FI73963C - New 9-deoxy-9a-methylene isosters and process for their preparation - Google Patents

Description

73963

NEW 9-DEXXY-9a-METHYLENE ISTERS AND METHOD FOR THEIR PREPARATION

(Separated from FI Patent Application No. 79 0178) This invention relates to compounds useful in the preparation of 9-deoxy-9a-methylene isomers of PG, also known as 6,9a-oxide -1ΓΧ, 15 (S) - as dihydroxy-Prosta-5 (Z), 13 (E)-dienoic acids and are described and the invention relating thereto is set out in the basic application of this application, FI patent application No. 79 01 78.

This invention relates to compounds of formula (I) 0

II

> »(CH2) p B (CH2) q

Hp * -, IIH

/ aj 1 R'2 ^ c - C - * - (CH2nnz-R7 R, 4 R6 wherein each of Rg and Rg, which are the same or different, may be hydrogen, -C1-6alkyl or halogen, Y is -CH -CH 2 - or -CH = CZ- (trans), wherein Z is hydrogen or ha-halogen, n 1 is zero or an integer from 1 to 4, p and q are, independently, zero, 1 or 2;

Ry is a ') hydrogen, b') -C 1-4 alkyl, c ') C 6 -C 7 monocycloalkyl radical, d *) a phenyl group which is unsubstituted or substituted by tri-halo-C 1 -C 6 alkyl, or e ') a five-atom heteromonocyclic ring containing one oxygen atom; 2,79693 X is -O- or a group - (CH 2) -, wherein m, is zero or 1; c. m 0 -j one of the groups and R'2 is hydrogen and the other is free or etherified hydroxy; one of R'3 and R'4 is hydrogen and the other is free hydroxy.

The present invention also relates to a process for the preparation of compounds of formula (I), wherein in process a) a compound of formula (II) is CH 2. [P ,, (CH 2> q 7-f (II)

ni [^ CHO

K 1 R'2 wherein p, q, R '^ and R'2 have the same meaning as above and G is a protected carbonyl group or a group ^ CH 0G' in which G1 is a silyl ether or acetal ether residue is reacted with a compound of formula (III) with the compound Z Rc I I5 E-CH-CCX- (CH9) -R7 (III),, «1 z n2 7 15 0 R6 wherein E is a group (C8H8 ^ P- or (R2O) 2P (O) in which each R 9 may be independently -C 1-6 alkyl or phenyl, Z, R 4, R 9, X, n 2 and R 2 are as defined above to give a compound of formula (IV)

tcH? rp%> q H ^ H

/ (IV) \ 1 R5 ^ C = CC— CX- (CH2) -R7 R 'R 2 I II i 2 ”2 7 H 0 R6 73963 3 where G, p, q, R' ^, Z, R '2>, R 9, X, n 2 and R 7 have the same meaning as above; b) converting a compound of formula (IV) to a compound of formula (V)

G

(ch2) (CH2) q y (v)

H "7 ~ ..... f * H

\ ί? '3? 5 • -' 'S ^ VC— CX- (CH,) „-R, R l R ·, li 2 n2 7 R, 4 R6 5 where G, p, q, R1 ^, R '2> R'3> R'4, R1, R8, X, n2 and R2? have the same meaning as above and Y * is -CH 2 -CH 2 - or -CH = CZ- (trans), Z has the same meaning as above; c) removing the protecting group in G to give a compound of formula (VI) (CH 2 i W W) q -H (VI) 1 R 5 R 5 - CX- (CH) - RR ·, R ', il 2 "2 7 2 R, 4 R6 10 where q, p, R'1, R'2, Y', R'3, R'4, Rg, Rg, X, n2 and R ? have the same meaning as above and G "is CH ΛΛλ. '· OH or ^' C = O; d) oxidizing a compound of formula (VI) wherein G" is -CH 2 wOH and other hydroxy groups, if present, protected.

4,73993

The conversion of a compound of formula (IV) to a compound of formula (V) is carried out by reactions such as, for example, nucleophilic addition to the carbonyl group in the U) chain, etherification of the alcohols formed, dehydrohydrogenation and Hydra us.

When G is a group '^ CH'v ^ OG1, the protecting group G' may be a silyl ether residue (e.g. a trialkylsilyl ether such as trimethyl, dimethyl tert-butyl, dimethyl isopropyl or dimethylethyl silyl ether, but preferably dime-10-style tert-butyl) or an acetal ether residue (e.g. tetrahydropyranyl ether, tetrahydrofuranyl ether, dioxanyl ether, oxathianyl ether, but preferably tetrahydropyranyl).

In the compound of formula (V), the protecting group G 'is selectively removed by F in the case of silyl ether and by acid hydrolysis in the case of acetal ether. When the protecting group G 'must be removed in the presence of other labile ether groups, the latter should be acetal ethers when -0G1 is silyl ether or silyl-20 1 ethers when -OG1 is acetal ether.

When G is a protected carbonyl group, it is preferably protected as an acetal or thioacetal, e.g. dimethoxyacetal, diethoxyacetal, dimethylthioacetal, diethylthioacetal, preferably dimethoxyacetal or as a ketal or thioketal with CH2-O-O-propylene, e.g. ethylene. enide thioketal

ChL-S CH, -O- \ 2, 2 (CH2-N-S-, propylenedioxy ketal (CH2-O-, ethylenedio-ch2-s-thioketal (Ih2-S-, preferably ethyl) eeni di ok si ketaal i.

The oxidation of a compound of formula (VI) wherein G "is hydroxy can be carried out using conventional oxidation methods for secondary alcohols: e.g. by treating the alcohol in an organic solvent such as acetone with a solution of sulfuric anhydride in sulfuric anhydride followed by conventional methods.

The compounds disclosed in the main patent application FI patent application No. 79 0178 brochure-5 have the following formula

CH 2 (CH 2) m -D- (CH 2) m -R

Il l m ^ 2 m 2 ^ C __

(CH2) p B

--r ^ H

V-U,? 3 R5 V "- (CH2) ni-eX- (cH2) n2-R7 R4 R6 wherein R is carboxy or -C8-alkoxycarbonyl or the group -C (OR ') 3> wherein each R 1 is -C 8 alkyl, D is -CH 2 -, -CH-OH, C = O or -O-, one of R 1 and R 2 is hydrogen and the other is hydrogen or hydroxy, or R 1 and R 2 are together form an oxo group, one of R 1 and R 2 is hydrogen, -C 1-4 alkyl, C 1 -C 4 alkenyl or C 2-4 alkynyl and the other is hydroxy or -C 1-4 alkoxy or R 1 and R 4 together each of Rg and Rg, which may be the same or different, may be hydrogen, -C1-6alkyl or halogen;

B

Y is -CH 2 -CH 2 -, -C = C-, (C = C (trans), -NH-CO;

B

X is -O- or a group - (CH 2) -, wherein m_ is zero or 1; m3 6 73963 m1 and m ^, which are the same or different, are zero or an integer from 1 to 3; n, j is zero; n2 is zero or an integer from 1 to 4; 5 p and q are, independently, zero, 1 or 2; is a 'hydrogen; b ') C ^ -C ^ -a 1 kyy! i; c1) a C 8 -C 4 monocyclic α 1 alkyl radical; d ') a phenyl group which is unsubstituted or substituted by tri-halo-C 1 -C 6 alkyl; e ') a five membered heteromonocyclic ring containing 10 single oxygen atoms.

The compounds defined above in the FI patent application No. 79 0178 are preferably prepared, using the novel compounds of this invention, by the following method: alkylation of a compound of formula (I) 0

II

(CH ^ 0Ct9q U) \ A ^ R.iVSy = '3? 5' 2 ^ | -tCH2> „1-jx- (c" 2 »„ 2- «7 R, 4 R6 where p, q, Y, n 1? n ?, X, R 1, R 8 and R 7 have the same meaning as above; 73,793 one of R 1 and R 12 is hydrogen and the other hydrogen, hydroxy or a protecting group which is attached to the bicyclic system by an ether bond, or R 1 'R 1 and R' 2 together form a protecting group for the ketone function e; one of R '3 and R' 4 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkenyl or C 1 -C 4 alkyl N-alkynyl and the other is hydroxy, -C 1-4 alkoxy or a protecting group bonded to the side chain by an ether bond or R'3 and R'4 together form a protecting group for the ketone function 1e, alkylated with a compound of formula (B) 10E -CH- (CH9) -D- (CHO) -R "'(B) (-) 2 m1 2 m2 where D, and m2 have the same meaning as above; E is (CgHg) 3P- or (RgOj ^ P (O ) a group in which each Rg may independently be C1-C8-alkyl or phenyl; R '"is free or salt-containing carboxy or C1-C8-alkoxycarbonyl or a group -C (OR') 3 in which R 'has the same meaning as above ä; followed, if desired, by removal of the protecting group 20 present.

The protecting groups for the hydroxyl functions are ether or ester residues which can be easily converted into hydroxyl groups under mild reaction conditions, e.g. by acid hydrolysis. Preferred groups are silyl ethers: e.g. triacyl ethers such as trimethyl, dimethyl tert-butyl, dimethyl isopropyl or dimethylethyl silyl ethers, and also acetal and enol ether residues; e.g. tetrahydropyranyl ether, tetrahydro-8,7963 furanyl ether, dioxanyl ether, oxathianyl ether, C 1-4 · LX-A lk 'L_Xo-Alk wherein A 1 is C 1 -C 6 alkyl.

The protecting groups for ketones are preferably ketal and thioketal residues: / X'R '\ / a 5 C groups in which X' and R * and R '

'd D

X'R »

D

mean the same as above. These protecting groups are usually removed by mild, acidic hydrolysis.

Alkylation reactions of a compound of formula (I) with a compound of formula (B) are carried out using an excess of at least 1.1 molar equivalents of the compound of formula (B) per mole of the compound of formula (I). The reaction may be carried out in any inert solvent, e.g. a linear or cyclic ether such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane; an aliphatic or aromatic hydrocarbon such as η-hexane, n-heptane, benzene or toluene; in a halogenated hydrocarbon such as dichloromethane or carbon tetrachloride as well as mixtures of these solvents.

In particular, when E in compound (B) is (CeHc) -P-, dimethyl-b b 3 lisulfoxide, hexamethylphosphoramide and other aprotic solvents are particularly preferred. Reaction of dimethyl sulfoxide with an alkali metal hydride gives dimethylsulfinylcarbanion, which in turn can produce carbanions of formula (B) from the corresponding phosphoranes and phosphonates; this solvent is therefore particularly preferred because the carbanions in the compounds of formula (B) can thus be produced in situ.

In the above alkylation reactions, the reaction temperature 30 may range from the freezing point of water to the boiling point, although room temperature is particularly preferred.

Reaction of a compound of formula CI) with a compound of formula (B) gives a mixture of geometric isomers in which the new exocyclic double bond formed in the reaction may be cis or trans.

If desired, the individual geometric isomers can be separated by fractional crystallization from a suitable solvent or by chromatography, either thin layer, column or liquid-liquid chromatography, under low, normal or high pressure.

Silica gel or magnesium silicate can be used as the carrier phase and solvents such as cyclohexane, n-hexane, benzene, methylene chloride, ethyl ether, isopropyl ether, ethyl acetate or methyl acetate-15 as the mobile phase.

If necessary, the ether protecting groups can be removed from the hydroxyl functions by mild acid hydrolysis, e.g. mono- or polycarboxylic acids such as acetic, formic, citric, oxalic or tartaric acid in a solvent such as water, acetone, tetrahydrofuran, alcohol or dimethoxyethane or low molecular weight. a sulfonic acid such as p-toluenesulfonic acid in a low molecular weight alcohol such as anhydrous ethanol or methanol, or a polystyrene sulfone residue. For example, 0.1-0.25N polycarboxylic acid (such as oxalic or citric acid) is used with a suitable, low-boiling, water-miscible solvent that can be easily removed in vacuo at the end of the reaction.

Silyl ether residues can be selectively removed in the presence of other protecting groups, with F ions in solvents such as tetrahydrofuran and dimethylformamide.

Ester protecting groups can be removed by typical saponification procedures.

10 73963

The ketal and thioketal protecting groups of ketones are generally removed as acetal or thioacetal groups by mild acid hydrolysis as described above.

Thioketals and thioacetals can be selectively removed in the presence of other protecting groups, e.g. mercuric chloride in aqueous acetone or acetonitrile, or a mixture thereof, in the presence of an alkaline earth carbonate such as calcium or magnesium carbonate.

The following examples illustrate, but in no way limit, ra-10 by this invention.

11 73963 EXAMPLE 1 (Starting material of Example 2) 1.1 g of sodium borohydride (0.029 mol) are added with stirring to a solution of 11.6 g of bicyclo [3.3.0] octane-3,7--2. --dione (8.4 x 10 moles) in 100 ml of methylene chloride and 5 100 ml of ethanol. After 45 minutes, at this temperature, the excess reagent is decomposed by the slow addition of 20 ml of acetone. The mixture is then neutralized with 1.4 ml of acetic acid and evaporated in vacuo to give a residue which is dissolved in water and methylene chloride. The organic phase is evaporated to dryness and filtered through silica gel (70:30, hexane / ethyl ether as eluent) to give 9.1 g of 7? -hydroxy-bicyclo [3.3.3] octan-3-one ·, I.R. (film) 3400, 1740 cm ”1.

