NO840960L - PROCEDURE FOR PREPARING SUBSTITUTED 7-OCSABICYCLOHEPTAN PROSTAGLANDIN ANALOGS - Google Patents

Description

The present invention relates to a method for the production of 7-oxabicycloheptane-prostaglandin analogues which are useful as cardiovascular agents, for example in the treatment of thrombocytic disorders. These compounds have the structural formula

where B is oxygen (-0-) or

where n' is 0 to 2, R is

hydrogen, lower alkyl, alkali metal or trihydroxymethyl-ammomethane, R 1 is alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkylalkyl, cycloalkylalkenyl or cycloalkynyl, A is -CH=CH- or -(CH2)2~, n is 1 to 4 and m is 1 to 8, including all stereoisomers thereof.

The term "lower alkyl" or "alkyl" herein includes both straight-chain and branched radicals of up to 12 carbon atoms, preferably 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl , heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, the various branched isomers thereof and furthermore such groups with a half-gene substituent, such as F, Br, Cl or I or CF^, an alkoxy substituent, a haloaryl substituent, a cycloalkyl substituent (ie cycloalkylalkyl) or an alkylcycloalkyl substituent.

The terms "alkenyl" and "alkynyl" shall cover similar hydrocarbon groups with a carbon-carbon double or triple bond, such as, for example, 2-propenyl, 2-hexenyl, 3-hexenyl, 3-hexynyl, and, in the case of one of the aryl substituents or cycloalkyl substituents defined below, 3-phenyl-2-propenyl, 3-phenyl-2-propynyl, 3-cyclohexyl-2-propenyl and

3-cyclohexyl-2-propynyl.

The term "cycloalkyl" includes saturated cyclic hydrocarbon groups of 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, all of which may be optionally substituted with 1 or 2 halogen atoms, 1 or 2 lower alkyl groups and/or lower alkoxy groups.

The term "aryl" or "Ar" refers here to monocyclic or bicyclic aromatic groups with 6 to 10 carbon atoms in the ring part, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl, where the substituent on the phenyl or naphthyl ring may be lower alkyl, halogen (Cl, Br or F), or lower alkoxy.

The terms "aralkyl", "aryl-alkyl" or "aryl-lower alkyl" refer to lower alkyl groups with the explanation given above, which have an aryl substituent, for example benzyl.

The terms "(CH2)m" and "(CH2)n" include a straight-chain or branched radical with 1 to 8 and 1 to 4 carbon atoms respectively in the normal chain and may contain one or more lower alkyl substituents. Examples of (CH2^m°^(CH2)n~ groups are CH2, CH2CH2, (CH^, (CH^, (CH^, (CH^g, (CH^,

-(CH2)2-CH-, CH3 -CH -CH—CH-CH,-, -CH„-CH-CH„-CH-,

CH^CHjCH 3 ^^3

and such.

The compounds of formula I (where R is alkyl) are prepared by a compound of formula II:

during ether or thioether formation, is reacted with the desired R 1 -OH or R 1 -SH or equivalent groups according to conventional methods.

The synthesis of ethers and thioethers is based on a Williamson synthesis (J. Chera. Soc, 4, 229 (1852)), where ethers (and later thioethers) were synthesized by alkylating alkoxides with alkyl halides:

R'(0 or S)Na + R"X —> R'(0 or S)R" + NaX

The modern version of the synthesis includes the use of other leaving groups in addition to the halides. In the case of formula II, the ether or thioether formation takes place by a compound of formula Ila

where X in addition to hydroxy can also be -SH or their sodium or potassium salts, chlorine, bromine, iodine and alkyl, aryl and aralkyl sulfonyloxy groups, react with a complementary R 1X compound to form the following types of formula I compounds:

The thioethers with formula IV can then be oxidized to the sulfinyl and sulfonyl derivatives (N'=1 or 2 in formula I) with the formula:

The compounds of formula I, where R is an alkali metal or hydrogen (free acid), can then be prepared from the above products, where R is alkyl, by ordinary basic hydrolysis with sodium or potassium hydroxide to form the sodium and potassium salts, which after acidification leads to the free acids.

The ether formation is usually carried out by reacting compound II with a compound of formula R X, where X is chlorine, bromine or iodine or methylsulfonyloxy or toluenesulfonyloxy, in the presence of a strong base such as sodium or potassium hydroxide, in a suitable solvent. The R X reactant is used below in a 0.25-5 mol excess in a solvent such as xylene, tetrahydrofuran, dimethylsulfoxide or dimethylformamide. If X is bromine or chlorine, an ether formation can be carried out during phase transfer, with tetrahydrofuran being used as solvent using a phase transfer reagent, such as Bu4NHS04 or (C^CH^(CH3>3NHS04. If R1 is aryl, it may be advantageous that the alcohol group in compound II is first reacted with triphenylphosphine and diethylazodicarboxylate dissolved in an inert solvent, such as tetrahydrofuran, and then with an R^(aryl) alcohol, such as phenol. As is known, the reaction sequence when reacting the alcohol II with R the X compound is allowed to achieve ether formation, is reversed by converting the alcohol II to a compound of formula II, where the alcohol group is replaced by another radical from the X group, followed by reaction with an R 1 alcohol or alkoxide to the product with formula I.

Thioether formation is usually achieved by first converting the alcohol II to another II-X derivative, as indicated above, followed by thioether formation with an R 1SH mercaptan in the presence of a base or with an alkali metal salt thereof.

Oxidation of the sulfide product, where n = 0, to the sulfinyl and sulfonyl analogues, where n' is 1 or 2, is easily achieved by reaction with sodium periodate in the presence of methanol and tetrahydrofuran, after which the obtained sulfinyl and sulfonyl derivatives can be separated chromatographically or by other usual methods separation methods.

The starting materials of formula II, where n is 1 (hydroxy-methyl group), are known from US patent 4,143,054 and can be prepared as described therein. These compounds can be used for the preparation of starting materials with formula II, where n is 2 to 4, by oxidizing the hydroxymethyl group to an aldehyde after a Collins oxidation, for example by reacting compound II with chromium trioxide in pyridine so that an intermediate product is formed with the formula

The aldehyde VII is then subjected to a series of homolog-forming reactions via a Wittig reaction with (C^ E^)^P^HOCH^ followed by hydrolysis (n-1) times and subsequent reduction of the aldehyde to the alcohol using reducing agents such as sodium borohydride or sodium cyanoborohydride, in a solvent, for example methanol, whereby the starting material of formula II is obtained:

The tris(hydroxymethyl)aminomethane salt of the acids I is formed according to the present invention by reacting a solution of the acid in an inert solvent, such as methanol, with tris(hydroxymethyl)aminomethane, whereupon the desired salt is obtained after evaporation of the solvent.

The compounds produced according to the invention have four centers of asymmetry, marked with an asterisk in formula I. However, the above-mentioned formulas which are not marked with an asterisk shall represent all possible stereoisomers, all of which shall be covered by the invention.

The different stereoisomeric forms of the compounds produced according to the invention, i.e. cis-exo, cis-endo and all transformer and stereoisomer pairs can be prepared as indicated in the following examples and by using starting materials and following the methods described in US patent 4.14 3,054. Examples of such stereoisomers are shown below.

For the sake of simplicity, the core of each compound produced according to the invention is shown as: The core of these compounds can of course also be rendered as

The compounds produced according to the present invention are cardiovascular agents that can be used as inhibitors of platelet aggregation, for example for the treatment of thrombocytic disorders, such as heart or brain thrombosis. They are also selective thromboxane A2 receptor antagonists and synthetase inhibitors, for example they have a cardiac dilating effect in the treatment of ischemic heart disease, such as angina pectoris. The compounds produced according to the invention are also inhibitors of arachidonic acid cyclooxygenase. They can be given orally or parenterally to various mammals which may have these disorders, for example cats, dogs and the like, in doses of 1-100 mg/kg, preferably 1-50 mg/kg or approx.

2-25 mg/kg given as a single dose or 2 to 4 divided daily doses.

The active substance can be used in preparation forms such as tablets, capsules, solutions or suspensions containing

about. 5-500 mg per dosage unit of a compound or mixture of compounds of formula I. They can be prepared in a conventional manner with a physiologically acceptable carrier, excipient, binder, preservative, stabilizer, flavoring agent, etc. as required. As mentioned above, some of these also serve as intermediates for other compounds within this group.

Example 1

[ 13, 2a ( 5Z), 3a, 433 - 7-[ 3-[( hexyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid, hexyl ester

A. [ 13/ 2a( 5Z)/ 3a, 43]- 7-[ 3-( hydroxymethyl)- 7-oxabicyclo 2. 2. 1] hept- 2- yl]- 5- heptenoic acid, methyl ester

a) A mixture of N-acetylpyridinium chloride was prepared by the dropwise addition of 9.6 ml (136 mmol) of acetyl chloride to 56 ml of pyridine. To this was added 5.0 g (27 mmol)

(exo)-3-(2-methoxyethenyl)-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 gave a yellow oil which was purified by passing through a short column of silica gel (150 mL) with dichloromethane; yield: 4.42 g of oil.

b) To a solution of 4.42 g (19.6 mmol) of this oil in 500 ml of tetrahydrofuran, containing 50 ml of water, 31.1 g (97.8 mmol) of mercury (II) acetate was added. The resulting yellow suspension was stirred for 10 minutes, after which the entire mixture was poured into a solution containing 200 g of potassium iodide in 2 liters of water. After shaking, the yellow color disappeared and the mixture was then extracted with benzene (3 x 500 mL). The combined benzene extracts were washed with potassium iodide and saline solution and dried over sodium sulfate. Concentration led to 3.7 g of a material which crystallized on standing in an icebox. c) A Wittig reagent was prepared in dimethylsulfoxide (dried over calcium hydride) by dropwise addition of a solution of sodium methylsulfinyl methide (prepared by heating 300 mg of sodium hydride in 60 ml of dimethylsulfoxide at 75° until hydrogen evolution ceased) to a solution of 5.32 g (12 mmol) of 4-carboxybutyl-triphenylphosphonium bromide in 100 ml of dimethylsulfoxide. After an initial orange color was formed lasting more than 10 seconds, an equivalent amount of base was added to prepare the ylide. To the dark orange solution was added a solution of the product from part (b) in 20 ml of dimethylsulfoxide, whereupon the resulting mixture was stirred at room temperature for 45 minutes. The reaction was stopped by the addition of 24 mmol of acetic acid and the mixture completely poured into salt solution (300 ml) and extracted with ether (3 x 200 ml). Concentration of these extracts gave an oil which was stirred with saturated sodium bicarbonate solution until crystalline triphenylphosphine oxide was formed. The mixture was washed with benzene and acidified with 10% hydrochloric acid. The aqueous layer was saturated with salt and extracted with ether, which after drying (sodium sulfate) and concentration gave 2.43 g of crude product. The mixture was stirred for 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 eluent, whereby 600 mg of acid, which crystallized on standing, was obtained. This was recrystallized 2 times from ethyl acetate-cyclohexane and led to 320 mg of [13, 2a(5Z), 3a, 43]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]-hept-2-yl ]-5-heptenoic acid, m.p. 59-63°C.

Analysis calculated for C-|4<H>22°4:

C, 66.11; H, 8.72

Found: C, 66.06; H, 8.79

The acid obtained was then converted to the corresponding methyl ester by treatment with diazomethane.

B. [13,2a(5Z),3a,43]-7-[3-[(hexyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, hexyl ester One suspension of 0.56 g of crushed KOH in 15 ml of dry xylene was heated to the boiling point and 7 ml of xylene distilled off. To the mixture was added a solution of 300 mg (1.12 mmol) of the alcohol ester from part Ai in 10 ml of dry xylene. The resulting mixture was heated to the boiling point and 9 ml of xylene distilled off. After addition of 1.0 g (5.6 mmol) of n-hexyl methanesulfonate, the resulting mixture was heated under reflux for 1 hour. The reaction mixture was cooled to room temperature and diluted with CH 2 Cl 2 (60 mL). The resulting solution was poured into 50 ml saturated NaHCO 3 . The layers were separated and the aqueous phase extracted (2 x 60 mL) with CH 2 Cl 2 .

The combined CH 2 Cl 2 extracts were dried over MgSO 4 and then concentrated under vacuum to give 0.9 g of crude product. The crude product was chromatographed on 33.4 g of silica gel 60 with hexameter (5:1), whereby 390 mg (83%) of the hexyl ester of the title compound was obtained.

Example 2

[ 13, 2a( 5Z), 3a, 433- 7-[ 3-[( hexyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

To a stirred solution of 115 mg (0.27 mmol) of the hexyl ester from Example 1 in 12.0 ml of distilled THF and 1.60 ml of H 2 O, under argon was added 2.40 ml of 1N aqueous lithium hydroxide solution. The mixture was flushed with argon for 40 minutes and stirred at room temperature for 24 hours. TLC analysis showed at this point that the reaction was not complete, and a further 1 ml of methanol and 1 ml of 1N aqueous lithium hydroxide were therefore added. The reaction mixture was stirred for an additional 4 hours and was then acidified to pH 4 by addition of 1N aqueous HCl solution. The resulting solution was poured into 25 ml saturated NaCl solution and then saturated with solid NaCl. The aqueous layer was extracted with EtOAc (4 x 40 mL). The combined EtOAc extracts were dried over anhydrous MgSO 4 , filtered and concentrated in vacuo to 124 mg of crude oil. This was chromatographed on 20.6 g of silica gel 60 with hexane:ether (2:3) as eluent, whereby 102 mg of the desired product contaminated with small amounts of hexyl alcohol were obtained. The mixture was placed under high vacuum at room temperature overnight to give 77 mg

(84%) of the pure title compound. TLC: silica gel, 8% CH 3 OH/CH 2 Cl 2 , R = 0.74, iodine.

