Keto reduction of carbacyclin intermediates

The invention relates to a new process for the reduction of 15-keto carbacyclin intermediates in the presence of cerium(III) Salts.

The invention relates to a new process for the reduction of 15-keto 
carbacyclin intermediates (PG nomenclature) in the presence of cerium(III) 
salts. 
In the syntheses of pharmacologically effective carbacyclin analogs 
Iloprost, Cicaprost or Eptaloprost, reduction of the 15 keto group to the 
15alpha hydroxy group is a very important step. Reduction with technically 
easily available reagents such as sodium borohydride leads to a mixture 
with undesirable 15beta hydroxy isomers. The two isomers must be separated 
from one another by chromatography. (For economical reasons the 15beta 
isomer must be reoxidized to the initial ketone and again reduced and 
separated into the 15 isomers, etc.) The expense necessary for the 
separation (adsorbent, amount of solvent) is higher, the more 15beta 
hydroxy isomer must be separated. 
According to present processes the portion of undesirable 15beta hydroxy 
isomers is always high, if reduction with simple hydride reagents is 
involved. 
Moreover, Iloprost, which represents a diastereomer mixture of 16-methyl 
compounds in a ratio of 16alpha:16beta=54:46, so far is obtained in this 
way only if said reoxidation is performed once or twice and all 15alpha 
hydroxy products (which by themselves exhibit different diastereomeric 
compositions), obtained after reduction and chromatography, are further 
processed together. The chemical reaction, as can easily be seen, requires 
exceptionally high expenses. 
In Iloprost synthesis the 15-keto group (3a, diagram 1) can also be reduced 
microbiologically (to 4a). But the total expense of performing a 
microbiological reduction, working up and purification of the product up 
to separation of the undesirable accompanying substances is very high. 
Microbiological reduction cannot be performed in the case of Cicaprost and 
Eptaloprost intermediate step 1. 
It cannot be performed in the case of 3b either. 3b can be produced by 
simultaneously filed syntheses by 
3alpha-hydroxy-cis-bicyclo[3.3.0]octan-7-one-2beta-carboxylic acid methyl 
ester derivatives, especially 7,7-neopentyl ketal, in a substantially 
simpler way than present precursor 3a. 
##STR1## 
The ketone 3c obtainable from the THP ether precursors (instead of said 
silyl ethers) leads, in the case of sodium borohydride reduction, to 
poorer yields and to an unsatisfactory 16-diastereomer distribution. 
Moreover, the 15-isomers can be separated only after cleavage of the 
protecting groups, which makes the usability of the 15beta portion by 
reoxidation difficult. The route by 3c therefore is less favorable than by 
3b. 
The object therefore was to improve the chemical reduction of the 15-keto 
group in the synthesis of carbacyclin analogs relative to the yield of 
15alpha-hydroxy product and also in Ilosprost synthesis relative to the 
16-diastereomer composition. 
Thus, the invention relates to a process for the production of 
alpha-hydroxy-bicyclo[3.3.0]octane derivatives of formula I 
##STR2## 
in which 
A means the double bond radical --O--X--O-- with X as straight-chain or 
branched-chain alkylene with 1-7 C atoms or the radicals 
.dbd.CH--(CH.sub.2).sub.3 --COOR', .dbd.CH--CH.sub.2 --O--CH.sub.2 --COOR' 
or .dbd.CH--(CH.sub.2).sub.3 --O--CH.sub.2 --CH.sub.2 -COOR' with R' as 
C.sub.1 -C.sub.7 alkyl, 
R means 
##STR3## 
with R" as hydrogen or phenyl or the radical --SiR.sub.1 R.sub.2 R.sub.3, 
and R.sub.1 , R.sub.2 and R.sub.3 can be the same or different and 
represent a straight-chain or branched-chain alkyl group with 1-7 C atoms 
or phenyl, 
B means a trans-CH.dbd.C(X) group with X as hydrogen or bromine, and the 
trans-configuration relates to the C chain, and 
D means an alkyl group with 1-10 C atoms, an alkenyl group with 2-10 C 
atoms or an alkynyl group with 2-10 C atoms, 
characterized in that, keto-bicyclo[3.3.0]octane derivatives of formula II 
##STR4## 
is the presence of cerium(III) salts. 
