IE50970B1 - Carbacyclin intermediates - Google Patents

Description

This invention relates to compounds which can be used as intermediates in the preparation of the carbacyclin analogues described and claimed in GB-A-2070597, either directly or via the intermediates described and claimed in GB-A-2122202.

Novel compounds according to the present invention are those of formulae A, B, C, D, E and F: wherein either Rg and R^ are independently selected from hydrogen, methyl and fluorine, provided that CR^R^ is not CFMe, and is c2-6 aTkyl, cis-CH-CH-CH^-CH^, - (CH^l^-CHORj θ-CH^ and R^g is an acid-hydrolysable blocking group, - (CH2) -j-CH=CH (CHg) 2 or optionally ringsubstituted phenoxy, phenyl, benzyl, phenylethyl or phenylpropyl in which there are no more than 3 ring substituents (no more than 2 of which are alkyl) independently selected from chlorine, fluorine, trifluoromethyl, C1_3 alkyl and C^_3 alkoxy, provided that neither nor R^ is fluorine when R? is optionally substituted phenoxy; or CRgR^-R? is 2-(2-furyl)ethyl, 2-(3-thienyl)ethoxy, 3-thienyloxymethyl, or C^_7 cycloalkyl optionally carrying up to three C^_5 alkyl substituents; M is ct-OR. ·. B-R_ or a-Rc: Β-OR-, n in which Rc is 6 105 510 5 hydrogen or methyl and R^g is as defined above; R^g is H, OH, CH2OH, OR|q CH2OR10 an<^ R10 an acid-hydrolysable blocking group; n is 1 or 2; Yy is trans-CH=CH~, cis-CH=CH~, -CH2CH2 or -CSC-; R32 is hydrogen or a replaceable blocking group; and R47 is Cj alkyl or CH2OH.

The nomenclature used for the prostacyclin and carbacyclin analogues described herein is the same as in GB-A-2070596. Reference should also be made to that specification for a description of examples of the 509Ϊ0 various groups in the compounds of the invention, and also for a description of blocking group introduction and removal.

The preparation of compounds of the invention will be described with reference to the accompanying Charts, in which either Rlg and R1? are each hydrogen or R16 and Rj7 together are -CH^-; either R^g is hydrogen and R^^ is alkyl or R^g and together are a second valence bond or -CH2~; R31 is a hydroxy-hydrogen protective group (as defined in GB-A-2070596); and R3g is H, -ORg^ or -CHjORjp R3i being as defined above.

The starting material for the procedure of Chart A is a known formula XXI bicyclic lactone. With respect to the Chart, thr formula XXI compourc ir transformed to the formula XXII compound by treatment with the anion of dimethyl methylphosphonate. Methods for such a reaction are known in the art; see Dauben et al, JACS 97 (1975) 4973.

The formula XXII lactol is transformed to the formula XXIII diketone by oxidation methods known in the art, e.g. using Collins or Jones reagent.

The formula XXIII diketone is cyclised to the formula XXIV compound by an intramolecular Horner-Emmons reaction; see Piers et al, Tetrahedron Letters (1979) 3279, and Clark et al, Synthetic Communications 5 (1975) 1.

The formula XXIV compound is transformed to the novel formula XXV compound wherein R^g is hydrogen and R37 is alkyl by treatment with lithium dialkyl cuprate, e.g. in diethyl ether. The lithium dialkyl cuprate is prepared by conventional means, e.g. reaction of anhydrous copper iodide in diethyl ether with an alkyllithium in diethyl ether.

The formula XXIV compound is transformed to the novel formula XXV compound wherein Rjg and R3? taken together are methylene (-CHj-) by one of two methods. By the first method, the formula XXV compound is prepared by treatment of the formula XXIV compound with the anion of trimethyloxosulfonium iodide; see, for reference, Corey et al, JACS 87 (1965) 1353. By this method, the anion is conveniently generated by treatment of trimethyloxosulfonium iodide in sodium hydride.