Analysis calculated for C2oH34°4:

C, 70.97; H, 10,12

Found: C, 70.60; H, 9.89

13 C NMR (CDCl 3 , 15.0 mHz) T 33.4, 22.6, 24/6, 129.4,

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

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[( hexyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid, hexyl ester

503 mg (1.88 mmol) [13, 2a(5Z), 3a, 43]-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 of tetrahydrofuran. To the mixture was then added 2.17 mL (15.46 mmol) of n-hexyl bromide, 173.4 mg (0.51 mmol) of tetrabutylammonium bisulfate (Bu4NHS04) and 2.17 mL of 50% NaOH solution and vigorously stirred at room temperature. A slightly yellowish-brown solution was formed which, after stirring overnight, formed a white precipitate.

The reaction mixture was poured into 25 ml saturated NaHCO 3 and extracted with CH 2 Cl 2 (4 x 25 ml). The combined CH 2 Cl 2 extracts were dried (MgSO 4 ), filtered and concentrated in vacuo to [13, 2a(5Z), 3a, 43]-7-[3-[(hexyloxy)methyl]-7-oxabicyclo[2.2.1] hept-2-yl]-5-heptenoic acid, hexyl ester (1272 mg) The ester was chromatographed on 40 g of silica gel with hexane:ether (4:1) as eluent to obtain the final product.

Example 4

( 13, 2a, 3a , 43)- 7-[ 3-[( hexyloxy) methyl]- 7- oxabicyclo[ 2. 2. 1]-hept- 2- ylJheptanoic acid, hexyl ester

A. (13, 2a, 3a, 43)- 7-[ 3-[( hydroxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl] heptanoic acid, methyl ester

To 800 mg (3.0 mmol) [13,2a(5Z), 3a, 43]-7-[3-[(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5 -heptenoic acid methyl ester according to example 1, dissolved in 120 ml of ethyl acetate, 160 mg of 5% Pd on charcoal were added under an argon atmosphere. The argon atmosphere was replaced with a slight overpressure of hydrogen and the reaction mixture stirred for 8 h at 25°, filtered through a plug of celite and evaporated to give 730 mg (90%) of the title compound A.

B. (13, 2a, 3a, 43)- 7-[ 3-[( hexyloxy) methyl]- 7-oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptanoic acid, hexyl ester By following the procedure in example 1 with the alcohol ester from part A instead of the alcohol ester from example 1A,

the title product was obtained.

Example 5

(13, 2a, 3a, 43)- 7-[ 3-[ (hexyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl] heptanoic acid

By following the procedure from example 2, but with the hexyl ester from example 4 instead of the hexyl ester from example 1, the title acid was obtained in the form of an oil.

[a]g<5>= _3fi (C = 1.37, CHCl 3 ); TLC (silica gel, 8% CH 3 OH)CH 2 Cl 2 Rf = 0.74.

Analysis calculated for C^H^O^:

C, 70.55; H, 10.66

Found: C, 70.30; H, 10.70

13 C NMR (CDCl 3 , 15.0 mHz) T 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

Example 6

[ 13, 2a( 5Z), 33, 4p]- 7-[ 3-[ (hexyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure from examples 3 and 2, but with [13,2a(5Z), 33, 43]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]-hept-2-yl]- 5-heptenoic acid methyl ester instead of [13, 2a(5Z),-3a, 43]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid- methyl ester, the title compound was obtained as an oil.

Analysis calculated for C20H34°4:

C, 70.97; H, 10,12

Found: C, 70.93; H, 10.33

13 C NMR (CDCl 3 , 15.0 mHz) t 178.7, 33.4, 24.6, 26.6, 128.7, 129.9, 32.6, 47.9, 79.1, 29, 5, 23.8, 80.5, 49.1, 71.7, 71.2, 31.6, 25.8, 29.9, 22.6, 13.9

Example 7

[ 13/ 2g( 5Z), 3a, 43]- 7-[ 3- methyloxy) methyl- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 1 and 2, but with methyl methanesulfonate instead of n-hexylmethanesulfonate, the title compound was obtained in the form of an oil.

[0]^= +10.4

(c=2.21, CHCl 3 ).

Analysis calculated for C15<H>2<4>°4:

C, 67.14; H, 9.01

Found: C, 67.03; H, 9.14

13 C NMR (CDCl 3 , 15.0 mHz) T 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.

Example 8

[ 13, 2a( 5Z), 33/433- 7-[ 3-( propyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl3- 5- heptenoic acid

By following the procedure of Example 6, but with n-propyl bromide instead of n-hexyl bromide, the title compound was obtained.

Example 9

( 13, 2a, 3a, 43 )- 7-[ 3-( butyloxy) methyl]- 7- oxabicyclo[ 2. 2. 1]-hept- 2- yl] heptanoic acid

By following the procedure of Examples 4 and 5, but with n-butylmethanesulfonate instead of n-hexylmethanesulfonate, the title compound was obtained.

Example 10

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[( octyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure from examples 1 and 2, but with n-octylmethanesulfonate instead of n-hexylmethanesulfonate,

the title compound obtained.

Example 11

[ 13, 2a( 5Z) , 3a, 43]- 7-[ 3-[( phenyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

(a) Phenol (1 mmol) was added to a solution of triphenylphosphine (1 mmol), diethyl azodicarboxylate (1 mmol) and the title A-alcohol from Example 1 (1 mmol) in 25 mL of THF and stirred under an argon atmosphere for 48 h at 23°C. The reaction mixture was concentrated under vacuum. The residue was triturated with ether and the solid filtered off. The filtrate was concentrated under vacuum and chromatographed on silica gel, whereby [13,2a(5Z),3a,43]-7-[3-[(phenyloxy)methyl]-7-oxabicyclo-[2.2.1]hept- 2-yl]-5-heptenoic acid, methyl ester. (b) Following the procedure described in Example 2, the ester from part (a) was converted to the title compound. Example 12 [ 13, 2a( 5Z), 33, 43 3- 7-[ 3-[( phenyloxy) methyl]- 7- oxabicyclo- [ 2. 2. 1] hept-2-yl]-5-heptenoic acid (a) Phenol (1 mmol) was added to a solution of triphenylphosphine (1 mmol), diisopropylazodicarboxylate (1 mmol) and the title A alcohol from Example 1 (1 mmol) in 25 ml THF and stirred under an argon atmosphere for 48 hours at 23°C. The reaction mixture was concentrated under vacuum. The residue was triturated with ether and the solid filtered off. The filtrate was concentrated under vacuum and chromatographed on silica gel to give [13,2a(5Z),33,433-7-[3-[(phenyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl] -5-heptenoic acid, methyl ester. (b) Following the procedure described in Example 2, the ester from part (a) was converted to the title compound.

Example 13

[ 1 3, 2a( 5Z), 3a, 4 3]- 7-[ 3- C( ethyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 3 and 2, but with ethyl bromide instead of n-hexyl bromide, the title compound was obtained.

Example 14

[ 13, 2a, 3a, 43]- 7-[ 3-[( phenyloxy) methyl] - 7- oxabicyclo[ 2 . 2. 1]-hept-2-ylheptanoic acid

By following the procedure in Example 11, but with (13,2a-3a,43)-7-[3-[(hydroxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-heptanoic acid, methyl ester instead of the alcohol in part (a) of Example 11, the title compound was obtained.

Example 15

[ 13, 2a( 5Z), 33, 43]- 7-[ 3-[( benzyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure in Example 6, but with benzyl bromide instead of n-hexyl bromide, the title compound was obtained.

Example 16

( 13, 2a, 3a, 43 )- 7-[ 3-[( benzyloxy) methyl]- 7- oxabicyclo[ 2. 2. 1]-hept- 2-yl] heptanoic acid

By following the procedure of Examples 4 and 5, but with benzyl methanesulfonate instead of n-hexylmethanesulfonate, the title compound was obtained.

Example 17

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[( cyclohexyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure in Examples 1 and 2, but with cyclohexyl methanesulfonate instead of n-hexylmethanesulfonate, the title compound was obtained.

Example 18

[ 13/ 2g( 5Z) , 33, 43]-7-[3-[( cyclopentyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure in Examples 1 and 2, but with cyclopentyl methanesulfonate instead of n-hexylmethanesulfonate and with [13, 2a(5Z), 33, 433-7-[3-(hydroxymethyl)-7-oxabicyclo-[2.2.1 ]hept-2-yl]-5-heptenoic acid, methyl ester (prepared as described in US Patent 4,143,054) instead of [13, 2cx (5Z) , 3a,-433-7-[3-(hydroxymethyl)- 7-Oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, the title compound was obtained.

Example 19

( 13/ 2a, 3a, 4 3)- 7-[ 3-[(cyclohexyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- ylJheptanoic acid

By following the procedure of Examples 4 and 5, but with cyclohexyl methanesulfonate instead of n-hexylmethanesulfonate, the title compound was obtained.

Example 20

[ 13, 2a( 5Z), 3a, 433- 7-[ 3-[ 2-( hexyloxy) ethyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

A. [ 13, 2a( 5Z), 3g, 433- 7-[ 3-( 2- oxo) ethyl]- 7- oxabicyclo[ 2. 2. 1] hept- 2- yl3- 5- heptenoic acid, methyl ester

In a dry 100 ml three-necked round flask, containing magnetic stirrers, were added dried 12.9 g (37.7 mmol) methoxymethyltriphenylphosphonium chloride ((CgH) 3P + -CH20CH3C1~) and 235 ml of distilled toluene (stored over molecular sieves) . The resulting suspension was stirred in an ice bath under argon and, after cooling, a 1.55 M solution of 18.3 ml (28.3 mmol) of potassium t-amylate in toluene was added dropwise. A strongly red colored solution was formed which was further stirred at 0°C

35 minutes. A solution of 4.97 g (18.8 mmol) [13,2a(5Z),~3a,43]-7-[3-formyl-7-oxabicyclo[2.2.1]hept-2-yl] -5-heptene-

acid, methyl ester in 60 ml toluene was then added by means of a dropping funnel over 35 minutes while continuing to use the ice bath. The reaction was then stopped by the addition of 2.3 g (39 mmol) of acetic acid in 5 ml of ether. The reaction mixture immediately turned pale yellow and was immediately poured into 200 ml of saturated NH 2 Cl and extracted with ether (4 x 200 ml). The combined ether phases were washed with saturated NaCl solution and dried (MgSO 4 ) and concentrated to give a yellow oil in a white crystalline solid (phosphine oxide). The white solid was triturated with EtOAc and the mother liquor purified by chromatography on an LPS-1 silica gel column. The fractions obtained were (A) [13,2a(5Z),3a,43]-7-[3-(2-oxo)ethyl-7-oxabicyclo[2.2.1]-hept-2-yl]-5- heptenoic acid, methyl ester, (B) [ 1 3 , 2a(5Z) ,3a,43]-7-[3-(2-methoxy)ethendiyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5 -heptenoic acid, methyl ester, and (C) [13,2a(5Z),3a,43]-7-[3-(2,2-dimethoxy)ethy1-7-oxabicyclo[2.2.1]hept-2-y1] -5-heptenoic acid, methyl ester.

Compounds (B) and (C) were both treated with trifluoroacetic acid to convert both to compound (A).

B. [ 13, 2a( 5Z), 3a, 43]- 7-[ 3-( 2- hydroxyethyl)-7-oxabicyclo [2. 2. 1]hept-2-yl]-5-heptenoic acid, methyl ester The aldehyde (1.4 g, 5 mmol) from part A in methanol (50 mL)

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 the addition of 2N HCl (to pH 2). The methanol was removed under vacuum and the reaction mixture taken up in ether. The ether solution was washed with saturated KHCO 3 , saturated NaCl and dried (MgSO 4 ). After evaporation of the ether, the title compound B was obtained.

C. [13,2a(5Z),3a,43]-7-[3-[2-(hexyloxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid

By following the procedure in Examples 1 and 2, but with the alcohol from Part B instead of the alcohol used in Example 1, the title compound was obtained.

Example 21

[ 13, 2a( 5Z) y33, 43]- 7-[ 3-[ 2-( hexyloxy) ethyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Example 20, but with [13,2a(5Z), 33,43]-7-[3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester instead of [13,2a(5Z),3a,43]-7-[3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, the title compound was obtained.

Example 22

(13, 2a, 3a, 43)- 7-[ 3-[ 2-( hexyloxy) ethyl]- 7- oxabicyclo[ 2. 2. 1]-hept- 2- yl]- 5-heptanoic acid

By following the procedure of Example 21, but with (13,2a,-3a,43)-7-[3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]heptanoic acid, methyl ester instead of [13 ,2α(5Z),33,43]-7-[3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, the title compound was obtained.

Example 2 3

[ 13, 2a( 5Z) , 33 # 43]- 7-[ 3-[ 2-( phenyloxy) ethyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure in example 11, but with [ 1 3,2a(5Z),3a,43]-7-[3-[2-(hydroxy)ethyl]-7-oxabicyclo-[2.2.1]hept-2 -yl]-5-heptenoic acid, methyl ester instead of [13,2a(5Z),3a,43]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]-hept-2-yl]- 5-heptenoic acid, methyl ester, the title compound was obtained.

Example 24

[ 1 3, 2a( 5Z) 33, 43]- 7-[ 3-[ 2-( phenyloxy) ethyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure in Example 12, but with [13,2a(5Z),33,43]-7-[3-[2-(hydroxy)ethyl]-7-oxabicyclo[2.2.1]-hept-2 -yl]-5-heptenoic acid, methyl ester instead of [13,2a(5Z),33,- 43]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]- 5-heptenoic acid, methyl ester, the title compound was obtained.

Example 25

(13, 2a, 3a, 43)- 7-[ 3-[ 2-( phenyloxy) ethyl]- 7- oxabicyclo[ 2. 2.1]-hept- 2- y1] heptanoic acid

By following the procedure in example 1.1, but with (13,2a,3a,43)-7-[3-[2-(hydroxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-heptanoic acid , methyl ester instead of [13,2a(5Z) ,3a,43]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, became the title compound achieved.