In attaining this object, two effects are important, which, individually, 
but especially combined with one another, are advantageous. 
a) Performance of the reduction with sodium borohydride in the presence of 
cerium(III) chloride leads to a marked yield increase in the desired 
15alpha-hydroxy product. 
______________________________________ 
Reac- Yield 
tion Reduction agent 
15.alpha.-OH:15.beta.-OH 
Increase 
Example 
______________________________________ 
NaBH.sub.4 40:60 1b 
1a.fwdarw.2a 35% 
NaBH.sub.4 /CeCl.sub.3 
54:46 1a 
NaBH.sub.4 46:54 2b 
1b.fwdarw.2b 22% 
NaBH.sub.4 /CeCl.sub.3 
56:44 2a 
1c.fwdarw.2c 
NaBH.sub.4 /CeCl.sub.3 
89:11 4 
______________________________________ 
The yield increase thus amounts to more than 100%, if the protecting group 
effect is also considered. 
Production of 1c takes place analogously to the production of 1a from the 
carbaldehyde described in example A 1. 
For using the obtained compound 2c the same processes are suitable, which 
are suitable for using compounds 2a and 2b. Cleavage of the protecting 
groups takes place analogously to example A 3. 
b) Influence of protecting groups 
This includes the replacement of 11-esters used so far with 11-silyl 
ethers. 
__________________________________________________________________________ 
Reduction Yield 
Reaction 
agent 15.alpha.-OH:15.beta.-OH 
16.alpha.-CH.sub.3 :16.beta.-CH.sub.3 
Increase 
Example 
__________________________________________________________________________ 
3a.fwdarw.4a 
NaBH.sub.4 
55:45 60:40 
NaBH.sub.4 /CeCl.sub.3 
55:45 60:40 
3b.fwdarw.4b 
NaBH.sub.4 /CeCl.sub.3 
89:11 54:46 60% 3a 
NaBH.sub.4 
74:26 59:41 3b 
3c.fwdarw.4c 
NaBH.sub.4 /CeCl.sub.3 
67:33 57:43 
__________________________________________________________________________ 
The high yield with the reduction according to the invention of 3b to 4b 
has the result that the 16-methyl diastereomer distribution is also 
correct, by which the reoxidation of the 15beta-OH portion can be 
eliminated, chromatography is made easier and a readily available initial 
material for synthesis of Iloprost can be used. 
(+)-3alpha-hydroxy-7,7-(2,2-dimethyl-trimethylenedioxy)-cisbicyclo[3.3.0]oc 
tane-2beta-carboxylic acid methyl ester, produced, e.g., according to 
German application P 36 38 758.4, is converted into silyl ether according 
to the process indicated by H. Wetter and K. Oertle, Tetrahedron Letters 
26, 5515 (1985) or S. Hanessian and P. Lavallee, Can. J. Chem. 53, 2975 
(1975) and the carboxylic acid methyl ester group is reduced analogously 
to the conditions described by K. Mori and M. Tsuji, Tetrahedron 42, 435 
(1986), but to -40.degree. C. The further reaction takes place as 
described in examples A1 and A 2. Thexyl dimethyl chlorosilane and 
tert-butyl-diphenyl chlorosilane are used as silyl chlorides. 
Cleavage of the protecting groups from resulting compound 4d takes place 
analogously to example A 3. In compound 4e cleavage of the protecting 
groups generally takes place successively. The silyl ether, is cleaved 
e.g., with tetrabutyl ammonium fluoride in tetrahydrofuran and the ketal 
is cleaved under the conditions of example A 3. These steps can be 
interchanged. In all cases compound 5 results. 
The addition of cerium(III) chloride in the reduction of 15-keto 
prostaglandin intermediates is known (J.-L. Luche, J. Amer. Chem. Soc. 