In the first step of the second method, the formula XXIV compound is converted to the corresponding formula XXVI hydroxymethyl compound by photochemical addition of methanol; see Bundy, Tetr. Lett. (1975) 1957. The resulting hydroxymethyl compound is treated with an excess (e.g. two equivalents) of p-toluenesulfonyl I chloride in a tertiary amine base to yield the corresponding formula XXVII tosylate which is treated with base, e.g. potassium t-butoxide, to yield the formula XXV cyclopropyl compound.

Chart B illustrates the preparation of formula LXII compounds (which can be converted to formula LXIII compounds af described in GB-B-2122202), and thus is analogous to the XXI to XXV conversion described above. Rgj and R^g may be the same or, preferably, different.

The following Examples illustrate the invention. EXAMPLE 1 Refer to Chart A. 50870 A. To a stirred solution of 19 ml (170 mmoles) dimethyl methylphosphonate and 600 ml of dry tetrahydrofuran at -78 °C under an argon atmosphere is added dropwise over 5 min 110 ml (172 mmoles) of 1.56 M n-butyl 1 ithiun in hexane. The resulting solution is stirred for 30 min at -78°C, treated with 25.4 g of 3a,5a-dihydroxy-2B-(3o-hydroxytrans-l-octenyl)-lo-cyclopentaneacetic acid, lactone, bis(tetrahydropyranyl ) ether, in 100 ml of dry tetrahydrofuran dropwise over one hr, and stirred for one hr at -78’C and four hr at room temperature. The reaction is then quenched by addition of 10 ml glacial acetic acid, diluted with 700 ml of brine, and extracted with diethyl ether (3 x 700 ml). The combined ethereal layers are washed with 200 ml bicarb and 500 ml brine and dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 37 g of formula XXII compound as oily white solid: 3-dimethy1phosphonomethyl-3-hydroxy-2-oxa-7<«tetrahydropyran-2-yloxy-6e[(3'S)-3'-tetrahydropyran-2-yloxy-trans-1 'octenyl]-bicyclo[3.3.0]octane. Crystallization of the crude product from hexane and ether yields 22.1 g of purified formula XXII product. Silica gel TLC R^ is 0.22 in ethyl acetate. The melting range is 89-93°C. NMR absorptions are observed at 3.72 (doublet, J=llHz) and 3.83 (doublet, J=llHz)4. Characteristic infrared absorptions are 3340, 1250, 1185, 1130, 1075, and 1030 cm .

B. To a solution of 10.0 g of the product of Part A in 75 ml acetone stirring under a nitrogen atmosphere at -10°C is added over 30 min 9.0 ml of Jones reagent. The resulting suspension is stirred for 30 min at -10°C and then quenched with 4 ml 2-propanol. The solvents are decanted away from the green residue and most of the acetone removed at reduced pressure. The acetone concentrate is then taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure yields 8.2 g of formula XXIII product: 2-decarboxy-6-desbutyl-6-dimethylphosphonomethyl-6-keto-PGE t, 11,15bis(tetrahydropyranyl ether). Chromatography of formula XXIII product on 600 g silica gel eluting with 20% acetone in methylene chloride yields 4.95 g of pure formula XXI11 product. Silica gel TLC R^ (in 20% acetone in methylene chloride) is 0.22. Characteristic NMR absorptions are observed at 3.14 (doublet, J=23 Hz) and 3.80 (doublet, J=ll Hz), 5.4-5.8 (m)6. Characteristic Infrared absorptions are observed at 1745, 1715, 1260, 1200, 1185, 1130, 1030, 970, 870 cm .

C. A suspension of 5.37 g of the product of Example 1, Part B, 1.33 g anhydrous potassium carbonate, and 5.37 g 18-Crown-6 ether in 200 ml toluene is heated at 75°C for six hr under a nitrogen atmosphere, cooled to O’C, and washed with 200 ml brine, 200 ml of 3:1 waterzbrine, and 200 ml brine, and dried over anhydrous sodi-ai sulfate. Most of the solvents are removed under reduced pressure and the residue is filtered through 50 g silica gel eluting with 250 ml ethyl acetate to give 3.9 g of fonnula XXIV product: 3-oxo-7a-tetrahydropyranyl-2-yloxy-6e[(3'S)-3'-tetrahydropyran-2-yl -trans-1'10 octenyl]bicyclo[3.3.0]oct-l-ene. The crude product is chromatographed on 300 g silica gel eluting with 60:40 hexane:ethy1 acetate to give 2.39 g of pure title product. Silica gel TLC Rf is 0.22 in 60:40 hexane:ethyl acetate. NMR absorptions are observed at 5.18-5.86 (m) and 5.94 (broad singlet)6. Infrared absorptions are observed at 1710 and 1632 cm1.