Example 26

[ 13, 2a ( 5Z), 3a, 433 - 7-[ 3-[ 2-( benzyloxy) ethyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure in Example 20, but with benzyl methanesulfonate instead of n-hexylmethanesulfonate, the title compound was obtained.

Example 27

[ 13, 2a ( 5Z) , 33, 43]- 7-[ 3-[ 2-( benzyloxy) ethyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure in Example 21, but with benzyl methanesulfonate instead of n-hexylmethanesulfonate, the title compound was obtained.

Example 28

[ 13, 2a ( 5Z) , 3a, 43]- 7-[ 3-[ 2-( cyclopentyloxy) ethyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure in Example 20, but with cyclopentyl methanesulfonate instead of n-hexylmethanesulfonate, the title compound was obtained.

Example 29

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[ 2-( cyclohexyloxy) ethyl 3- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure in Example 20, but with cyclohexyl methanesulfonate instead of n-hexylmethanesulfonate, the title compound was obtained.

Example 30

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[ 4-( hexyloxy) butyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

A. [ 13, 2a( 5Z), 3a, 43]~ 7-[ 3-( 3- oxo) propyl- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid, methyl ester

By following the procedure of Example 20, part A, but with [13,2a(5Z),3a,43]-7-[3-(2-oxo)ethyl-7-oxabicyclo[2.2.1]hept-2- yl]-5-heptenoic acid, methyl ester instead of [13,2a(5Z),3a,43]-7-[3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, the title compound A was obtained.

B. [ 13, 2a( 5Z), 3a, 433- 7-[ 3-( 4- oxo) butyl- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl3- 5- heptenoic acid, methyl ester

By following the procedure of Example 20, Part A, but with the aldehyde from Part A above in place of [13,2a (5Z),3a,433-7-[3-formyl-7-oxabicyclo[2.2.1]hept- 2-yl]-5-heptenoic acid, methyl ester, the title B-aldehyde was obtained. C. [ 13, 2a( 5Z), 3a, 433- 7-[ 3-( 4- hydroxybutyl)- 7- oxa bicycle [ 2 . 2. 1] hept-2-yl]-5-heptenoic acid, methyl ester By following the procedure of Example 20, part B, but with the title B aldehyde instead of [13 , 2a(5Z),3a,433 -7 -[3-(2-oxo)ethyl-7-oxabicyclo[2.2.13hept-2-yl3-5-heptenoic acid, methyl ester, the title C-alcohol was obtained. d.

By following the procedure in Examples 1 and 2, but with the above-mentioned part-C alcohol instead of the alcohol used in Example 1, the title compound was obtained.

Example 31

[ 13, 2a ( 5Z) , 301, 43]- 7-[ 3-[ 4-( cyclohexyloxy) butyl]- 7- oxabicyclo [ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Example 30, but with cyclohexyl methanesulfonate instead of n-hexylmethanesulfonate, the title compound was obtained.

Example 32

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[ 4-( phenyloxy) butyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure in Example 11, but with [13,2a(5Z),3a,43]-7-[3-(4-hydroxybutyl)-7-oxabicyclo[2.2.1]-hept-2-yl]- 5-Heptenoic acid, methyl ester instead of [13,2a(5Z),~3a,4 3]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid , methyl ester, the title compound was obtained.

Example 33

[ 13, 2a ( 5Z) , 3a, 43]- 7-[ 3-[ 4-( benzyloxy) butyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure in Example 30, but with benzyl methanesulfonate instead of n-hexylmethanesulfonate, the title compound was obtained.

Example 34

Tris(hydromethyl)aminomethane salt of

[ 13/ 2a ( 5Z) , 3a, 43]- 7-[ 3-[( hexyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

A solution of the compound formed in Example 2 in methanol was treated with an equivalent amount of tris(hydromethyl)aminomethane. The solvent was removed by evaporation to give the title compound as a solid, m.p. 68.5-70°C. TLC (silica gel, 8% CH 3 OH/CH 2 Cl 2 ) Rf=0.74.

Analysis calculated for C^H^j-O^N:

C, 62.72; H, 9.87; N, 3.04

Found: C, 62.71; H, 9.80; N, 3.10

Example 35

[ 13, 2a( 5Z) , 3a , 43] - 7-[ 3-[ 2-( pentyloxy) ethyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

A. [ 13, 2a( 5Z), 3a, 43 3 - 7-[ 3-[ 2-( pentyloxy) ethyl]- 7-oxabicyclo 2. 2. 1] hept- 2- yl]- 4- heptenoic acid, pentyl ester A mixture of crushed KOH (0.36 g) in 15 ml of dry xylene was heated under reflux in an argon atmosphere and 8 ml of xylene removed by distillation. To the mixture was added a solution of 200 mg (0.71 mmol) of the alcohol methyl ester from Example 20, Part B, in 17 mL of dry xylene. The volume of the reaction mixture was reduced by distilling off 15 ml of xylene. To the reaction mixture was then added a solution of

0.5 g (3.55 mmol) pentyl mesylate in 10 ml dry xylene. The mixture was refluxed for 2 hours. The cooled reaction mixture was diluted with 50 mL saturated NaHCO 3 solution and extracted with CH 2 Cl 2 (3 x 60 mL). The combined CH 2 Cl 2 extracts were dried (MgSO 4 ), filtered and concentrated in vacuo. Purification was carried out by chromatography on 33 g of silica gel 60 with hexane:ether (5:1) as eluent. This gave 238 mg of the title pentyl ester (83%) as a colorless oil. TLC: silica gel, hexane:ether (1:1).

B. [13,2a(5Z),3a,43]-7-[3-[2-(pentyloxy)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid

To a stirred solution of 238 mg (0.58 mmol) pentyl ester from Part A, 26 mL distilled THF, 2.1 mL CH 3 OH and 3.4 mL H 2 O was added under argon 6.4 mL 1N aqueous lithium hydroxide solution. The mixture was purged vigorously with argon for 30 min.

and stirred at room temperature for 7 hours. The reaction mixture was acidified to pH 3 by addition of 1N HCl. The resulting solution was poured into 50 ml saturated NaCl solution and saturated with solid NaCl. The aqueous layer was extracted with EtOAc (4 x 60 mL). The combined EtOAc extracts were dried (MgSO 4 ), filtered and concentrated in vacuo. The residue was chromatographed on 24 g of silica gel 60 with 3% CH 2 OH in CH 2 Cl 2 as eluent, whereby 181 mg (92%) of the pure title acid was obtained.

TLC: silica gel, 4% CH 3 OH/CH 2 Cl 2 , Rf=0.3, vanillin.

Analysis calculated for C^H^O^:

C, 70.97; H, 10,12

<C>20<H>34°4 °'22 H2°

C, 70.16; H, 10,14

Found: C, 70.16; H, 9.87

13 C NMR (CDCl 3 , 15.0 mHz) T 173.5, 33.8, 24.7, 26.7, 129.5, 130.1, 28.0, 43.8, 79.8, 29, 5, 29.5, 80.3, 47.3, 29.7, 71.0, 70.3, 28.7, 22.4, 28.3, 13.9, 64.3, 28.3, 22.2, 28.3, 13.9

Example 36

[ 1 3, 2a( 5Z), 3a, 43]- 7-[( 3- phenylpropoxy)- methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

A. [13,2a(5Z),3a,43]-7-[(3-phenylpropoxy)-methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, phenylpropyl ester

A mixture of crushed KOH (0.59 g) in 16 ml of dry xylene was heated under reflux in an argon atmosphere and 9 ml of xylene distilled off. To the mixture was added a solution of 410 mg (1.53 mmol) of the alcohol methyl ester from Example 1, Part A, in 10 ml of dry xylene. The volume of the reaction mixture was reduced by distilling off 6 ml of xylene. To the reaction mixture was then added a solution of 1.66 g (7.58 mmol) of 3-phenylpropyl mesylate in 36 ml of dry xylene and refluxed for 1 hour. The cooled reaction mixture was diluted with 50 mL saturated NaHCO 3 solution and extracted with CH 2 Cl 2 (3 x 50 mL). The combined CH 2 Cl 2 extracts were dried (MgSO 4 ), filtered and concentrated under vacuum. Purification was carried out by chromatography on 40 g of silica gel 60 with hexane:ether (3:1) as eluent. This gave 0.61 g of the title phenylpropyl ester (81%) as a colorless oil. TLC: silica gel, 2% CH3OH/CH2Cl2, Rf=0.60, iodine.

B. [13,2a(5Z),3a,4&]-7-[(3-phenylpropoxy)-methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid

To a stirred solution of 610 mg (1.24 mmol) of the phenyl-propyl ester of title compound A, 55 mL of distilled THF, 4.40 mL of CH 3 OH, and 7.30 mL of H 2 O, under argon was added 13.7 mL of 1N aqueous lithium hydroxide solution . The mixture was flushed thoroughly with argon for 30 minutes and stirred at room temperature for 14 hours. The reaction mixture was diluted with 100 ml of 0.1N aqueous lithium hydroxide solution and washed once with 100 ml of hexane. The reaction mixture was acidified to pH 3 by adding 1N HCl and poured completely 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 (MgSO 4 ), filtered and concentrated in vacuo. The residue was chromatographed on 44 g of silica gel 60 with 4% CH 3 OH in CH 2 Cl 2 as eluent, whereby 380 mg (82%) of the pure title acid was obtained. TLC: silica gel, 4% CH3OH/CH2Cl2, Rf=0.30, iodine.

Analysis calculated for C23H32°4: C'74'16;H'8.66

C23H32°40.35 H2O: C'72'94; H'8'70 Found: C, 72.94; H, 8.49

13 C NMR (CDCl 3 , 15.0 mHz) t 178.7, 33.4 24.5 25.7 129.5, 130, 1-, 26.6 46.3, 79 .3, 29.5, 80r1 , 46.8, 70.2, 69.9, 31 .2, 32.3, 141.9, 128.4, 128.4

Example 37

[ 13# 2a( 5Z), 3a, 4&]- 7-[ 3-[( octyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

A. [13,2a(5Z),3a,43]-7-[3-[(octyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, octyl ester

To a stirred solution of 508 mg (1.89 mmol) of the ester alcohol from Example 1, Part A, in 2.69 mL of THF, 2.69 mL (15.6 mmol) of n-octyl bromide was added sequentially, 6.42 mg (1.89 mmol) of tetrabutylammonium hydrogen sulfate and 2.69 ml of 50% aqueous sodium hydroxide solution. The mixture was stirred at room temperature in the dark for 19 hours. The reaction mixture was poured into 25 ml of saturated sodium bicarbonate solution and extracted with four 25 ml portions of CH_Cl_. The combined CH Cl„-c 2 22 2 extracts were dried (MgSO 4 ), filtered and concentrated under vacuum. Purification was carried out by chromatography on 39.6 g of silica gel 60 with hexane:ether (3:1) as eluent, whereby 333 mg (37%) of octyl ester and 250 mg of a mixture of octyl ester and corresponding methyl ester were obtained. TLC: silica gel, 3% CH 3 OH/CH 2 Cl 2 , Rf: octyl ester, 0.85; methyl ester, 0.80, iodine.

B. [13,2a(5Z),3a,43]-7-[3-[(octyloxy)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid

To a stirred solution of 333 mg (0.70 mmol) of the octyl ester from Part Ai in 31 mL of distilled THF, 2.50 mL of CH 3 OH and 4.1 mL of H 2 O under argon was added 7.70 mL of 1N aqueous lithium hydroxy solution. The mixture was thoroughly flushed with argon for 20 minutes and stirred at room temperature for 16 hours. The mixture of octyl ester and corresponding methyl ester was hydrolyzed in exactly the same way. To a stirred solution of this mixture (250 mg) in 29 mL of distilled THF, 2.40 mL of CH 3 OH, and 3.9 mL of H 2 O, was added 7.30 mL of 1N aqueous lithium hydroxide. The mixture was flushed thoroughly with argon for 20 minutes and stirred at room temperature for 16 hours.

The two reaction mixtures were combined and diluted with a solution of 120 ml of 0.1N aqueous lithium hydroxide solution and 50 ml of H 2 O. The resulting mixture was extracted once with 220 ml of hexane. The aqueous layer was acidified to pH 3 by addition of 1N aqueous HCl solution saturated with solid NaCl and extracted with EtOAc (4 x 150 mL). The hexane extract and EtOAc extracts (the hexane extract contained the desired acid) were combined, dried (MgSO 4 ), filtered and concentrated in vacuo to 0.53 g of crude product. This was chromatographed on 48 g of silica gel 60 with 3% CH 3 OH in CH 2 Cl 2 , whereby 222 mg (45%) of the desired title acid was obtained. TLC: silica gel, 4% CH 3 OH/CH 2 Cl 2 , Rf=0.40, vanillin. Analysis calculated for C22<H>38°4<:>C'72'09; H'10#45

C22H38°40.24 H2O: C'71'25; H'10'45 Found: C, 71.25; H, 10.20

13 C NMR (CDCl 3 , 15.0 mHz) T 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

[ 1 3 , 2a ( 5Z ), 3a , 43]- 7-[ 3-( cyclohexylmethoxy) methyl]- 7- oxabicyclo [ 2 . 2. 1]hept-2-yl]-5-heptenoic acid

A. [ 13 , 2a( 5Z ) , 3a , 43]- 7-[ 3-( cyclohexylmethoxy) methyl]-7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid, cyclohexyl methyl ester

A mixture of crushed KOH (0.56 g) in 15 ml of dry xylene was heated under reflux in an argon atmosphere and 7 ml of xylene distilled off. To the mixture was added a solution of 300 mg (1.12 mmol) of the alcohol methyl ester from Example 1, Part A, in 10 ml of dry xylene. The volume of the reaction mixture was reduced to 11 ml by distilling off the xylene. To the reaction mixture was then added a solution of 2.47 g (12.9 mmol) of cyclohexylmethyl mesylate in 10 ml of dry xylene. This mixture was refluxed for 5 hours and, after cooling, diluted with 50 mL saturated NaHCO 3 solution and extracted with CH 2 Cl 2 (3 x 50 mL). The combined CH 2 Cl 2 extracts were dried (MgSO 4 ), filtered and concentrated under vacuum. Purification was carried out by chromatography on 35 g of silica gel 60 with 1% CH 2 OH in CH 2 Cl 2 as eluent. This gave 0.46 g of the title hexyl ester (93%) as a colorless oil. TLC: silica gel, 2% CH3OH/CH2Cl2, Rf=0.80, iodine.