100, 2226 (1978), J. C. S. Chem. Comm. 1978, 601). However, it serves to 
avoid undesirable 1,4-additions, i.e., the reduction of the C.sub.13 
-C.sub.14 double bond. Nothing is known so far about an improvement of the 
15alpha/beta ratio in the products. On the contrary, with the use of this 
method of operation no change but rather a worsening of the yield of 
15alpha-hydroxy products is noted, as is represented in the following 
table of two examples. 
__________________________________________________________________________ 
Feedstock Reduction agent 
15.alpha./15.beta.-OH 
__________________________________________________________________________ 
##STR5## NaBH.sub.4 NaBH.sub.4 /CeCl.sub.3 
50:50 45:55 
##STR6## NaBH.sub.4 NaBH.sub.4 /CeCl.sub.3 
50:50 50:50 
__________________________________________________________________________ 
Therefore, it is surprising that cerium(III) chloride markedly increases 
the 15alpha-hydroxy portion in the reduction of the compounds of formula 
II. 
Initial materials are preferred which can be produced from easily available 
carbacyclin precursors with the use of commercial and sufficiently stable 
protecting groups. However, the use of the reaction according to the 
invention is not to be limited by this choice. 
Use of sodium borohydride and cerium(III) chloride is preferred, because 
they are easily obtainable in a large amount. But the reduction could also 
be performed with other borohydrides and other cerium(III) salts, if they 
do not decompose under the reaction conditions. 
Sodium borohydride must be used in at least stoichiometric amounts. 
Cerium(III) salts, on the other hand, can even be limited to catalytic 
amounts Cerium(III), which can be used both in anhydrous form and as 
hydrate or solution, is preferred. 
Suitable solvents have a sufficient solubility for the reactants and do not 
react with them in the selected temperature range. Methanol is preferred; 
further there can be used by themselves or in mixture: ethanol, 
tetrahydrofuran, dimethylformamide and others, optionally with addition of 
water. 
Low temperatures (-100.degree. to 0.degree. C.) promote the formation of 
15alpha-hydroxy isomers. Depending on the choice of the reaction 
conditions, the reaction times are between a few minutes and a few hours. 
Production of 1a and 3a as well as the reaction of compounds 2a, 4a and 5 
to carbacyclin analogs is known (1a, 2a: European Patent Application 119 
949; 3a, 4a, 5: European Patent Specification 11 591). 
Analogously to the known processes (diagram 2), 3b is produced from 
(1S,2S,3R,5R)-3-tert-butyldimethylsilyloxy-7,7,-(2,2-dimethyltrimethylened 
ioxy-2-hydroxy-methyl-bicyclo[3.3.0]octane (6) (examples A1 and A2). The 
protecting groups can be removed in reduction product 4b by acid treatment 
with formation of the already known 5. 
##STR7## 
The process can also be extended to series, represented by formulas 8 and 
9, with the naturally configured subchain (example 7). 
##STR8## 
Production of initial material 8 takes place according to example A 4. 
Use of reduction product 9 for synthesis of unsubstituted carbacyclin 11 
takes place by cleavage of the protecting groups according to example A 5 
to compound 10. Production of carbacyclin from 10 was already described by 
Kojima et al., Chem. Phar. Bull. 33, 2588 (1985). 
If X means a straight-chain or branched-chain alkylene radical with 1-7 C 
atoms, the following radicals are meant by it: --CH.sub.2).sub.2 with 
n=1-7 (methylene, ethylene, tri-, tetra-, penta-, hexa- and 
hepta-methylene, --C(CH.sub.3).sub.2 --, --CH(CH.sub.3)--, 
--CH(CH.sub.3)--CH.sub.2 --, --C(CH.sub.3).sub.2 --CH.sub.2 --, --CH.sub.2 
--CH(CH.sub.3)--, CH.sub.2 --C(CH.sub.3).sub.2 --, --CH.sub.2 
--CH(CH.sub.3)--CH.sub.2 --, --CH.sub.2 --C(CH.sub.3).sub.2 --CH.sub.2 --, 
--CH(C.sub.2 H.sub.5)--, --C(C.sub.2 H.sub.5).sub.2, --CH(C.sub.2 
H.sub.5)--CH.sub.2 --, --C(C.sub.2 H.sub.5).sub.2 --, --CH.sub.2 
--CH(C.sub.2 H.sub.5), --CH.sub.2 --C(C.sub.2 H.sub.5).sub.2 --, 
--CH.sub.2 --CH(C.sub.2 H.sub.5)--CH.sub.2 --, --CH.sub.2 --C(C.sub.2 
H.sub.5).sub.2 - etc. 
