 Found: C, 70.16; H, 9.87 13CNMR (CPC13, 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, 35 64.3, 28.3, 22.2, 28.3, 13.9 •••* ;.'t V «, - ■ ■' < ■-Hft2 9 0/-2 8-6- -35- Example 3 6 flfl.2a(5Z).3a.4fll-7-f(S-PhenvlPcopoxvl-methvl 1-7-oxabicyclo f 2.2.llhept-2-vll-5-heptenoic acid 5 A. f lfl.2a(52K3a.4fl1-7-r f 3-Phenvlproporv)- methyl1-7-oxabicyclor2.2.llhept-2-yl1-5-heptenoic acid, phenvlpropyl ester A mixture of powdered KOH (0.59. g) in 16 ml of dry xylene was heated to reflux under argon 0 atmosphere and 9 ml of xylene was removed by distillation.' To this mixture was added a solution of 410 mg (1.53 mmol) of Example 1. part A. alcohol methyl ester in 10 ml of dry xylene. The volume of the reaction mixture was reduced 6 ml by 5 distillative removal of xylene-. To the reacton mixture was then added a solution of 1.66 g (7.58 mmol) of 3-phenylpropylmesylate in 36 ml-of dry xylene. This mixture was refluxed for L hour. The cooled reaction mixture was diluted with 50 ml of saturated NaHC03 solution and extracted with CH2C12 (3 x 50 ml). -The combined CH2C12 extracts were dried (MgS04). filtered, and concentrated .in vacuo. Purification was effected by flash chromatography on 40 g of silica gel 60 using hexane:ether (3:1) as eluant. This gave 0.61 g of title phenylpropyl ester (81%) as a colorless oil. TLC: silica gel. 2% CH30H/CH2C12. Rf:.60. iodine. I -36- B. f lfl. 2a( 5Z"). 3o. 4fl 1 -7- T (3-Phenylpropoxy) - roethvl1-7-oxabicycIor2 .2. nhept-2-yll-5-heptenoic acid To a stirred solution of 610 mg (1.24 mmole) 5 of title A phenylpropyl ester, 55 ml of distilled . THF, 4.40 ml of CHjOH and 7.30 ml of H20 under argon was added 13.7 ml of IN aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for 30 minutes and stirred at room • 10 temperature for 14- hours. The. reaction mixture was diluted with 100 ml of 0.1 N aqueous lithium hydroxide solution and washed once with 100 ml of hexane. The reaction mixture was acidified to pH 3 by the addition of IN aqueous HCl solution and was 15 poured into 100 ml of saturated NaCl solution. The resulting mixture was saturated with solid NaCl and extracted with EtOAc (4 x 150 ml). The combined EtOAc extracts were dried (MgS04), filtered and. concentrated in vacuo. This was chromatographed on 20 44 g of silica gel 60 using 4% CH3OH in CH2C12 as eluant to give 380 mg (82%) of pure title acid. TLC: silica gel, 4% CH30H/CH2C12, Rf=0.30, iodine. 25 Anal Calcd for C23H32°4: C. 74.16; H, 8.66 C H O 0.35 HO; C. 72.94; H. 8.70 23 32 4 2 Found: C, 72.94; H. 8.49 13C NMR (CDC13, 15.0MHz)tau 173.7, 33.4, 24.5, 25.7, 129.5, 130.1, 26.6, 46.3, 79.3, 29.5, 30 30.1, 46.8, 70.2, 69.S, 31.2, 32.3, 141.9, 128.4, 128.4. 35 Example 37 rifl.2o(5Z). 3a. 4131-7-f 3 - T (Octyloxy)methyl 1 -7-oxabicyclor2.2.11 hept-2-yl1-5-heptenoic acid A. rIB.2a(5Z).3a. 4fl1-7-f3-f(Octyloxv)- • methyl1-7-oxabicyclo T 2.2.11 hept-2-yl1-5-heptenoic acid, octyl ester To a stirred solution of 508 rag (1.89 mmol) of Example 1. Part A. ester alcohol in 2.69 ml THF was added in order 2.69 ml (15.6 mmol) of n-octyl bromide, 642 rag (1.89 mmol) of tetrabutylamraoniura hydrogen sulfate and 2.69 ml of 50% aqueous sodium hydroxide solution. This mixture was stirred at room temperature in darkness for 19 hours. The reaction mixture was poured into 25 ml of saturated sodium bicarbonate solution and extracted with four 25 ml portions of CH2C12. The combined CH^Cl^ extracts were dried (MgSC>4), filtered, and concentrated in. vacuo. Purification was effected by flash chromatography on 39.S g of silica gel 60 using hexane:ether (3:1) as eluant to give 333 mg (37%) of octyl ester and 250 mg of a mixed band of octyl ester and corresponding methyl ester. TLC: silica gel. 3% CH30H/CH2C12, R^:octyl ester, Q.85; methyl ester, 0.80, iodine. B. rIB.2a(5Z).3a.4B1-7-f 3 — T(Octyloxy)-methvl1-7-oxabicvclor 2.2.11hept-2-vll-5-heptenoic acid To a stirred solution of 333 mg (0.70 mmol) of Part A octyl ester in 31 ml of distilled THF, .1 . . \ A;. BP*®* HA200/280 -38- 2.50 ml of CH^OH and 4.1 ml of H^O under argon was added 7.70 ml of IN aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for 20 minutes and stirred at room 5 temperature for 16 hours and 30 minutes. The mixture of octyl ester and corresponding methyl ester was hydrolyzed in the exact same manner. To a stirred solution of this mixture (250 mg) in 29 ml of distilled THF. 2.40 ml of CH30H and 10 3.9 ml of HjO, was added 7.30 ml of IN aqueous lithium hydroxide. This mixture was purged with argon vigorously for 20 minutes and stirred at room temperature for 16 hours and 30 minutes. These 2 reaction mixtures were combined and 15 diluted with a solution of 120 ml of 0.1 N aqueous lithium hydroxide solution and 50 ml of H^O. The resulting mixture was extracted once with 220 ml of hexane. The aqueous layer was acidified to pH 3 by the addition of IN aqueous HCl solution saturated 20 with solid NaCl, and extracted with EtOAc (4 x 150 ml). The hexane extract and EtOAc extracts (hexane extract contained the desired acid) were combined, dried (MgS04), filtered and concentrated in. vacuo to give 0.53 g of crude 25 product. This was chromatographed on 48 g of silica gel 60 using 3% CH3OH in CH2C12 to give 222 mg (45%) of desired title acid. TLC: silica gel. 4% CH30H/CH2C12, R =0.40, vanillin 30 Anal, calcd for C22H3804: C. 72 .09; H. 10.45 C22H38°4 0-24 H2° * C' 71-25: H' 10,45 Found: C, 71.25; H. 10.20 35 70 c NMR (CDC13, 15.OmHz)tau 178.7, 33.8, 24.9, 26.2, 129.6, 130.0, 26.8, 46.5, 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, 14.0. Example 38 rLB.2a(5Z).3tt.4fll-7-f3-(Cyclohexvlmethoxy)-methyl1-7-oxabicyclof2.2.llhept-2-vl1-5- heptenoic acid A. rifl.2aC5Z1. 3a.4fl^-7-r3-(Cyclohexvl- methoxy)methyl^l-7-oxabicyclo^2. 2. llhept-2-yll-5- heptenoic acid, cyclohexylmethyl ester A mixture of powdered KOH (0.56 g) in 15 ml of dry xylene was heated to reflux under argon atmosphere and 7 ml of xylene was removed by distillation. To this mixture was added a solution of 300 mg (1.12 mmol) of Example 1. Fart A, alcohol methyl ester in 10 ml of dry xylene. The volume of the reaction mixture was reduced to 11 ml by distillative removal of xylene. To the ceacton mixture was then added a solution of 2.47 g (12.9 mmol) cyclohexylraethylraesylate in 10 ml of dry ■xylene. This mixture was refluxed for 5 hours. The cooled reaction mixture was diluted with 50 ml of saturated NaHCO^ solution and extracted with CH2C12 (3x50 ml). The combined CH2C12 extracts were dried (MgS04), filtered and concentrated in vacuo. Purification was affected by flash chromatography on 35 g of silica gel 60 using 1% CH3OH in CH2C12 as eluant. This gave 0.46-g of title hexyl ester (93%) as a colorless oil. TLC: silica gel, 2% CH30H/CH2C12< Rf = 0.80. iodine. ' -IIA290/y -40- B. rifl.2a(5Z).3a.4fl^-7-^3-(Cyclohexvl- methoxy)laethy^ -7-oxabicyclo f 2.2.11hept-2-yll-5- heptenoic acid To a stirred solution of 460 mg (1.03 mmol) 5 of Part A cyclohexylmethyl ester, 45 ml of distilled THF. 3.80 ml of OLjOH and 5.10 ml of H^O under argon was added 11.4 ml of IN aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for 20 minutes and 10 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 acidified to pH 3 by the addition of IN aqueous HCl 15 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 20 chromatographed on 34.6 g of silica gel 60 using 3% CH^OH in CH^C^ as eluant to give 278 mg (77%) of pure title acid. TLC=silica gel, 4% CH30H/CH2C12. Rf=0.28, iodine. 25 Anal. Calcd for C2]H3404: C. 71.96: H. 9.78 C-.H..O. 0.31 H_0: C. 70.84. H. 9.80 21 34 4 2 Found: C. 70.84; H. 9.68 13c 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.G, 30 79.2, 46.8, 70.0, 77.0, 37.9, 30.0, 26.7, 25.8, 26.7, 30.0, 69.3, 37.1,-29.1, 26.3, 25.6, 26.3, 29.1 J -HA290/28Q— -41- Example 39 1[g,20(Z) ,30,4g]-7-[3-[[ (1-inethylhexyl) oxy] -methyl]-7-oxobicyclo[2.2.1]hept-2-yl]-5-heptenoic acid 5 By following the procedures of Examples 1 and 2 except substituting 1-methylhexyl methane sulfonate for n-hexylmethanesulfonate, the titled compound is obtained, TLC (selica gel, 4% CH30H/CH2C12) Rf = 0.47. 