B. [ 1 3 , 2a ( 5Z ), 3a , 43 ]- 7-[ 3-( cyclohexylmethoxy) methyl]-7- oxabicyclo[ 2. 2. 1] hept-2- yl]- 5-heptenoic acid

To a stirred solution of 460 mg (1.03 mmol) of the cyclohexyl methyl ester from Part A, 45 mL of distilled THF, 3.80 mL of CH 3 OH and 6.10 mL of H 2 O , under argon was added 11.4 mL

1N aqueous lithium hydroxide solution. The mixture was flushed thoroughly with argon for 20 minutes and stirred at room temperature i

16 hours. The reaction mixture was diluted with 83 ml of 0.1N aqueous lithium hydroxide solution and washed once with 83 ml of hexane. The aqueous layer was acidified to pH 3 by addition of 1N HCl and saturated with solid NaCl. The resulting aqueous layer was extracted with EtOAc (4 x 120 mL). The combined EtOAc extracts were dried (MgSO 4 ), filtered and concentrated in vacuo to 0.32 g of crude product. This was chromatographed on 34.6 g of silica gel 60 with 3% CH3OH in CH2Cl2 as eluent, whereby 278 mg (77%) of pure title acid was obtained. TLC: silica gel, 4% CH3OH/CH2Cl2, Rf=0.28, iodine. Analysis calculated for c2iH34°4: C'71 '96'H'9'78 C21H34°4 0.31 H2°: C'70'84; H'9'80 Found: C, 70.84; H, 9.68 13 C NMR (CDCl 3 , 15.0 mHz) T 173.5, 33.7, 24.9, 25.8, 129.5, 129.9, 26.0, 46.4, 79 ,2, 29.6, 29.6, 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 Example 39 1[ a, 2 3( Z), 33, 4a]- 7-[ 3-[[( 1 - methylhexyl)oxy]-methyl]-7-oxo-bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid By following the procedures from examples 1 and 2, but with 1-methylhexylmethanesulfonate instead of n -hexyl methanesulfonate, the title compound was obtained. TLC (silica gel, 4% CH 3 OH/CH 2 Cl 2 ) Rf=0.47.

Analysis calculated for C^H^O^:

C, 71.55; H, 10.29

Found: C, 71.73; H, 10,21

13 C NMR (CDCl 3 , 15.0.mHz) T 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, 31.9, 22.6, 14.0, 19.7

Example 40

[ 1a , 23( Z ), 33 , 4a]- 7-[ 3-[( 3- hexynyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 13hept- 2- yl]- 5- heptenoic acid

Following the procedure of Examples 1 and 2, but with 3-hexynyl methanesulfonate, the title compound was obtained as an oil. TLC = silica gel, 4% CH 3 OH/CH 2 Cl 2 , Rf=0.32.

Analysis calculated for <-20H30°4:

C, 71.82; H, 9.04

Found: C, 71.66; H, 9.21

13 C NMR (CDCl 3 , 15.0 mHz) t 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

Example 41

[ 13, 2ot( Z) , 3ot( Z) , 433- 7-[ 3-[ ( 3- hexenyloxy) methyl ]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 1 and 2, but with cis-3-hexene-1-mesylate instead of n-hexyl methanesulfonate, the title compound was obtained as an oil. TLC = silica gel,

4% CH 3 OH/CH 2 Cl 2 , Rf=0.3.

Analysis calculated for C2oH32°4:

C, 71.39; H, 9.59

Found: C, 71.10; H, 9.59

13 C NMR (CDCl 3 , 15.0 mHz) x 178.9, 33.4, 24.5, 25.6, 129.5, 130.1, 27.7, 46.3, 79.3, 29.4, 80.1, 46.7, 70.7, 69.8, 26.6, 133.6, 124.8, 20.6, 14.2

Example 42

[ 13, 2a( Z), 3a( Z), 433- 7-[ 3-[( 2- hexenyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure from Examples 1 and 2, but with 2-1-hex-2-enyl mesylate instead of n-hexyl methanesulfonate,

the title compound was obtained as an oil. TLC (silica gel,

2% CH 3 OH/CH 2 Cl 2 ) Rf=0.22, vanillin.

Analysis calculated for c2oH32°4: C'71'39; H'9'59

Found: C, 70.97; H, 9.64

13 C NMR (CDCl 3 , 15.0 mHz) t 178.8, 33.4, 24.5, 25.8, 129.5, 130.1, 26.7, 46.4, 79.5, 29, 5, 29.5, 80.1, 46.9, 69.3, 66.6, 133.5, 126.2, 29.5, 22.6, 13.6

Example 43

[ 13, 2a ( Z), 3a^ 4 3 ] - 7- [ 3- [ 2- propenyloxy) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid and methyl ester

To a stirred solution of 310 mg (1.16 mmol) [13,2a(5Z)-3a,43]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl] - 5-heptenoic acid, methyl ester in 1.34 ml of tetrahydrofuran, 1.34 ml of allyl bromide, 107 mg of tetrabutylammonium hydrogen sulfate and 1.34 ml of 50% aqueous sodium hydroxide solution were added in order. The mixture was stirred at room temperature in the dark for 23 hours and then poured into 30 ml saturated 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 under vacuum. Purification was carried out by chromatography on 35 g of silica gel 60 with hexane:ether (2:1) as eluent, whereby 220 mg of the methyl ester product was obtained. TLC (silica gel, hexane-ether (1:1). Rf=0.4, iodine.

The ester was dissolved in 36 ml of tetrahydrofuran, a little hydroquinone, 6 ml of water and 7 ml of 1N aqueous lithium hydroxide solution were added and stirred at room temperature for 5 hours, after which the reaction mixture was poured into 80 ml of saturated aqueous sodium chloride solution and saturated by further addition of solid sodium chloride. The aqueous layer was extracted with four portions of ethyl acetate (125 mL each), dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was chromatographed on 30 g of silica gel with 4% CH 3 OH/CH 2 Cl 2 as eluent, whereby 190 mg of the acid product was obtained.

TLC (silica gel, hexameter (1:1)) Rf=0.15.

Analysis calculated for C,_H_,0.:

C, 69.36; H, 8.96

Found: C, 69.72; H, 9.05

13 C NMR (CDCl 3 , 15.0 mHz) t 178.9, 33.4, 24.5, 25.7, 129.5, 130.0, 26.6, 46.3, 79.3, 29, 4, 80.1, 46.7, 69.3, 72.0, 134.7, 117.0

Example 44

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[(hexylthio) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid, methyl ester

A. [ 13, 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 was prepared by dropwise addition of 9.6 mL (136 mmol) of acetyl chloride to 56 mL of pyridine. To this was added 5.0 g (27 mmol)

(exo)-3-(2-methoxyethenyl)-7-oxabicyclo[2.2.1]heptane-2-methanol dissolved in 5 ml of pyridine. The resulting mixture was stirred at room temperature for 1 hour and poured into saline. The product was extracted into ether (3 x 200 ml) and the ether extracts washed with 5% hydrochloric acid (2 x 400 ml) and brine (1 x 200 ml) and dried over sodium sulfate. Concentration gave a yellow oil which was purified through a short column of silica gel (150 mL) with dichloromethane, yielding 4.42 g of oil. (b) To a solution of 4.42 g (19.6 mmol) of the oil in 500 ml of tetrahydrofuran, containing 50 ml of water, was added 31.1 g (97.8 mmol) of mercuric (II) acetate. The resulting yellow suspension was stirred for 10 minutes, after which the entire mixture was poured into a solution containing 200 g of potassium iodide in 2 liters of water. After 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 and saline solution and dried over sodium sulfate. Concentration led to 3.7 g of material which crystallized on standing in ice. (c) A Wittig reagent was prepared in dimethylsulfoxide (dried over calcium hydride) by adding dropwise a solution of sodium methylsulfinyl methide (prepared by heating 300 mg of sodium hydride in 60 ml of dimethylsulfoxide at 75° until hydrogen evolution had ceased) to a solution of 5.32 g (12 mmol) of 4-carboxybutyltriphenylphosphonium bromide in 100 ml of dimethylsulfoxide. After an orange color was first formed lasting more than 10 seconds, an equivalent amount of base was added to prepare the ylide. To the deep orange solution was added a solution of the product from part (b) in 20 ml of dimethylsulfoxide, whereupon the resulting mixture was stirred at room temperature for 45 minutes. The reaction was stopped by the addition of 24 mmol of acetic acid and the mixture completely poured into salt solution (300 ml) and extracted with ether (3 x 200 ml). Concentration of these extracts gave an oil which was stirred with saturated sodium bicarbonate solution until crystalline triphenylphosphine oxide was formed. The mixture was washed with benzene and acidified with 10% hydrochloric acid. The aqueous layer was saturated with salt and extracted with ether, which after drying (sodium sulfate) and concentration gave 2.43 g of crude product. The mixture was stirred for 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 eluent, whereby 600 mg of acid, which crystallized on standing, was obtained. This was recrystallized twice from ethyl acetate-cyclohexane and led to 320 mg of [13,2fl(5Z),3a,43]-7-[3-(hydroxymethyl)-7-oxabicyclo [2. 2. 1]hept-2-yl]-5-heptenoic acid.

B. [13,2g(5Z),3a,43]-7-[3-(p-toluenesulfonyloxymethyl)-7-oxabicyclo[2.2.1]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, 427 mg (2.24 mmol) of tosyl chloride was added. The mixture was stirred at room temperature under an argon atmosphere for 10 hours. The reaction mixture was diluted with 300 mL of ether, washed with 1N aqueous HCl solution (3 x

100 ml) and 0.5N aqueous NaOH solution (3 x 100 ml). The ether layer was dried over anhydrous magnesium sulfate and concentrated below

vacuum. Purification was carried out by chromatography on 30 g of silica gel 60 with 50% hexane in ether as eluent, whereby 450 mg of the title compound (95%) was obtained. TLC: silica gel, 4% CH3OH in CH2Cl2, Rf=0.80, iodine.

C. 1 , 2 ( 5Z), 3 , 4 - 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, 378 mg (3.21 mmol) of 1-hexanethiol was added under argon. To this mixture was added 450 mg (1.07 mmol) of tosylate from part B dissolved in 5 ml of THF. The reaction mixture was stirred at room temperature under argon for 2 hours and then heated under reflux for 5 hours. The cooled reaction mixture was diluted with 300 ml of ether and poured into 100 ml of saturated NaHCO 3 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) and brine (100 mL) then dried (MgSO 4 ), filtered and concentrated in vacuo to 0.55 g crude oil. Purification was carried out by chromatography on 25.2 g of silica gel 60 with 5:1 petroleum ether:ether as eluent, whereby 328 mg (84%) of the title product was obtained as an oil. TLC: silica gel, petroleum ether:ether (3:2), Rf=0.55, iodine.

Example 4 5

[ 1 3 , 2g ( 5Z ), 3a , 43 ] - 7- [ 3- [ (hexylthio) methyl] - 7- oxabicyclo[ 2. 2. 1]-hept- 2- yl]- 5- heptenoic acid

To a stirred solution of 328 mg (0.89 mmol) of the methyl ester from Example 1 in 4 3.8 ml THF and 6.6 7 ml H 2 O, 8.40 ml 1N aqueous lithium hydroxide solution was added under argon. The mixture was flushed thoroughly with argon for 20 minutes and stirred at room temperature for 12 hours. The reaction mixture was acidified to pH 4 by addition of 1N HCl and completely over

in 50 ml 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 4 ), filtered and

concentrated under vacuum to 295 mg crude acid. Purification was accomplished by chromatography on 25 g of siliCAR CC-7 with petroleum ether: ether (2:3) as eluent, whereby the title product (250 mg, 79%) was obtained as an oil. TLC: silica gel, petroleum ether: ether (2:3), Rf=0.25, iodine.

Analysis calculated for C^^ H^^ O^ S'.

C, 67.80; H, 9.61; S, 9.04

Found: C, 67.80; H, 9.85; S, 9.14 13 C NMR (CDCl 3 , 15.0 mHz) T 173.5, 33.1, 24.5, 25.6, 129.9, 128.8, 26.5, 45.9, 79 .9, 29.2, 28.8, 78.3, 45.9, 69.5, 144.5, 129.7, 127.6, 132.1, 127.6,

129.7, 21.3, 51.1

Example 46

(13, 2a, 3a, 43)- 7-[ 3-[(hexylthio) methyl 3- 7- oxabicyclo[ 2. 2. 1]-hept- 2- yl]- 5- heptenoic acid, methyl ester

A. ( 13 , 2a, 3a, 43)- 7-[ 3-( hydroxymethyl)- 7- oxabicyclo-[ 2. 2. 13hept- 2- yl3heptanoic acid, methyl ester

To 800 mg (3.0 mmol) [13,2a(5Z),3a,433-7-[3-(hydroxy-methyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid , the methyl ester according to example 1, dissolved in 120 ml of ethyl acetate, 160 mg of 5% Pd on carbon were added under an argon atmosphere. The argon atmosphere was replaced with a slight overpressure of hydrogen and the reaction mixture stirred for 8 h at 25°, filtered through a plug of celite and evaporated to give 730 mg (90%) of the title compound A.