A solution of this compound (0.065 mol) in 27 ml of anhydrous dimethylformamide is treated with 12.8 g of dimethyl tert-butylsilyl chloride and 8.85 g of imidazole. The resulting mixture is heated at 60 ° C for 5 hours, cooled, diluted with two volumes of water and extracted with ethyl ether (3 x 40 mL and 2 x 20 mL). The combined organic extracts are washed with 5% NaHCO 3 and then neutralized with water and evaporated to dryness to give 15.8 g of crude product (95% yield). Purification on silica gel gives 2.85 g of 7-exo-hydroxy-bicyclo [3.3.3] octan-3-one dimethyl-tert-butylsilyl ether, m.p. 40-42 ° C and 11.8 g of 7-endo-hydroxy-bicyclo [3.3.3] factan-3-one-7-dimethyl-tert-butylsilyl ether, m.p. 51-52 ° C.

. . -2 A solution of the latter (11.8 g, 4.63 x 10 moles) in 295 ml of methyl carbonate (Me 2 CO 3) is stirred, protected from moisture, under an inert atmosphere and carefully treated with 6.95 g of 80% sodium hydride. When hydrogen formation ceases, the reaction mixture is heated at 75-80 ° C for forty minutes. After cooling, the mixture is diluted with two volumes of ethyl ether 12 73963 and carefully treated with 13 g of glacial acetic acid. The organic phase is then separated with a buffer having a pH of 5.2-5.5 and the aqueous phase is extracted with ethyl ether. The combined organic extracts are dried over sodium sulfate and evaporated to dryness to give 12.82 gd of 1-7-endo-hydroxy-bicyclo [3.3.3] octan-3-one-2-carboxymethyl ester-7-dimethyl -tert-butylsilyl ether (85% of the theoretical yield of 14.49 g), which is purified on silica gel (45 g / g, eluent hexane: ethyl 10 ether, 97: 3) to give 10.81 g of a slurry of product. »H max = 254 nm, = 7000.

Starting from the exo-isomer, the same method gives d, 1-7-exo-hydroxy-bicyclo [3.3.0] octan-3-one-2-carboxymethyl ester-7-dimethyl-tert-butylsilyl ether; 15 ^ max = 254 nm '= 6500 · EXAMPLE 2 (Starting material of Examples 3,4)

A solution of 7.5 gd of 1-7-endo-hydroxy-bicyclo [3.3.3] octan-3-one-2-carboxymethyl-7-dimethyl-tert-butylsilyl ether (DMtB- silyl ether) in 75 ml of dichloromethane and 75 ml of ethanol, cooled to -20 ° C and treated, with stirring, with 0.9 g of sodium borohydride. Stir for 15 minutes, then destroy the excess reagent by adding 12 ml of acetone.

The mixture is brought to 0 [deg.] C., 20 ml of 20% strength hydrochloric acid are added, the solvent is evaporated off under vacuum and the residue is extracted several times with ethyl ether. The combined organic extracts are washed with 5 ml of water and evaporated to dryness to give a residue which is crystallized from n-hexane to give 4.8 gd, 1,3,7-endo-dihydroxy-bicyclo [3.3.0] -3 O-octane-2-exo-carboxymethyl ester-7-DMtB-silyl ether, m.p. 68-70 ° C. The mother liquor is adsorbed onto 25 g of silica gel; eluting with n-heptane: ethyl ether (90:10) to give a further 2 g of product which is pure enough to be used as such.

13 73963

A solution of 6 gd, 1,3,7-endo-dihydroxy-bicyclo [b, o, O] [octane-2-exo-carboxymethyl] teri-7-DMtB-sylyl ether in 100 ml of methanol: water (80:20), treated with 2 g of potassium hydroxide and heated to reflux for 30 minutes. After concentration in vacuo, the mixture is acidified to pH 5.1 and extracted with ethyl acetate. After evaporation of the organic layer, 5.1 g of d, 1-3,7-endo-dihydroxy-2-carboxy-bicyclo [3.3.0] octane-7-DMtB-silyl ether are obtained. A solution of this compound 150 in 10 ml of acetonitrile is then treated with 2.81 g of d - (+) - ephedrine. The mixture is kept at room temperature for 4 hours to give 2.9 g of a salt which is crystallized twice from acetonitrile to give 1.85 g of (+) - 3,7-endo-dihydroxy-2-exo-carboxy-bicyclo [3.3.0] octane. 7-DMtB-silyl ethers-15 tert-d (+) - ephedrine salt; (o = D = + 52 °. All mother liquors are collected and evaporated to dryness to give a residue which is dissolved in water and treated with 0.68 g of sodium hydroxide in water. d - (+) - ephedrine is recovered by benzene extraction and The sodium salt solution is acidified to pH 5 and extracted with ethyl acetate The organic phase is evaporated to dryness to give a residue which is treated with 2.2 g of 1-ephedrine, after several crystals 2.3 g of (-) - 3.7- endo-dihydroxy-2-exo-carboxy-bicyclo-β 3 3,0 * 3 octane-7-DMtB-7-silyl ether-1-ephedrine salt; 25 (1¾ = -9 °.

EXAMPLE 3

A solution of 6.28 g of 1,1,3-endo-dihydroxy-bicyclo-1- [3,3,3-octane-7-DMt-β-silyl ether-2-exocarboxymethyl ester in 30 ml of anhydrous methylene chloride is treated with -30 to 2.19 g of 2,3-dihydropyran and 39 mg of p-toluenesulfonic acid. After 3 h at room temperature, the reaction mixture is washed with 5% NaHCO 3 (2 x 5 mL). Evaporate the organic phase to dryness to give 8 gd, 1-3,7-endo-dihydroxy-bicyclo [3,3] octane-7-35-DMtB-silyl ethers-3-THP-ethers-2-carboxymethyls. blades, 14 73963 which is then dried by dissolving in anhydrous benzene (2 x 15 ml) and evaporated to dryness. This compound in 30 ml of anhydrous ethyl ether is added dropwise over 15 minutes to a stirred suspension of 0.6 g of LiAlH in 40 ml of anhydrous ethyl ether. Stirring is continued for 30 minutes before the excess reagent is destroyed by careful addition of 5 ml of acetone, followed by ethyl ether saturated with water. 10 g of anhydrous sodium sulphate are then added. The organic solution is filtered and evaporated to dryness to give 7.2 g of 1,1,3,7-endo-dihydroxy-2-exo-hydroxymethyl-bicyclo [3.3.0] octane-7-DMtB-silyl ether-3 -THP ether, M + 370.

EXAMPLE 4 (Starting material of Example 5) A solution of 3.8 gd of 1-3,7-endo-dihydroxy-bicyclo [3- (3,3,0)] octane-2-exo-carboxymethyl ester-7-DMtB-silyl ether in 40 ml of benzene, first treated with 3.66 g of benzoic acid and 7.9 g of triphenylphosphine and then, while stirring, 5.30 g of ethyl azo-20-bis-carboxylate in 15 ml of benzene . After stirring for 40 minutes, the organic phase is washed with 2M sulfuric acid (2 x 20 ml) and then with sodium carbonate (3 x 15 ml) and finally with water until neutral. Evaporate to dryness to give 1,1,3-exo-7-endo-dihydroxy-bicyclo [3.3.0] -25-octane-2-exo-carboxymethyl ester-7-DMtB-silyl ether-3-benzoate: NMR : 3 endo (H 5.8 (Sm) 2 endo (H 3.32 S d, d) CO 2 CH 3 (3H, 3.64 £, J) ·, 7 endo (H, 4.4 μm), and d, 1-7-endo-hydroxy-bicyclo [3.3.3] oct-3-ene-2-exo-carboxymethyl ester-7-DMtB-silyl ether, M + 296.

The crude reaction product is dissolved in anhydrous methanol, stirred for 3 hours and treated with 0.5 g of anhydrous potassium carbonate. Evaporate to dryness to give a residue which is dissolved in ethyl acetate and saturated with KH 2 PO +. The organic phase is washed neutral and evaporated to dryness. The residue is adsorbed onto silica gel and eluted with hexane and hexane: ethyl ether to give a) 1.01 gd of 1,7-endo-hydroxy-bicyclo [3.3.0] oct-3-ene-2-carboxymethyl ester-7- DMtB silyl ether dissolved in methanol is treated with 0.3 g of 5%

Pd / CaCO 3 and hydrogenated at room temperature and pressure to give d, 1-endo-hydroxy-bicyclo [3.3.0] octane-2-carboxymethyl ester-7-DMtB-silyl ether, M * 298; b) 2.01 gd of 1,1-exo-7-endo-dihydroxy-bicyclo [3.3.0] octane-2-carboxymethyl ester-7-DMtB-silyl ether, which is also saponified according to Example 2, with 1% potassium carbonate in methanol: water (80:20) to give d, 1-3-exo-7-endo-dihydroxy-bicyclo [3.3.0] octane-2-exo-carboxylic acid-7-DMtB-silyl ether, M + 300.

This is then separated into individual optical antipodes with (+) - and (-) - amphetamine.

Reaction with ethereal diazomethane converts (+) - 3-exo-7-endo-dihydroxy-bicyclo [3.3.6] [octane-2-exo-carboxylic acid-7-DHtB-silyl ether methyl ester derivative to 20]. . Subsequent reaction with 2,3-dihydropyran followed by reduction with LiAlH 2 in ethyl ether affords (+) - 3-exo-7-endo-dihydroxy-2-exo-hydroxymethyl-bicyclo [3.3.10] octane. - 3-N'Hn-ether-7-DMtB-silyl ether, M + 370.

The (-) enantiomers and racemic mixtures are prepared in a similar manner.

EXAMPLE 5 (Starting material of Example 6) 5 gd of 1-7-endo-hydroxy-bicyclo [3.3.3] octane-DMtB-silyl ether-3-exo-carboxymethyl ester in 100 ml of aqueous methanol are saponified with 2 g : 11a K0H boiling, refluxing. The methanol is removed in vacuo, after which the aqueous solution of potassium salt is extracted to remove impurities, acidified and extracted with ethyl ether. The latter extracts are combined and evaporated to dryness to give 4.5 g of 1,1-acid, which is then separated into optical antipodes (+ ) and (-) - efed-5 rine.

1.32 g of (-) - 7-endo-hydroxy-bicyclo [3.3.0] octane-7-DMtB-silyl ether-2-exo-carboxylic acid are then dissolved in 20 ml of THF and treated with 10 ml of : 11a IM BH 2 in THF. After 4 hours at room temperature, destroy the excess reagent by carefully adding 20 ml of 1.5N

NaOH. The THF is then removed in vacuo and the aqueous phase is extracted with ethyl ether. The combined organic extracts are washed neutral and evaporated to dryness to give 1.02 g of (-) - 7-endo-hydroxy-2-exo-hydroxymethyl-bicyclo [3.3.1] octane-7-DMtB-silyl ether, M + 270.

The (+) - isomer and the racemic mixture are prepared in a similar manner.

EXAMPLE 6 A solution of 2.7 gd of 1,1-erido-hydroxy-2-exo-hydroxymethyl-bicyclo [3.3.0] octane-7-DMtB-silyl ether in 20 ml of methylene chloride is treated 0.95 g of 2,3-dihydropyran and 20 mg of p-toluenesulfonic acid for 3 hours at room temperature. Wash with 7% -25 L of aqueous NaHCO 3 followed by water, then evaporate the organic phase to dryness to give crude d, l-7-endo-hydroxy-2-exo-tetrahydropyranyl-oxymethyl-bicyclo [3.3.3.1], θ '] octane-7-DMtB-silyl lyet te ri, M ^ · 354.

This is dissolved in 15 ml of THF and treated with 4.5 g of tetrabutylammonium fluoride for 10 hours while stirring. The reaction mixture is then concentrated in vacuo, adsorbed onto silica gel and eluted with benzene: ethyl ether to give 2.1 gd of 1,7-endo-hydroxy-2-exo-THP-oxymethyl-bicyclo [3.3.10] octane. , IR film 3400, 12 80 cm ”1 M + 240. A solution of this product in 25 ml of acetone is cooled to -20 ° to -8 ° C, while stirring, and treated with 4.2 ml of 8- percent

Jones reagent (CrO 2 in aqueous sulfuric acid) for 15 minutes until a faint pink color persists. Stir for a further 14-20 minutes, after which 1.5 ml of isopropanol are added dropwise and the green solution thus obtained is diluted with 6 volumes of benzene.

The organic phase is washed with 20% (NH 4) until neutral and the combined aqueous phases are re-extracted with benzene. The combined benzene extracts are dried and evaporated to dryness to give 1.82 g of 1,1-15-exo-THP-oxymethyl-bicyclo [3.3.0.0 octan-7-one, IR film 1740, 1228 cm-1 M * 238.