10 Anal. Calcd for C2iH3s°4: C' 71>55; H, 10.29 Found: C, 71.73; H, 10.21 13 C NMR (CPC13, 15.0MHz)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, 15 31.9, 22.6, 14.0, 19.7 Example 40 [la,20(2),30,4g]-7-[3-[(3-hexynyloxy)methyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid By following'the procedures of Examples 1 20 and 2 except substituting 3-hexynylmethane- sulfonate, the titled compound is obtained as an oil, TLC (silica gel, 4% CH3OH/CH2Cl2) Rf 0.32 Anal, calcd for C20H30°4: C' -82; H,9.04 Found: C, 71.66; H,9.21 25 13C MMR (CDC13, 15.0MHz)tau 178.9, 33.4, 22.0, 24.5, 129.5, 130.0, 26.7, 46.4, 79.4, 29.4, 29.5; 80.0, 46.7, 69.0, 58.8, 76.1, 86.8, 22.0, 25.8, 13.4 -42-Exaniple 41 [lfl,2a(Z),3a(Z),4g]-7-[3-[(3-hexenyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid By following the procedure of Examples 1 and 5 2 except substituting cis-3-hexen-1-mesylate for the n-hexylmethanesulfonate, the titled compound is obtained as an oil. TLC (silica gel, 4% CH3OH/CH2Cl2) Rf = 0.3. Anal, calcd. for C-nH-,_0.: C, 71.39; H, 9.59 20 32 4 10 Found: C, 71.10; H, 9.59 13C NMR CPC13/ 15.0MHz)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 15 Example 42 [13,2a(Z),3a(Z),4p]-7-[3-[(2-hexenyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid By following the' procedure of Examples 1 and 2 and substituting 2-l-hex-2-enyl-mesylate 20 for n-hexylmethanesulfonate, the titled compound is prepared as an oil, TLC (silica gel, 2% CH30H/CH2C12) Rf = 0.22, vanillin. Anal, calcd. for C^H^O^: C, 71.39; H, 9.59; Found: C, 70.97; H, 9.64 25 I3C NMR (CDC13, 15.0MHz)tau 178.8, 33.4, 24.5, 2.5.8, 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 -43- Example 43 [10,2a(Z),3a,4a]-7-[3-[2-propenyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, and methyl ester •5 To a stirred solution of 310 mg (1.16 mmol) of [10,2a(5Z),3a,40]-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, 10 1.34 ml of allyl bromide, 107 mg of tetrabutylammonium hydrogen sulfate and 1.34 ml of 50% aqueous sodium hydroxide solution. The mixture was stirred at room temperature in darkness for 23 hours and then poured into 30 ml of saturated 15 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 20 on 35 g of silica gel 60 using hexane-ether (2:1) as eluant to give 220 mg of the methyl ester product, TLC (silica gel, hexane-ether (1:1) Rf = 0.4, iodine. The ester was dissolved in 36 ml of tetrahydrofuran along with a small amount of hydroquinone, 25 6 ml of water and 7 ml of IN aqueous lithium hydroxide solution and stirred at room temperature for 5.5 hours whereupon the reaction mixture was poured into 8 0 ml of saturated aqueous sodium chloride solution and was saturated with additional 30 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 chromatographed on 30 g of silica gel using 4% CH^OH/Cf^C^ 35 as eluant to give 190 mg of the acid product, TLC (silica gel, hexane-ether (1:1)) Rf = 0.15. S&2SX6/2Q0 -44- Anal. Calcd"for C17H2604: C, -69 /36 ; H, 8.96 Found: C, 69.72; H, 9.05 13C NMR (CDC13, 15.0MHz)tau 178.9, 33.4, 24.5, 25.7, 129.5, 130.0, 26.6, 46.3, 79.3, 5 29.4, 80.1, 46.7, 69.3, 72.0, 134.7, 117.0 Example 44 [13,2a(52),3a,43]-7-[3-[ (Hexylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, 10 • methyl ester A. [l3,2a(5Z),3a,43]-7-[3-(Hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl] -5-heptenoic-acid (a) A mixture of N-acetylpyridinium chloride 15 was prepared by adding 9.6 ml (136 mmole) of acetyl chloride dropwise to 56 ml of pyridine. To this was added 5.0 g (27 mmole) of (exo)-3-(2-methoxy-ethenyl)-7-oxabicyclo [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 which was purified by passage through a short column of silica gel (150 ml) with dichloromethane, yield 4.42 g of an oil. 20 25 30 35 (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 L0 minutes and then the entire mixture was poured into a solution containing 200 g of potassium iodide in 2 1. of water. LJpon f • - IIA2Q0/2#0— -45- shaking, the yellow color disappeared and the mixture was extracted with benzene (3 x 500 ml). The combined benzene extracts were washed with potassium iodide solution-and brine and dried 5 over sodium sulfate. Concentration yielded 3.7 g of material which crystallized on standing in an ice box. (c) A Wittig reagent was prepared in ]_g dimethyl sulfoxide (dried over calcium hydride) by adding a solution of sodium methylsulfinylmethide (prepared by heating 300 mg of sodium hydride in 6 0 ml of dimethyl sulfoxide at 75° until hydrogen evolution stops) dropwise to a solution of 5.32 g 15 (12 mmole) of 4-carboxybutyl triphenylphosphonium bromide in 100 ml of dimethyl sulfoxide. After the first orange color lasting more than 10 seconds formed, an equivalent amount of base was added to form the ylide. To this deep orange solution was 2Q 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 mixture poured into brine 25 (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 mixture. This mixture was washed with benzene and acidified with 10% hydrochloric acid. i I Y OTP ~UA23dH2S^~ ■ -46- The aqueous layer was saturated with salt and extracted with ether which on drying (sodium sulfate) and concentration gave 2.4 3 g of crude product. The mixture was stirred 2 4 hours with 10% aqueous 5 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 10 twice from ethyl acetate-cyclohexane to yield 320 mg of [10,2a(5Z),3a,40]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid. B. [13,2a(5z),3a,4g]-7-[3-(p-Toluenesulfonyl-15 oxymethyl)-7-oxabicyclo[2.2.l]hept-2-yl]- 5-heptenoic acid, methyl ester 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 mmol) of tosyl chloride. 2Q The mixture was stirred at room temperature under an argon atmosphere for 10 hours. The reaction 25 mixture was diluted with 300 ml of ether, washed with IN aqueous HCl solution (3 x 10 0 ml), and 0.5 N aqueous NaOH solution (3 x 100 ml). The ether layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification 30 was effected by flash chromatography on 30 g of I -47- silica gel 60 using 50% hexane in ether as eluant to give 450 mg of title compound (95%). TLO.silica gel, 4% CH^OH in R^=0.80, iodine. 5 C. [13,2a(5 Z),3a,43]-7-[3-[(Hexylthio)methyl]- 7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester To a solution of 132 mg (1.17 mmol) of potassium t-butoxide in 10 ml of dry THF under argon ]_q was added 378 mg (3.21 mmol) of 1-hexanethiol. To this mixture was added a solution of 450 mg (1.0 7 mmol) of Part B tosylate in 5 ml of THF. The reaction mixture was stirred at room temperature under argon for 2.5 hours and then heated to reflux for 5.5 hours. The cooled reaction was diluted with 300 ml of ether and poured into 100 ml of saturated NaHCO^ solution. The aqueous layer was extracted with ether (2 x 100 ml). The combined ether extracts (500 ml) were washed with 0.5N aqueous sodium hydroxide (2 x 100 ml), brine (100 ml), and then dried (MgSO^), filtered and concentrated in vacuo to give 0.55 g of crude oil. Purification was effected 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, R^=0.55, iodine. Example 45 [13,2a(52),3a,43]-7-[3—[(Hexylthio)methyl]-7-oxabicy-clo [2.2.l]hept-2-yl]-5-heptenoic acid To a stirred solution of 328 mg (0.89 mmol) 15 20 25 35 ./ ■-HA2 9Q/20Q- ~48" of the Example 1 methyl ester in 4 3.8 ml of THF and 6.67 ml of f^O under argon was added 3.40 ml of IN aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for 5 20 minutes and stirred at room temperature for 12.5 hours. The reaction mixture was acidified to pH 4 by the addition of IN aqueous HCl solution and poured into 50 ml of saturated NaCl solution. The.resulting solution was saturated with solid 10 NaCl and extracted with EtOAc (4 x 50 ml). The combined EtOAc extracts were dried (MgSO^), filtered and concentrated in vacuo to give 2 95 mg of crude acid. Purification was effected by flash chromatography on 25 g of siliCAR CC-7 using 2:3 15 petroleum ether:ether as eluant to give title product (250 mg, 79%) as an oil. TLC:silica gel, 2:3 petroleum ether:ether, R^= 0.25, iodine. Anal. Calc'd for C2qH2403S: C, 67.80; H, 9.61; S, 9.04 20 Found: C, 6 7.80; H, 9.85; S, 9.'14 13C NMR (CDC13, 15.0MHz)tau 173.5, 33.1, 24.5, 25.6, 129.9, 128.8, 26.5, 45.9, 79.9, 29.2, 23 .8, 7 8.3, 45.9, 69 .5, 144'.5, 25- 129.7, 127.6, 132.1, 127.6, 129.7, 21.3, 51.1 Example 46 30 35 (13,2a,3a,43)-7-[3-[(Hexylthio)methyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester A. (13,2a,3a,46)-7-[3-(Hydroxymethyl)-7-oxabicvclo [2.2.l]hept-2-vl]heptanoic acid, methyl ester To 800 mg (3.0 mmolej of the [1(3,2a (5Z) ,-3a, 4(3 ] -7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]- <iUji2jirL/20-e- ■ -49- hept-2-yl]-5-heptenoic acid, methyl ester as prepared in Example 1, dissolved in 120 ml of ethyl acetate was added, under an argon atmosphere, 160 mg of 5% Pd on carbon. The argon atmosphere 5 was exchanged for a slight positive 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. 10 B. (10,2a,3a,46)-7-[3- [ (Hexylthio)methyl]-7- oxabicyclo [2.2.1 ]hept-2-yl] -^-~heptanoic acid, methyl ester Following the procedure of Example 1 except substituting the Part A alcohol-ester for 15 the Example 1A alcohol ester, the title product is obtained. Example 47 (l3,2a,3a,40)-7-[3-[(Hexylthio)methyl]-7-oxabicyclo-20 [2. 