B. (13, 2a, 3a, 43)- 7-[ 3-[(hexylthio) methyl 3- 7- oxabicyclo-[ 2. 2. 13hept- 2- yl3-heptanoic acid, methyl ester

By following the procedure in Example 1, but with the alcohol ester from part A instead of the alcohol ester from Example 1A, the title product was obtained.

Example 47

(13, 20, 30, 43)- 7-[ 3-[(hexylthio) methyl]- 7- oxabicyclo[ 2. 2. 1]-hept- 2- yl]-heptanoic acid

By following the procedure in Example 45, but with the methyl ester from Example 46 instead of the methyl ester from Example 45, the title acid was obtained.

Example 48

[ 13, 2a( 5Z), 33/ 43]- 7-[ 3-[( pentylthio) methyl]- 7- oxabicyclo[ 2. 2. 1 ]-hept- 2- yl]- 5- heptenoic acid, methyl ester

[ 13, 2a( 5Z), 33, 43]- 7-[ 3-( hydroxymethyl)- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid, methyl ester To a solution of 2 .68 g of [13,2a(5Z),3a,43]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid in 175 ml of dimethylformamide, it was added 13.16 g of pyridinium dichromate. The mixture was stirred at room temperature and after 19 hours a further 8 g of pyridinium dichromate was added. The mixture was then stirred for an additional 24 hours. The reaction mixture was diluted with 500 mL of ether and the resulting black, gummy precipitate was filtered off through a plug of celite.

The filtrate was concentrated under vacuum. The resulting dark brown oil was passed through 60 g of silica gel 60 and eluted with 5% MeOH/CH 2 Cl 2 to give 1.86 g of brown oil.

The oil was purified by chromatography on 150 g of silica gel 60 with 1:1:0.01 pentane-ether-acetic acid as eluent. This gave 0.6 3 g of [ 1 3 r 2a(5Z) ,3a,43]-7-[3-(carboxy)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester and 0.31 g of [13,2α(5Z),33,43]-7-[3-(carboxy)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester.

13 C NMR (CDCl 3 , 15.0 mHz) T 177.0, 174.0, 130.6, 127.7, 81.5, 77.9, 54.7, 51.3, 46.2, 33, 4, 32.3, 29.2, 26.6, 25.8, 24.7

A solution of 350 mg of [13,2a(5Z) ,33,43]-7-[3-(carboxy)--7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester and 0 .35 mL of triethylamine in 3.0 mL of dry THF was cooled to 0°C under argon. To the stirred solution was added dropwise 0.24 ml of ethyl chloroformate. 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 MgSO4 and concentrated under vacuum. The residue was dissolved in 2 ml of absolute EtOH and 3.3 ml of dry THF. The solution was cooled in an ice bath and then 80 mg of NaBH 2 was added. The mixture was stirred for 30 minutes at 0°C, after which the ice bath was removed. After 15 minutes, the reaction mixture was poured into 25 ml of ice-cold 1N HCl. The aqueous layer was extracted with three 25 mL portions of ether. The ether layers were combined, dried over. MgSO^, filtered and concentrated under vacuum to a crude product. Purification was carried out by chromatography on 22 g of silica gel with 2% MeOH/CH2Cl2 as eluent. This gave 250 mg of [13,2a(5Z),33,43]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester. 13 C NMR (CDCl 3 , 15.0 mHz) T 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. [l3,2a(5Z),33,43]-7-[3-(p-toluenesulfonyloxymethyl)-7-oxobicyclo[2.2.1]hept-2-yl-5-heptenoic acid, methyl ester

To a solution of 300 mg (1.12 mmol) [13,2a(5Z),33,43]-7-t 3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5 -heptenoic acid, methyl ester from part A in 4 ml of dry pyridine was added 4 27 mg (2.24 mmol) tosyl chloride. The mixture was stirred at room temperature under an argon atmosphere for 10 hours. The reaction mixture was diluted with 300 mL of ether, washed with 1N aqueous HCl

(3 x 100 ml) and 0.5N aqueous NaOH solution (3 x 100 ml). The ether layer was dried over anhydrous magnesium sulfate and concentrated under vacuum. Purification was carried out by chromatography on 30 g of silica gel 60 with 50% hexane in ether as eluent, whereby 450 mg of title compound B was obtained.

C. [ 13, 2a( 5Z), 33, 4&]- 7-[ 3-[( pentylthio) 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, 378 mg (3.21 mmol) of 1-pentanethiol was added under argon. To the mixture was added a solution of 450 mg (1.07 mmol) of tosylate from Part B in 5 mL of THF. The reaction mixture was stirred at room temperature under argon for 2 h and then heated under reflux for 5 h. The cooled reaction mixture was diluted with 300 ml of ether and poured into 100 ml of saturated NaHCO3 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) and brine (100 mL) then dried (MgSO 4 ), filtered and concentrated in vacuo to 0.55 g of a crude oil. Purification was carried out by chromatography on 25.2 g of silica gel 60

with petroleum ether:ether (5:1) as eluent, whereby 328 mg of the title compound was obtained.

Example 49

[ 13, 2a( 5Z), 33, 43]- 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 methyl ester from Example 48 in 43.8 ml of THF and 6.67 ml of H 2 O, 8.40 ml of 1N aqueous lithium hydroxide solution was added under argon. The mixture was flushed thoroughly with argon for 20 minutes and stirred at room temperature for 12 hours. The reaction mixture was acidified to pH 4 by the addition of 1N HCl and poured completely into 50 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 4 ), filtered and concentrated under vacuum to 295 mg of crude acid. Purification was carried out by chromatography on 25 g of siliCAR CC-7 with petroleum ether:ether (2:3) as eluent.

Example 50

[ lp , 2g( 5Z ), 3g , 4p ]- 7-[ 3-[( methyltlo ) methyl]- 7- oxabicyclo[ 2. 2. 1]-hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 44 and 45, but with methylmercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 51

[ 13, 2g( 5Z), 33, 4 3]- 7-[ 3-[( propylthio) methyl]- 7- oxabicyclo[ 2. 2. 1]-hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 48 and 49, but with propylmercaptan instead of 1-pentanethiol, the title compound was obtained.

Example 52

( 1 3, 2g, 3g, 4 3)- 7-[ 3-( butylthio) methyl]- 7- oxabicyclo[ 2. 2. 1]-hept- 2- yl] heptanoic acid

By following the procedure of Examples 46 and 47, but with butyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 53

[ 13, 2g( 5Z), 3g, 43]- 7-[ 3-[( octylthio) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 44 and 45, with 1-octanethiol instead of 1-hexanethiol, the title compound was obtained.

Analysis calculated for <C>22<H>3<g>°3S:

C, 69.06; H, 10.01; S, 8.38 Found: C, 69.08; H, 9.75; S, 8.20 13 C NMR (CDCl 3 , 15.0 mHz) T 178.7, 32.6, 29.1, 29.4, 129.8, 129.8, 29.4 46.9, 80, 6, 29.7, 31.7, 80.4, 47.5, 33.4, 32.1 , 29.1 , 28.8, 26.7, 26.2,

24.5, 22.5, 13.9.

Example 54

[ 13, 2a ( 5Z), 3a, 4p]- 7-[ 3-[( phenylthio) methyl]- 7- oxabicyclo[ 2. 2. 1]-hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 44 and 45, but with phenylmercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 55

( 13, 2a, 3a, 43 )- 7-[ 3-[( phenylthio) methyl]- 7- oxabicyclo[ 2. 2. 1]-hept- 2- yl] heptanoic acid

By following the procedure of Examples 46 and 47, but with phenylmercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 56

[ 1 3, 2a ( 5Z), 3a, 43]- 7-[ 3-[ ( ethylthio) methyl]- 7- oxabicyclo [ 2 . 2. 1]-hept-2-yl]-5-heptanoic acid

By following the procedure of Examples 44 and 45, but with ethyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 57

[ 13, 2a( 5 Z), 33, 43]- 7-[ 3-[( phenylthio) methyl]- 7- oxabicyclo[ 2. 2. 1]-hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 48 and 49, but with phenylmercaptan instead of 1-pentanethiol, the title product was obtained.

Example 58

[ 13, 2a( 5Z), 33, 4p]- 7-[ 3- t( benzylthio) methyl]- 7- oxabicyclo[ 2. 2. 13-hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 48 and 49, but with benzyl mercaptan instead of 1-pentanethiol, the title product was obtained.

Example 59

( 13, 2a, 3a, 4 3)- 7-[ 3-[( benzylthio) methyl]- 7- oxabicyclo[ 2. 2. 1]-hept- 2-yl] heptanoic acid

By following the procedure of Examples 46 and 47, but with benzyl mercaptan instead of 1-hexanethiol, the title product was obtained.

Example 60

[ip, 2ct( 5Z) , 3a, 43]- 7-[ 3-[ (cyclohexylthio) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 44 and 45, but with cyclohexyl mercaptan instead of 1-hexanethiol, the title product was obtained.

Example 61

[13/2ot (5Z).

By following the procedure of Examples 48 and 49, but with cyclopentyl mercaptan instead of 1-pentanethiol, the title product was obtained.

Example 62

( 13 > 2a, 3a, 43)- 7-[ 3-[(cyclohexylthio) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- ylheptanoic acid

By following the procedure of Examples 46 and 47, but with cyclohexyl mercaptan instead of 1-hexanethiol, the title product was obtained.

Example 63

[ 13 , 2a( 5Z), 3a, 433- 7-[ 3-[ 2-( hexylthio) ethyl 3- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

A. [ 13, 2ot( 5Z) >3a, 43 3- 7-[ 3-( 2- oxo) ethyl- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid, methyl ester

In a 100 ml three-necked round flask with a stirring magnet, 12.9 g (37.7 mmol) of methoxymethyltriphenylphosphonium chloride ( (C^HC) ,P+-CH_0CH-,C1~) and 235 ml of distilled toluene (stored over molecular sieve) were placed. . The resulting suspension was stirred in an ice bath under argon and, after cooling, a 1.55 M solution of 18.3 ml (28.3 mmol) of potassium t-amylate in toluene was added dropwise. A strong red colored solution formed which was stirred at 0°C for a further 35 minutes. A solution of 4.97 g (18.8 mmol) [13,2a(5Z),3a,433-7-[3-formyl-7-oxabicyclo[2.2.1]hept-2-yl3-5- heptenoic acid, methyl ester in 60 ml toluene, was then added by means of a dropping funnel over 35 minutes while continuing to use the ice bath. The reaction was then stopped by the addition of 2.3 g

(39 mmol) of acetic acid in 5 ml of ether. The reaction mixture immediately turned pale yellow and was immediately poured into 200 ml of saturated NH 2 Cl and extracted with ether (4 x 200 ml). The combined ether phases were washed with saturated NaCl solution and dried (MgSO 4 ) and concentrated to give a yellow oil in a white crystalline solid (phosphine oxide). The white solid was triturated with EtOAc and the mother liquor purified by chromatography on an LPS-1 silica gel column. The fractions obtained amounted to

(A) [13,2a(5Z),3a,433-7-[3-(2-oxo)ethyl-7-oxabicyclo[2.2.1]-hept-2-yl3-5-heptenoic acid, methyl ester, (B ) [13,2 a(5Z),3a,433 -

7-[3-(2-Methoxy)ethendiyl-7-oxabicyclo[2.2.1]hept-2-yl3-5-heptenoic acid, methyl ester and (C) [13,2a(5Z),3a,433-7-[ 3-(2,2-Dimethoxy)ethyl-7-oxabicyclo[2.2.13hept-2-yl]-5-heptenoic acid, methyl ester.

Compounds (B) and (C) were both treated with trifluoroacetic acid to convert both to compound (A).

B. [ 13, 2a( 5Z), 3a, 433- 7-[ 3-( 2- hydroxyethyl)- 7- oxabicyclo [ 2 . 2. 1]hept-2-yl3-5-heptenoic acid, methyl ester The aldehyde (1.4 g, 5 mmol) from Part A in methanol (50 mL) was treated with NaBH^ (0.19 g, 5 mmol) under an argon atmosphere at 0°C. After stirring at 0°C for 1 hour, the reaction was quenched by the addition of 2N HCl (to pH 2). The methanol was removed under vacuum and the reaction mixture was taken up in ether. The ether solution was washed with saturated KHCO 3 , saturated NaCl and dried (MgSO 4 ). After evaporation of the ether, the title compound B was obtained.

C. [ 13, 2ot( 5Z) , 3a, 4B ]- 7-[ 3-[ 2-( hexylthio) ethyl]- 7- oxabicyclo [ 2. 2. 13hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 44 and 45, but with the alcohol part B instead of the alcohol used in Example 44, the title compound was obtained.

Example 64

[ 1p, 2a( 5Z), 33, 43]- 7-[ 3-[ 2-( hexylthio) ethyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Example 63, but with [13,2a(5Z),33,43]-7-[3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester instead of [13,2a(5Z),3a,433-7-[3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, the title compound was obtained.

Example 6 5

( 13, 2g, 3g, 43 )- 7-[ 3-[ 2-( hexylthio) ethyl]- 7- oxabicyclo[ 2. 2. 1 ]-hept- 2-yl] heptanoic acid

By following the procedure from Example 64, but with (13,2<g>,3<g>,43)-7-[3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]-heptanoic acid, methyl ester instead of [13,2<g>(5Z),3<g>,43]-7-[3-formyl-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester , the title compound was obtained.