The nat and enant isomers are prepared by the same method. EXAMPLE 7

A solution of 0.74 g of 1,1-exo-hydroxymethyl-3-exo-20-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0 *} octane in 15 ml of anhydrous methylene chloride is added in one portion to a solution of 3.1 g of Collin's reagent * CrOg in 40 ml of anhydrous methylene chloride while stirring and cooling to 0-5 ° C. After stirring for 15 minutes, filter aid is added and the mixture is filtered to give a clear solution of the corresponding d, 1-2-exo-formyl derivative. The solvent is evaporated in vacuo, the residue is dissolved in anhydrous benzene and added to a solution of sodium dimethyl (2-oxooctyl) phosphonate.

(The latter compound is prepared by adding a solution of 0.59 g of (2-oxooctyl) dimethyl phosphonate in 10 ml of benzene dropwise to a suspension of 0.07 g of 80% NaH in 20 ml of benzene. , and stirring the resulting mixture for about an hour until hydrogen evolution ceases). Stirring is continued for 20 minutes after ib 73963 has been added to the aldehyde solution in the phosphonate-carbanion solution. The organic phase is then neutralized by the addition of an excess of 25% aqueous Na 2 SO 4 and separated. After drying, the organic phase 5 is evaporated to dryness to give a residue which is purified on silica gel (eluent cyclohexane: ethyl ether) to give 0.81 gd of 1,2-exo- [1'-oxo-non-1'-trans-1 β-enyl-3-exo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] octane, oil; 10 ^ max = 228 ^ 5 8 · 940 · EXAMPLE 8

A solution of 1.05 gd of 1,2-exo-hydroxymethyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] octane in 8 ml of benzene: DMSO (75:25) is treated with 0.89 g of dicyclohexylcarbodiimide and then, with stirring, 1.1 ml of pyridinium trifluoroacetate solution. After stirring for 3 hours, 20 ml of benzene are added and the excess carbodiimide is quenched with 0.13 g of oxalic acid in 3.8 ml of water. The benzene-20 niphase is separated, washed neutral and concentrated in vacuo to give a solution of 2-exo-formyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.1] octane (uninsulated). compound).

The d, l-, nat- and enantio-formyl derivatives are prepared using this method. Similarly, if 7-exo-hydroxy-bicyclo [3.3.3] octan-3-one-7-dimethyl-tert-butylsilyl ether is used in the methods of Examples 1, 2 and 3, 2-exo-formyl-3- endo-THP-oxy-7-exo-DMtB-silyloxy-bicyclo [3.3.3] oloctane.

30 EXAMPLE 9

A solution of 322 mg of (2-oxo-heptyl) dimethyl phosphonate in 5 ml of benzene is added to a suspension of 4.35 mg of 4.35 mg of 80% NaH in 10 ml of benzene and the mixture thus obtained. the mixture is stirred until the evolution of hydrogen ceases. 258 mg of finely divided N - bromosuccinimide are added in the dark and stirring is continued for a further 5 5 minutes. 0.37 g of 2-exo-formyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo 1,3,3,01-octane in 5 ml of benzene are then added and the mixture thus obtained is stirred for a further 15 minutes. for one minute, after which the reaction mixture is partitioned between benzene and 15% NaH 2 O 2.

The organic phase is dried, concentrated to a small volume, adsorbed onto silica gel and eluted with cyclohexane: ethyl ether (80:20) to give 0.42 g of 2-exo-12'-bromo-5'-oxo-oct-1'-enyl. -S-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo 3, 3.3 octane, δ (λmax = 251 nm λmax · · 250) ·

If (2-oxo-3R-fluoro-heptyl) -dimethyl-phosphonate is used, the corresponding 2-exo- [2'-bromo-31-oxo-41R-fluoro-oct-1'-trans-enyl- derivative; ^ max s 252 £ = 8,940. (Starting material of Example 12).

20 EXAMPLE 10 (Starting material of Example 11)

A solution of 0.3 γ-oxo-4 (2 ') - tetrahydrofuryl butyl dimethyl phosphonate is added dropwise to a stirred suspension of 36 mg of 80% sodium hydride in 5 ml of benzene. Stirring is continued until the evolution of hydrogen ceases and then a solution of 0.37 g of 2-exo-formyl-3-endo-THP-oxy-7-exo-DMtB-silyloxy-bicyclo After stirring for 20 minutes, the mixture is dissolved in benzene and 20% aqueous monosodium phosphate. The organic phase is separated, concentrated to a small volume, adsorbed onto silica gel and eluted with benzene: ethyl ether to give 0.35 g of 2-exo- [3'-oxo-5 '(2 ”) - tetrahydrofuryl-pent-1'-trans-73963 -enyl: Q-3-endo-THP-oxy-7-exo-DMtB-silyloxy-bicyclo-1,3-octane; λ max = 229 nm, - 8,800). (Starting material of Example 13). EXAMPLE 11 If 2-exo-formyl-3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] octane which was 2-exo-formyl-7-exo -bicyclo derivative, was used in the process of Example 10 and if the following phosphates were used: (2-oxo-heptyl) -dimethylphosphonate; 10 (2-oxo-octyl) -dimethylphosphonate; (2-oxo-3S-methyl-heptyl) -dimetyylifosfonaatti; (2-oxo-4-cyclohexyl-butyl) -dimetyylifosfonaatti; (2-oxo-4-phenyl-butyl) -dimetyylifosfonaatti; (2-oxo-3-m-trifluoromethylphenoxypropyl) dimethyl phosphonate; (2-oxo-3-methyl-3-butoxy-butyl) -dimetyylifosfonaatti; the following compounds could be prepared: 3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo- (3'-oxo-oct-1'-trans-1'-enyl) -bicyclo [3.3 , ooctane, 20> max = 228 £ = 8-7 ° 3 3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo- (3'-oxo-non-1'-trans- 1'-enyl) -bicyclo [3.3.0] octane, λmax = 228 mH e = 8'950i 3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo- (3 ' -oxo-25 -4'S-methyl-oct-1'-trans-1'-enyl) -bicyclo [3.3.0] octane; '228 "V £ = 8-800¾ 3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo- (3'-oxo-5'-cyclohexyl-pent-1'-trans- 1'-enyl) -bicyclo [3.3.0] {(octane), (m) <s = 22 8 πψ tl = 9.100; 21 73963 3-endo-THP-oxy-7-exo-DMtB-silyloxy- 2-exo- (3'-oxo-5'-phenyl-pent-1'-trans-1'-enyl) -bicyclo [3.3.3] octane, 2'-ox = 1,2, ϊ ί3ΐ « .250> 3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo- (3'-oxo-5 -4'-m-trifluoromethylphenoxy-but-1'-trans-1'-enyl) -bicyclo [3.3.3] octane, unregistered; 3-endo-THP-oxy-7-exo-DMtB-silyloxy-2-exo- (3'-oxo-M'-methyl-4'- butoxy-pent-1'-trans-11-enyl) -bicyclo-3,3] [octane, not registered.

EXAMPLE 12

A solution of 0.3 gd of 1,2-exo- (2'-bromo-3'-oxo-4'R-fluoro-oct-1'-trans-1 * -enyl) -3-endo- THP-oxy-7-endo-DMtB-silyloxy-bicyclo] -3.3 octane in 10 ml of anhydrous ether is added dropwise over 15 minutes to a 0.1M solution of zinc-borohydride in ethyl ether (10 ml).

After stirring for 2 hours, the reaction mixture is quenched with saturated sodium chloride and 2N sulfuric acid. The ether layer is separated and washed with water, 5% NaHCO 3 and again with water. Evaporate to dryness to give a mixture of 3 * S- and 3'R-hydroxy alcohols, which is separated by liquid-liquid chromatography as the solvent isopropyl ether to give 0.11 gd of 1,2-exo- (2'-bromo). 3'S-hydroxy-4 '(fluoro-oct-1'-trans-1'-enyl) -3-endo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.3] octane, 25 M + -H 2 O 2 -H (C 5 H 10 O 2) = 41 + 2.444 m / e, and 0.1 g of 3'R- epimer.

EXAMPLE 13

Solution of 0.3 g of 2-exo-γ3'-oxo-5 '(2 ") - tetrahydrofuryl-pent-1'-trans-1'-enyl--3-endo-THP-oxy-7 -exo-30-DMtB-silyloxy-bicyclo [3.3.0] octane in 3 ml of methylene chloride and 3 ml of ethanol, cooled to -10 ° to -15 ° C and then treated with 25 mg: After stirring for 30 minutes, the reaction mixture is quenched with 1.5 ml of acetone and 3 ml of saturated Na 2 SO 4, evaporated in vacuo, then extracted with methylene chloride-5a. The organic phase is dried over Na 2 O and evaporate to dryness to give a residue which is purified on silica gel (eluent hexane: ethyl ether) to give 0.1 g of 2-exo-1'S-hydroxy-5 '(2 ") - tetrahydrofuryl-pent-1'-trans- 1'-enyl} -3-endo-THP-oxy-7-exo-DMtB-10-silyloxy-bicyclo [3.3.0] octane and 0.11 g of 3'R-epi- + y-0 mere , both M / - "OH 374 m / e.

EXAMPLE 14

Following the procedure of Examples 12 and 13 and using a »/ • '' - unsaturated ketone prepared as in Examples 9, 10 and 11, the following compounds are prepared: 3-endo-THP-oxy-7-endo-DMtB-silyloxy 2-exo- (2'-bromo-3'S-hydroxy-oct-1'-trans-1'-enyl) -bicyclool, 3,0} octane, M + -H 2 O-102: 424.426 m / e; 3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'S-hydroxy-oct-1'-trans-1'-enyl) -bicyclo [3.3.3] octane, [m + -20202 344; 3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'S-hydroxy-4'S-methyl-oct-1'-trans-1 '-enyl) -bicyclo [3.3.3] -25 octane,} m + -? 0-102 (362-), 3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'S-hydroxy-non-1'-trans-1'-enyl) -bicyclo [3.3.3} octane, [_M + -H2O-102] 360; 3-endo-THP-oxy-7-endo -DMtB-silyloxy-2-exo- (3'S-hydroxy-30-cyclohexyl-pent-1'-trans-1'-enyl-O-bicyclo) -1,3-octane, m + -1- ^ 0-102 ^ 3 86 -, 23 73963 3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'S-hydroxy-5'-phenyl-pent-1'-trans- 1'-enyl) -bicyclo [3,3,6] octane, [m + -H 2 O-102-38080 / 3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'S-hyd -5-roxy-4'-m-trifluoromethylphenoxy-but-1'-trans-1'-enyl) -bicyclo [3.3.6] octane, [m + -H2O-102] 450 m / e ·, 3- endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'S-hydroxy-4'-methyl-4'-butoxy-pent-1'-trans-1'-enyl) - bi-cyclo [§, 3, o] [octane, [m + -102 ^ 396 m / no 10 3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (2'-bromo-3 (R-hydroxy-oct-1'-trans-1'-enyl) -bicyclo [3.3.1] octane, [m + -1 ^ 0-102-424.426 m / no 3-endo-THP-oxy- 7-endo-DMtB-silyloxy-2-exo- (3'R-hydroxy-oct-11-trans-1 * -enyl) -bicyclo [3.3.3] octane, 15 [_M + -H2O-102] ] 346i 3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'R-hydroxy-4'S-methyl-oct-1'-trans-1'-enyl) -bicyclo] 3,3,0-octane,] -M + -1 ^ 0-102 ^ 3601 3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'R-hydroxy-20-hydroxy-non -1'-trans-1'-enyl) -bicyclo [3.3.3] octane, -h2-ioyl 360 m / no 3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'R-hydroxy -roxy-5'-cyclohexyl-pent-1'-trans-1'-enyl) -bicyclo [3.3.3] octane, [m + -H 2 O-102] 386i 25 3-endo-THP-oxy-7-endo -DMtB-silyloxy-2-exo- (3'R-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl) -bicyclo [3.3.0] octane, [m + - H20-102] 380 i 3-endo-THP-oxy-7-endo-DMtB-silyloxy-2-exo- (3'R-hydroxy-4'-m-trifluoromethylphenoxy-but-1'-trans-1 1'-enyl-30β) -bicyclo [3.3.0] octane, N, N + - ^ 0-102 *] 450 m / Fe 24 73963 3-endo-THP-oxy-7-endo-DMtB-silyloxy-2 -exo- (3'4-hydroxy-4'-methyl-4'-butoxy-pent-1'-trans-1'-enyl-bicyclo, 3'-octane,] 396.