2.l]hept-2-yl]-heptanoic acid Following the procedure of Example 45 except substituting the Example 4 6 methyl ester for the Example 4 5 methyl ester, the title acid is obtained. Example 48 [13,2a(5Z),33,40]-7- [3-[(Pentylthio)methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptanoic acid, methyl ester [I0,2a(5z),33,43]-7-[3- hydroxy- methyl)-7-oxabicyclo[2.2.1]hept-2-vl]-5-heptenoic acid, methyl ester 35 / 3-0— -50- To a solution of 2.68 g of [13,2a(5Z),3a,40]-7-[3- (hydroxymethyl)-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid in 17 5 ml of dimethylformamide was added 13.16 g of pyridinium dichromate. This 5 mixture was stirred at room temperature for 19 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 and the resultant 10 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/CI^C^ to give 1.86 g of brown 15 oil. This was purified by chromatography on 150 g of silica gel 60 using 1:1:0.01 pentane-ether-acetic acid as eluant. This gave 0.63 g o'f [13,2a,-' (5Z),3a,43]-7-[3 - (carboxy)-7-oxabicyclo[2.2.1]hept-20 2-yl]-5-heptenoic acid methyl ester and 0.31 g of [IP,2a,(5Z),33,43]—7—[3—(carboxy)-7-oxabicyclo-[2.2.l]hept-2-yl]-5-heptenoic acid methyl ester. 13C NMR (CDC13,15.0MHz)tau 177.0, 174.0, 130.6, 127.7, 81.5, 77.9, 54.7, 51.3, 46.2, 33.4, 25 32.3, 29.2, 26.6, 25.8, 24.7. A so.lution of 350 mg of [13 ,2a (5Z) , 33 ,40] -7-[3-(carboxy)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid methyl ester and 0.35 ml of triethyl-amine in 3.0 ml of dry THF under argon was cooled 30 to 0°C. To this stirred solution was added dropwise 0.24 ml of ethylchloroformate. The resulting mixture was stirred at 0°C for 50 minutes and then diluted with 20 ml of anhydrous ether. The mixture was filtered through a pad of MgSO^ and concentrated 35 in vacuo. The residue was dissolved in 2 ml of J . -51- absolute EtOH and 3.3 ml of dry THF. This solution was cooled in an ice bath and then 80 mg of NaBH^ was added. The mixture was stirred for 3 0 min. at 0°C and then the ice bath was removed. After 15 minutes, the reaction 5 mixture was poured into 25 ml of ice-cold IN HCl. The aqueous layer was extracted with three 25 ml portions of ether. The ether layers were combined dried over MgSO^, filtered, and concentrated in vacuo to afford the crude product. Purification 10 was effected by flash chromatography of 22 g of silica gel 'using 2% MeOft/Cf^Clj as eluant. This gave 250 mg of [1(3 , 2a(5Z) , 3(3,43] -7-[ 3- (hydroxymethyl) -7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid methyl ester; 15 13C NMR (CDC13, 15.0MHz)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'. [ 13 ,2a (5Z) ,33, 4(3]-7-[3- (p-Toluenesulf onyl-oxymethyl)-7-oxobicyclo[2.2.1]hept-2-yl-2 0 5-heptenoic acid, methyl ester J . IIA29 0/200 -52- To a solution of 300 mg (1.12 mmol) of [10,2a(5Z),30,40]-7-[3—(hydroxymethyl)-7-oxabicyclo [ 2 . 2. 1] hept-2-yl]-5-heptenoic acid, methyl ester from part A in 4 ml of dry pyridine 5 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 IN aqueous HCl solution (3 x 100 ml), 10 and 0.5 N aqueous NaOH solution (3 x 100 ml). The ether layer is dried over anhydrous magnesium sulfate and concentrated in 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 15 of title B compound. C. [13/2a(5Z),33,40]-7-[3-[(Pentylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester 20 To a solution of 132 mg (1.17 mmol) of potassium t-butoxide in 10 ml of dry THF under argon 'is added 378 mg (3.21 mmol) of 1-pentanethiol. To this mixture is added a solution of 4 50 mg (1.07 mmol) of Part B tosvlate in'5 ml of THF. The 2^ 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 I flWv -fi-ttS-erfTfrOr -53- 300 ml of ether and poured into 100 ml of saturated NaHC03 solution. The aqueous layer is extracted with ether (2 x 100 ml). The combined ether extracts (500 ml) are washed with 0.5 N aqueous 5 sodium hydroxide (2 x 100 ml), brine (100 ml), and then dried (MgSO^), filtered and concentrated in vacuo to give 0.55 g of crude oil. Purification was effected by chromatography on 25.2 g of silica gel 60 using 5:1 pet. ether:ether as 10 eluant to give 328 mg of title compound. Example 49 [13,2a(5Z),30,40]—7—[3—[(Pentylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid To a stirred solution of 328 mg (0.89 mmol) of Example 48methyl ester in 4 3.8 ml of THF and 6.6 7 ml of H2O under argon is added 8.40 ml of IN aqueous lithium hydroxide solution. This mixture is purged with argon vigorously for 20 minutes and stirred at room temperature for 12.5 hours. The reaction mixture is acidified to pH 4 by the addition of IN aqueous HCl solution and poured into 50 ml of saturated NaCl solution. The resulting solution is saturated with solid NaCl and extracted with EtOAc (4 x 50 ml). The combined EtOAc extracts are dried (MgSO^), filtered and concentrated in vacuo to give 295 mg of crude acid. Purification is effected by flash chromatography on 25 g of siliCAR CC-7 using 2:3 petroleum ether:ether as eluant to give the acid. Example 50 [10,2a(5Z). ,3a,48l-7-[3-[ (Methyl thio) methyl ] -7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 14 and 45 except substituting methyl mercaptan for 1-hexane-thiol, the title compound is obtained. 15 20 25 30 dltijjm -54- Example 51 [13,2a(5Z) ,30,40] — 7—[ 3— [ (Propyl thio) methyl] -7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 4 8 and 49 5 except substituting propylmercaptan for 1-pentanethiol, the title compound is obtained. Example 52 (13 > 2a,3a,43)-7-[3-(Butylthio)methyl]-7-oxabicyclo-10 [2.2.l]hept-2-yl]heptanoic acid Following the procedure of Examples 4 6 and 47 except substituting butylmercaptan for 1-hexanethiol, the title compound is obtained. 15 Example 53 [13,2a(5Z), 3a,43]-7-[3-[ (Octylthio)methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 44 and 45 except substituting 1-octanethiol for 1-hexanethiol, ' the title compound is obtained. Anal. Calcd. for C22H38°3S: C' H,iU.01; S,8.38 Found: C, 69.08; H, 9.75; S,8.20 13C NMR (CDC13, 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, 25 80.4, 47.5, 33.4, 32.1, 29.1, 28.8, 26.7, 26.2, 24.5, 22.5, 13.9 Example 5 4 [13,2a(5Z) ,3a,43]-7-[3- [ (Phenylthio)methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 44 and 45 except substituting phenylmercaptan for 1-hexanethiol, the title compound is obtained. 35 Example 55 (13 , 2a,3a,40)-7- [3-[(Phenylthio)methyl]-7-oxabicyclo-[2. 2.l]hept-2-yl]heptanoic acid Following the procedure of Examples 46 and 47 except substituting phenylmercaptan for 1-hexanethiol, the title compound is obtained. Example 5 6 [13,2a(5Z),3a,43]-7-[3-[(Ethylthio)methyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptanoic acid • Following the procedure of Examples 4 4 and 45 except substituting ethylmercaptan for 1-hexanethiol, the title compound is obtained. Example 57 [13,2a(5Z),33,40]—7—[3—[(Phenylthio)methyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 4 8 and 49 except substituting phenylmercaptan.for 1-pentane-thiol, the title product is obtained. Example 58 [13,2a(5Z),30,40]—7—[3—[(Benzylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 4 8 and 4 9 except substituting -benzylmercaptan for 1-pentanethiol, the title product is obtained. Example 59 (10,2a,3a,40)-7-[3-f(Benzylthio)methyl]-7-oxabicyclo [2.2.1]hept-2-vl]heptanoic acid Following the procedure of Examples 4 6 and 4 7 except substituting benzylmercaptan for 1-hexanethiol, the title product is obtained.. I -5_6-Example 6 0 [13,2a (5Z) , 3oc ,46] — 7— [ 3— [ (Cyclohexyl thio) methyl] -7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 44 and 45 5 except substituting cyclohexylmercaptan for 1-hexanethiol, the title product is obtained. Example 61 [13,2a(5Z),30,40]-7-[3- [ (Cyclopentylthio)methyl]-7-10 oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 48 and 49 except substituting cyclopentylmercaptan for 1-pentanethiol, the title product is obtained. 15 Example 6 2 (13, 2oc, 3a, 4 8 ) -7- [3- [ (Cyclohexylthio)methyl] -7-oxabicyclo[2.2.1]hept-2-yl]heptanoic acid Following the procedure of Examples 4 6 and 4 7 except substituting cyclohexylmercaptan for 20 1-hexanethiol, the title product is obtained. Example fi3 [10 , 2a (5Z) , 3a, 43 ]-7- [3- [2-(Hexylthio) ethyl] -7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid A. [10,2a(5Z),3a,40]-7-[3-(2-Oxo)ethvl- 7-oxabicyclo[2.2.l]hept-2-ylJ-5-heptenoic acid, methyl 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 ((CgH5)3P+-CH2OCH3Cl") and 235 ml distilled 25 30 35 -57- toluene (stored over molecular sieves). 