Following the procedure of Example 1, but employing the various 3a,5a-hydroxy-2-substituted-la-cyclopentaneacetic acid δ-lactones of fonnula XXI, there are prepared each of the various corresponding fonnula XXIV products wherein n is one.

Further, following the procedure of Example 1, but employing each of the various 3a,5a-dihydroxy-2-substituted-la-cyclopentanepriopionic acid, δ-lactones of formula XXI, there are prepared each of the various formula XXIV compounds wherein n is 2.

Further, following the procedure of Example 1, but employing each of the various 5a-hydroxy-2-substituted-la-cyclopentaneal kanoic acid lactones of formula XXI, there are prepared each of the various formula XXIV compounds wherein R18 is hydrogen. Finally, following the procedure of Example 1, but employing each of the various 3ahydroxymethyl-5a-hydroxy-2-substituted-la-cyclopentaneal kanoic acid lactones of fonnula XXI, there are prepared each cf the various fonnula XXIV compounds wherein Rj8 is -CH2ORio.

Example 2 3-oxo-8a-tetrahydropyran-2-yloxy-Υβ[(3 1S)-3'-tetrahydropyran-2-yl oxy-trans-1 '-octenyl]bicyclo[4.3.0]non-lene (Fonnula XXIV: R18, Yj, M6, R7 are defined in Example 1 and n is the integer 2).

Refer to Chart A.

A. A solution of 2.05 ml (18.9 mmoles) of dimethyl methyl phosphonate and 100 ml of dry tetrahydrofuran is stirred at -78°C under a nitrogen atmosphere and treated dropwise with 11.8 ml (18.9 mmoles) of 1.6 molar n-butyllithium in hexane. After stirring for 30 min at -78’C, the resulting mixture is treated dropwise over 25 min with 4.25 g of 3a,5a-dihydroxy-20-(3a-hydroxy-trans-l-octenyl) la-cyclopentane propionic acid, δ-lactone, ll,15-bis(tetrahydropyranyl ether), in ?0 ml of dry tetrahydrofuran. The resulting mixture is then stirred for one hr at 78°C. The solution is then allowed to stir at ambient temperature for 2 hr and is quenched by addition of 1.2 ml of acetic acid. The mixture is then added to 250 ml of brine and 200 ml of diethyl ether. The aqueous and organic layers are then separated and the aqueous layer extracted twice with diethyl ether. The ethereal extracts are then washed with brine, dried over anhydrous sodium sulfate, and concentrated to yield 5.6 g of crude formula XXII compound, as an oil: 3-(dimethylphosphonomethyl)-3-hydroxy-2-oxa-8atetra-hydropyran-2-yl-oxy-7e[(31S)-31-tetrahydropyran-2-yloxy-transl'octeny1]-bicyclo[4.3.0]nonane. Chromatography on silica gel eluting with 4:1 ethyl acetate‘.acetone yields 4.1 g of purified formula XXII product. Characteristic NMR absorption is observed at 5.15-5.65 (multiplet)6. Silica gel TLC Rf is 0.34 in 4:1 ethyl acetate:acetone.

Characteristic infrared absorptions are observed at 3350, 1235, and _i 1030 cm .

B. A suspension of 3.42 g of chromium trioxide and 80 ml of methylene chloride is treated with 5.8 ml of pyridine, stirred at ambient temperature under a nitrogen atmosphere for 30 min, and combined with 3 scoops of dry diatomaceous earth. The resulting mixture is then treated with 3.25 g of the reaction product of Part A and 8 ml of dry dichloromethane, stirred for 30 min at ambient temperature under nitrogen, filtered through 30 g of silica gel (eluting with 200 ml of ethylacetate and acetone, 2:1) and concentrated under reduced pressure. Chromatographing the residue (3.73 g) on 120 g of silica gel, eluting with ethyl acetate and acetone (4:1) yields 2.07 g of formula XXI11 product: 2-decarboxy-5-despropyl-6diinethyl phosphonomethyl-5-keto-PGEi, 11,15-bi s(tetrahydropyranyl ether). Characteristic infrared absorptions are observed at 1740 and 1715 cm .