EXAMPLE 15 A solution of 1.17 g of 2-exo- (3,5-hydroxy-oct-1'-trans-1,1-enyl) -3-endo-THP-oxy-7-endo-DMtB-silyloxy -bicyclo [3.3.3] octane in 12 ml of anhydrous methylene chloride, treated with 120 mg of 2,3-dihydropyran and 5 mg of p-toluenesulfonic acid, after 4 hours at room temperature the organic phase is washed first for 5 hours. -prosenttisella

NaHCO 3 followed by evaporation to dryness with water to give 1.45 g of crude 2-exo- (3'S-THP-oxy-oct-1'-trans-1'-enyl) -3-endo- THP-oxy-7-endo-DMtB-silyloxy-bicyclo [3.3.0] octane. This product is dissolved in 12 ml of THF and treated with 2 g of tetrabutylammonium fluoride. The mixture thus obtained is stirred for 12 hours at room temperature and concentrated to a small volume to give a residue which is purified on silica gel (ethyl ether as eluent) to give 920 mg of 2-exo- (3'S-hydroxy-oct-1,1-trans-1,1-enyl) -3-endo-7-endo-dihydroxy-bicyclo [3.3.3] octane-3,3'-bis-THP-ether, IR film 3400 cm EXAMPLE 16 (Starting materials of Example 19) Using the procedure of Example 15 The following bicyclo [3.3.3] octane-3,3'-bis-THP ether derivatives are prepared according to the compounds prepared according to 12, 13 and 14: 2-exo- (2'-bromo-3'S-hydroxy-4'-fluoro-oct- 1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy, IR film 3400 cm 3 2-exo- (2'-bromo-3'R-hydroxy-4'R-fluoro-oct -1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy, IR film 3400 cm 2 25 7 3 9 6 3 2-exo- (3'S-hydroxy-5 '(2 ") -tetrahydrofuryl-pent-1'-trans-1'-enyl) -3-endo-7-exo-dihydroxy, IR film 3400 cm -1 '(starting material of Example 17) 2-exo- (3'R- hydroxy-5 '(2') - tetrahydrofurfuryl uryl-pent-1'-5-trans-1'-enyl) -3-endo-7-exo-dihydroxy, IR film 3400, 1250 cm -1; 2-exo- (2'-bromo-3'S-hydroxy-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy, IR film 3400, 1250 cm-1; 2-exo- (2'-bromo-3'R-hydroxy-oct-1'-trans-1'-enyl) -10 -3-endo-7-endo-dihydroxy, IR film 3400, 1250 cm-1; 2-exo- (3'R-hydroxy-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy, IR film 3400, 1250 cm-1; (Starting material of Example 18) 2-exo- (3'R-hydroxy-oct-1'-trans-1'-enyl) -3-endo-7-15-endo-dihydroxy, IR film 3400, 1250 cm-1; 2-exo- (3'S-hydroxy-4'S-methyl-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy, IR film 3400, 1250 cm-1; 2-exo- (3'R-hydroxy-4'S-methyl-oct-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy, IR film 3400, 1250 cm-1; 2-exo- (3'S-hydroxy-non-1'-trans-1 * -enyl) -3-endo-7-endo-dihydroxy, IR film 3400, 1250 cm-1; 2-exo- (3'R-hydroxy-non-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy, IR film 3400, 1250 cm-1; 2-exo- (3'R-hydroxy-5'-cyclohexyl-pent-1'-trans-1'-25-enyl) -3-endo-7-endo-dihydroxy, IR film 3400, 1250 cm-1; 2-exo- (3'S-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy, IR film 3400, 1250 cm-1; 26 73963 2-Exo- (3'R-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy, IR film 3400, 1250 cm -1 2-exo- (3'S-hydroxy-4'-m-trifluoromethylphenoxy-but-11-trans-1'-enyl) -3-endo-7-endo-dihydroxy, IR film δ 3400, 1250 cm -1; 2-exo- (3'R-hydroxy-4'-m-trifluoromethylphenoxy-but-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy, IR film 3400, 1250 cm-1 2-exo- (3'S-hydroxy-4'-methyl-4'-butoxy-pent-1'-trans-10'-enyl) -3-endo-7-endo-dihydroxy, IR film 3400, 1250 cm "1; 2-exo- (3'R-hydroxy-4'-methyl-4'-butoxy-pent-1'-trans-1'-enyl) -3-endo-7-endo-dihydroxy EXAMPLE 17 15 Chromic anhydride 0, The 4 g solution is added in successive portions to 4 ml of pyridine while stirring. As soon as the complex forms, this mixture is treated with 0.36 g of 2-exo- (3'S-hydroxy-5 '(2 ") - tetrahydrofuryl-pent-1'-trans-1'-enyl) -3-endo -7-exo-dihydroxy-bicyclo [3.3.0} octane-3,3'-bis-THP-ether in 4 ml of pyridine.

The reaction mixture is kept overnight at room temperature, diluted with 3 volumes of benzene and filtered. The filtrate is then evaporated to give a residue which is partitioned between benzene and 2N sulfuric acid. The aqueous portion is re-extracted with benzene, washed first with water, then with NaHCO 3 and again with water, evaporated to dryness to give 0.31 g of 2-exo- (3'S-hydroxy-5 '(2 ") - tetrahydrofuryl-pent-- 1'-trans-1'-enyl) -3-endo-hydroxy-bicyclo [3.3.3] octan-7-one-3,3'-bis-THP ether; 30 IR film 1740, 1220 cm-1 "1.

EXAMPLE 18 27 7 3 9 6 3 A stirred and cooled (-10 to -6 ° C) solution of 0.8 g of 2-exo- (3'S-hydroxy-oct-1'-trans-1'-enyl) - 3-endo-7-endo-dihydroxy-bicyclo], 3,0-octane-3,3'-bis-THP-ethers-5 in 20 ml of acetone, treated with 1.6 ml of Jones' in the reagent for 15 minutes. Stir for another 15 minutes, then add 80 ml of benzene. The organic phase is separated, washed neutral with 15% aqueous (NH 4 SO 4), dried and evaporated to dryness to give 0.71 g of 2-exo- (3'S-hydroxy-oct-1'-trans-1'- enyl) -endo-hydroxy-bicyclo [3.3.3] octan-7-one-3,3'-bis-tetrahydropyranyl ether; IR film 1741 cm-1.

EXAMPLE 19 Using either of the oxidation methods set forth in Examples 17 or 18 for the triols of Example 16, the following 3-endo-hydroxy-bicyclo [3.3.3] [octan-7-one-3,3'-bis-THP is prepared. ethers: 2-exo- (2'-bromo-3'S-hydroxy-4'R-fluoro-oct-1'-trans-20 -1'-enyl), IR film 1740 cm-1; 2-exo - (2'-bromo-3'R-hydroxy-4'R-fluoro-oct-11-trans-1'-enyl), IR film 1740 cm -1; 2-exo- (3'S-hydroxy-5 ' (2 ") - tetrahydrofuryl-pent-1'-trans-1'-enyl), IR film 1740 cm-1; 2-exo- (3'R-hydroxy-5 '(2 ") - tetrahydrofuryl-pent-1'-trans-1'-enyl), IR film 1740 cm-1; 2-exo- (2'- bromo-3'S-hydroxy-oct-1'-trans-1'-enyl), IR film 1740 cm -1; 2-exo- (2'-bromo-3'R-hydroxy-oct-1'-trans-1 '-enyl), 30 IR film 1740 cm-1, 28 73963 2-exo- (3'S-hydroxy-oct-1'-trans-1'-enyl), IR film 1740 cm-1; 2-exo- (3 (R-hydroxy-oct-1'-trans-1'-enyl), IR film 1740 cm-1, 5-exo- (3'S-hydroxy-4'S-methyl-oct-1'-trans-1'- enyl), IR film 1740 cm -1; 2-exo- (3'R-hydroxy-4'S-methyl-oct-1'-trans-1'-enyl), IR film 1740 cm -1; 2-exo- ( 3β-hydroxy-non-1'-trans-1'-enyl), 10 IR film 1740 cm -1 '; 2-exo- (3'R-hydroxy-non-1'-trans-1'-enyl) ), IR film 1740 cm-1, 2-exo- (3'S-hydroxy-5'-cyclohexyl-pent-1'-trans-1'-enyl), IR film 1740 cm-1, 2-exo- ( 3'R-hydroxy-5'-cyclohexyl-pent-1'-trans-1'-enyl), IR film 1740 cm -1; 2-exo- (3'S-hydroxy-5'-phenyl-pent-1 ' -trans-1'-enyl), IR film 1740 cm -1; 2-exo- (3'R-hydroxy-5'-phenyl-pent-1'-trans-1'-enyl) , 20 IR film 1740 cm-1; 2-exo- (3'S-hydroxy-4'-m-trifluoromethylphenoxy-but-1'-trans-1'-enyl), IR film 1740 cm-1; 2-exo- (3'R-hydroxy-4'-m-trifluoromethylphenoxy-but-1'-trans-1'-enyl), IR film 1740 cm-1; 2-exo- (3'S-hydroxy-4'-methyl-4'-butoxy-pent-1'-trans--1'-enyl), IR film 1740 cm-1; 2-exo- (3'R-hydroxy-4'-methyl-4'-butoxy-pent-1'-trans-1'-enyl), IR film 1740 cm-1.

EXAMPLE 20 29 73963

A solution of 2.1 gd of 1,2-exo- (3'-oxo-non-1H-trans-1'-enyl) -3-exo-THP-oxy-7-endo-DMtB-silyloxy- bicyclo [3.3.3] ct, octane (prepared according to Example 7), 5 is reduced at -15 ° C in methylene chloride: ethanol to 0.17 g of NaBH4, by the method of Example 13, to give 2.01 gd, 1-2-exo- (3 '(S, R) -hydroxy-non-1'-trans-1'-enyl) -3-exo-THP-oxy-7-endo-DMtB-silyloxy-bicyclo_3, 3, 10 octane * Without separating the 3'S and 3'R alcohols, this compound is reacted in 0.4 ml of methylene chloride with 0.4 g of 2,3-dihydropyran in the presence of 25 mg of p-toluenesulfonic acid to give the corresponding d, 1-exo- (3 '(S, R) -hydroxy-non-1'-trans-1'-enyl) -3-exo-hydroxy-7-endo-DMtB-silyloxy-bicyclo [3 .3, oj -15 octane-3,3'-bis-THP-ether. Without purifying any of this compound, it is treated with 2.5 molar equivalents of tetrabutylammonium fluoride in THF to remove the silyl ether.

The product d, then-2-exo- (3 '(S, R) -hydroxy-non-20 -1'-trans-1'-enyl) -3-exo-7-endo-dihydroxy-bicyclo [3,3,10] [octane-3,3'-bis-THP ether (1.660 g) is oxidized with pyridine chromic anhydride to give 1.25 gd of 1,2-exo- (3 '(S, R) -hydroxy-non-1'-trans-1'-enyl) -3-exo-hydroxy-bicyclo [3.3.3] octan-7-one 3,3'-bis-THP-ether; 25 IR film 1740 cm ”1.

EXAMPLE 21

A solution of 0.45 g of 2-exo- (3'S-hydroxy-oct-1'-trans-1'-enyl) -3-endo-hydroxy-bicyclo [3.3.1] octan-7-one -3,3'-bis-THP ether in ethyl acetate, hydrogenated at ambient temperature and pressure in the presence and presence of 0.1 g of 5% Pd / CaCO 3 until 1.01 equivalents of hydrogen have been absorbed. Filter and evaporate to dryness to give 0.42 g of 2-exo- (3'S-hydroxy-octan-1'-yl) -3-endo-hydroxy-bicyclo [3.3.3] octan-7-one. 3'-bis-THP-73,7963 ether. Treatment of this compound with Wittig's reagent prepared from 4-carboxybutylphosphonium bromide affords the product which is esterified with diazomethane and depyranylated to give 0.12 g of 11β, 1,5S-dihydro-5-hydroxy-9α-deoxy -9a-methylene-prostacyclo-5-enoic acid methyl ester, M + 366 m / e. The 5-cis- and 5-trans geometric isomers are separated by liquid-liquid chromatography.

EXAMPLE 22

A solution of 2.2 g of 3-endo-hydroxy-bicyclo [3.3.3] oc-10-tan-7-one in 100 ml of anhydrous benzene is treated with 4 ml of ethylene glycol and 0.2 g of p-toluenesulfone. -acid monohydrate and boiled under reflux for 12 hours, the water formed during the reaction is collected.

0.25 ml of pyridine are then added and the mixture is cooled. The organic phase is washed with water, NaHCO 3 and then with water, evaporated to dryness to give 2.32 g of 3-endo-hydroxy-bicyclo [3.3.3] oloctan-7-one-7,7-ethylene dioxide, IR film 3450 cm ”\ no absorption 1745 cm” ^.

A solution of this product in 40 ml of acetone is cooled to -5 ° C and treated at this temperature with 4.1 ml of Jones reagent. After 20 minutes at -5 ° C, the excess oxidant is quenched with 4 mL of isopropyl alcohol. 150 ml of benzene are added and the benzene phase is washed successively with 20% (NH 4 Cl 2, water, 5% NaHCO 3 and water) and evaporated to dryness to give 2.1 g of 1,1-bicyclo 1,3,3-octane-3,7-dione-7,7-ethylenedioxide, mp 40-42 ° C.

According to the procedure of Example 1, this compound is reacted with methyl carbonate to give d, l-bicyclo [3.3.0] octane-3,7-dione-2-carboxymethyl ester-7,7-ethylene dioxide; max * ”1 *» ^ = 7000.

31 73963

According to the procedure of Example 2, a solution of this product in 20 mL of CHCl 3 and 20 mL of ethanol is reduced with NaBH 4 at -20 ° C to give 1.72 gd of 1-3-endo- hydroxy-bicyclo [3.3.0] octan-7-one-2-exo-5-carboxymethyl ester-7,7-ethylenedioxide, IR film 3400 cm-1 1720 cm-1.