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 toluene was added dropwise. A bright red solution formed which was stirred at 0°C for an additional 35 minutes. Thereafter, a solution of 4.97 g (18.8 mmol) [IP,2a(5Z),3a,43]-7- [ 3-formyl-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid, methyl ester in 60 ml toluene was added by means of a dropping funnel over a 35 minute period with the ice-bath still in place. The reaction was then quenched by addition of 2.3 g (39 mmol) acetic acid in 5 ml ether. The reaction mixture immediately turned pale yellow and was immediately poured into 200 ml saturated NH^Cl, and extracted with ether- (4 x 200 ml). The combined ether phases were washed with MaCl, saturated solution, and dried (MgSO^) and concentrated to yield a 'yellow oil in a white crystalline solid (phosphine oxide). The white solid was triturated with EtOAc and the mother liquor was purified by chromatography on an LPS-1 silica column. The fractions obtained were (A) [10,2a (5Z),3a,43]-7- [3-(2-oxo)ethyl-7-oxabicyclo[2.2.1]hept-2-yl]-S^heptenoic acid, methyl ester, (3) [10,2a(5Z) ,3a,40]-7-[3-(2-methoxy)-ethendiyl-7-oxabicyclo[2.2.l]hept-2-vl]-5-heptenoic acid, methyl ester, and (C) [10,2a(5Z),3a,40]-7-[3-(2,2-dimethoxy)ethyl-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid, methyl ester. Compounds (B) and (C) are each treated with trifluoroacetic acid to convert each to compound (A). -58- B. [13,2a(5Z),3a,43]-7- [3- (2-Hydroxyethyl)-"7-oxabicyclo[2.2.l]hept-2-vl]-5-heptenoic acid, methyl ester The aldehyde (1.4 g, 5 mmol) from part A in methanol (50 ml) is treated with NaBH^ (0.19 g, 5 mmol) in an argon atmosphere at 0°C. After stirring at 0° for 1 hour, the reaction 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. The ether solution is washed with •saturated KHCO^, saturated NaCl and dried (MgSO^) .. The ether is evaporated to yield the title B compound C. [13,2a(52) , 3a,4(3 ]-7-[3-[2-(Hexyl thio) -ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 44 and 4 5 except substituting the above part B alcohol for the. alcohol used in Example 44,the title compound is obtained. Example 64 [13 , 2a (5Z) , 33 , 43 ] -7- [3- [2-< Hexyl thio) ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Example 63, except substituting [13,2a(5Z), 33,43 ]-7- [3-farmy1-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid, methyl ester for [13,2a(5Z),3a,43]-7-[3-formyl-7-oxabicvclo-[2.2.l]hept-2-yl]-5-heptenoic acid, methyl ester, the title compound is obtained. Example 6 5 (1(3 , 2a, 3a, 4g)—7— [3— [2-(Hexylthio) ethyl] -7-oxabicyclo-[2.2.1]hept-2-yl]heptanoic acid Following the procedure of Example 64 except substituting (10,2a,3a,40)-7-[3-formyl-7-oxabicyclo-[2.2.l]hept-2-yl]heptanoic acid, methyl ester for [10,2a(5Z),3a,40]-7-[3-formyl-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid, methyl ester, the title compound is obtained. Example 66 [10 , 2a (5Z) , 3a, 40 ]-7- [3-[2-(Phenylthio) ethyl] - 7-oxabicyclo [2.2.l]hept-2-yl]-5-heptenoic acid Following the procedure of Example 6 3 except substituting phenylmercaptan for 1-hexanethiol, the title' compound is obtained. Example 67 [10 , 2a (52) , 30 , 40 ]-7- [3- [2-(Phenylthio ) ethyl ] -7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Example 64 except substituting phe'nylniercaptan for 1-hexanethiol, the title compound is obtained. Example 6 8 (13, 2a, 3a, 40) -7- [3- [2-(Phenylthio) ethyl ] -7-oxabicyclo-[2.2.1]hept-2-yl]heptanoic acid Following the procedure of Example 65 except substituting phenylmercaptan for 1-hexanethiol, the title compound is obtained. _ 60- Example 69 [13,2a(5Z) ,3a, 4Q ]—7— [3— [2-(Benzvlthio)ethyl ] -7— oxabicyclo [2.2.1]hept-2-yl1 -5-heptenoic acid Following the procedure of Example 63 5 except substituting benzylmercaptan for 1-hexanethiol, the title compound is obtained. Example 70 [13 , 2a (5Z) , 33 , 43 ]-7-[3-[2-(Benzylthio) ethyl] -7-10 oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Example 64 except substituting benzylmercaptan for 1-hexanethiol, the title compound is obtained. 15 Example 71 [IB,2a(5Z) , 3ct,43 )-7-[3-[2-(Cyclbpentyl) thio) ethyl] -7-oxabicyclo [2.2.l]hept-2-yl]heptenoic acid Following the procedure of Example 63 except substituting cyclopentylmercaptan for 20 1-hexanethiol, the title compound is obtained. Example 72 [13 , 2a (5Z) ,3a,4B }-7— [3— [2- (Cyclohexylthio) ethyl ] -7-oxabicyclo [2.2.1]hept-2-vl]-5-heptenoic acid 25 Following the procedure of Example 6 3 except substituting cyclohexylmercaptan for 1-hexanethiol, the title product is obtained. Example 7 3 3Q [13 , 2a (5Z) , 3a, 48 J-7- [3- [4-(Hexylthio) butvl] -7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid A. [l3,2a(5Z),3a,40]-7-[3-(3-Qxo)propy1-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester 35 HP i -61- Following the procedure of Example 63, part A except substituting [10,2a(5Z),3a,40]-7-[3-(2-oxo)-ethyl-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester for [10,2a(5Z),3a,40]-7-[3-formyl-7-5 oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid, methyl ester, the title A compound is obtained. B. [10 ,2a (5Z) ,3a,40]-7-[3- (4-Oxo)butyl-7-oxabicyclo[2. 2'. l]hept-2-yl] -5-heptenoic acid, methyl ester • Following the procedure of Example 63, part A, except substituting the aldehyde from part A above, for [10,2a(5Z),3a,40]-7-[3-formyl-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid, methyl ester, the title B aldehyde is obtained. C. [10,2a(5Z),3a,40]-7-[3-(4-Hydroxybutyl)-7-oxabicvclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester 20 Following the procedure of Example 63, part B, except substituting the title B aldehyde for [10,2a(5Z),3a,40]-7-[3-(2-oxo)ethyl]-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, the title C alcohol is obtained. 25 D. [10 , 2a (5Z) , 3a, 40 J-7- [3-[4- (Hexylthio) -butyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 44 and 45, 3q except substituting the above part C alcohol for the alcohol used in Example 44, the title compound is obtained. 10 15 35 2073 . , BSM/Mtr -62- # Example 7 4 [13,2a(5Z) ,3a, 43 3-7- [3- [4- (Cyclohexyl thio) butyl] -7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Example 73 except substituting cyclohexylmercaptan for 1-hexan.ethiol, the title compound is obtained. Example 7 5 [13 ,2a(52), 3a, 43 ]-7-[3-[4-(Phenylthio) butyl] -7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid •Following the procedure.of Example 73 except substituting phenylmercaptan for 1-hexanethiol, the title compound is obtained. Example 7 6 [13,2a(52),3a, 43']—7— [3-[4-(Benzylthio) butyl] -7-oxabicyclo [2.2.1]hept-2-vl]heptenoic acid Following the procedure of Example 7 3 except substituting benzylmercaptan for 1-hexanethiol, the title compound is obtained. Examples 77. 7 8 and 7 9 [13,2a(52),3a,43]-7-[3-[(Hexylsulfinyl)methyl]-7-oxabicvclo [2.2.1]hept-2-yl]-5-heptenoic acid, methyl. ester (fast moving isaier) , [13,2a (52) , 3a, 43 ] - 7-[3-[(Hexylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept- 2-yl]-5-heptenoic acid, methyl ester (slow moving isomer) an d [13 , 2a (52 ) , 3a,43]-7-[3-[ (Hexyl sulfonyl.) -methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester To a solution of 634 mg (1.72 mmol) of -63- [10,2a(5 Z),3a,40]-7-[3-[(hexylthio)methyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid, methyl ester (prepared as described in Example 44) in 6.78 ml of methanol at 0°C was added dropwise 5 over 4 minutes 8.37 ml of 0.5M aqueous sodium periodate solution. Tetrahydrofuran (2 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 10 washed with ether (3 x 50 ml). The filtrate was washed with 60 ml of saturated aqueous NaHCO^ solution and dried over anhydrous magnesium sulfate. Concentration in vacuo afforded 648 mg of an oily crude product. This was chromatographed on 15 54.16 g of silica gel 60 using 0.5-1.0% CH^OH in CI^C^ as eluent. This gave FMI (fast moving isomer) sulfoxide (Example 77) (211 mg, 32%), SMI (slow moving isomer) sulfoxide (Example 78) (142 mg, 21%) and sulfone (Example 79) (165 mg, 20 24% ). These products were oils which solidified on storage in the freezer. TLC = silica gel, 2% • (CH^OH/CI^C^, Rf: Example 77 sulfoxide, 0.28; Example 78 sulfoxide, 0.21; Example 7 9 sulfone, 0.74; iodine. 