By R, R.sub.1, R.sub.2 and R.sub.3 as C.sub.1 -C.sub.7 alkyl are understood 
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 
tertbutyl, n-pentyl, isopentyl, sec-pentyl, neopentyl, n-hexyl, isohexyl, 
heptyl, etc. 
D as alkyl groups with 1-10 C atoms means, besides the above-named alkyl 
radicals, also octyl, nonyl, decyl and the respective branched isomers. 
D as alkenyl group with 2-10 C atoms preferably means 
##STR9## 
D as alkynyl group with 2-10 C atoms means, for example 
##STR10## 
The following embodiments should explain the invention in greater detail.

EXAMPLE A 1 
(1S,2R,3R,5R)-7,7-(2,2-dimethyl-trimethylenedioxy)-3-tertbutyldimethylsilyl 
oxy-bicyclo[3.3.0]octane-2-carbaldehyde 
1.38 g of oxalyl chloride is dissolved in 20 ml of dichloromethane, cooled 
to -60.degree. C. and mixed with 1.87 g of dimethyl sulfoxide in 6 ml of 
dichloromethane. After 10 minutes a solution of 2.886 g of 
(-)-(1S,2S,3R,5R)-7,7-(2,2-dimethyltrimethylenedioxy)-3-tert-butyldimethyl 
silyloxy-2-hydroxy-methylbicyclo[3.3.0] octane in 13 ml of dichloromethane 
is added and stirred for 30 minutes. Then 2.42 g of triethylamine is 
instilled into 5 ml of dichloromethane. After 2 hours, it is allowed to 
warm to 0.degree. C., 260 ml of ice water is added, the organic phase is 
separated, it is washed with sodium chloride solution, dilute citric acid 
solution and again with sodium chloride solution. After drying with sodium 
sulfate and removal of the solvent in a vacuum, about 3.0 g of the title 
compound is obtained as raw product, which can be used without further 
purification. 
EXAMPLE A 2 
(1S,2S,3R,5R)-7,7-(2,2-dimethyl-trimethylenedioxy)-3-tertbutyldimethylsilyl 
oxy-2-[(4R,S)(1E)-4-methyl-3-oxo-oct-1-en-6-inyl]bicyclo[3.3.0]octane 
0.447 g of sodium hydride (55%) is suspended in 39 ml of tetrahydrofuran, 
cooled in an ice bath and mixed with 2.58 g of racemic 
3-methyl-2-oxo-hept-5-in-yl phosphonic acid dimethyl ester in 20 ml of 
tetrahydrofuran. It is stirred for 20 minutes and the 3.0 g of the 
carbaldehyde, obtained in example A 1, is added in 39 ml of 
tetrahydrofuran. After 3 hours at ice bath temperature and 45 minutes at 
room temperature it is neutralized with acetic acid, concentrated in a 
vacuum, taken up in dichloromethane, washed with sodium bicarbonate and 
sodium chloride solution, dried with sodium sulfate, the solvent is 
removed and the residue is chromatographed on silica gel with hexane-ethyl 
acetate mixtures. 3.68 g of the product with [alpha].sub.D +1.0.sup.o, 
[alpha].sub.365 +26.6.sup.o (CHCl.sub.3, c=1) is obtained, which is 
suitable for further reaction. 
EXAMPLE A 3 
(1S,2S,3R,5R)-3 
-hydroxy-2-[(3S,4RS)(E)-3-hydroxy-4-methyl-oct-1-en-6-inyl]-bicyclo[3.3.0] 
octan-7-one 
2.278 g of the nonpolar product obtained according to example 3a is 
dissolved in 9 ml of tetrahydrofuran, 32.5 ml of acetic acid and 17.5 ml 
of water and heated for 4 hours to 45.degree. C. Then it is distilled off 
in a vacuum, finally with addition of toluene, it is taken up in 
dichloromethane, extracted with water, dried with sodium sulfate, 
concentrated in a vacuum and chromatographed on silica gel with 
hexane-ethyl acetate mixtures. 1.26 g of the title compound is obtained 
which is chromatographically and spectroscopically identical with the 
material according to the synthesis method described earlier, which 
exhibits the composition of the 16-diastereomers necessary for the 
production of Iloprost and whose enantiomer purity (determined by HPLC of 
the MTPA esters) is greater than 99%. 