A solution of 1.57 g of this compound in 3 ml of dimethylformamide is treated with 1.3 g of dimethyl tert-butylsilyl chloride and 0.885 g of imidazole and then washed at 0 ° C. at 5 hours. After cooling, add water and work up as usual to give 2.3 gd, 1-3-endo-hydroxy-bicyclo [3.3.3] octan-7-one-2-exo-carboxymethyl-7, 7-Ethylene dioxide-3-dimethyl-tert-butyl-silyl ether, 15 IR film 1710 cm-1, Reaction with LiAlH 2 in anhydrous ethyl ether as shown in Example 3 gives d, 1-3-endo-hydroxy-2- Exo-hydroxymethyl-7,7-ethylenedioxy-bicyclo [3.3.3] octan-7-one-3-dimethyl-tert-butyl-silyl ether quantitatively, 20 IR film 3400 cm-1.

EXAMPLE 23 Using dithioethylene glycol in the process of Example 22 instead of ethylene glycol, the corresponding 7,7-ethylenedithio analogs are prepared.

EXAMPLE 24 1.8 gd, 1,3-Endo-hydroxy-2-exo-hydroxymethyl-7,7-ethylenedioxy-bicyclo [3.3.0] octan-7-one-3-dimethyl- the tert-butyl silyl ether is oxidized by the method of Example 8 to give the corresponding 2-for-30-methyl derivative. This is then reacted with (2-oxo-heptyl) -dimethylphosphonate as described in Example 10 to give 1.23 gd of 1-3-endo-hydroxy-2-exo- (3'-oxo- oct-1'-trans-1'-enyl) -32,7963 -7,7-ethylenedioxy-cyclo [3,5] oloctan-7-one-3-dimethyl-tert-butyl-silyl ether (λmax 228 nm * = 6 * 980). According to the procedure of Example 12, this is reduced with zinc borohydride in ether to give 1.22 gd of 1-3-endo-hydroxy-2-exo- (3 '(S, R) -hydroxy-oct-1'- trans-1'-enyl) -7,7-ethylenedioxy-bicyclo [3.3.3} octan-7-one-3-dimethyl-tert-butyl-silyl ether.

A solution of this compound in 25 mL of methanol is treated with 10 mL of 1N HgSO 4 by refluxing for 10 to 50 minutes. The methanol is evaporated in vacuo, the residue is extracted with ethyl ether and the organic phase is evaporated to dryness to give 0.72 g of crude d, 1,3-endo-hydroxy-2-exo- (31 (S, R) -hydroxy-oct-1 'l'-trans-enyl) -bisyk-lo ^ 3.3, cQoktan-7-one. The individual isomers are separated chromatographed on silica gel with silica gel, hexane: ethyl ether as eluent and then converted into tetrahydropyranyl ether by treatment with 2,3-dihydropyran in methylene chloride as in Example 15. In this way, a compound identical to all 3'S-hydroxy isomers is prepared. 2-exo- (3'S-hydroxy-oct-11-trans-1'-enyl) -3-endo-hydroxy-bicyclo-Ϊ3.3, octan-7-one-3.3 prepared in 20 ratios according to Example 18. with 1'-bis-tetrahydropyranyl ether.

In a similar manner, by the method of Examples 22 and 24, all of the compounds prepared in Examples 17, 18 and 19 can be prepared.

* EXAMPLE 25 33 73963

Ethylene glycol (15 ml) and p-toluenesulfonic acid (0.9 g) are added to a solution of 2-exo-bromo-3-endo-hydroxy-bicyclo, 2,6-heptan-6-one in benzene and the mixture is refluxed for 12 hours. , the water formed during the reaction is removed, then pyridine (0.6 ml) is added to the mixture and cooled to room temperature.

The organic phase is washed with water, 2.5% aqueous NaHCO 3 and water, dried. The benzene (100 mL) is removed in vacuo, then the mixture is treated with tributyltin hydride (41 g) under a nitrogen atmosphere at 55 ° C for 8 hours. After cooling to room temperature, the organic phase is washed with saturated aqueous NaH 2 PO 4, dried and evaporated to dryness. The residue obtained is purified on SiO 2 (240 g) as eluent with benzene-ethyl ether to give 14.9 g of 3-endo-hydroxy-bicyclo [3.2.2] (T [heptan-6-one i -6.6- ethylene dioxide, IR film 3460 cm -1 M + 242 as trimethyl-20-silyl ether.

EXAMPLE 26 7 3963 34 A stirred solution of 3-endo-hydroxy-bicyclo [3.2.2] heptan-6-one-6,6-ethylenedioxide (12.75 g) in benzene (340 ml) and DMSO: treated with dicyclohexylcarbodiimide (46.35 g), pyridine (5.9 g) and trifluoroacetic acid (5.4 g), after 6 hours the mixture is diluted with benzene (600 ml) and water (50 ml). ml), filtered from dicyclohexylurea and the organic phase is washed with water, dried over MgSO 4 and evaporated to dryness to give bicyclo [2.2.1] octa-3,6-dione-6,6-diethylene dioxide, IR film 1742 cm-1 M + 168.

A solution of this crude product in dimethyl carbonate (70 ml) is added to a suspension of sodium hydride (80% in mineral oil, 4 g). The mixture is stirred at room temperature until the evolution of Hg ceases, after which it is heated at 75-80 ° C for 40 minutes.

After cooling, the reaction mixture is diluted with benzene (350 ml) and acetic acid (8.4 g), washed with water, dried and evaporated to dryness to give a mixture of 20 (1: 1) d, 1-bicyclo [3.2.0] hta-3.6 -dione-2-carboxymethyl ether-6,6-ethylene dioxide, M + 226 (p = 0, q * 1) and d, l-bicyclo [3.2.1] hta-3,6-dione-4-carboxymethyl ester- -6,6-ethylene dioxide, M + 226 (p * 1, qsO), chromatographed on SiO 2 (Fe, Fe-free) using hexane-ethyl ether as eluents.

EXAMPLE 27 Using the procedure of Example 26, 14.85 g of 3-endo-hydroxy-bicyclo [4.3.3] nonan-7-one-7,7-ethylenedioxide are obtained by the oxidation method to give 13.9 g of bicyclo [4.3.3] ( 3-non-3,7-30-dione-7,7-ethylenedioxide, IR film 1740 cm -1 M + 196 m / e, the carbomethoxylation process yields 4.2 gd, 1-bi-cyclo [4.3.3] o -3,7-dione-2-carboxymethyl ester-7,7-ethylene dioxide, M + 254 m / e (p * 1, q * 2) and 4.8 g of 35 7 3 9 6 3 dtl-bicyclo [4.3. θΊ nona-3,7-dione-H-carboxymethyl ester - 7,7-ethylene dioxide, which is also called d, 1-bicyclo [3,5] nona-3,8-dione-2-carboxymethyl ester- 8 , 8-ethylene dioxide (p * 2, q = 1), M + 254 m / e.

EXAMPLE 28 A stirred solution of bicyclo [3.3.3] quanan-7-en-3-one (90 g) in dimethyl carbonate (350 ml) is added to a suspension of sodium hydride (80% mineral oil dispersion, 42 g) in dimethyl carbonate. 10 (550 ml). After the evolution of hydrogen has ceased, the mixture is heated for 4.5 hours at 75-80 ° C, cooled to room temperature, diluted with benzene (2.7 L) and washed with 25% aqueous NaH 2 PO 4 solution, evaporated to dryness to give bicyclo 3-O-nonan-15-7-en-3-one-2-carboxymethyl ester (91 g) (1 v <= = 252 n », g., 8,200).

A solution of this compound in methylene chloride (1.2 L) and ethanol (1.2 L) is cooled to -20 ° C and treated, with stirring, with NaBH 4 (14.4 g). The mixture is stirred for 30 minutes at -20 ° C, then treated with acetic acid (23 ml), warmed to room temperature and the solvents evaporated in vacuo.

The residue is partitioned between ethyl acetate and water, the organic layer is dried and evaporated in vacuo to give d, l-25-bicyclo [4.3.0] nonan-7-ene-3-endo-hydroxy-2-exo-carboxymethyl ester, M + 268 as trimethylsilyl ether · * '** · (64 g) dissolved in dry tetrahydrofuran v. · (THF) and treated with 2,3-dihydropyran (33 g) and p-toluenesulfonic acid (0.63 g) for 3 hours at room temperature. temperature. Pyridine (0.4 g) is added to the reaction mixture, which is then cooled to 0 ° C and added over 45 minutes, with stirring, 1.2M BH · .n - '. "V o ^ solution in THF, Stirring is continued for 1 hour at 0 ° C, after which water is added to destroy the remaining 36 7 3 9 6 3 hydride. Boron formed with vigorous stirring and external cooling at -5 ° to 0 ° C is oxidized by the slow simultaneous addition of 110 ml of 3M sodium hydroxide and 110 ml of 30% hydrogen peroxide, keeping the internal temperature at 20-25 [deg.] C. The oxidation mixture is diluted with benzene (21) and the layers are separated. the layers are combined, washed successively with 1% sodium carbonate, saturated sodium sulfite and saturated sodium chloride, and dried over MgSO 4, after evaporation of the solvents to give a crude mixture of 7- and 8-hydroxy combinations, which is separated on a SiO 2 (300 g) column. Chromatography, eluting with ethyl ether, gives: 15 d, 1-bicyclo [4.3.0] nonane-3-endo, 7β-dihydroxy-2-exo-carboxymethyl ester-3-THP-ether C2 * 4 g ), M + 370 trimeth as over-silyl ether, and d, 1-bicyclo, N, N-nonane-S-endo-N-dihydroxy-2-exo-carboxymethyl ester-3-THP-ether (.27 g), M + 370 as trimethyl-20-silyl ether.

A solution of 7β-hydroxy alcohol (24 g) in dry DMF (30 ml) is treated with dimethyl tert-butylsilyl chloride (15.8 g) and imidazole (8.85 g) and heated after 5 hours at 60 ° C, cooled to room temperature, diluted with water (90 mL) and then extracted with ethyl ether. The organic layers are collected, washed with water and evaporated to dryness to give d, l-bicyclo [3S] 0n-nonane-S-endo,? N-dihydroxy-2-exo-carboxymethyl ester-3-THP-ether-7-DMtB-silyl ether, 30 M + 412.

To a stirred solution of this compound in dry toluene (220 mL) cooled to -70 ° C is added a solution of 1.4M DIBA in toluene over 45 minutes, maintaining the temperature between -70 ° and -60 ° C. Stirring is left for 2 hours, the remaining hydride is destroyed by adding 2M isopropyl alcohol in toluene.

The reaction mixture is warmed to room temperature and 30% aqueous Na 2 PO 4 (60 '5 mL) and NagSO 4 (50 g) are added sequentially. After filtration, the organic phase is washed with water and evaporated in vacuo to give d, 1-bicyclo [4.3.3] nonane-3-endo, 7β-dihydroxy-2-exo-formyl-3-THP-ether-7-DMt3- silyl ether <p * 2, qsl), M + 382.

Using the 8β-hydroxy compound in this process, the following is obtained: d, 1-bicyclo [3,3,0] nonane-3-endo, 8β-dihydroxy-2-exo-carboxymethyl ester-3-THP-ether-8-DMtB -silyl ether, M + 412, and 15 d, 1-bicyclo [4.3.3] nonane-3-endo, 8β-dihydroxy-2-exo-formyl-3-THP-ether-8-DMtB-silyl ether, M * 382.

EXAMPLE 29: A solution of (2-oxo-heptyl) -dimethylphosphonate: (0.33 g) in dry benzene (5 ml) is added with stirring; 20% suspension of NaH (80% mineral oil dispersion 43.5 mg) in dry benzene (10 mL).

After 1 hour, N-Br-succinimide (260 mg) is added, followed after 5 minutes by a solution of bicyclo [4.3.3] nonane-3-endo, 8'-dihydroxy-2-exo-formyl-3- 25-THP-ether-8-DMtB-silyl ether (0.4 g) in toluene (ml).

Stirring is continued for 15 minutes, then the reaction mixture is washed with aqueous 15% Na 2 PO 4, dried and evaporated in vacuo to give: · · 2-exo - 2 '- bromo-3'-oxo-oct -1'-trans-enyl-N-S-endo-THP-30-oxy-8'-DMtB-silyloxy-bicyclo [4.3.0] nonane, λmax 251 nm λmax 8,900.

38 EXAMPLE 30 7 3 9 6 3

A solution of (3-phenoxy-2-oxo-propyl) -dimethylphosphonate (2.85 g) in benzene (10 mL) is added to a stirred suspension of NaH (80% mi-5 mineral oil dispersion, 0 .33 g) in benzene (50 ml). Stirring is continued for 45 minutes, then a solution of 2-exo-formyl-3-endo-THP-oxy-7H-DMtB-silyloxy-bicyclo [4.3.0 g] nonane (3.82 g) in toluene is added. After 20 minutes, the organic phase is washed with aqueous 20% Na 2 PO 4 and water, dried and evaporated to dryness to give, after filtration through SiO 2 (38 g), using benzene-ethyl ether as eluent. 1,2-exo- [3, -oxo-4, -phenoxy-but-1,1-trans-enyl]: β-3-endo-THP-oxy-7-DMtB-silyloxy-bi-15 cyclo 0.0 [nonane (3.97 g), M + -102 412 m / e.