25 Example 80 [10,2a(52),3a,40]-7-[3-[(Hexylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid To a stirred solution of 16 5 mg (0.41 mmol) 2Q of [10/2a(5Z),3a,40]-7-[3-[(hexvlsulfonvl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, -- -HA2 9 0-/-2-8-0 -64- ' methyl ester (Example 7 9 in 20.3 ml of THF and 3.09 ml of H^O under argon was added 3.90 ml of IN 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 acidified to pH 4 by addition of IN aqueous HCl solution and poured 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 (MgSO^), filtered and concentrated in vacuo to give 165 mg of crude acid. Purification was effected by flash chromatography on 20 g of silica gel 60 using 3% CH^OH ill CH2Cl2 as eluant. This afforded title acid (145 rug, 91%) which solidified on storage in the freezer. TLC=silica gel, 4% CH30H/CH2C12, Rf 0.32, iodine. Anal. Calcd for ^2QE34°5S: C, 62.18; H, 8.81; S, 8.29 Found: C, 61.99; H, 9.01; S, 8.33 13C NMR (CDC13, 15.0MHz)tau 178.4, 33.1, 24.3, 26.7, 123.9, 130.3, 28.0, 39.9, 79.8, 31.1, 28.8, 80.9, 47.0, 54.1, 51.7, 29.4, 27.1, 22.2, 21.9, 13.7 Example 81 [13,2a(5Z),3a,43]-7- [3- [ (Hexylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (fast moving isomer) To a stirred solution of 211 mg (0.55 mmol) of [13,2a(5 Z),3a,40]-7-[3-[(hexylsulfinyl)methyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid, methyl ester (fast, moving isomer) prepared.in Example 77 in 27.0 ml of THF and 4.11 ml of H20 under argon was added 5.19 ml of IN aqueous lithium • I v . ,x- ■*.- .*< !. - '•< ,*■■■■ f t ] : 'Jvz, A. . --' " IIA20 0/20Q ■ -65- hydroxide solution. This mixture was purged with argon vigorously for ten minutes and stirred at room temperature for 6 hours. The reaction mixture was acidified to pH 4 by addition of IN aqueous 5 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 (MgSO^), filtered and concentrated in vacuo -to give 216 mg of 10 crude acid. Purification was effected by flash chromatography on 20.2 g of silica gel 60 using 3% CH^OH in CH2CI2 as eluant to give the title acid (172 mg, 85%) as a white solid. TLC = silica gel, 4% CH30H/CH2C12, Rf 0.10, iodine. 15 Anal. Calcd for C2C)H3404S: C, 64.83; H, 9.25;. &, 8.65 Found: C, 64.71; H, 9.17; S, 3.55 • 13c NMR (CDC13, 15.0'MHz) 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, 13.8 Example 8 2 [16,2a(52) ,3a, 43]-7- [ 3- [ (Hexylsulfinvl)methyl]-7-oxabicyclo[2.2.l]hept-2-vl1-5-heptenoic acid (slow 25 moving isomer) To a stirred solution of 142 mg (0.37 mmol) of [10,2a(5Z),3a,46]-7-[3-[(hexylsulf inyl ) methyl ]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester (slow moving isomer) prepared as described in Example 78 in IB.2 ml of THF and 2.77 ml of H2O under argon was added 3.50 ml of IN aqueous lithium hydroxide solution. This' mixture was purged with argon vigorously for 15 minutes and stirred at room temperature for 35 ■ IIA2D0/LIG0 — -66- 4 hours and 40 minutes. The reaction mixture was acidified to pH 4 by addition of IN aqueous HCl solution and poured into 30 ml of saturated NaCl solution. The resulting solution was saturated with 5 solid NaCl and extracted with EtOAc (3 x 70 ml). The combined EtOAc extracts were dried (MgSO^), filtered and. concentrated in vacuo to give 152 mg of crude acid. Purification was effected by flash chromatography on 20.8 g of silica gel SO using 10 4% CH^OH in CH2C12 as eluant to give title acid (116 mg, 85%)'. TLC: silica gel, 4% CH30H/CH2C12, R^ 0.6, iodine. Anal. Calcd for C2QH3404S: C, 64.83; H, 9.25; S, S.65 Found: C, 64.44; H, 9.15; S, 8.58 15 13C NMR (CDC13, 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, '52.8, 29.4, 27.1, 22.4, 22.4, 13.8 20 • Example 83 [13,2a(52),3a,43]-7-[3-[(Methylsulfinyl)methyl]- 7-oxabicvclo [2.2.1]hept-2-vl]-5-heptenoic acid (fast moving isomer) Following the procedure of Examples 44, 7 7 and 25 81 except substituting methyl mercaptan for 1-hexanethiol, the title compound is obtained. Example 84 [lg,2a(5Z),3a,4B]-7-[3- [(Octylsulfinyl)methyl]-7-oxabicvclo[2.2.l]hept-2-vl]-5-heptenoic acid (slow moving isomer) Following the procedure of Examples 44, 77 and 82 except substituting 1-octanethiol for 1-hexanethiol, the title compound is obtained. 30 35 _ - -67- Example 8 5 [IB ,2a(5Z),33,40 3—7—[3—[(Phenylsulfinvl)methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid (fast moving isomer) 5 Following the procedure of Examples 48, 77 and 81 except substituting phenylmercaptan for 1-pentanethiol, the title compound is obtained. Example 86 10 [13,2a(5Z),3a,43]-7-[3-[(Ethylsulfinyl)methyl]-7-oxabicyclo [2.2.l]hept-2-yl]-5-heptenoic acid (slow moving isomer) Following the procedure of Example 48 , 77 and 82 except substituting ethylmercaptan for 1-pentane-15 • thiol, the title compound is obtained. Example 8 7 (13,2a,3a,46)-7-[3-[(Heptylsulfinyl)methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptanoic acid 20 (fast moving isomer) Following the procedure of Examples 46, 77 and 8]_ except substituting 1-heptanethiol for 1-hexanethiol, the title compound is obtained. 25 Example 88 " [16,2a(5Z) ,3a,43]-7-[3- [ (Benzylsulfinyl)methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-hepteno ic acid Following the procedure of Examples 44, 77 and 81 except substituting benzylmercaptan for 30 1 -hexanethiol, the title compound is obtained. Example 8 9 [IB , 2a (52) , 3(3, 40 ]-7- [3- [ (Ben-zylsulfinyl) methyl] -7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (slow moving isomer). Following the procedure of Examples 48, 77 and 82 except substituting benzylmercaptan for 1-pentanethiol, the title compound is obtained. Example 90 [13,2a(52),3a,40]-7-[3-[(Cyclohexylsulfinyl)methyl]-7-oxabicyclo [2. 2.1]hept-2-yl] -5-rheptenoic acid (fast moving isomer) Following the procedure of Examples 44, 77 and 81 except substituting cyclohexylmercaptan for 1-hexanethiol, the title compound is obtained. Example 91 [13,2a(5Z),3a,48]-7-[3-[ (Cyclopentylsulfjnyl)-methyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid (fast moving isomer) Following the procedure of Examples 44, 77 and 81 except substituting cyclopentylmercaptan for 1-hexanethiol, the title compound is obtained. Example 92 [10,2a(5Z),3a,43]-7-[3- [ (Octylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 44, 77 and 8 0 except substituting octylmercaptan for 1-hexanethiol, the title compound is obtained. - 69- HA290/280 Example 9 3 [13,2a(5Z),3a,43]-7-[3-[(Propylsulfonyl)methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure, of Examples 44, 77 and 80 except substituting propylmercaptan for 1-hexanethiol, the title compound is obtained. Example 94 [13 , 2a(5Z) ,3a,48]-7-[3-[ (Phenylsulfonyl) methyl ] -7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 44, 77 and 80 except substituting phenylmercaptan for 1-hexanethiol, the title compound is obtained. Example 95 [lS,2a(5Z),3a,48]-7- [3-[(Benzylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 44, 77 and 80 except substituting benzylmercaptan for 1-hexanethiol, the title compound is obtained. Example 96 [18,2a(5Z),3a,48]-7-[3-[(Cyclohexylsulfonyl)methyl] 7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 44, 77 and 80 except substituting cyclohexylmercaptan for 1-hexanethiol, the title compound is obtained. Example 97 [13,2a C5Z),3B,4B]-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 1-heptanethiol for 1-pentanethiol, the title compound is obtained. -70-Example 98 [,13 ,2a(5Z) ,30,40]—7— [3—[ (Benzyl sulfonyl) methyl 1-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 48, 77 5 and 80 except substituting benzylmercaptan for 1-pentanethiol, the title compound is obtained. Example 99 [13 , 2oe (5Z) , 30 ,43 ] - 7- [3- [ (Cyclopentylsulfonyl)methyl ] -10 7-oxabicyclo [2.2.1 ]hept-2-yl ].-5-heptenoic acid Following' the procedure of Examples 48, 77 and 80 except substituting cyclopentylmercaptan for 1-pentanethiol, the title compound is obtained. 15 Example inn [1(3, 2a (5Z) , 30 ,40 ] - 7- [3- [ (Phenyl sulfonyl) methyl ] -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 1-pentanethiol, the title compound is obtained. 25 Example 101 (13,2a,3a,43)-7-[3-[(Cyclopropvlsulfinyl)methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptanoic acid Following the procedure of Examples 46, 77 and 80 except substituting cyclopropylmercaptan for 1-hexanethiol, the title compound is obtained. 30 -71- -HA290/280 Example 102 (13,2a,3a,43)-7- [3-[(Benzylsulfinyl)methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptanoic acid Following the procedure of Examples 47, 77 and 81 5 except substituting benzylmercaptan for 1-hexanethiol, the title compound is obtained. Example 10 3 [13/2a(5Z) ,3a,43 }-7- [3-[2- (Pentyl sulfinyl) ethyl ] -7-10 oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 63, 44, 77 and 81 except substituting 1-pentanethiol for 1-hexanethiol, the title compound is obtained. 