Example 66

[ 13, 2a( 5Z), 3a, 4 3 3- 7-[ 3-[ 2-( phenylthio) ethyl 3- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl3- 5- heptenoic acid

By following the procedure of Example 63, but with phenylmercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 67

[ 13, 2a( 5Z), 33, 433- 7-[ 3-[ 2-( phenylthio) ethyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Example 64, but with phenylmercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 68

(13, 2a, 3a, 43)- 7-[ 3-[ 2-( phenylthio) ethyl 3- 7- oxabicyclo[ 2. 2. 1]-hept- 2- yl3 heptanoic acid

By following the procedure of Example 65, but with phenyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 69

[ 13, 2a( 5Z), 3a, 433- 7-[ 3-[ 2-( benzylthio) ethyl 3- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Example 63, but with benzyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 70

[ 13, 2a( 5Z), 33, 433- 7-[ 3-[ 2-( benzylthio) ethyl 3- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure from Example 64, but with benzyl mercaptan instead of 1-hexanethiol, the title

connection achieved.

Example 71

[ 13, 2a( 5Z), 30, 43]- 7-[ 3-[ 2-( cyclopentyl) thio) ethyl]- 7- oxabicyclo-[ 2. 2. 1jhept- 2- yl] heptenoic acid

By following the procedure of Example 63, but with cyclopentyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 72

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[ 2-( cyclohexylthio) ethyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure from Example 63, but with cyclohexyl mercaptan instead of 1-hexanethiol, the title product was obtained.

Example 73

[ 13, 2a( 5Z), 3a, 433- 7-[ 3-[ 4-( hexylthio) butyl3- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl3- 5- heptenoic acid

A. [13,2a(5Z),3a,43]-7-[3-(3-oxo)propyl-7-oxabicyclo-[2.2.1]hept-2-yl]-5-heptenoic acid methyl ester

By following the procedure of Example 63, part A, but with [13,2a(5Z),3a,43]-7-[3-(2-oxo)ethyl-7-oxabicyclo[2.2.1]-hept-2 -yl]-5-heptenoic acid, methyl ester instead of [13,2a(5Z),~3a, 4 33-7-[3-formyl-7-oxabicyclo[2.2.1]hept-2-yl3-5-heptenoic acid , methyl ester, the title compound was obtained.

B. [ 13, 2a( 5Z) , 3a, 43 3- 7-[ 3-( 4- oxo) butyl- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid, methyl ester

By following the procedure of Example 63, part A, but with the aldehyde from part A instead of [13,2a (5Z),3a,433-7-[3-formyl-7-oxabicyclo[2.2.1]hept-2 -yl]-5-heptenoic acid, methyl ester, the title B-aldehyde was obtained. C. [ 13, 2a( 5Z) , 3g, 43]- 7-[ 3-( 4- hydroxybutyl)- 7-oxa bicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester By following the procedure of Example 63, part B, but with the title B-aldehyde instead of [13,2a(5Z),3a ,43]-7-[3-(2-oxo)ethyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester, the title C alcohol was obtained. D. [13,2a(5Z),3a,43]-7-[3-[4-(hexylthio)butyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid

By following the procedure of Examples 44 and 45, but with the C-alcohol instead of the alcohol used in Example 44, the title compound was obtained.

Example 74

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[ 4-( cyclohexylthio) butyl]- 7- oxabicyclo [ 2 . 2. 1] hept-2-yl]-5-heptenoic acid

By following the procedure of Example 73, but with cyclohexyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 75

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[ 4-( phenylthio) butyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Example 73, but with phenylmercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 76

[ 13, 2a( 5Z), 3g, 43]- 7-[ 3-[ 4-( benzylthio) butyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl] heptenoic acid

By following the procedure of Example 73, but with benzyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Examples 77, 78 and 79

[ 1p, 2a( 5Z), 3a, 43]- 7-[ 3-[( hexylsulfinyl) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid, methyl ester ( fast wandering in somers), [ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[( hexylsulfinyl) methyl]- 7-oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid , methyl ester (slow-migrating isomer) and [ 13, 2a( 5Z), 3a, 431- 7-[ 3-( hexylsulfonyl)-methyl]- 7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5 - heptenoic acid, methyl ester

To a solution of 634 mg (1.72 mmol) [ 1 3,2a(5Z) ,3a,43]-7-[3-(hexylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl ]-5-heptenoic acid, methyl ester (prepared as described in example 44) in 6.78 ml of methanol, 8.37 ml of 0.5 M aqueous sodium periodate solution was added dropwise over the course of 4 minutes at 0°C. Tetrahydrofuran (2 mL) was then added and the resulting reaction mixture stirred at room temperature for 15 h. A white precipitate was filtered off and washed with ether (3 x 50 mL). The filtrate was washed with 60 ml of saturated aqueous NaHCO 3 solution and dried over anhydrous magnesium sulfate. Concentration under vacuum afforded 648 mg of an oily crude product. This was chromatographed on 54.16 g of silica gel 60 with 0.5-1.0% CH 3 OH in CH 2 Cl 2 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, 24%). These products were oils that turned into solid form when left in a freezer. TLC = silica gel, 2% CH 3 OH/CH 2 Cl 2 , Rf: Example 77 sulfoxide, 0.28; Example 78 sulfoxide, 0.21; Example 79 sulfone, 0.74, iodine.

Example 80

[ 1 3/ 2 g( 5Z) , 3 a, 4 3]- 7-[ 3- [( hexylsulfonyl) methyl 3- 7- oxabicyclo-[ 2. 2. 1 ] hept- 2- yl]- 5- heptenoic acid

To a stirred solution of 165 mg (0.41 mmol)

[1 3.2 g(5Z) .3 g, 4 &]-7-[3-[ (hexylsulfonyl) methyl]-7-oxabicyclo-[2 . 2.1]hept-2-yl]-5-heptenoic acid, methyl ester (Example 79) in 20.3 ml of THF and 3.09 ml of H 2 O, under argon was added 3.90 ml

1N aqueous lithium hydroxide solution. The mixture was purged vigorously with argon for 10 minutes and stirred at room temperature for 6 hours. The reaction mixture was acidified to pH 4 by adding 1N aqueous HCl solution and poured completely 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 4 ), filtered and concentrated under vacuum to 165 mg of crude acid. Purification was carried out by chromatography on 20 g of silica gel 60 with 3% CH 3 OH in CH 2 Cl 2 as eluent. This led to the title acid (145 mg, 91%), which turned into solid form on standing in a freezer. TLC = silica gel,

4% CH3OH/CH2Cl2, Rf=0.32, iodine.

Analysis calculated for C2QH34O^S:

C, 62.18; H, 8.81; S, 8.29 Found: C, 61.99; H, 9.01; S, 8.33 13 C NMR (CDCl 3 , 15.0 mHz) T 178.4, 33.1, 24.3, 26.7,

128.9, 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, 4p3- 7-[ 3-[(hexylsulfinyl) methyl]- 7- oxabicyclo-[ 2. 2. 1jhept- 2- yl]- 5- heptenoic acid (fast migrating isomer)

To a stirred solution of 211 mg (0.55 mmol) [13,2a(5Z), 3a,43]-7-[3-[(hexylsulfinyl)methyl]-7-oxabicyclo[2.2.1]-hept-2 -yl]-5-heptenoic acid, methyl ester (fast migrating isomer), prepared in Example 77, in 27.0 ml of THF and 4.11 ml of H 2 O, 5.19 ml of 1N aqueous lithium hydroxide solution was added under argon. This mixture was thoroughly flushed with argon for 10 minutes and then stirred at room temperature for 6 hours. The reaction mixture was acidified to pH 4 by adding 1N aqueous HCl solution and poured completely 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 4 ), filtered and concentrated under vacuum to 216 mg of crude acid. Purification was accomplished by chromatography on 20.2 g of silica gel 60 with 3% CH 3 OH in CH 2 Cl 2 as eluent, whereby the title acid (172 mg, 85%) was obtained as a white solid. TLC = silica gel, 4% CH3OH/CH2Cl2, Rf=0.10, iodine. Analysis calcd for C2qH34<0>4S: C, 64.83; H, 9.25; S, 8.65 Found: C, 64.71; H, 9.17; S, 8.55 13 C NMR (CDCl 3 , 15.0 mHz) t 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, 26.7, 22.6, 22.3, 13.8 Example 82 [ 13, 2ot( 5Z) , 3a, 43 3 - 7-[ 3-[ (hexylsulfinyl) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid ( slow migrating isomer) To a stirred solution of 142 mg (0.37 mmol) [13,2a(5Z) ,3a,43]-7-[3-[(hexylsulfinyl)methyl]-7-oxabicyclo-[2.2.1]hept -2-yl]-5-heptenoic acid, methyl ester (slow migrating isomer) prepared as described in Example 78, in 18.2 ml of THF and 2.77 ml of H 2 O, under argon was added 3.50 ml of 1N aqueous lithium hydroxide solution. The mixture was flushed thoroughly with argon for 15 minutes and stirred at room temperature for 4 hours and 40 minutes. The reaction mixture was acidified to pH 4 by the addition of 1N aqueous HCl solution and poured completely into 30 ml of saturated sodium chloride solution. The resulting solution was saturated with solid NaCl and extracted with EtOAc (3 x 70 mL). The combined EtOAc extracts were dried (MgSO 4 ), filtered and concentrated under vacuum to 152 mg of crude acid. Purification was carried out by chromatography on 20.8 g of silica gel 60 with 4% CH 3 OH in CH 2 Cl 2 as eluent, whereby the title acid (116 mg, 85%) was obtained. TLC = silica gel, 4% CH3OH/CH2Cl2, Rf=0.6, iodine. Analysis calculated for C20H34°4S: C, 64.83; H, 9.25; S, 8.65

Found: C, 64.44; H, 9.15; S, 8.58

13 C NMR (CDCl 3 , 15.0 mHz) t 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

Example 83

[ 13, 2a( 5Z), 3a, 43l- 7-[ 3-[( methylsulfinyl) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid (fast migrating isomer)

By following the procedure of Examples 44, 77 and 81, but with methylmercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 84

[ 1 3, 2a( 5Z), 3a, 43]- 7-[ 3-[( octylsulfinyl) methyl]- 7- oxabicyclo-[ 2. 2. 1 ] hept- 2- yl]- 5- heptenoic acid ( slow migrating isomer)

By following the procedure of Examples 44, 77 and 82, but with 1-octanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 85

[ 13, 2a( 5Z), 33, 43]- 7-[ 3-[( phenylsulfinyl) methyl]- 7- oxabicyclo-[ 2. 2. 1 ] hept- 2- yl]- 5- heptenoic acid ( fast migrating isomer )

By following the procedure of Examples 48, 77 and 81, but with phenylmercaptan instead of 1-pentanethiol, the title compound was obtained.

Example 86

[ 1 3 , 2a( 5Z ), 3a , 43]- 7-[ 3-[( ethylsulfinyl) methyl]- 7- oxabicyclo-[ 2. 2. 1 ] hept- 2- yl]- 5- heptenoic acid ( slow migrating isomer)

By following the procedure of Examples 48, 77 and 82, but with ethyl mercaptan instead of 1-pentanethiol, the title compound was obtained.

Example 87

(13,2a,3a,43)-7-[3-[(heptylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptanoic acid (fast migrating isomer)

By following the procedure of Examples 46, 77 and 81, but with 1-heptanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 88

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[( benzylsulfinyl) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 44, 77 and 81, but with benzyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 89

[ 13, 2g( 5Z), 33, 43]- 7-[ 3-[( benzylsulfinyl) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid ( slow migrating isomer )

By following the procedure of Examples 48, 77 and 82, but with benzyl mercaptan instead of 1-pentanethiol, the title compound was obtained.

Example 90

[ 13/ 2a( 5Z), 3g, 43]- 7-[ 3-[( cyclohexylsulfinyl) methyl]- 7- oxabicyclo[ 2 . 2. 1] hept-2-yl]-5-heptenoic acid (fast migrating isomer)

By following the procedure of Examples 44, 77 and 81, but with cyclohexyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 91

[ 13, 2g( 5Z), 3a, 43]- 7-[ 3-[( cyclopentylsulfinyl) methyl]- 7- oxabicyclo [ 2 . 2. 1 ]hept-2-yl]-5-heptenoic acid (fast migrating isomer)

By following the procedure of Examples 44, 77 and 81, but with cyclopentyl mercaptan instead of 1-hexanethiol,

the title compound obtained.

Example 92

[ip, 2g( 5Z), 3g, 4p]- 7-[ 3-[(octylsulfonyl) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 44, 77 and 80, but with octyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 93

[ lp, 2a( 5Z) , 3ot, 4&]- 7-[ 3-[ ( propylsulfonyl) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 44, 77 and 80, but with propyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 94

[ 13, 2a( 5Z), 3g, 4p]- 7-[ 3-[(phenylsulfonyl) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 44, 77 and 80, but with phenylmercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 95

[ 1p, 2g( 5Z) , 3g, 4p]- 7-[ 3-[( benzylsulfonyl) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 44, 77 and 80, but with benzyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 96

[ 1P, 2a( 5Z), 3a, 4p]- 7-[ 3-[( cyclohexylsulfonyl) methyl]- 7- oxabicyclo [ 2. 2. 1] hept- 2- yl3- 5- heptenoic acid

By following the procedure of Examples 44, 77 and 80, but with cyclohexyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 97

[ 1P, 2a ( 5Z), 33, 4p]- 7-[ 3-[( heptylsulfonyl) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 48, 77 and 80, but with 1-heptanethiol instead of 1-pentanethiol, the title compound was obtained.

Example 98

[ip, 2g( 5Z), 33, 4p]- 7-[ 3-[(benzylsulfonyl) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 48, 77 and 80, but with benzyl mercaptan instead of 1-pentanethiol, the title compound was obtained.

Example 99

[ iP, 2a( 5Z), 3>p, 4p] - 7- [ 3- [ ( cyclopentylsulf onyl) methyl ] - 7- oxabicyclo [ 2 . 2. 1]hept-2-yl]-5-heptenoic acid

By following the procedure of Examples 48, 77 and 80, but with cyclopentyl mercaptan instead of 1-pentanethiol, the title compound was obtained.