Characteristic NMR absorptions are observed at 3.1 (doublet, J=23 Hz) and 3.8 (doublet, J=ll Ηζ)δ.

C. A suspension of 12 mg of 50Ϊ sodium hydride in mineral oil 30970 and 3 ml of diglyme is stirred at O’C. under an argon atmosphere. The suspension is then treated with 150 mg of the product of Part B in 3 ml of diglyme. After 1 hr, the cooling bath is removed and the resulting solution is stirred at ambient temperature under argon.

After a total of 20 hr from addition of the formula XXIII reactant, the resulting solution is then added to 30 ml of water and extracted with 90 ml of diethyl ether. The ethereal extract is washed with brine (30 ml), dried over anhydrous sodium sulfate, concentrated under reduced pressure to a brown oil (110 mg) and chromatographed on 10 g of silica gel eluting with hexane and ethyl acetate (1:1). There is accordingly prepared 15 mg of formula XXIV compound: 3-oxo-8a-tetrahydropyran-2-yl oxy-76-((3'S)-31-tetrahydropyran-2-yloxy-trans-1 1octenyl]bicyclo(4.3.0]non-l-ene. NMR absorptions are observed at 4.7 (broad singlet) and 5.3-6.0 (mul tiplet)6. IR absorption is observed at 1670 cm” .

Al ternatively, the formula XXIV compound above is prepared as follows: A solution of 150 mg of the product of Part B and 5 ml of dry tetrahydrofuran at O’C under an argon atmosphere is treated dropwise with 0.5 ml of 0.52 M potassium hydride and 18-crown-6 ether (Aldrich Chemical Co. Catalog Handbook of Fine Chemic’ls 1979-1980, Milwaukee, Wisconsin, p. 133; Pedersen, J.C., JACS 92:386 (1970)) in tetrahydrofuran (prepared from 800 mg potassium hydride and 1.0 g 18crown-6 ether in 8.7 ml of dry tetrahydrofuran). After stirring for one hr at O’C under argon, the mixture is added to 30 ml of water, extracted with 90 mg of diethyl ether and the ethereal extract is washed with brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and chromatographed on 9 g of slica gel eluting with ethyl acetate and hexane. Formula XXIV product (40 mg) is thereby obtained. Silica gel TLC R^ is 0.30 in ethyl acetate and hexane (1:1).

Example 3 16-Methyl-3-oxo-7a-tetrahydropyran-2-yl-oxy-66[(3 'S)-3 '-tetrahydropyran-2-yl oxy-trans-1‘-octenyllbicyclo-(3.3.0]octane (Formula XXV: Ri8, Yy, M8, n, Ly, R? are as defined in Example 1, R16 is hydrogen and R37 is methyl).

Refer to Chart A.

A suspension of 2.70 g of anhydrous copper iodide is stirred in 5097ο 100 ml of anhydrous diethyl ether at -20°C under an argon atmosphere and is treated dropwise with 20.0 ml of 1.4 M ethereal methyllithium. The resulting solution is then stirred for 15 min at -20°C and treated over 2.5 hr at -20°C with a solution of 2.00 g of the title product of Example 1 in 100 ml of anhydrous diethyl ether. Stirring is continued for an additional 1.5 hr at -20°C and the resulting mixture added to 200 ml. ol 1 M aqueous ammonium chloride. The aqueous and organic layers are then separated and the aqueous layer extracted with diethyl ether (400 ml). The combined organic extracts are then washed with 200 ml of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 2.4 g of title product as a pale green oil. Chromatography on 25 g of silica gel eluting with hexane in ethyl acetate (3:1) yields 2.0 g of title product as a colourless oil. Characteristic NMR absorptions (CDCl^) are observed at 1.18, 3,20-4.43, 4.70 and 5.2-5.96. Characteristic infrared absorptions are observed at 1745, 1665, 1200, 1130, 1110, 1075, 1035, 1020, 980 and 870 cm 1, Silica gel is 0.26 in ethyl acetate and hexane (1:3).