15 Example 104 [13 / 2a (52) , 3a", 43 }-7- [3-[2-(Phenylsulfonvl) ethyl ] -7-■ oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid .Following the procedure of Examples 63, 44, 77 and 80 except substituting phenylmercaptan for 20 1-hexanethiol, the title compound is obtained. Example 105 [13 , 2a (5Z) , 3a, 43 }-7- [3- [2-(Cvclohexylsulfonvl) ethyl ] -7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid 25 Following the procedure of Examples 63, 44, 77 and 80 except substituting cyclohexylmercaptan for 1-hexanethiol, the title compound is obtained. Example 10 6 30 [13,2a(5Z) , 3a,43 h7- [3- [2- (Benzylsulf iny 1) ethyl ] -7-oxabicyclo[2.2.1]hept-2-vl]-5-heptenoic acid Following the procedure of Examples 63, 44, 77 and 81 except substituting benzylmercaptan for 1-hexanethol, the title compound is obtained. 35 -IIA20Q/2 09— -72- Example 107 [13 , 2a( 5Z) , 33 , 43 ]-7- [3-[2-(Butylsulfony 1) ethyl] - 7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 63, 48, 77 5 and 80 except substituting butylmercaptan for 1-pentanethiol, the title compound is obtained. Example 108 [10, 2a (5Z) , 30 , 4g J-7-[3-[2-(Phenylsulf inyl) ethyl ] -7-10 oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid ■Following the procedure of Examples 63, 48, 77 and 81 except substituting phenylmercaptan for 1-pentanethiol, the title compound is obtained. 15 Example 109 [lg,2a(5Z) ,30 ,431—7— [3- [2-(Benzyl sulfinyl) ethyl] -7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 63, 48, 77 and 31 except substituting benzylmercaptan for 20 1-pentanethiol, the title compound is obtained. Example 110 [10 , 2g (5Z) , 30 , 40 ]-7- [3- [2-(cvcloheptylsulfonyl) -ethyl]-7-oxabicyclo [2.2.l]hept-2-yl]-5-heptenoic acid 25 Following the procedure of Examples 63, 40 77 and 80 except substituting cyclbheptylmercaptan for 1-pentanethiol, the title compound is obtained. Example 111 30 (10 , 2a, 3a, 40 )-7- [3- [2-(Pentylsulfonyl) ethyl] -7-oxabicyclo [2 . 2 . l]hept-2-yl] -5-'neptanoic acid Following the procedure of Examples 63, 46. 77 and 80 except substituting 1-pentanethiol for 1-hexanethiol, the title compound is obtained. 35 J 707361 ^1.^290/280 — " 73- Example 112 (13 ,2a, 3a, 43)—7— [3- [2- (Phenylsulfinyl) ethyl] -7-oxabicyclo [2.2.1]hept-2-yl]-5-heptanoic acid Following the procedure of Examples 63, 46, 77 and 81 except substituting phenylmercaptan for 1-hexanethiol, the title compound is obtained. Example 113 (13 ,2a, 3a, 43)-7-[3-[2- (Benzylsulfinyl) ethyl]-7-oxabicyclo [2.2.l]hept-2-yl]-5-heptanoic acid Following the procedure of Examples 63, 46 77 and 81 except substituting benzylmercaptan for 1-hexanethiol, the title compound is obtained. Example 114 (13 , 2a, 3a, 43 >-7- [3-[2- (Cyclohexylsulfonyl) ethyl] - 7-oxabicvclo [2.2.1]hept-2-yl]-5-heptanoic acid Following the procedure of Examples 63, 48 77 and 80 except substituting cyclohexylmercaptan for 1-hexanethiol, the title compound is obtained. Example 115 [IP , 2a (5Z) , 3a, 4 3 ]-7-[3- [4- (Pentylsulfonyl) butyl] -7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 73, 63, 44 77 and 80 except substituting pentylmercaptan for 1-hexanethiol, the title compound is obtained. Example 116 [13 , 2a (5Z) ,3a,43 ]-7- [3- [4-(Cyclohexylsulfinyl) butyl] -7-oxabicvclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 73, 63 44 , 77 and 81 except substituting cyclohexylmercaptan for 1-hexanthiol, the title compound" is obtained.- . i A .... ■- ■- ■f fin*** . ' —HA2D0/20 0— --74-. Example 117 [lg,2a(5Z) ,3a,43 ]-7- [3-[4-(Phenylsulfinyl) butyl] -7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 73, 63, 5 44, 77 and 81 except substituting phenylmercaptan for 1-hexanethiol, the title compound is obtained. Example 1 1 a [13,2a(5Z) ,3a,40 ]-7- [3-[4-(Benzylsulfonyl) butyl ] -7-10 oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 73, 63 44, 77 and 80 except substituting benzylmercaptan for 1-hexanethiol, the title compound is obtained. 15 Example 11° [IB,2a(5Z) , 30,43 ]-7- [3- [4- (Cyclopentylsulfinvl) butyl ] -7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 73, S3 48, 77 and 8] except substituting cyclopentylmercaptaii 20 1-pentanethiol, the title compound is obtained. Example 120 [IB., 2a (52) , 33, 48 ]-7~ [3- [4- (Benzylsulf invl) butyl ] -7-oxabicyclo [2.2.1] hept-2-yl ] -5-hep-tenoic acid 25 Following the procedure of Examples 73, 6 3 48, 77 and 80 except substituting benzylmercaptan for 1-pentanethiol, the title compound is obtained. Example 121 30 [13,2a(5Z) , 3B , 43 ]-7- [3-[4- (Propylsulfinyl) butyl ] -7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 73, 63, 48, 77 and 81 except substituting propylmercaptan for 1-pentanethiol, the title compound is obtained. 35 - ^HA290/280 -75- Example 122 [IS , 2a(5Z) , 33, 4&]-7— [3— [4- (Phenylsulfonvl)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 73, 63 5 48 , 78 and 80 except substituting phenylmercaptan for 1-pentanethiol, the title compound is obtained. Example 123 (13., 2d, 3a, 43)-7- [3-[4-(Nonylsulfinyl) butyl] -7-10 oxabicyclo[2.2.l]hept-2-yl]-5-heptanoic acid Following the procedure of Examples 73, 63 46, 77 and 81 except substituting 1-nonanethiol for 1-hexanethiol, the title compound is obtained. 15 Example 12 4 (13 , 2a, 3a, 43 )-7- f3-[4- (Pentylsulfonyl)butyl ] -7-oxabicyclo[2.2.1]hept-2-yl]-5-heptanoic acid Following the procedure of Examples 73 , 63, 46 77 and 80 except substituting 1-pentanethiol for 20 1-hexanethiol, the title compound is obtained. Example 125 (13 , 2a, 3q, 43)-7-[3-[4-(Phenylsulfinyl) butyl] -7-oxabicyclo[2.2.1]hept-2-vl]-5-heptenoic acid 25 Following the procedure of Examples 77, 6 3 46, 77 and 81 except substituting phenylmercaptan for 1-hexanethiol, the title compound is obtained. Example 126 30 (13 , 2a, 3a, 4g)—7— [3-[4-(Cvclohexylsulfonyl) butyl ] -7-oxabicyclo[2.2.1]hept-2-yl]-5-heptanoic acid Following the procedure of Examples 73, 63, 46 77 and 8C except substituting cyclohexylmercaptan for 1-hexanethiol, the title compound is obtained. 35 I '£i -76- Example 127 [13,2g(5Z) ,3a,43]-7-[3-[[(Cyclohexylmethyl) thio]-methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid A. [13, 2op (5Z) ,3a,4[3]-7--[3-[[ (Cyclohexylmethyl) 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 5 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 mixture was added a solution of 300 mg (0.71 mmol) of [13,2a. (5Z) , 3a, 43 ]-7- [3-(p-toluenesulfonyloxymethyl)-7-oxabicyclo[2.2.1]-hept-2-yl]-5-heptenoic acid, methyl ester, prepared as described in Example 44B, in 5.5 ml of dry THF. The reaction mixture was heated to reflux for 7 hours. The cooled reaction mixture was.diluted with 250 ml of ether and poured into 100 ml of saturated NaHCO^ solution. The aqueous 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 extracts were dried over anhydrous MgSO^ and concentrated in 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 25 3 mg of title A methyl ester as an oil (94%). TLC:silica gel, petroleum ether:ether (3:2), R^=0.70, iodine. -11- B. [13, 2a(5Z) ,3a,43]-7- [3-[[(Cyclohexylmethyl) thio]methyl]-7-oxabicyclo [2.2.1]-hept-2-yl]-5-heptenoic acid To a stirred solution of 243 mg (0.64 mmol) 5 of Part A methyl ester in 31.4 ml of THF and 4.80 ml of ^0 under argon was added 6.0 0 ml of IN aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for 25 minutes and stirred at room temperature for 16 hours. The 10 reaction mixture was acidified to pH 5 by addition of IN aqueous HCl solution and poured into 4 0 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 15 were dried (MgSO^), filtered and concentrated in vacuo to give 253 mg of crude acid. Purification was effected by flash chromatography on 20.6 g of silica gel 60 using petroleum-ether:ether (2:3) as eluant to give pure title product (117 mg, 50%) 20 along with 108 mg (46%) of mixed fractions of which title product was the major component. TLCrsilica gel, Pet-ether:ether (2:3), = 0.32, iodine. Anal. Calcd for C22H34°3S: C, 68.85; H, 9.29; S, 8.74 Found: C, 68.90; H, 9.43; S, 8.66 25 I3C NMR (CDC1,, 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, 32.9, 29.5, 26.1, 29.5, 32.9 30 -78- Example 128 [13,2a(52),3g,40]-7-[3 —[[(2-Phenylethyl)thio]methyl]-7-oxabicyclo[2.2.l]hept-2-vl]-5-heptenoic acid A. [10,2a(5Z),3g,40]-7 - [3- [ [(2-Phenylethyl)- • thio]methyl]-7-oxabicyclo[2.2.l]hept-2-yl]-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. To this mixture was added a solution of 189 mg (0.45 mmol) of [10,2a(5Z),3a,43]-7-[3-(p-toluene-sulfonyloxymethyl)'-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 reaction 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 60 ml of saturated N&HCO^ solution. The aqueous layer was extracted with ether (2 x 60 ml). The combined ether extracts (280 ml) were washed with 0.5 N aqueous sodium hydroxide