Example 100

[ iP, 2a( 5Z), 3p, 4p]- 7-[ 3[( phenylsulfonyl) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 48, 77 and 80, but with phenylmercaptan instead of 1-pentanethiol, the title compound was obtained.

Example 101

(13, 20, 30, 43)-7-[3-[( cyclopropylsulfinyl) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptanoic acid

By following the procedure of Examples 46, 77 and 80, but with cyclopropyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 102

( 13 f 2a, 3a, 43)- 7-[ 3-[( benzylsulfinyl) methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptanoic acid

By following the procedure of Examples 47, 77 and 81, but with benzyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 103

[ 13, 2o( 5 Z), 3g, 4 3]- 7-[ 3-[ 2-( pentylsulfinyl) ethyl 3- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 63, 44, 77 and 81, but with 1-pentanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 104

[ 13, 2a( 5Z), 3a, 433- 7-[ 3-[ 2-( phenylsulfonyl) ethyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 63, 44, 77 and 80, but with phenylmercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 105

[ 13, 2a( 5Z), 3a, 4 3 3- 7-[ 3-[ 2-( cyclohexylsulfonyl) ethyl 3- 7- oxabicyclo [ 2 . 2. 1 3hept-2-yl]-5-heptenoic acid

By following the procedure of Examples 63, 44, 77 and 80, but with cyclohexyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 106

[ 13, 2a( 5 Z), 3a, 4 3 3- 7-[ 3-[ 2-( benzylsulfinyl) ethyl]- 7- oxabicyclo-[ 2. 2. 13hept- 2- yl3- 5- heptenoic acid

By following the procedure of Examples 63, 44, 77 and 81, but with benzyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 107

[ 13/ 2a( 5Z), 33, 43 3- 7-[ 3-[ 2-( butylsulfonyl) ethyl 3- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl3- 5- heptenoic acid

By following the procedure of Examples 63, 48, 77 and 80, but with butyl mercaptan instead of 1-pentanethiol, the title compound was obtained.

Example 108

[ 13, 2a( 5Z), 33, 433- 7-[ 3-[ 2-( phenylsulfinyl) ethyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 63, 48, 77 and 81, but with phenylmercaptan instead of 1-pentanethiol, the title compound was obtained.

Example 109

[ 13, 2a( 5Z), 33, 433- 7-[ 3-[ 2-( benzylsulfinyl) ethyl 3- 7- oxabicyclo-[ 2. 2. 13hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 63, 48, 77 and 81, but with benzyl mercaptan instead of 1-pentanethiol, the title compound was obtained.

Example 110

[ 13, 2a ( 5Z), 33, 43]- 7-[ 3-[ 2-( cycloheptylsulfonyl) ethyl 3- 7- oxabicyclo [ 2. 2. 13hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 63, 48, 77 and SO, but with cycloheptyl mercaptan instead of 1-pentanethiol, the title compound was obtained.

Example 111

(13, 2a, 3a, 43)- 7-[ 3-[ 2-( pentylsulfonyl) ethyl]- 7- oxabicyclo-[ 2. 2. 13hept- 2- yl]- 5- heptanoic acid

By following the procedure of Examples 63, 46, 77 and 80, but with 1-pentanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 112

(13, 2g, 3g, 4 3)- 7-[ 3-[ 2-( phenylsulfinyl) ethyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptanoic acid

By following the procedure of Examples 63, 46, 77 and 81, but with phenylmercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 113

( 13/ 2g, 3g, 43)- 7-[ 3-[ 2-( benzylsulfinyl) ethyl 3- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptanoic acid

By following the procedure of Examples 63, 46, 77 and 81, but with benzyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 114

( 13, 20, 30, 43)- 7-[ 3-[ 2-( cyclohexylsulfonyl) ethyl]- 7- oxabicyclo [ 2. 2. 13hept- 2- yl3- 5- heptanoic acid

By following the procedure of Examples 63, 48, 77 and 80, but with cyclohexyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 115

[ 13, 2a( 5Z), 3a, 433- 7-[ 3-[ 4-( pentylsulfonyl) butyl]- 7- oxabicyclo[ 2. 2. 13hept- 2- yl]- 5- heptenoic acid

Following the procedure of Examples 73, 63, 44, 77 and 80, but with pentyl mercaptan instead of 1-hexanethiol,

the title compound was achieved.

Example 116

[ 13/ 2o( 5Z), 3a, 43 3- 7-[ 3-[ 4-( cyclohexylsulfinyl) butyl3- 7-oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 73, 63, 44, 77 and 81, but with cyclohexyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 117

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[ 4-( phenylsulfinyl) butyl]- 7- oxabicyclo [ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 73, 63, 44, 77 and 81, but with phenylmercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 118

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[ 4-( benzylsulfonyl) butyl]-7-oxabicyclo [2. 2. 1]hept-2-yl]-5-heptenoic acid

By following the procedure from examples 73, 63, 44, 77

and 80, but with benzyl mercaptan instead of 1-hexanethiol,

the title compound was achieved.

Example 119

[ 13, 2a( 5Z), 3B, 43 3 - 7-[ 3-[ 4-( cyclopentylsulfinyl) butyl]- 7-oxabicyclo[ 2. 2. 1] hept- 2- yl3- 5- heptenoic acid

Following the procedure of Examples 73, 63, 48, 77 and 81, but with cyclopentyl mercaptan instead of 1-pentanethiol, the title compound was obtained.

Example 120

[ 13, 2a( 5Z), 33, 433- 7-[ 3-[ 4-( benzylsulfinyl) butyl3-7-oxabicyclo [2.2. 13hept-2-yl]-5-heptenoic acid

By following the procedure of Examples 73, 63, 48, 77 and 80, but with benzyl mercaptan instead of 1-pentanethiol, the title compound was obtained.

Example 121

[ 13, 2a ( 5Z) , 33, 43 3- 7-[ 3-[ 4-( propylsulfinyl) butyl3-7-oxabicyclo [2. 2. 13hept-2-yl]-5-heptenoic acid

By following the procedure of Examples 73, 63, 48, 77 and 81, but with propyl mercaptan instead of 1-pentanethiol, the title compound was obtained.

Example 122

[ 13, 2a( 5Z), 33, 433- 7-[ 3-[ 4-( phenylsulfonyl) butyl]- 7- oxabicyclo [ 2 . 2. 13hept-2-yl3-5-heptenoic acid

By following the procedure of Examples 73, 63, 48, 78 and 80, but with phenylmercaptan instead of 1-pentanethiol, the title compound was obtained.

Example 123

(13, 2a, 3a, 4 3)-!-[ 3-[ 4-( nonylsulfinyl) butyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptanoic acid

Following the procedure of Examples 73, 63, 46, 77 and 81, but with 1-nonanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 124

(13, 2a, 3a, 4 3)- 7-[ 3-[ 4-( pentylsulfonyl) butyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl3- 5- heptanoic acid

By following the procedure of Examples 73, 63, 46, 77 and 80, but with 1-pentanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 125

( 13, 2a, 3a, 4 3)- 7-[ 3-[ 4-( phenylsulfinyl) butyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

Following the procedure of Examples 77, 63, 46, 77 and 81, but with phenylmercaptan instead of 1-hexanethiol,

the title compound was achieved.

Example 126

( 13, 2a, 3a, 4 3)- 7-[ 3-[ 4-( cyclohexylsulfonyl) butyl]- 7- oxabicyclo [ 2. 2. 1] hept- 2- yl]- 5- heptanoic acid

By following the procedure of Examples 73, 63, 46, 77 and 80, but with cyclohexyl mercaptan instead of 1-hexanethiol, the title compound was obtained.

Example 127

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[[( cyclohexylmethyl) thio] methyl]- 7-oxabicyclo[ 2. 2. 13hept- 2- yl3- 5- heptenoic acid

A. Mg, 2a( 5Z), 3a, 433- 7-[ 3-[[( cyclohexylmethyl) thio]-methyl]- 7- oxabicyclo[ 2. 2. 13hept- 2- yl3- 5- heptenoic acid, methyl ester

To a solution of 88 mg (0.78 mmol) of potassium t-butoxide

in 5 ml of dry THF, 277 mg (2.13 mmol) of cyclohexylmethanethiol (prepared from cyclohexylmethanol according to Volante: Tetrahedron Letters 1981, 22^, 3119) was added under argon. To the mixture was added a solution of 300 mg (0.71 mmol) [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 4 4B, in 5.5 mL dry THF. The reaction mixture was refluxed for 7 hours. The cooled reaction mixture was diluted with 250 ml of ether and poured into 100 ml of saturated NaHCO 3 solution. The aqueous layer was extracted with ether (2 x 100 mL). The combined ether extracts (450 ml) were washed with 0.5N aqueous sodium hydroxide solution (2 x 100 ml) and brine (100 ml). The ether extracts were dried over anhydrous MgSO 4 and concentrated under vacuum to an oily product. Purification was carried out by chromatography on 20.2 g of silica gel 60 with hexane:ether (3:1) as eluent, whereby 250 mg of the title A methyl ester was obtained as an oil (94%).

TLC = silica gel, petroleum ether:ether (3:2), Rf=0.70, iodine.

B. [ 13, 2a( 5Z), 3a, 433- 7-[ 3-[[( cyclohexylmethyl) thio3-methyl]- 7- oxabicyclo[ 2. 2. 13hept- 2- yl3- 5- heptenoic acid

To a stirred solution of 243 mg (0.64 mmol) of the methyl ester from Part Ai, 31.4 mL of THF and 4.80 mL of H2O, under argon was added 6.00 mL of 1N aqueous lithium hydroxide solution. The mixture was flushed thoroughly with argon for 25 minutes and stirred at room temperature for 16 hours. The reaction mixture was acidified to pH 5 by adding 1N aqueous HCl solution and poured completely into 40 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 4 ), filtered and concentrated under vacuum to 253 mg of crude acid.

Purification was carried out by chromatography on 20.6 g of silica gel 60 with petroleum ether:ether (2:3) as eluent, whereby the pure title product (117 mg, 50%) was obtained together with 108 mg (46%) of mixed fractions where the title product formed the main component. TLC = silica gel, petroleum ether:ether (2:3) R^=0.32, iodine.

Analysis calculated for C^H^O^S:

C, 68.85; H, 9.29; S, 8.74 Found: C, 68.90; H, 9.43; S, 8.66 13 C NMR (CDCl 3 , 15.0 mHz) t 178.7, 32.9, 24.6, 26.1,

129.7, 129.9, 29.5, 47.1, 80.4, 26.7, 26.3, 80.7, 47.6, 33.4, 40.4, 38.0, 32.9, 29.5, 26.1, 29.5, 32.9

Example 128

[ 13, 2q( 5Z), 3a, 4&]- 7-[ 3-[[( 2- phenylethyl) thio] methyl]- 7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

A. [ 13, 2a( 5Z), 3a, 4&]- 7-[ 3-[[( 2- phenylethyl) thio] methyl]- 7- oxabicyclo[ 2. 2. 1] 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, 185 mg (1.35 mmol) of phenylethanethiol was added under argon. To this mixture was added a solution of 189 mg (0.45 mmol) [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 6 mL of dry THF. The reaction mixture was refluxed for 4 hours. The cooled reaction mixture was

diluted with 160 ml of ether and poured completely into 60 ml of saturated NaHCO^ solution. The aqueous layer was extracted with ether (2 x 60 mL) The combined ether extracts (280 mL) were washed with 0.5N aqueous sodium hydroxide solution (2 x 60 mL) and brine

(75ml). The ether extracts were dried over MgSO4 and concentrated under vacuum to an oily product. Purification was carried out by chromatography on 21.6 g of silica gel 60 with petroleum ether:ether (5:1) as eluent, whereby 157 mg of title compound A was

obtained as an oil (90%). TLC = silica gel, petroleum ether:ether (2:1), Rf=0.60, iodine.

B. [ 13, 2a( 5Z), 3a, 433- 7-[ 3-[[( 2- phenylethyl) thio] methyl]- 7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

To a stirred solution of 150 mg (0.39 mmol) of the methyl ester from Part A in 19 mL of freshly distilled THF and 2.91 mL of H 2 O, under argon was added 3.64 mL of 1N aqueous lithium hydroxide solution. The mixture was flushed thoroughly with argon for 25 min. and stirred at room temperature for 6 hours. The reaction mixture was acidified to pH 5 by adding 1N aqueous HCl solution and poured completely into 40 ml of saturated NaCl solution. The resulting solution was washed with solid NaCl and extracted with EtOAc (4 x 60 mL). The combined EtOAc extracts were dried (MgSO 4 ), filtered and concentrated under vacuum to 147 mg of crude acid. Purification was carried out by chromatography on 20 g of silica gel 60 with 2% CH 3 OH in CH 2 Cl 2 as eluent, whereby the title product (122 mg, 84%) was obtained as an oil. TLC = silica gel, 6% CH 3 OH in CH 2 Cl 2 , Rf=0.32, iodine.

Analysis calculated for C22H3Q03S:

C, 70.55; H, 8.07; S, 8.56 Found: C, 7 0.54; H, 8.08; S, 8.48 13 C NMR (CDCl 3 , 15.0 mHz) T 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, 128.4

Example 129

[ ip, 2a( 5Z), 3a, 43]- 7-[ 3-[[( 3- phenylpropyl) thio] methyl3- 7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

A. [ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[[( 3- phenylpropyl) 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, 324 mg (2.13 mmol) of 3-phenylpropyl mercaptan was added under argon. To the mixture was added a solution of 300 mg (0.71 mmol) [13,2a(5Z),3a,43]-7-[3-(p-toluenesulfonyloxymethyl)-7-oxabicyclo[2.2.1]hept- 2-yl]-5-heptenoic acid, methyl ester in 7 mL of dry THF. The reaction mixture was refluxed for 6 hours. The cooled reaction mixture was diluted with 250 ml of ether and poured into 100 ml of saturated NaHCO 3 solution. The aqueous layer was extracted with ether (2 x 100 mL). The combined ether extracts (450 ml) were washed with 0.5N aqueous sodium hydroxide solution (2 x 100 ml) and brine (100 ml). The ether extracts were dried over MgSO4 and concentrated under vacuum to an oily product. Purification was carried out by chromatography on 25 g of silica gel 60

with hexane-ether (3:1) as eluent, whereby 280 mg of title compound A was obtained as an oil (98%). TLC = silica gel, petroleum ether:ether (2:1), R^=0.60, iodine.