EXAMPLE 4 28-(t-butyldimethylsilylmethyl)-58-methyl7-oxo-3a-tetrahydropyran-2-yloxybicyclo[3.3.0) octane Refer to Chart B.

A. A solution of 40.6 g of 3a-benzoyloxy-5ahydroxy-28-hydroxymcthy1-1π-cyclopentaneacetic acid, D-lactone in 250 ml of dimethylformamide, stirring at 0°C under a nitrogen atmosphere, is treated with 25 g of imidazole in 28 g of t-butyldimethylsilyl chloride. The resulting solution is then stirred for 67 hr at ambient temperature, added to 500 ml of water, extracted with three 500 ml portions of diethyl ether, washed with 500 ml of 10% aqueous potassium bisulfate, 500 ml of aqueous sodium bicarbonate and 500 ml of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 59.9 g of 3a-benzoyloxy-5a-hydroxy-2B-(t-butyldimethylsilyloxymethyl)-la-cyclopentaneacetic acid ω-lactone as a white solid. NMR absorptions (CDC13) are observed at 0.06, 0.91, 2.1-3.12, 3.74, 4.94-5.54 τ.24-7.76 and 7.9-8.26. Infrared absorptions are observed at 1780, 1720, 1600, 1585, 1490, 1270, 1255, 1180, 1115, 1100, 1070, 1050, 830, 790 and 710 cm1. Silica gel TLC Rf is 0.20 in ethyl acetate and hexane (1:4). Β. A solution of 59.1 g of the reaction product of Part A and 500 ml of absolute methanol, stirring at ambient temperature under a nitrogen atmosphere, is treated with 35 ml of a 25% solution of sodium methoxide and methanol. The resulting reaction mixture is then stirred for 90 min at ambient temperature and quenched by addition of 9.5 ml of glacial acetic acid. Methanol is removed under reduced pressure and the resulting residue diluted with 500 ml of saturated aqueous sodium bicarbonate. The resulting mixture is then extracted with two 500 ml portions of ethyl acetate, washed with 300 ml of saturated aqueous sodium bicarbonate in 200 ml of brine, dried over sodium sulfate, and concentrated under reduced pressure to yield 58 g of an oily solid, crude 3a,5a-dihydroxy-2fl-(t-butyldimethylsilyloxymethyl)-la-cyclopentaneacetic acid, ω lactone. This crude product is then chromatographed in 800 g of silica gel, eluting with 20-75% ethyl acetate in hexane to yield pure title product as a white crystal solid. Melting range is 60.5°C to 62°C. NMR absorptions (CDCl3) are observed at 0.06, 0.90, 1.7-3.0, 3.67, 3.9-4.4, and 4.7-5.136. Silica gel TLC Rg is 0.3 in 50% ethyl acetate in hexane.

C. A solution of 37.3 g of reaction product of Part B in 400 ml of methylene chloride, stirring at 0°C under a nitrogen atmosphere, is treated with 18 ml of dihydropyran and 0.14 g of pyridine hydrochloride. The resulting solution is stirred at ambient temperature for 13 hr, treated with an additional 3 ml of dihydropyran and 30 mg of pyridine hydrochloride, stirred for an additional 4 hr, washed with two 400 ml portions of saturated aqueous sodium bicarbonate and 400 ml of brine, dried over anhydrous sodium sulfate, and concentrated under reduced presssure to yield 49 g of a pale yellow oil, crude 5ahydroxy-3a-tetrahydropyran-2-yloxy-2s-(t-butyldimethylsilyl oxymethyl )Ια-cyclopentaneacetic acid, ω lactone. Chromatography on 800 g of silica gel, eluting with 0-75% ethyl acetate in hexane yields 37 g of pure product as a colorless oil. NMR absorptions (CDC13) are observed at 0.05, 0.90, 1.62, 2.0-3.0, 3.6, 3.2-4.4, 4,67, and 4.8-5.24. Infrared absorptions are observed at 1780, 1255, 1175, 1160, 1116, 1080, 1035, 1020, 1005, 975, 835, and 775 cm’ . Silica gel TLC Rg is 0.25 in hexane and ethyl acetate (2:1).