solution (2 x 60 ml) and brine (75 ml). The ether extracts were dried over MgSO^ and concentrated in vacuo to give an oily product. Purification was effected by chromatography 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), = 0.60, iodine. H!A2W23-0'~' -79- B. [13,2a(5Z),3a,43]-7- [3- [[(2-PhenyIethyl)-thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid To a stirred solution of 150 mg (0.39 mmol) of Part A methyl ester in 19 ml of freshly distilled THF and 2.91 ml of H2O under argon was added 3.64 ml of IN aqueous lithium hydroxide solution. This mixture was purged with argon vigorously for 25 minutes and stirred at room temperature for 6 hours. The reaction mixture was acidified to pH 5 by addition of IN aqueous HCl solution and. poured into 40 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 were dried (MgSO^), filtered and concentrated in vacuo to give 147 mg of crude acid. Purification was effected by flash chromatography on 20 g of silica gel 60 using 2% CH^OH in CH2CI2 as eluant to give title product (122 mg, 84%) as an oil. TLC:silicagel, 6% CH^OH in CH2CI2, Rf = 0.32, iodine. Anal. Calcd for C22H30°3S: C' 70,55; S, 3.56 Found: C, 70.54; H, 8.08; S, 8.48 13C NMR -(CDC1,, 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, 123.4 Example 129 [13 > 2a (5Z),3a,40]—7— [3— [[(3-Phenylpropvl)thio]-methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid A. [13,2a(5Z),3a,43]-7-[3-[[(3-Phenylpropvl)-thio]methyl]-7-oxabicyclo[2.2.1]hept-2-vl]-5-heptenoic acid, methyl ester To a solution of 88 mg (0.78 mmol) of potassium t-butoxide in 5 ml of dry THF under argon I -80- 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 [13,2a(5Z),3a,40]-7-[3-(p-toluenesulfonyloxymethyl)-7-oxabicyclo [2.2.1]-5 hept-2-yl]-5-h.eptenoic acid, methyl ester in 7 ml of dry THF. The reaction mixture was heated to • reflux for 6 hours and 30 minutes. The cooled reaction mixture was diluted with 250 ml of ether • and poured into 100 ml of saturated NaHC03 solution. 10 The aqueous layer was extracted with ether (2 x 100 ml). The combined ether extracts (450 ml) ■ was washed with 0.5 N aqueous sodium hydroxide solution (2 x 100 ml) and brine (100 ml). The ether extracts were dried over MgS04 and concentrated 15 in vacuo to give an oily product. Purification was effected by chromatography on 25 g of silica gel 60 using hexanerether (3:1) as eluant to give 280 mg of title A compound as an oil (98%). TLC:silica gel, petroleum ether.-ether (2:1), 20 0.60, iodine. B. [lg,2g(5Z),3a,40]-7-[3-[[(3-Phenylpropyl)-thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid 25 To a stirred solution of 280 mg (0.70 mmol) of Part A methyl ester in 34.4 ml of freshly distilled THF and 5.30 ml of ^0 under argon was added 6.6 0 ml of IN aqueous lithium hydroxide solution. This mixture was purged with argon for an hour and stirred 30 at room temperature for 3 hours. The reaction mixture was acidified to pH 5 by addition of IN aqueous HCl solution and poured into 50 ml of saturated NaCl solution. The resulting solution was saturated with solid NaCl and extracted with 35 EtOAc (4 x 60 ml). The combined EtOAc extracts I1A29Q/2OT— -81- ' were dried (MgSO^), filtered and concentrated in vacuo to give 280 mg of crude acid. Purification was effected by flash chromatography on 2 9 g of' silica gel 60 using 2% CH^OH in CI^C^ eluant to 5 give title product (205 mg, 76%). TLC:silica gel, 6% CH30H/CH2C12, Rf=0.34, iodine. Anal. Calcd for C23H32C>3S: C, 71.09; H, 8.30; S, 8.25 Found: C, 70.81; H, 8.36; S, 8.14 10 13C NMR (CDC13, 15.0MHz)tau 179.0, 33.4, 24.7, 26.7, 129.7, 129.8, 29.5, 46.9, 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 15 Example 130 [IP,2a(5Z),33,4g] — 7—[3-[[(Cyclohexylmethyl)- . . thio]methyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 48 and 49 2o except substituting cyclohexylmethanethiol for 1-pentanethiol, the title compound is obtained. Example 131 [IP,2a(5Z),36,4g1-7-[3-[[(3-Cyclohexylpropvl)thio]-25 methyl1-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 48 and 4 9 except substituting 3-cyclohexylpropanethiol for 1-pentanethiol, the title compound is obtained. 30 Example n? (16,2a,3a,40)- 7-[3-[[(2-CyclohexyLethvl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-vlj-5-heptanoic acid Following the procedure of Examples 45 and 47 except substituting 2-dyclohexylethanethiol for 1-hexanethiol, the title compound is obtained. " 82- SA2 9 0/2-g-Q Example 133 [IB,2a(5Z) ,38,43 ] -7- [ 3- [ [ (2-Phenylethy1)thio] methyl 1 -7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 48 and 4 9 5 except substituting 2-phenylethanethiol for 1-pentane-thiol, the title compound is obtained. Example 134 [13,2a(5Z),33,48]-7-[3-[[(3-Phenylpropyl) thio]methyl]-10 7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 4£> and 49 except substituting 3-phenylpropane thiol for 1-pentane-thiol, the title compound is obtained. 15 Example 135 (l3,2a,3a,43)-7-[3-[[(2-Phenylethyl)thio]methyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptanoic acid Following the procedure of Examples 4g-and 47 except substituting 2-phenylethane thiol for 1-hexane-20 thiol, the title compound is obtained. Example I3fi (13 , 2a( 3a, 43 ) -7- [3- [ [ (3-Phenylpropyl)thin] methyl] -7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid 25 Following the procedure of Examples 4 6 and 43 except substituting 3-pKenylpropanethiol for 1-hexanethiol, the title compound is obtained. Example 137 [13/2a(52),3a,43]-7-[3-[[(Cyclohexylmethyl)sulfinyl]-methyl]-7-oxabicyclo [2.2.1]hept-2-vl]-5-heptenoic acid (slow moving isomer) Following the procedure of Examples 44, 77. and 81 except substituting cvclohexylmethanethiol for 1-hexanethiol, the title compound is obtained. -83- -Hft290/2SG Example 138 [13/2a(5Z),30,40]—7—[3—[[(Cvclohexylmethyl)sulfinyl]-methyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid (fast moving isomer) Following the procedure of Examples 48, 77 and 81 except substituting cyclohexylraethanethiol for 1-pentanethiol, the title compound is obtained. Example 13 9 [10,2a(5Z),33,433—7—[3—[C(2-Phenylethyl)sulfinyl]-methyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid (fast moving isomer) Following the procedure of Examples '44 , 77 and 81 except substituting 2-phenvlethanethiol for 1-pentanethiol, the title compound, is obtained. Example 140 [13,2a(5Z) ,3a,43]-7- [3-[[(3-Phenylpropyl)sulfinyl]-methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (slow moving isomer) Following the procedure of Examples 48, .77 and 82 except substituting 3-phenylpropanethiol for 1-pentanethiol, the title compound is obtained. Example 141 (l3,2ar3a,40)-7-[3-[[(2-Phenvlethyl)sulfinyl]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptanoic acid (fast moving isomer) Following the procedure of Examples 46, 77 and 81. except substituting 2-phenylethanethiol for 1-hexanethiol, the title compound is obtained. Example 142 [13,2a(5Z) ,3g,40]-7- [3- [ [ (Cyclohexylmethyl)sulfonyl]-methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 44, 77 and 80 except substituting cyclohexylmethanethiol for 1-hexanethiol, the title compound is obtained. Example 14 3 [l0,2a(5Z),3a,48]-7- [3- [ [ (2-Phenylethyl)sulfonyl]-methyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 44, 77 and 80 except substituting 2-phenylethane thiol for 1-hexanethiol, the title compound is obtained. .Example 144 [10,2a(5Z), 3a,48]-7-[3- [ [ (3-Phenylpropyl)sulfonyl]-methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 44, 77 and 80 except substituting 3-phenylpropane thiol for 1-hexanethiol, the title compound is obtained. Example 145 [13 , 2a ( 5Z) ,3a,4g]-7-[3-[2-[ (Cyclohexylmethyl) thio] -ethyl]-7-oxabicyclo[2.2.1]hept-2-vl]-5-heptenoic acid Following the procedure of Examples 63 and 44 except substituting cyclohexylmethanethiol for 1-hexanethiol, the title compound is obtained. Example 14 6 [13, 2a (5Z) , 3a, 43 ] -7- [3- [2- [ (Cyclohexylmethyl) sulfinyl ] -ethyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 63, 4 4 77 and 81 except substituting cyclohexylmethanethiol for 1-hexanethiol, the title compound is obtained. -85- Example 14,7 [13,2g(5Z),3a,4g]-7-[3- [2-f(Cyclohexylmethyl)-sulfonyl]ethyl]-7-oxabicyclo[2.2.l]hept-2-yl1-5-heptenoic acid 5 Following the procedure of Examples 63, 44, 11 and 80 except substituting cyclohexylmethanethiol for 1-hexanethiol, the title compound is obtained. Example 148 10 [13,2g(5Z),3a,43]-7-[3- [2-[(2-Phenylethyl)thio]- ethyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic'acid Following the procedure of Examples 63 and 44 except substituting 2-phenylethanethiol for 1-hexane-thiol, the title compound is obtained. 