EXAMPLE A 4 
(1S,2S,3R,5R)-7,7-(2,2-dimethyl-trimethylenedioxy)-3-tertbutyldimethylsilyl 
oxy-2-[(1E)-3-oxo-oct-1-enyl]-bicyclo[3.3.0]octane 
113 mg of sodium hydroxide (55%) is suspended in 10 ml of tetrahydrofuran 
and mixed at 20.degree. C. with 630 mg of 2-oxo-heptylphosphonic acid 
dimethyl ester in 4.5 ml of tetrahydrofuran. It is stirred for 30 minutes 
and then 1.0 g of the carbaldehyde obtained as in example A 1 is added in 
9 ml of tetrahydrofuran. After 5 hours it is neutralized with acetic acid, 
concentrated in a vacuum, taken up in dichloromethane, washed with sodium 
chloride solution, dried with sodium sulfate, the solvent is removed and 
the residue is chromatographed on silica gel with hexane/tert- butyl 
methyl ether mixtures. 1.19 g of product with [alpha].sub.D +2.3.sup.0 
(chloroform, c=1) is obtained. 
EXAMPLE A 5 
(1S,2S,3R,5R)-3-hydroxy-2-[(3S) 
(E)-3-hydroxy-oct-1-enyl]-bicyclo[3.3.0]octan-7-one 
0.54 g of the nonpolar product obtained according to example 7 is dissolved 
in 9 ml of ethanol, mixed with 6 ml of water and 0.06 ml of conc. 
hydrochloric acid and stirred for 3 hours at room temperature. Then it is 
neutralized with sodium bicarbonate, distilled off in a vacuum, taken up 
in ethyl acetate, extracted with sodium chloride solution, dried with 
sodium sulfate, concentrated in a vacuum and chromatographed on silica gel 
with hexane/ethyl acetate mixtures. 0.27 g of the title compound is 
obtained with [alpha].sub.D -11.2.sup.o (methanol, c=1). Kojima et al. 
(1.c.) indicate -11.5.sup.o (methanol, c=1). 
EXAMPLE 1 
(1S,2S,3R,5R)-2-[(1Z)(3S,4S)-2-bromo-3-hydroxy-4-methyl-non-1-en-6-inyl]-7, 
7-ethylenedioxy-3-benzoyloxy-bicyclo[3.3.0]octane 
a) According to the invention 
107.53 g 
(1S,2S,3R,5R)-2-[(1Z)(4S)-2-bromo-4-methyl-3-oxonon-1-en-6-inyl]-7,7-ethyl 
enedioxy-3-benzoyloxybicyclo[3.3.0]octane is dissolved in 2 liters of 
methanol, cooled to -40.degree. C., mixed with 11.68 g of cerium(III) 
chloride heptahydrate, stirred for 15 minutes, then 12.37 g of sodium 
borohydride is introduced in portions, stirred 30 minutes, acetone in 
excess is instilled, stirred another 30 minutes, neutralized with acetic 
acid, warmed and distilled off in a vacuum. The residue is dissolved in 
dichloromethane and water, washed with water, dried with sodium sulfate, 
concentrated in a vacuum and chromatographed on silica gel with 
dichloromethane/ethyl acetate mixtures. 
55.2 g of the title compound is obtained as nonpolar isomer besides 47.0 g 
of polar 3'R isomer (15alpha:15beta=54:46). 
b) Comparison batch 
The reaction described under a) is performed but without cerium(III) 
chloride. To achieve complete reaction, the amount of sodium borohydride 
must be increased. The isomers are obtained in a ratio of 40:60. 