D. A solution of 28 ml of dimethyl methylphosphonate in 800 ml of dry tetrahydrofuran at -70°C under a nitrogen atmosphere is treated with 160 ml of 1.56 M n-butyllithium in hexane, stirred for 30 min at -70°C. The resulting mixture, maintained at -70°C, is then treated dropwise over 30 min with 41.7 g of reaction product of Part C in 200 ml of tetrahydrofuran. The resulting solution is then stirred at -70°C for 1 hr, allowed to warm, stirred for an additional 2.5 hr at ambient temperature, quenched by addition of 14 ml of glacial acetic acid, added to 1 I of brine, extracted with three 700 ml portions of diethyl ether, washed with 500 ml of brine, dried over anhydrous sndium sulfate, and concentrated under reduced pressure to yield 63 g of a yellow oil, crude 6B-(t-butyldimethylsilyloxymethyl)-3-dimethyl10 phosphonomethyl-3-hydroxy-2-oxa-7a-tetrahydropyranyloxy-bicyclo[3.3.0] octane. Chromatography on 800 g of silica gel eluting with 50-75% ethyl acetate in hexane yields 44.2 g of pure title product as a colorless oil. NMR absorptions (CDC13) are observed at 0.05, 0.89, 1.23-3.02, 2.2-4.37, 4.70, and 4.996. Infrared absorptions are observed at 3380, 1255, 2235, 1120, 1050, 1035, 835, and 775 cn/1. Silica gel TLC R^ is 0.25 in ethyl acetate.

E. A suspension of 29.2 g of chromium trioxide in 700 ml of methylene chloride, stirring at ambient temperature under a nitrogen atmosphere, is treated rapidly with 50 ml of pyridine, treated with dry diatomaceous earth, stirred for 5 min, and then treated with 23.8 g of title product of Part 0 in 60 ml of methylene chloride. The resulting suspension is then stirred for 45 min at ambient temperature under a nitrogen atmosphere and filtered through 300 g of silica gel, eluting with 2 £ of ethyl acetate in acetone (2:1). Concentration under reduced pressure yields 24 g of a brown yellow oil, crude 3e-( t-butyIdimethylsilyloxymethyl)-2a-(2‘-dimethylphosphonomethyl-2’oxoethyl)-4a-tetrahydropyranyloxy-pentanone. High pressure liquid chromatography of 12 g of the crude product on silica gel eluting with 20% acetone in methylene chloride yields 4.54 g of pure product as a colorless oil. NMR absorptions (CDC13) are observed at 0.05, 0.88, 2.8-4.5, 3.77, and 4.866. Infrared absorptions are observed, at 1745, 1715, 1255, 1130, 1115, 1060, 1025, 835, 810, and 775 cm . Silica gel TLC Rf is 0.27 in 20% acetone in methylene chloride and 0.3 in ethyl acetate.

F. A degassed suspension of 0.52 g reaction product of Part E, 0.15 g anhydrous potassium carbonate, and 0.59 g 18-crown-6 ether in 20 ml toluene are stirred at 75°C for 6 hr under a nitrogen atmosphere and thereafter cooled to 0°C. The resulting solution is then washed successively with 20 ml brine, a solution of 15 ml water and 5 ml brine, and 20 ml brine, dried over anhydrous sodium sulfate, and concentrated to yield a brown residue crude δβ-t-butyldiniethylsilyloxymethyl-7a-tetrahydropyran-2-yl-oxybicyclo[3.3.0]oct-l-en-2-one, filtering through 7 g of silica gel and eluting with hexane and ethyl acetate (70 ml, 1:1) yields 0.31 g of product as an oil. High pressure liquid chromatography (10 ml fractions, 3.8 ml/minute flow rate) on silica gel, eluting with hexane and ethyl acetate (3:1) yields 0.20 g of pure product as a colorless oil. NMR absorption (CDC13) of the trimethylsilyl derivative are observed at 0.06, 0.90, 1.20-3.20, 3.20-4.85, and 5.85-6.0«. Infrared absorptions are observed at 1710, 1630, 1250, 1130, 1115, 1075, 1030, 965, 870, 835, 810, 775 cm . Silica gel TLC R^ is 0.34 in hexane and ethyl acetate (2:1).