Using (5-cyclohexyl-2-oxo-butyl) -dimethylphosphonate in the process and starting from the aldehydes of Example 28, the following is obtained: 2-exo-β-oxo-5'-cyclohexyl-pent-1'-trans-enyl-3 -20-endo-THP-oxy-7H-DMtB-silyloxy-bicyclo [4.3.3] nonane, λmax 228 nm λmax 399.30 ° 2 2-exo- [3'-oxo-5 '-cyclohexyl-pent-1'-trans-enyl] -3-endo-THP-oxy-8β-DMtB-silyloxy-bicyclo [4.3.3], [α] nonane, λmax 228.6 nm, s 9,450 .

EXAMPLE 31 DMtB silyl ether β-unsaturated ketones prepared by the method of Examples 29 and 30 are (a) reduced to allyl alcohols and (b) the new hydroxy group is protected as a THP ether; after which (c) the DMtB-si-30 ethyl ether protecting group is selectively removed to give a secondary alcohol which is (d) oxidized to a ketone; finally (e) after removal of all remaining protecting groups (f) the epimeric allyl alkoxols are separated by HPLC chromatography on SiO 2.

Λ

When working in ΣχΙΟ * molar solution, the following method is used:.

.o (a) reduction: 1x10 mol (0.32 g) of NaBH4 are added to a stirred solution of -unsaturated -ketone-BMtB-silyl ether (2x10 m) in methylene chloride-ethanol (1: 1, 180 ml). cooled to -10 to -15 ° C.

After 30 minutes, the remaining hydride is destroyed by the addition of acetone (10 mL) and aqueous saturated NaH 2 PO 4 (25 mL). The solvents are removed in vacuo and the residue is partitioned between water and methylene chloride. The organic layer is separated, dried and evaporated to dryness to give a mixture of silyl ethers of S'SjS'R-allyl alcohols (2x10 "2m).

(B) protection of allyl alcohols as THP ether: a crude mixture of 3 * S, silyl ether of 3'R-allyl alcohols (2x10 m) is treated with methylene chloride (30 ml) and 2,3-dihydropyran is added to the stirred solution ( 2g) and p-toluenesulfonic acid (0.038 g). The reaction is complete in 2 hours, then quenched by the addition of pyridine (0.5 ml) and the solvents removed by evaporation in a vacuum to give a crude mixture of 3'S. "R-THP-ether-silyl ethers.

(c) desilylation: a solution of the material obtained above in dry THF (80 ml) is treated for 12 hours at room temperature with dry tetrabutylammonium fluoride (14: **. g). Concentrate in vacuo to a small volume, which residue is taken up in Si 2 O (40 g) and eluted. with ethyl ether to give secondary alcohols. 30, -3'S, 3'R-THP ethers (about 2x10 ** 2m).

(d) oxidation: dicyclohexylcarbodiimide (6.5 g), pyridine (1 ml) and trifluoroacetic acid (0.5 ml) are added successively to a stirred solution of secondary 40 7 3963 alcohol-3'S, 3'R-THP ether in benzene-DMSO (75:25, 60 mL). After 4.5 hours, the reaction mixture is diluted with benzene (100 mL) and a solution of 3 g of oxalic acid in water; the dicyclohexylurea formed is filtered off, the organic layer is washed neutral, dried and evaporated to dryness.

(e, f) de-pyranylation and chromatographic separation: a solution of 3'S, 3'R-THP-ether ketones in methanol (30 ml) is stirred at room temperature for 3 hours with p-to-10 v luenesulfonic acid (0.18 g) with; after addition of pyridine (0.5 ml) it is evaporated to dryness. The residue is dissolved in cyclohexane-ethyl acetate (80:20) and injected into an HPLC apparatus to give the following keto alcohols: 2-exo -? '- bromo-3'S-hydroxy-oct-1'-trans-enyl] -5-endo - hydroxy-bicyclo [4.3.0] [nonan-8-one, M + -H 2 O 340, 342; 2-exo- [2'-bromo-S'R-hydroxy-oct-1'-trans-enyl] -5-endo-hydroxy-bicyclo] -4,3,3-danonan-8-one, M + -H2 O 340, 342; 2-Exo- [3S-hydroxy-4'-phenoxy-but-1'-trans-enyl] -3-20-endo-hydroxy-bicyclo [4,3, d] nonan-7-one, M 460 as bis-trimethylsilyl ether ; 2-Exo- [R-hydroxy-4'-phenoxy-but-1'-trans-enyl] -3-endo-hydroxy-bicyclo [4.3.0] nonan-7-one, M + 460 bis- of trimethylsilyl ethers; 2-exo-'S-hydroxy-S-cyclohexyl-pent-1 * -trans-enyl] -3-endo-hydroxy-bicyclo [3.3.0] nonan-7-one, M + -H2O 302; 2-exo-β-3'R-hydroxy-5-cyclohexyl-pent-1'-trans-enyl] -3-endo-hydroxy-bicyclo [3.3.0] nonan-7-one, 30 H * -H 2 O 302 m / e; 41 73963 2-Exo-β, S-hydroxy-5-cyclohexyl-penβ-1,1-trans-enyl-3-endo-hydroxy-bicyclo [4.3.3] quanan-8-one, M + -H2O 302 m [e] 2-exo- [3'R-hydroxy-5-cyclohexyl-pent-1'-trans-enyl] -5 -3-endo-hydroxy-bicyclo [b, 3,02] nonan-8-one, M + -H2 O 302 we.

EXAMPLE 32 Using the procedure of Example 25, 30 g of 2-acetoxyperhydro-azulen-6-one, also known as 3-endo-hydroxy-bicyclo-10β, 5,3-decan-8-one acetate (prepared according to the method set forth in DK, Banarjee et al., Indian J.

Chem. 10, 1, 1972) is converted to ethylene dioxide (29.1 g). The compound is then saponified by treatment with 2% K 2 CO 2 in aqueous methanol to give 3-endo-hydroxy-bicyclo [3, 3, ([decan-8-one-8,8-ethylene dioxide and oxidation using the method of Example 26, and treatment with dimethyl carbonate (see method of Example 26) gives d, 1-bicyclo [1-3,3,0] deca-3,8-dione-2-carboxymethyl ester-8,8-ethylene dioxide 21, 2 g,;

: .V EXAMPLE 33

The bicyclo / β-ketoester ethylene dioxides prepared in Examples 26, 27 and 32 are reduced by the following method:

Add NaBH 4 (0.9 g) portionwise to a stirred solution of bicyclo-p-ketoester ethylene dioxides (2.5 x 10 m) in methylene chloride-ethanol (1: 1, 150 mL), • - * * cooled to -20 ° C. Stir for 30 minutes at -20 ° C

Ct, after which the remaining hydride is destroyed by adding acetone (12 ml). The reaction mixture is warmed to room temperature, treated with aqueous 20% KH 2 PO 4, after removal of solvents and dilution with water (20 mL), extracted with methylene chloride. The organic phases are combined, washed neutral with water, dried and evaporated to dryness. The residue is equilibrated by treatment with absolute methanol (20 ml) and sodium methoxide (0.54 g) for 12 hours at room temperature, acetic acid (0.59 g) is added, after which the solvents are evaporated and extracted with methylene chloride to give about 0.22 x 10 m the following bicyclo3-hydroxyester-ethylene dioxides: d, 1,3-endo-hydroxy-bicyclo [b], 2,53-heptan-6-one-2-exo-10-carboxymethyl ester-6,6-ethylene dioxide, M + 300 trimethylsilyl ether sample d, 1 -3-endo-hydroxy-bicyclo, 2,0,3-heptan-6-one-4-exo-carboxymethyl ester-6,6-ethylene dioxide, also known as d, 1,3-endo-hydroxy-bicyclo [3.2.1] o "] heptan-7-15-one-2-exo-carboxymethyl ester-7,7-ethylene dioxide, M + 300 m / e as trimethylsilyl ether; .

d, 1-3-endo-hydroxy-bicyclo [4.3.0 [[nonan-7-one-2-exo-carboxymethyl ester-7,7-ethylene dioxide, M + 328 m / e as trimethylsilyl ether], 20 d, 1 - 3-endo-hydroxy-bicyclo [4.3.0] nonan-8-one-2-exo-carboxymethyl ester-8,8-ethylene dioxide, M + 328 m / e as trimethylsilyl ether; d, 1,3-endo-hydroxy-bicyclo [3,3,3-decan-8-one-2-exo-carboxymethyl ester-8,8-ethylene dioxide, 25 M + 342 m / e as trimethylsilyl ether.

Each of these compounds was then reacted with 2,3-dihydropyran (2 g) and p-toluenesulfonic acid (38 mg, 2x10 m) as a solution in 2x10 mL, dry methylene chloride (25 mL) for 2 hours at room temperature. temperature. The reaction is quenched by the addition of pyridine (0.1 mL) and the mixture is evaporated to dryness in vacuo to give the corresponding 3-THP ethers which are used without further purification.

43 7 3 9 6 3 EXAMPLE 34 3-Endo-hydroxy-2-exo-carboxymethyl esters and their 3-THP ethers obtained according to the method of Example 33 are reduced to give the corresponding 2-exo-hydroxymethyl derivatives according to the following method:

A solution of 2x10 m / 4 ketoester (both alcohol and 3-THP ether) in dry ethyl ether (25 mL) is added dropwise to a stirred suspension of • LiAlH 2 (0.4 g) in dry ethyl ether (50 mL). ).

After stirring for 30 minutes, the remaining hydride is destroyed by adding acetone (5 ml) and water-saturated e-style blades. Dry MgSO 4 (12 g) is added, after which the organic phase is filtered and evaporated to dryness.

The following 3-endo-hydroxy-2-exo-hydroxymethyls are obtained: bicyclo (2) (2H-heptan-6-one-6,6-ethylenedioxide, M + 342 as bis-trimethylsilyl ether; ... "bicyclo | 3.2 .0- heptan-7-one-7,7-ethylene dioxide, M2 342 as bis-trimethylsilyl ether ·, • · · 20 bicyclo [4.3.0] nonan-7-one-7,7-ethylene dioxide, M + 370 as bis-trimethylsilyl ether; ** bicyclo [4.3.3] olnonan-8-one-8,8-ethylene dioxide, M + 370 as bis-trimethylsilyl ether; bicyclo [5.3.3] [decan-8-one-8,8-ethylene dioxide , 25 M * 384 as bis-trimethylsilyl ether, and their 3-endo-hydroxy-THP ethers in both racemic and optically active form (nat, ent), when the optically active substance obtained from the optical separation described below is used in the reduction process. 30 methods.

EXAMPLE 35 44 73963 • Starting from the 2-exo-hydroxymethyl-THP-ether compounds of Example 34 and 12β-hydroxymethyl-11-acetate, the corresponding aldehydes are obtained by the following oxidation method:

Dicyclohexylcarbodiimide (0.64 g), pyridine (0.1 ml) and trifluoroacetic acid (0.05 ml) are added sequentially to a stirred solution of hydroxymethyl compounds (2x10 ~ m) in benzene-DMSO (75:25, 6 ml). ). After 4.5 hours, the reaction mixture is diluted with benzene (20 mL) and water (10 mL) and stirred for an additional 30 minutes. The dicyclohexylurea is filtered off and the organic layer is washed with water until neutral and concentrated to 10 ml to give a dry benzene solution of the following aldehydes: 3-endo-THP-oxy-2-exo-formyl-bicyclo3,2,2-hheptan-6-one - -6,6-ethylene dioxide, M + -102 180 m / e; 3-endo-THP-oxy-2-exo-formyl-bicyclo [3.2.1] heptan-7-one-7,7-ethylene dioxide, M + -102 180 m / e; 3-endo-THP-oxy-2-exo-formyl-bicyclo [4.3.1] nonan-7-one-20-7,7-ethylene dioxide, M + -102208 m / e; 3-endo-THP-oxy-2-exo-methyl-bicyclo [4.3.0] nonan-8-one-8,8-ethylenedioxy dioxide, M + -102 208 m / e; 3-endo-THP-oxy-2-exo-formyl-bicyclo [5.3.1] decan-8-one - 8,8-ethylene dioxide, M + -102,222 m / e; 25 ly) - (20 -> 12) -octanor-12β-formyl-11β-hydroxy-9α-deoxy-9α, 9b, 7-homo-trimethylene-2-nor-prostacyclo-5-enoic acid methyl ester II acetate (5 (Z, E); 5c; 5t), M + 322 m / e; U- (20-12) -octanor-12 / e-formyl-11α-hydroxy-9α-deoxy-9α, 7α-homo-dimethylene-prostacyclo-5-enoic acid methyl ester-30β-11-acetate (5 (Z, E); 5c; 5t), M + 322 m / e.

· *. * 45 73963 These compounds are used, in the following Wittig-Horner reactions, without any purification.