15 Example 149 [13 > 2a (5Z) ,33,40]-7- [ 3 — [2 —[ (2-Phenylethyl)sulfinyl]-ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 63, 44, 77 2o and 81 except substituting 2-phenylethanethiol for 1-hexanethiol, the title compound is obtained. Example 15 0 [13,2a(5Z),3a,43]-7-[2-f(3-Phenylpropyl)thiol ethyl]-25 7-oxabicyclo [2.2.l]hept-2-yl1-5-heptenoic acid Following the procedure of Examples 63 and 44 except substituting 3-phenylpropane thiol for 1-hexane-thiol, the title compound is obtained. 30 Example 151 [l3,2a(5Z),3a,431-7-[3- [2-f (3-Phenylpropyl)sulfinyl]-ethyl]-7-oxabicyclo[2.2.1]hept-2-v]1-5-heptenoic acid Following the procedure of Examples 63, 44 77 and 81 except substituting 3-phenylpropane thiol for 1-hexanethiol, the title compound is obtained. " 86- Example 152 [13 r 2a(5Z),3a,4S]-7-[3-[2-[(2-Phenylethyl)sulfonyl]-ethyl]-7-oxabicyclo[2.2.l]hept—2-vl]-5—heptenoic acid Following the procedure of Examples 63, 44 5 77 and 80 except substituting 2-phenylethanethiol for 1-hexanethiol, the title compound is obtained. Example 15 3 [13,2a(5 Z),3a,43]-7-[3-[2-[(3-Phenylpropyl)sulfonyl]-10 ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 63, 44, 77 and 80 except substituting 3-phenylpropane thiol for 1-hexanethiol, the title compound is obtained. 15 Example 154 [13,2a(5Z),3a,43]-7-[3-[4-[(Cyclohexylmethyl)thio]-butyl]-7-oxabicyclo [2.2.l]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 73, 6 3 and 44 except substituting cyclohexylmethanethiol 2o for 1-hexanethiol, the title compound is obtained. Example 15 5 [13,2a(5Z),3a,43]-7-[3-[4-[(Cyclohexylmethyl)-sulfinyl]butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-25 heptenoic acid Following the procedure of Examples 73, 63, 44, 77 and 31 except substituting cyclohexylmethanethiol for 1-hexanethiol, the title compound is obtained. 30 Example 156 [13,2a(5Z) , 3a, 43 ] -*7- [3— [4— [ (Cyclohexylmethyl) -sulfonyl]butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5 -heptenoic acid Following the procedure of Examples 7 3, 63 35 - 8J- UA290/2M— 44, 77 and 80 except substituting cyclohexylmethanethiol for 1-hexanethiol, the title compound is obtained. Example 157 5 [13,2a(52),3g,40]-7-[3-[4-[(2-Phenylethyl)thio]- butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 73, 63, and 44 except substituting 2-phenylethanethiol for 1-hexanethiol, the title compound is obtained. 10 Example 158 [10,2a(5Z) ,3a,40]-7-[3-[4-[ (2-Phenylethyl) sulfinyl ] -butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 73, 63, 15 44, 77 and 81 except, substituting 2-phenylethanethiol for 1-hexanethiol, the title compound is obtained. Example 15 9 [10,2a(52),3a,40]-7- [3- [4-[(2-Phenylethyl)sulfonyl]-2 0 butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid Following the procedure of Examples 73, 63, 44, 7.7 and 80 except substituting 2-phenylethanethiol for 1-hexanethiol, the title compound is obtained. 25 </div>

Claims

<div class="application article clearfix printTableText" id="claims"> '-88-Example 16 0 [13,2a(5 Z) (3a,43)-7-[3-[2-(heptylthio)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid and methyl ester By reacting [I0,2a(5z),3a,43]-7-[3-(2-hydroxyethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester (see 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% CH3OH/CH2Cl2) Rf = .23. Anal, calcd. for ^22H38^3^: ^,69.06; H,10j01; 5-,8.38 Found: C,68.80; H, 9.99; S,8.24 I3C NMR (CDC13, 15.0MHz)tau 178.8, 33.4, 22.5, 24.5, 129.5 , 130. 1, 26. 6 , 46.1, 80.1,' 29.7, 29.7, 80 47.3, 32.3, 31.7, 31.7, 29.5, 28.8, 32.3, 28.8, 26.6, 13.9 Example 161 [13,2a(5Z),3q(E),46]-7-[3-[[(3-phenyl-2-propenyl)-thio]methyl]oxabicyclo]2.2.1]hept-2-yl]-5-heptenoic acid and methyl ester By following the procedure of example 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: 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% CH30H/CH2C12), Rf = 0.25 Anal, calcd. for C23H3qC>3S: C,71.46; H,7.82; S,8.30 Found: C,71.31; H,7.87; S,8.26 207361 Uu -89- . What io olQimad-iij. "

1. A compound having the structural formula CH.,-A-{CH0) -CO.R 2 2 m 2 <CH2'n"E-Rl and including all stereoisomers thereof, wherein A is -CH=CH- or -(CH2)2~; B is oxygen (-O-) or -S- «*>n- wherein n1 is 0 to 2; m is 1 to 8; n is 1 to 4; R is hydrogen, alkyl, alkali metal or tris( hydroxymethyl )arainome thane; and R* is alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, or cycloalkylalkynyl (all as hereinbefore defined).

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

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

4. A compound as defined in Claims 1-3 wherein A is -CH=CH-.

5. A compound as defined in Claims 1-3 wherein R is H.

6. A compound as defined in Claims 1-3 wherein n is 1. 7. A compound as defined in Claims 1-3 wherein n is 2. 8. A compound as defined in Claims 1-3 wherein n is 3 or 4. 207361 HA290/280-A -90- 9. -A• . compound as defined in Claims 1-3 wherein A is -CH=CH-, m is 2 to 4, n is 1 or 2, R is H and R1 is lower alkyl or cycloalkyl. 10. A compound as defined in Claims 1-3 wherein A is -CH=CH-, m is 3, n is 1, R is_H, CH_ or 1 . C6^13' anc* R ls l°wer alkyl. 11. The compound as defined in Claim 1 having the name [1p,2a(5Z),3a ,4p]-7-[3-[(hexyloxy)-methyl]-7-oxabicyclo[2.2.lJhept-2-yl]-5-heptenoic acid or its.n-hexyl ester. 12. The compound as defined in Claim 1 having the name [lf5, 2a(5Z), 3a , 4(3 ]-7-[3-[2-(pentyloxy )-ethyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid. 13. The compound as defined in Claim 1 having the name [lp, 2a(5Z), 3a ,4p]-7-[(3-phenylpropoxy)-methyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid. 14. The compound as defined in Claim 1 having the name [ 1 p ,2a.( 5Z), 3a, 4p ]-7-[3-[ (octyloxy)-methyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid. 15. The compound as defined in Claim 1 having the name [ip,2a.(5Z), 3a, 4p ]-7-[3-j( cyclohexyl-methoxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid. 207361 HA290/280-A - -91- t 16. A compound as defined in Claim 1 wherein A is -CH=CH-, m is 3, n is 1, n' is 1 and R* is lower alkyl. 17. A compound as defined in Claim 1 wherein A is -CH=CH-, m is 3, n is 1, n' is 2 and r! is lower alkyl. 18. The compound as .defined in Claim 1 having the name [13,2a(5Z),3a,43]-7-[3-[ (hexylthio)-methyl]-7-oxabicyclo [2.2.l]hept-2-yl]-5-heptenoic acid or its methyl ester. 19. The compound as defined in Claim 1 having the name [13,2a(5Z),3a,43]-7-[3-[(hexyl-sulfinyl) methyl]-7-oxabicyclo[2.2.l]hept-2-yl]-5-heptenoic acid or its methyl ester (both the fast moving arid slow moving isomers). 20. The compound as defined in Claim 1 having the name [13 , 2a {5Z) , 3a,43 ] -7-[3-[(hexylsulfonyl)-methyl] -7-oxabicyclo [2.2. l]hept-2-yl] -7-heptenoic acid or the methyl ester thereof. 21. The compound as defined in Claim 1 having the name [13,2a(5Z),3a,43]-7- [3-[[(cyclohexylmethyl) thio]methyl] -

7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid or the methyl ester thereof. 22. The compound as defined in Claim 1 having the name [13,2a {5Z) , 3a,43]-7- [3-[[(2-phenyl-ethyl)thio]methyl]-7-oxabicyclo [2.2.1]hept-2-yl] -5-heptenoic acid or the methyl ester thereof. 23.. The compound as defined in Claim 1 having the name [13,2a (5Z),3a,43]-7- [3-[[(3-phenyl-propyl)thio]methyl]-7-oxabicyclo [2.2.1]hept-2-yl]-5-heptenoic acid or the methyl ester thereof. I -92- 207361 HA290/280-A 24. A method of inhibiting platelet aggregation and bronchoconstriction, which comprises administering to the circulatory system of a non human mammal an effective amount of a compound as defined in Claim 1 or a pharmaceutically acceptable salt thereof. 25. A composition for use in inhibiting platelet aggregation and bronchoconstriction in non human mammals comprisinq an effective amount of a compound as defined in Claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefor. •26. A method of inhibiting platelet aggregation which comprises administering to a non human mammal an effective amount of a compound as defined in Claim 1 or a pharmaceutically acceptable salt thereof. 27. A method of inhibiting bronchoconstriction associated with asthma, which comprises administering to a non human mammal an effective amount of a compound as defined in Claim 1 or a pharmaceutically acceptable salt thereof. 28. A method for inhibiting platelet aggregation and bronchoconstriction by inhibiting production of thromboxane by blocking the action of thromboxane synthetase, which comprises administering to a non human mammal ■ an effective amount of a compound as defined in Claim 1 or a pharmaceutically acceptable salt PER bit t-crrc/| agents for the applicants </div>