G. A suspension of 0.35 g of anhydrous copper iodide in 12 ml of anhydrous diethyl ether at -20°C under an argon atmosphere is treated dropwise with 2.0 ml of 1.4 M methyl lithium. The resulting solution is then stirred at -20°C for 15 min, treated at -20°C dropwise over 1.5 hr with a solution of 0.22 g of the reaction product Of Part F in 12 ml of anhydrous diethyl ether. The resulting suspension is then stirred at -20°C for 2 hr, added to 50 ml of 1 M aqueous ammonium chloride, extracted with 150 ml of diethyl ether, washed with 50 ml of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 0.23 g of crude title product as a pale yellow oil. Chromatography on 30 g of silica gel, eluting with ethyl acetate and hexane (1:4) yields 0.22 g of pure title product as a colorless oil. NMR absorptions (CDCl3) are observed at 0.05, 0.90, 1.16, 1.3-2.9, 3.3-4.4, and 4,636. Infrared absorptions are observed at 1745, 1255, 1135, 1110, 1095, 1075, 1035, 1020, 835, and 775 cm . Silica gel TLC Rf is 0.32 in ethyl acetate and hexane (1:4).

Example 5 8a-hydroxy-7¢- (3a-hydroxy-trans-l-octenyl )-tricyclo[4.3.1]nonan-4-one, 8,3'-bis(tetrahydropryanyl ether) (Formula XXV ) Refer to Chart A.

A. The fonnula XXIV title product of Example 1 (4.0 g) and benzophenone (2 g) in one liter of methanol is photolyzed (3500 A lamp) for 3 hr while argon is bubbled through the solution. The methanol is then removed by concentration under reduced pressure and the residue chromatographed on 600 . g of silica gel eluting with a m’xture ranging from ethyl acetate in hexane (1:3) to 100% ethyl acetate. Compound XXVI, lS-hydroxymethyl-7a-hydroxy-6B-(6'a-hyd'roxy-trans10 11-octenyl) bicyclo[3.3.0]octan-3-one, 7,3'-bis(tetrahydropyranyl ether) is obtained as a white solid (3.45 g). Crystallization from ethyl acetate in hexane yields a white solid with melting range 65-70°C. NMR absorptions (CDC13) are observed at 0.89, 1.17-2.90, 2.92-4.40, 4.69, and 5.24-5.77S. Infrared aborptions are observed at 15 3420, 1730, 1200, 1125, 1110, 1070, 1040, 1020, and 970 cm’1. Silica gel TLC Rf is 0.29 in hexane and ethyl acetate (1:4).

B. A solution of 0.6 g of the reaction product of Part A and 0.49 g of p-tol uenesul fonyl chloride in 30 ml of pyridine is cooled to 0°C under argon for 70 hr, added to 100 ml of ice, diluted with 300 ml of water, and extracted with diethyl ether (800 ml). The ethereal extracts are then washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and chromatographed eluting with 50% to 80% hexane in ethyl acetate to yield 0.49 g of formula XXVII compound, 3-oxo-7a-tetrahydropyran-2-yloxy-6B-[(3's)-3'-tetrahydro25 pyran-2-yloxy-trans-l'-octenyl3-1β-(p-tolueneso,fonyl )-oxymethylbicyclo[3.3.0]octane, as a colorless oil. NMR absorptions (CDC13) are observed at 0.88, 1.06-2.9, 2.45, 3.17-4.35, 4.52-4.83, 5.2-5.8, 7.37, and 7.81 δ. Infrared absorptions are observed at 1740, 1600, 1360, 1200, 1190, 1175, 1130, 1110, 1075, 1035, 1020, 970, and 820 cm'1.

Silica gel TLC Rf is 0.45 or 0.26 in ethyl acetate ar.d hexane (1:1 or 1:2).