EXAMPLE 36

A solution of (2-oxo-heptyl) -dimethylphosphonate in 5 v (0.49 g) in benzene (6 ml) is added dropwise with stirring; to a suspension of NaH (80% mineral oil dispersion, 66 mg, 2.2 x 10 m) in benzene (15 mL). Stir for 45 minutes, then add 5t-L '- (20 - (12)) - octanor-12/3-formyl-(- - hydroxy-9a-deoxy-10 -9a, 9b, 7-homo-trimethylene). 2-N10 solution of 2-nor-prostacyclo-5-enoic acid methyl ester II in benzene (10 ml) After 1 hour the reaction is quenched by the addition of a solution of acetic acid (132 mg) in benzene (5 ml) and the organic phase is washed neutralized with water, dried and evaporated to dryness, the residue (1.2 g) is absorbed

Graft (10 g) and eluted with cyclohexane-ethyl acetate to give 5t, 13t-11 ° C-hydroxy-15-oxo-9a-deoxy-9a, 9b, 7-homo-trimethylene-2-nor-prostacyclate. 5,13-dienoic acid methyl ester-11-acetate (0.76 g), 20 -X max s 228 nm * s 9 * 800, M + 418 M + -CH 3 CO 2 H 35 δ.

The following β-unsaturated ketones are obtained when the aldehydes of Example 35 are used in the above method: 5c, 13t-11 (hydroxy-15-oxo-9a-deoxy-9a, 9b, 7 -homo-trime-25-ethylene-2-nor-prostacyclo-5,13-dienoic acid methyl ester 11-acetate, m.p. * 228 nm λg 900 · 900 »0a a mixture of these 5CZ, E) -isomers, M + 418 M + -CH 2 CO 2 H 358; five-1S-11β-hydroxy-1S-oxo-ga-deoxy-ga, 7α-homo-dimethyl- • # *. lene-prostacyclo-5,13-dienoic acid methyl ester-11-acyl * ;;; 30 δ, λ max 229 nm, λ 10,000, and its 5t and -5 (Z, E) isomers, M + 418 M + -CH 2 CO 3 H 358; / 46'-Λ 73963 and the following 2-exo- [3, -oxo-oct-1,1-trans * phenyl] -3-endo-hydroxy-THP ethers: bicyclo, 2, (¾-haptan-6-one -6,6-ethylene dioxide, M + -102 276 m / e 5 bicyclo [2, 2, (Cheptan-7-one-7,7-ethyl dioxide, M + -102 276 m / e; bicyclo [4.3.3] nonane) -7-one-7,7-ethylene dioxide, M + -102 304 m / e, bicyclo, 3,5 [nonan-8-one-8,8-ethylene dioxide, 10 M + -102 304 m / e; bicyclo , 3,0J-decan-8-one-8,8-ethylene dioxide, M + -102 318 m / e.

EXAMPLE 37 Using various dimethylphosphonates in the process of Example 36, the following β-unsaturated ketones are prepared: (a) by the reaction of »wherein 3-endo-THP-oxy-2-exo-formyl-bicyclo [2.2.0] [ Heptan-7-one-7,7-ethylene dioxide (2x10 3m) is reacted with (2-oxo-3 (S, R) -fluoro-heptyl) -dimethylphosphonate (0.54 g) to give 3-endo- THP-oxy-2-exo-oxo-4 1 (R, S) -fluoro-oct-1'-trans-enyl] -bicyclo [3.2.0] Heptan-7-one-7.7 -ethylene dioxide (0.72 g), • λmax * 229 nm> S · '9'900 »* + 98 ° <CKCl3)' (b) by reaction with heptan-6-one-6,6-ethylenedioxy dioxide -aldehyde (2x10 m) reacts with (2-oxo-octyl) -dimethylphosphonate to give 3-endo-THP-oxy-2-exo-3'-oxo-non-. -N-trans-enyl [bicyclo [2.2.0]] [heptan-6-one-6,6-ethylene dioxide, λ max 8 228 nm λ max 9,300, M + -102 290 m / e *, 47 73963 Γ (c) reaction of heptan-7-one-7,7-ethylenedioxide aldehyde with (2-oxo-t-phenylbutyl) dimethylphosphonate (0.565 g) gives 3-endo- THP-oxy-2-exo-j'-oxo-5, -phenyl-pent-1'-trans-enyl] bisyclo [3.2.2] [[5] heptan-7-one-7,7-ethylene dioxide, M + -102 310 m / e, (d) a reaction in which nonan-7-one-7,7-ethylene dioxide reacts with 0.52 g of (2-oxo-3S-methylheptyl) and (2-oxo -3R-methyl-heptyl) -dimethylphosphonate, are obtained, respectively: 3-endo-THP-oxy-2-exo-1'-oxo-4'S-methyl-oct-1'-trans-enyl-bicyclo ^ 4,3,0 ^ nonan-7-one-7,7-ethylene dioxide, M + -102 318 m / e, and 3-endo-THP-oxy-2-exo- [3'-oxo-4'R- methyl-oct-1'-trans-entyl-bicyclo) -3,3 (non [nonan-7-one-7,7-ethylene dioxide, 15 M + -102 318 m / e).

EXAMPLE 38 0.8 g of pyridine hydrobromide perbromide (C 18 H 17 Br 2) is added to a stirred solution of 3-endo-THP-oxy-2-exo-n-oxo-4 '(R S) -fluoro-oct-1'-trans-enyl-bicyclo-20 [1,2,3] heptan-7-one-7,7-ethylenedioxide in dry pyridine (15 ml). After stirring for 4 hours at room temperature, the precipitate is filtered off and the organic eluate is partitioned between ice, 2N H 2 SO 4 and ethyl acetate. The organic layer is washed with chilled 0.5N H 2 SO 4 saturated brine, 1% sodium carbonate and water to give neutral. 0.71 g of the 2'-bromo-4 '(R, S) -fluorine compound, which is a mixture of two diastereoisomeric 4'S-; and a mixture of the 4'R derivative. HPLC chromatography on pigs, eluting with CH 2 Cl 2 -ethyl ether (85:15), gives the individual isomers: <0.22 g of 3-endo-THP-oxy-2-exo- [2'-bromo-3'-oxo- 4 * R-fluoro-. -oct-1H-trans-enyl-3-cyclo [3.2.0] heptan-7-one-7,7-ethylene dioxide, λmax 8 250 nm, = 9 · 830; and 48 73963 0.19 g of the 4'S-fluoroisomer, λ maJ <s 8 251 nm, = 9.750, M + -102 372.373, Using the various methods described above, the following compounds are prepared. -5 teas: 3-endo-THP-oxy-2-exo-2'-bromo-3, -oxo-non-1'-trans-enyl-bicyclo [2.2.2] heptan-6-one -6,6-ethylene dioxide, M + -102 368, 370 m / e, and 3-endo-THP-oxy-2-exo- [g'-bromo-3'-oxo-oct-1'-trans- -enyl] [bicyclo] -1,3,3- [nonan-7-one-7,7-ethylene dioxide, M + -102 382, 384 m / e.

EXAMPLE 39 Starting from the unsaturated ketones of Examples 36, 37 and 38, secondary allyl alcohol% 15 holes are prepared using the following procedure:

A solution of β-unsaturated ketone (2 x 10 mL) in dry ethyl ether (20 mL) is added dropwise over 30 minutes to a stirred solution of 0.25 M zinc borohydride (48 mL) in dry ethyl ether. After stirring for 2 hours, the remaining hydride is destroyed by the addition of saturated NaCl. The organic layer is separated, washed neutral, dried over Na 2 SO 4 and evaporated to dryness. Using preparative HPLC chromatography on SiO 2 as eluent methylene / ethyl acetate, give: 5c, 13t-11β, 1,5S-dihydroxy-9a-deoxy-9a, 9b, 7a-homo-trimethyl-2-nor-prostacyclo-5, 13-dienoic acid methyl ester II acetate, M + 420 m / e and its 5 (Z, E) and 5t geometric isomers; 5β-13t-11β, 15S-dihydroxy-9α-deoxy-9α, 7α-homo-dimethylene-prostacyclo-5,13-dienoic acid methyl ester-11-acetate, M * 420 m / e and its 5 (Z, E) - and 5c-geometric 49 7 3 9 6 3 isomers.

The following 2-exo-β, S-hydroxy-oct-1,1-trans-enyl [-3-endo-THP-oxy compounds: bicyclo [3.2.2] (β-heptan-6-one-6,6 -ethylene dioxide, M + 380; 5-bicyclo [3.2.2] (β-heptan-7-one-7,7-ethylene dioxide, M + 380; bicyclo [4.3.3] g, nonan-7-one-7,7-ethylene dioxide, M + 408, bicyclo [4.3.0] nonan-8-one-8,8-ethylene dioxide, M + 408, and the following 3-endo-THP-oxy: 2-exo-2'-bromo-3'S-hydroxy- 4'R-fluoro-oct-1'-trans-10-enyl [bicyclo [3.2.0] heptan-7-one-7,7-ethylenedioxy dioxide, M + 476, 478; 2-exo- [2 '- bromo-3'S-hydroxy-4'S-fluoro-oct-1'-trans-enyl 13¾-bicyclo [3.2.1] heptan-7-one-7,7-ethylene dioxide, M + 476, 478;: Y: 2 2 -exo- [2'-bromo-3'S-hydroxy-non-1'-trans-enyl [bicyclo [3.2.2] heptan-6-one-6,6-ethylene dioxide, M + 472, 474; * 2-exo- [s 'S-hydroxy-non-1' trans-enyl] bisyclo [3.2.1] p-heptan-6-one-6,6-ethylene dioxide, M + 394; [3'S-hydroxy-5'-phenyl-pent-1'-trans-enyl] -bicyclo [3.2.2] [[heptan-7-one-7,7-ethylene dioxide, M + 414; 2 -exo- '-bromo-3'S-hydroxy-oct-1'-tr ans-enyl "] bicyclo-1,3,3-on-7-one-7,7-ethylenedioxide, M + 486, 488; ψ · 2-exo- [3'S-hydroxy-4'S-methyl-oct-1'-trans-enyl] bicyclo [4.3.0] nonan-7-one-7,7-ethylene dioxide, M + 422; 2-exo- [3'S-hydroxy-4'R-methyl-oct-1'-trans-enyl] -bicyclo [4.3.1] nonan-7-one-7.7 -ethylene dioxide, M + 422; 50 73963 5c, 13t-11c, 15R-dihydroxy-9a-deoxy-9a, 9b, 7a-homo-trimethylene-2-nor-prostacyclo-5,13-dienoic acid methyl ester-11-acetate, M + 420 and its 5 (Z, E) · and 5t geometric isomers; .

5 · 5t, 13t-11β, 15R-dihydroxy-9a-deoxy-9a, 7a-homo-dimethylene-prostacyclo-5,13-dienoic acid methyl ester-11-acetate, «φ» M 420 and its 5 (Z, E) and 5c geometric isomers.

The following 2-exo-1R-hydroxy-oct-1'-trans-enyl-3-endo-THP-oxy-: 10-bicyclo [3.2.2] heptan-6-one-6,6-ethylene dioxide , M * 380; bicyclo [3.2.0] heptan-7, on-7,7-ethylene dioxide, M 380; bicyclo [3.3.3] [nonan-7-one-7,7-ethylene dioxide, M + 408; bicyclo j [4,3,10-non-8-one-8,8-ethylene dioxide, M + 40 8; and the following 3-endo-THP-oxy: 2-exo-1- [2'-bromo-3 'R-hydroxy- 4'R-fluoro-oct-1'-trans-enyl-bicyclo [3.2.2] heptan-7-one-7,7-ethylene dioxide, M + 476, 478;, 2-exo-N'-bromo- 3'R-hydroxy-4'S-fluoro-oct-1'-trans-enyl] bicyclo [3.2.1] heptan-7-one-7,7-ethylene dioxide, 20 M + 476, 478; [2'-bromo-3'R-hydroxy-non-1'-trans-enyl] bicyclo [b] 2,2-heptan-6-one-6,6-ethylene dioxide, M + 472, 474; ] [3'R-hydroxy-non-1'-trans-enyl [bicyclo 2,0 *] heptan-6-one-6,6-ethylene dioxide, M + 394; 2-exo- [3'R- hydroxy-5'-phenyl-pent-1'-trans-enyl] bicyclo [3.2.0} heptan-7-one-7,7-ethylene dioxide, M + 414; 2-exo-1'-bromo-3 "R-hydroxy-oct-1'-trans-enyylijbisykl o-j * 4.3, cT [nonan-7-one-7,7-ethylene dioxide, M + 486, 488; 51 73963 2-Exo- [3'-R-hydroxy-4H-methyl-oct-1H-trans-enyl [bicyclo [4.3.3] nonan-7-one-7,7-ethylene dioxide, M + 422; 2-exo- 'R-hydroxy-4'R-methyl-oct-1'-trans-enyl] bicyclo [4.3.3] nonan-7-one-7,7-ethylene dioxide, M + 422.