B. [ 13, 2a( 5Z) , 3a , 43]- 7-[ 3-[[ ( 3- phenylpropyl) thio] methyl] -

7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid

To a stirred solution of 280 mg (0.70 mmol) of the methyl ester from Part A in 34.4 mL of freshly distilled THF and 5.30 mL of H 2 O, under argon was added 6.60 mL of 1N aqueous lithium hydroxide solution. The mixture was flushed thoroughly with argon for 1 hour and stirred at room temperature for 3 hours. The reaction mixture was acidified to pH 5 by adding 1N aqueous HCl solution and poured completely into 50 ml of saturated NaCl solution. The resulting solution was saturated with solid NaCl and extracted with EtOAc (4 x 60 mL). The combined EtOAc extracts were dried (MgSO 4 ), filtered and concentrated in vacuo to 280 mg of crude acid. Purification was carried out by chromatography on 29 g of silica gel 60 with 2% CH 3 OH in CH 2 Cl 2 as eluent, whereby the title product was obtained (205 mg, 76%). TIC = silica gel,

6% CH3OH/CH2Cl2, Rf=0.34, iodine.

Analysis calculated for C23<H>32<0>3<S:>

C, 71.09; H, 8.30; S, 8.25

Found: C, 70.81; H, 8.36; S, 8,14

13 C NMR (CDCl 3 , 15.0 mHz) T 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

Example 130

[13,2a(5Z),33,43]-7-[3-[[(cyclohexylmethyl)thio]methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid

By following the procedure of Examples 48 and 49, but with cyclohexylmethanethiol instead of 1-pentanethiol, the title compound was obtained.

Example 131

[ 13, 2a( 5Z), 33, 43]- 7-[ 3-[[( 3- cyclohexylpropyl) thio] methyl]- 7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 48 and 49, but with 3-cyclohexylpropanethiol instead of 1-pentanethiol, the title compound was obtained.

Example 132

( 1 3 , 2a, 3a, 43)- 7-[ 3-[[( 2- cyclohexylethyl) thio] methyl]- 7- oxabicyclo [ 2 . 2. 1]hept-2-yl]-5-heptanoic acid

By following the procedure of Examples 46 and 47, but with 2-cyclohexyl enthiol instead of 1-hexanethiol, the title compound was obtained.

Example 133

[ 13, 2a( 5Z), 33, 43]- 7-[ 3-[[( 2- phenylethyl) thio] methyl]- 7- oxabicyclo [ 2 . 2. 1]hept-2-yl]-5-heptenoic acid

By following the procedure of Examples 48 and 49, but with 2-phenylethanethiol instead of 1-pentanethiol, the title compound was obtained.

Example 134

[ 1 3, 2g( 5Z), 3B, 4p]- 7-[ 3-[[( 3- phenylpropyl) thio] methyl]- 7- oxabicyclo[ 2. 2. 1 ] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 48 and 49, but with 3-phenylpropanethiol instead of 1-pentanethiol, the title compound was obtained.

Example 135

( 1 3, 2g, 3g, 4 3)- 7-[ 3-[[( 2- phenylethyl) thio] methyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptanoic acid

By following the procedure of Examples 46 and 47, but with 2-phenylethanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 136

( 1 3, 2 g, 3a, 4 3)- 7-[ 3-[[( 3- phenylpropyl) thio ] methyl ]- 7- oxabicyclo-[ 2. 2. 1 ] hept- 2- yl ]- 5- heptenoic acid

By following the procedure of Examples 46 and 48, but with 3-phenylpropanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 137

[ 1 3/ 2g( 5Z) , 3g, 4 3]~ 7- [ 3- [ [ ( cyclohexylmethyl) sulfinyl ] methyl] - 7- oxabicyclo [ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid (slow migrating isomer)

By following the procedure of Examples 44, 77 and 81, but with cyclohexylmethanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 138

[ 13, 2a( 5Z), 33, 43]- 7-[ 3-[[( cyclohexylmethyl) sulfinyl] methyl]- 7-oxabicyclo[ 2. 2♦ 1] hept- 2- yl]- 5- heptenoic acid ( fast traveling isomer)

By following the procedure of Examples 48, 77 and 81, but with cyclohexylmethanethiol instead of 1-pentanethiol, the title compound was obtained.

Example 139

[ 13, 2a ( 5Z) , 33, 43]- 7-[ 3-[[( 2- phenylethyl) sulfinyl] methyl]- 7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid (fast migrating isomer)

By following the procedure of Examples 44, 77 and 81, but with 2-phenylethanethiol instead of 1-pentanethiol, the title compound was obtained.

Example 140

[13,2a(5Z),3a,43]-7-[3-[[(3-phenylpropyl)sulfinyl]methyl3-7-oxabicycloE2. 2. 1]hept-2-yl]-5-heptenoic acid (slow migrating isomer)

By following the procedure of Examples 48, 77 and 82, but with 3-phenylpropanethiol instead of 1-pentanethiol, the title compound was obtained.

Example 141

( 13, 2a, 3a, 43)- 7-[ 3-[[( 2- phenylethyl) sulfinyl] methyl]- 7- oxabicyclo [ 2. 2. 1] hept- 2- yl]- 5- heptanoic acid ( fast migrating isomer)

By following the procedure of Examples 46, 77 and 81, but with 2-phenylethanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 142

[13,2a (5Z),3a,4p]-7-[3-[[(cyclohexylmethyl)sulfonyl]methyl]-7-oxabicyclo2. 2. 1]hept-2-yl]-5-heptenoic acid

By following the procedure of Examples 44, 77 and 80, but with cyclohexylmethanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 143

[ 13, 2a( 5Z), 3a, 433- 7-[ 3-[[( 2- phenylethyl) sulfonyl] methyl]- 7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 44, 77 and 80, but with 2-phenylethanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 144

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[[( 3- phenylpropyl) sulfonyl] methyl]- 7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 44, 77 and 80, but with 3-phenylpropanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 145

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[ 2-[( cyclohexylmethyl) thio] ethyl]- 7-oxabicyclo[ 2. 2. 1jhept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 63 and 44, but with cyclohexylmethanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 146

[ lp , 2a( 5Z ), 3a , 43]- 7-[ 3-[ 2-[( cyclohexylmethyl) sulf inyl Jety. l] - 7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 63, 44, 77 and 81, but with cyclohexylmethanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 147

[ 13/ 2a( 5Z), 3a, 43]- 7-[ 3-[ 2-[( cyclohexylmethyl) sulfonyl] ethyl]-7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 63, 44, 77 and 80, but with cyclohexylmethanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 148

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[ 2-[( 2- phenylethyl) thio] ethyl]- 7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5 - heptenoic acid

By following the procedure of Examples 6 3 and 44, but with 2-phenylethanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 149

[ 13, 2a( 5Z) , 33, 43]- 7-[ 3-[ 2-[ ( 2- phenylethyl) sulfinyl] ethyl]- 7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5 - heptenoic acid

By following the procedure of Examples 63, 44, 77 and 81, but with 2-phenylethanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 150

[ 13/ 2a( 5Z), 3a, 43]- 7-[ 2-[( 3- phenylpropyl) tjo] ethyl]- 7- oxabicyclo [ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure from Examples 63 and 44, but with 3-phenylpropanethiol instead of 1-hexanethiol,

the title compound obtained.

Example 151

[ 13, 2g( 5Z)/ 3g, 43]- 7-[ 3-[ 2-[( 3- phenylpropyl) sulfinyl3 ethyl]- 7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 63, 44, 77 and 81, but with 3-phenylpropanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 152

[ 13, 2a( 5Z) , 3a, 43]- 7-[ 3-[ 2-[( 2- phenylethyl) sulfonyl3-ethyl3- 7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 63, 44, 77 and 80, but with 2-phenylethanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 153

[ 13f2a( 5Z), 3a, 43]- 7-[ 3-[ 2-[( 3- phenylpropyl) sulfonyl] ethyl]- 7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 63, 44, 77 and 80, but with 3-phenylpropanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 154

[ 1 3, 2a( 5Z), 3a, 4 3]- 7-[ 3-[ 4-[( cyclohexylmethyl) thio] butyl]- 7-oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5 - heptenoic acid

Following the procedure of Examples 73, 63 and 44, but with cyclohexylmethanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 155

[ iP, 2a( 5Z), 3a/ 43]- 7-[ 3-[ 4-[( cyclohexylmethyl) sulfinyl] butyl]-7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

By following the procedure of Examples 73, 63, 44, 77 and 81, but with cyclohexylmethanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 156

[ 13f2a( 5Z), 3a, 4p]- 7-[ 3-[ 4-[( cyclohexylmethyl) sulfonyl] butyl]-7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid

Following the procedure of Examples 73, 63, 44, 77 and 80, but with cyclohexylmethanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 157

[ 13/ 2a( 5Z) , 3a, 4p]- 7-[ 3-[ 4-[( 2- phenylethyl) thio] butyl]- 7- oxabicyclo [ 2. 2. 1] hept- 2- yl]- 5-heptenoic acid

By following the procedure of Examples 73, 63 and 44, but with 2-phenylethanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 158

[ 13/ 2a( 5Z ), 3a , 43 ]- 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, 44, 77 and 81, but with 2-phenylethanethiol instead of 1-hexanethiol,

the title compound was achieved.

Example 159

[ 13, 2a( 5Z), 3a, 43]- 7-[ 3-[ 4-[( 2- phenylethyl) sulfonyl] butyl]- 7- oxabicyclo[ 2. 2. 1] hept- 2- yl]- 5 - heptenoic acid

By following the procedure of Examples 73, 63, 44, 77 and 80, but with 2-phenylethanethiol instead of 1-hexanethiol, the title compound was obtained.

Example 160

[ 1 3, 2a( 5Z), 3a, 43 3 - 7-[ 3-[ 2-( heptylthio) ethyl]- 7- oxabicyclo-[ 2. 2. 1] hept- 2- yl]- 5- heptenoic acid and methyl ester

By reacting [13,2a(5Z),3a,43]-7-[3-(2-hydroxyethyl)-7-oxabicyclo2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester (see Example 20B) with tosyl chloride as in Example 44B and with heptanethiol according to the procedure in 4 4C, the title product was obtained as the methyl ester in the form of a colorless oil,

TLC = silica gel, hexane:ether (2:1), Rf=0.45. Hydrolysis according to the procedure in example 45 led to a free acid in the form of an oil, TLC = silica gel, 3% CH3OH/CH2C12, Rf=0.23.

Analysis calculated for C22H38°3S:

C, 69.06; H, 10.01; S, 8.38 Found: C, 68.80; H, 9.99; S, 8.24 13 C NMR (CDCl 3 , 15.0 mHz) t 178.8, 33.4, 22.5, 24.5,

129.5, 130.1, 26.6, 46.1, 80.1, 29.7, 29.7, 80.1, 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), 3a( E), 433- 7-[ 3-[[( 3- phenyl- 2- propenyl) thiolmethyl3-. oxabicyclo[2.2.1]hept-2-yl3-5-heptenoic acid and methyl ester

By following the procedure from Example 44, but with 3-phenyl-2-propenylthiol instead of 1-hexanethiol used in Example 44(C), the title methyl ester was obtained. TLC = silica gel, hexane:ether (2:1) R^=0.35. By proceeding with the hydrolysis described in Example 45, the free acid was obtained,

TLC = silica gel, 3% CH 3 OH/CH 2 Cl 2 , Rf=0.25

Analysis calculated for C23H3<q0>3S:

C, 71.46; H, 7.82; S, 8.30

Found: C, 71.31; H, 7.87; S, 8,26

Claims (10)

1. Procedure for the preparation of a compound with the structural formula: and all of its stereoisomers, where A is -CH=CH- or -(CH )--; B is oxygen (-0-) or -S- (0)n. m is 1 to 8; n is 1 to 4; R is hydrogen, alkyl, alkali metal or tris(hydroxymethyl)aminomethane; and R is alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl or cycloalkylalkynyl, characterized by ether formation or thioether formation between a compound of formula and the desired R^-OH or R^-SH group, optionally followed by oxidation of a prepared thioether to the corresponding sulfinyl or sulfonyl derivative, and eventual conversion of the group "alkyl" to another specified meaning for R, e.g. by hydrolysis and possibly acidification. 2. Method according to claim 1, characterized in that a compound is produced where B is -0-. 3. Method according to claim 1, characterized in that a compound is produced where B is -S-. 4. Method according to claims 1-3, characterized in that a compound is produced where A is -CH=CH-. 5. Method according to claims 1-3, characterized in that a compound is prepared where R is H. 6. Method according to claims 1-3, characterized in that a compound is produced where n is 1. 7. Method according to claims 1-3, characterized in that a compound is produced where n is 2. 8. Method according to claims 1-3, characterized in that a compound is produced where n is 3 or 4. 9. Method according to claims 1-3, characterized in that a compound is prepared where A is -CH=CH-, m is 2 to 4, n is 1 or 2, R is H and R i is lower alkyl or cycloalkyl. 10. Method according to claims 1-3, characterized in that a compound is produced where A is -CH=CH , m is 3, n is 1, R is H, CH 3 or CgH 2 , and R 1 is lower alkyl.