C. A degassed solution of 0.49 g of the reaction product of Part 8 and 1 ml of t-butanol in 50 ml of dry tetrahydrofuran at 0°C under an argon atmosphere is treated with 0.8 ml of 1.7 M potassium t-butoxide in tetrahydrofuran. After 5 min the reaction is allowed to warm and the resulting brown solution stirred for 3 hr at ambient temperature. Thereafter 90 ml of brine is added and the mixture is 50S70 extracted with 270 ml of ethyl acetate. The ethyl acetate extracts are then washed with 100 ml of saturated agueous sodium bicarbonate, 100 ml of brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, yielding 0.37 g of a brown oil, and chromatographed on 40 g of silica gel eluting with hexane and ethyl acetate (2:1) to yield 0.32 g of pure formula XXV title product as a colourless oil. 0. Alternatively , a suspension of 207 mg of 57% sodium hydride in mineral oil and 1.08 g of trimethyloxosulfonium iodide is treated dropwise under a nitrogen atmosphere with 6 ml of dimethylsulfoxide. The resulting grey slurry is then stirred at ambient temperature for 20 min, treated with 2.03 g of the title product of Example 1 in 4 ml of dry dimethylsulfoxide and stirred for 2 hr at ambient temperature. Thereafter stirring is continued for 1 hr at 50°C, the reaction mixture is cooled and diluted with 200 ml of water and thereafter extracted with three 100 ml portions of diethyl ether. The comDined ethereal extracts are then washed with 200 ml of water, washed with 100 ml of brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, yielding a brown oil, and chromatographed on 250 g of silica gel eluting with ethyl acetate and hexane (1:2) to yield 453 mg of pure title product.

E. For title product prepared according to Part C or Part 0 above, NMR absorptions (CDC13) are observed at 0.25-2.75, 3.15-4.39, 4.68, and 5.2-5.86. Infrared absorptions are observed at 1725, 1665, 1135, 1080, 1040, 1020, 980 cm'l.

The mass spectrum exhibits a molecular ion at 446 and silica gel TLC Rf is 0.30 in ethyl acetate and hexane.

Claims (6)

1. A compound of the formula wherein either and are independently selected from hydrogen, methyl and fluorine, provided that CR-jR^ is not 5 CrMe, and R ? is C 2 _ fi alkyl, cis-CH=CH-CH ? -CH 3 , -(CH-^-CHORjq-CHj and R 1Q is an acid-hydrolysable blocking group, -(CH 2 ) 3 -CH=CH(CH 3 ) 2 or optionally ringsubstituted phenoxy, phenyl, benzyl, phenylethyl or phenylpropyl in which there are no more than 3 ring 10 substituents (no more than 2 of which are alkyl) independently selected from chlorine, fluorine, trifluoromethyl, Cj_ 3 alkyl and alkoxy, provided that neither nor R^ is fluorine when R ? is optionally substituted phenoxy; or CR^R^-R^ is 2-(2-furyl)ethyl, 2-(3-thienyl)eth15 oxy, 3-thienyloxymethyl, or cycloalkyl optionally carrying up to 3 alkyl substituents; M, is a-OR,.:0-R c or a-R c :6-0R. n in which R c is 6 10 5 5 10 5 hydrogen or methyl and is as defined above; n is one or 2; 20 y is trans-CH=CH-, cis-CH=CH~, -CH 2 CH 2 or -C5C-; R 13 is H, OH, CHjOH, ORyg ot CH 2 OR 10 and R 10 35 defined above; and R., is C, . alkyl or CH_OH. 47 1-4 J 2 5097ο

2. A compound of the formula wherein n, Rg, R^, R?, Rjg, M g and Xj are as defined in claim 1. 53. A compound of the formula wherein n, R 3 , R 4 , R ? , R lg , M g and Y } are as defined in claim 1.

3. 4. A compound of the formula 80970 wherein n, R lg and R 4? are as defined in claim 1, and R 32 i-s hydrogen or a replaceable blocking group.

4. 5. A compound of the formula ι 5 wherein n and R^g are as defined in claim 1, as defined in claim 4.

5.

6. A compound of the formula and R 32 is R 18 wherein n and R^g are as defined in claim X, and R 32 is 10 as defined in claim 4.