5 EXAMPLE 40

Sodium borohydride (2.5 g) is added portionwise to a stirred solution of bicyclo [4.3.1] nonan-7-en-3-one (11.42 g) in ethanol (80 ml). After stirring for 2 hours, acetic acid (5 ml) is added and the mixture is evaporated to dryness. The residue is partitioned between water and CH 2 Cl 2 and the organic layer is evaporated to dryness. A solution of the resulting bicyclo [4,3,3-non] -7-ene-3-hydroxy (11 g) in dry DMF is heated with dimethyl-tert-butylsilyl chloride (15.6 g) and imidazole (10.85 g). ), heated at 60 ° C for 6 hours, cooled and diluted with water (66 mL). Extract with ethyl ether and work up in the usual manner to give bicyclo, 3.0'-nonan-7-ene-3-hydroxy-3-DMtB-silyl ether (19.1 g). Its solution in dry THF (100 mL) is cooled to 0 ° C and treated (with stirring under a nitrogen atmosphere) with a solution of BHg in THF (75 mL). After 2 h, maintaining the temperature at 25 ° C, NaOH (25 mL) and 30% hydrogen peroxide (25 mL) are added. The mixture is heated at 60 ° C for 2 h, cooled and diluted with benzene (400 mL). The organic layer is washed with 1% Na 2 O, saturated sodium sulfite, saturated NaCl, dried and evaporated to dryness to give crude bicyclo [4.3, (N-nonane-7 (8) -4-dihydroxy-3- DMtB-silyl ether (20.3 g) A solution of the resulting alcohol 30 in benzene-DMSO (75/25, 150 ml) is treated successively with dicyclohexylcarbodiimide (16 g), pyridine (2 ml) and trifluoroacetic acid. After 5 hours, the mixture is diluted with benzene (400 mL), water (50 mL) and a solution of oxalic acid (52 g) in water (75 g) and after stirring for 30 minutes. The organic phase is washed with water until neutral to give bicyclo [4.3.1] nonan-7 (8) -one-3-hydroxy-DMtB-silyl ether (18.25 g) which is dissolved in methanol ( 60 ml) and treated with 1.8 g of p-toluenesulphonic acid, after 12 hours the mixture is treated with pyridine (1.95 ml) and evaporated to dryness. The residue is filtered through SiO2 (ethyl acetate as eluent). ether-ethyl acetate) to give bicyclo [3.3.3] nonan-7 (8) -one-3-hydroxy 10 (10 g).

A solution of this compound in benzene (50 ml) is boiled, refluxing in the presence of dry ethylene glycol (5.2 g) and p-toluenesulphonic acid (0.62 g), removing the water formed during the reaction. After 14 h, pyridine (2 mL) is added and the organic phase is cooled, washed with water, 2% Na 2 CO 3 and saturated NaCl until neutral. Evaporation of the solvents gives bicyclo [4.3.3] nonan-7 (8) -one-3-hydroxy-7,7 (8,8) -ethylene dioxide, oil IR film 20 300 cm -1, M * 198, EXAMPLE 41 Saponification of d, 1- 3-endo-hydroxy-bicyclo, 3,0-nonan-8-one-8,8-diethylenedioxy-2-exo-carboxymethyl ester (4.5 g) with 2% CO 2 in 80% aqueous methanol yields the free acid (4.2 g).

To a solution of the free acid (4.2 g) in acetonitrile (120 ml) is added d (+) - ephedrine (2.3 g); After 4 hours at room temperature, 2.8 g of salt crystallize out, recrystallizing from acetonitrile to give 2.15 g of (+) bi-30-cyclo [4.3.3], (N, nonan-8-one-8,8-ethylenedioxy-3-endo-hyd - roxy-2-exo-carboxylic acid-d (+) - ephedrine salt All aqueous solutions are combined, evaporated to dryness, the residue is dissolved in water and treated with NaOH to an alkaline pH (12-13), d (+) - ephedrine is recovered in ether. After extraction, then the alkaline aqueous solution is acidified to pH 5 and extracted with ethyl acetate and the organic layer is combined and evaporated to dryness, the residue is diluted with acetonitrile and the procedure is repeated using (-) - ephedrine to give to obtain the (-) - bicyclo [3.3.3] nonan-8-one-8,8-ethylenedioxy-3-endo-hydroxy-2-exo-carboxylic acid-1 (-) - ephedrine salt. NaOH, the optically active base is recovered by extraction with ethyl ester, the alkaline aqueous phase is acidified to pH 5 to 5.1 and with ethyl acetate to give: (+) - bicyclo [3,3,3] nonan-8-one-8,8-ethylenedioxy-3-endo-hydroxy-2-exo-carboxylic acid, and (-) - bicyclo 4,3, (Qonanan-8-one-8,8-ethylenedioxy-3-endo-15-hydroxy-2-exo-carboxylic acid, which is converted to the methyl ester by treatment with diazome; to compare.

EXAMPLE 42

A solution of 26 g of d, 1,3-endo-hydroxy-bicyclo] 4.3,3-2-20-exo-carboxymethyl ester-7-one-7,7-ethylene dioxide

. in acetone (100 mL), reflux with 2N

With H 2 SO 4 (20 mL) for 4 hours.

The acetone is evaporated in vacuo and the aqueous phase is extracted with ethyl acetate. The combined organic extracts are washed neutral, dried and evaporated to give 21.2: g of d, 1,3-endo-hydroxy-bicyclo4,3,10-exo-carboxymethyl ester-7-one. To a solution of the ketone in dry acetonitrile (250 ml) is added d-1-phenyl-1-ethylamine (12.1 g) and 50 ml of solvent are slowly distilled off over 30 minutes. Mixture 30 is slowly cooled to room temperature and then 12.12 g of (+) - 3-endo-hydroxy-7,7- (1,1-phenyl-1'-ethylidenoimino) -2-exo-carboxymethyl ester-bicyclo- 3, recovered by filtration. The aqueous solutions are further concentrated to give 6 g of racemic material. Finally, the solution is concentrated to 80 mL to give 11.2 g of compound. (-) - 3-Endo-hydroxy-7,7- (1 * -phenyl-1'-ethylidenoimino) -2-exo-carboxymethyl ester-5-bicyclo [3.3.1].

The two Schiff bases are decomposed, separately, by refluxing with methanol-2N H 2 SO 4 (80:20, 200 ml) for 2 hours. The solvent is evaporated off in vacuo and the residue is extracted with ethyl acetate, after which the combined organic phases are washed neutral, dried and evaporated in vacuo to give: 8.1 g of (+) - 3-endo-hydroxy-bicyclo [4.3.0] o - [2-exo]. -carboxymethyl ester-7-one, and 7.2 g of (N, N-endo-hydroxy-bicyclo] -3,3,2-exo-carboxymethyl ester-7-one, respectively.

Using this method, all bicyclo- [3-hydroxycarboxylic ester-ethylenedioxides of Example 33 are subjected to optical resolution to give the following 3-endo-hydroxy alcohols: 20 (♦) -bicyclo [3.2.0] heptane- 6-one-2-exo-carboxymethyl ester; (+) - Bicyclo [3.2.2] heptan-7-one-2-exo-carboxymethyl ester; (+) - Bicyclo, 3,1-nonan-7-one-2-exo-carboxymethyl-ester; (+) - Bicyclo, 3,5-nonan-8-one-2-exo-carboxymethyl ester; (+) - Bicyclo [5.3.3] ocdecan-8-one-2-exo-carboxymethyl ester; (-) - bicyclo [3.2.3] heptan-6-one-2-exocarboxymethyl ester; (-) - Bicyclo [3.2.1] heptan-7-one-2-exo-carboxymethyl ester; 55 73963 * (-) - Bicyclo [3,3] nonan-7-one ** 2-exo-carboxymethyl ester; (-) - bicyclo [3,3] nonan-8-one-2-exocarboxymethyl ether; 5 (-) - Bicyclo [5.3.0.0] decan-8-one-2-exo-carboxymethyl ester.

Using the method of Example 32, these ketones can be converted to their ethylene dioxide derivatives *

Claims (6)

56 73963 Novel compounds of formula (I) 0 0 c useful in the synthesis of carbo-prostacyclic compounds according to FI patent application No. 79 0178. (CVP B> Λ (I) / A!, V ^ Y? '3 h R'1 R, 2 \ -! -X- <CH2VR7 R * 4 R6 5 wherein each of Rg and Rg which are the same or different , may be hydrogen, -C 1-4 alkyl or halogen, Y is -CH 2 -CH 8 - or -CH = CZ- (trans), wherein Z is hydrogen or ha-1 halogen, 10 r 1 is zero or an integer from 1 to 4 p and q are, independently of one another, zero, 1 or 2, Ry is a ') hydrogen, b') C 1 -C 4 alkyl, c ') C 8 -C 7 monocycloalkyl radical, d') a phenyl group which is unsubstituted or substituted tri-halo-C 1 -C 6 -alkyl or e ') a five-membered heteromonocyclic ring containing one oxygen atom; X is -O- or a group - (CHO) m, wherein m, is zero or 1; “M3 J one of R 1 and is hydrogen and the other is free or etherified hydroxy; one of R'g and R'^ is hydrogen and the other is free hydroxy. 57 7 3 9 6 3 Process for the preparation of compounds of formula (I) as claimed in claim t above, characterized in that a) a compound of formula (II) is \ (II) .. 'f'THO R ·', R'2 5 in which p , q, and R'2 have the same meaning as in claim 1 and G is a protected carbonyl group or a group ^ CH2 OG ', in which G' is a silyl ether or acetyl ether residue, is reacted with a compound of formula (III) 1 -5 I §b E-CH-C - CX- (CH0) -R7 (III) (.) Il k 2 "2 7 ::: 1'° r6 10 where E is (CgHg) 3P- or (Re0) A 2P -> (O) group in which each Rg may, independently of one another, be C1-C8-alkyl or phenyl; Z, Rg, Rg, X, n2 and R2 have the same meaning; as in claim 1, for the preparation of a compound of formula (IV): G, ru <^ (CH,) „(CH ^ P 2 q H / (IV) \ I f? 5 rs — r <cH2v7 H ° * 6 58 7 3 Wherein G is as defined above and p, q, R ', Z, R'2> Rg, Rg, X, n2 and R7 are as defined in claim 1. b) according to formula (IV) The compound of formula (V) is converted to the compound of formula (V) 5 [CH) (cTp / q (v) 'x? 13? 5 - | - X- (CH2) n2-R7 2 R, 4 R6 wherein G is as defined above and p, q, R'j, R'2> R13, R'4> Rg, Rg, X, n2 and R7 are as defined in claim 1 and Y * is -CH2 -CH 2 - or -CH = CZ - (trans), Z is as defined above; C) deprotection in G to give a compound of formula (VI) (CVp <PV, (vi> \ 1? '3 h r', '"rV" I-R6 where q, p, R1, R2, R 2 »R 2» R g »^ 6 * ^ ^ ® R 7 59 7 3 9 6 3 have the same meaning as in claim 1 and G" is -CH 2 OH or ^ -C = O and Y 1 is as defined above; d ) oxidizing a compound of formula (VI) wherein G "is ^ CHwOH and the other hydroxy groups, if present, 5 are in protected form. 60 7 3 9 6 3 t. Nya föreningar med formuleln (I), vilka är användbara i syntesen av carboprostacyclic compounds according to FI Patent No. 79 0178 0 H (I) (CHe) B (CH2) q H '' '*' H / A / 1 ^ Y; * 3? 5 R, i 'R'2 vc-cx - (CH2) n2- * 7 R, 4 R6 5. vilken vardera av grupperna Rg och Rg, vilka är lika eller olika, kan prophet, C 1 -C 4 -alkyl or halogen, Y is -CH = CZ- (trans), i vilken Z är väte ell halogen; 10 n2 är n o11 eller ett heltal 1-4; p och q är, oberoende av varandra, no 11, 1 eller 2; R7 är a ') väte, b') C 1 -C 4 alkyl, C 1 -C 7) C 5 -C 7 -monocyclic a 1-radical, d ') en phenyl group, preferably substituted or substituted with tri-halo-C, J-C8-alkyl or e') en 15 femium atom heteromonocyclic ring med en syreatom; X is -O- or a group - (CH 2) -, i is m, m is 11 or 1; 3 is a group R '^ and R1 ^ är väte oc and den andra 20 är en fri eller företrad hydroxi; the group consisting of R '^ and R' ^ är väte oct den andra är en fri hydroxi. 61 73963 2. A formulation for the preparation of formula (I) according to claim 1, which is derived from the formula (II) (CH2) q H (id Λ ~> CHO 5), p, q, R '^ och R'2 betecnar decamma somam i patentkravet 1 och G is a carbonyl group or a group "^ CH ^ OG', and a G1 2 3 is a silyl ether or an acetal ether group, having the same formula ( III) 1 h I = 5 10 E-CH-C-CX- (CH91 -R, (III),) Il 4 2 n2 7 ° R6 i flashes E ären (CgHgJ ^ P- eller (Re0) 2P-i> (0) group, and Z, Rg, Rg, X, n2 and R7 are as defined in claim 1, for the purpose of obtaining a formulation. (IV) (CH «1 iCH2) q ^ h R * 1 V2> ^ cCCX- (cH2) n2-R7 H 0 Rg vilken G betecknar decamma som ovan och p, q, R11, Z, 2 R'2, Rg , Rg, X, n2 and R7 are as defined in claim 3;