EXAMPLE 2 
(1S,2S,3R,5R)-2-[(Z)(3S,4S)-2-bromo-3-hydroxy-4-methyl-non-1-en-6-inyl]-7,7 
-(2,2-dimethyl-trimethylenedioxy)-3-(4-phenylbenzoyloxy)-bicyclo[3.3.0]octa 
ne 
a) According to the invention 
56.5 g of 
(1S,2S,3R,5R)-2-[(Z)(3S,4S)-2-bromo-4-methyl-3-oxo-non-1-en-6-inyl)-7,7-(2 
,2-dimethyl-trimethylenedioxy)-3-(4-phenyl-benzoyloxy)-bicyclo[3.3.0]octane 
is reacted, according to the conditions of example 1, with 5.28 g of 
sodium borohydride in the presence of 4.96 g of cerium(III) chloride 
heptahydrate, and 30.06 g of nonpolar 3'S compound, besides 23.62 g of 
polar 3'R compound, (15alpha:15beta=56:44) is obtained. 
b) Comparison batch 
The reaction described under a) is performed but without cerium(III) 
chloride and with an increased amount of sodium borohydride. Isomers in a 
ratio of 15alpha:15beta=46:54 are obtained. 
EXAMPLE 3 
(1S,2S,3R,5R)-7,7-(2,2-dimethyl-trimethylenedioxy)-3-tertbutyldimethylsilyl 
oxy-2-[(3S,4RS)(1E)-4-methyl-3-hydroxy-oct-1-en-6-inyl]bicyclo[3.3.0]octane 
a) According to the invention 
3.50 g of the ketone of example A 2 is dissolved in 100 ml of methanol and 
cooled to -75.degree. C. 2.76 g of cerium(III) chloride heptahydrate is 
added, stirred for 1 hour, mixed with 0.51 g of sodium borohydride and 
stirred another 45 minutes at -75.degree. C. After addition of acetone, it 
is slowly warmed, neutralized with acetic acid and concentrated in a 
vacuum. The residue is dissolved in dichloromethane, extracted with water, 
dried with sodium sulfate and concentrated in a vacuum. It is 
chromatographed on silica gel with hexane/tert-butylmethylether mixtures 
and 2.52 g of the title compound [non polar isomer, [alpha].sub.D 
+8.8.sup.o, [alpha].sub.365 +24.2.sup.o (CHCl.sub.3), c=1)] and 0.25 g of 
the polar 3'R isomer are obtained. 
HPLC measurements show that in the title compound the methyl isomers are 
present in a ratio of alpha:beta=54:46. 
b) Comparison batch 
The reaction described under a) is performed but without cerium(III) 
chloride and with an increased amount of sodium borohydride. Isomers in a 
ratio of 3'S:3'R=74:26 are obtained. 
Methyl isomers are present in the 3'S portion in a ratio of 
alpha:beta=59:41. 
EXAMPLE 4 
(1S,2S,3R,5R)-2-[(1Z) 
(3S,4S)-2-bromo-3-hydroxy-4-methyl-non-1-en-6-inyl]-7,7-(2,2-dimethyl-trim 
ethylenedioxy)-3-(4-tertbutyldimethylsilyloxy-bicyclo[3.3.0]octane 
106.0 g of (1S,2S,3R,5R)-2-[(1Z) 
(3S)-2-bromo-4-methyl-3-oxo-non-1-en-6-inyl]-7,7-(2,2-dimethyl-trimethylen 
edioxy)-3-(4-tert-butyldimethylsilyloxy-bicyclo[3.3.0]octane is reduced 
according to example 3. The 15alpha/15beta isomers according to HPLC are 
present in the raw product in a ratio of 88.9:11.1. In the separation of 
the mixture by chromatography, 92.2 g of the nonpolar 15alpha-hydroxy 
isomer [alpha].sub.D +21.sup.o (chloroform, c=1) and 8.0 g of polar 
15beta-hydroxy isomer are obtained. 
EXAMPLE 5 
(1S,2S,3R,5R)-7,7-(2,2-dimethyl-trimethylenedioxy)-3-(2,3-dimethyl-but-2-yl 
)-dimethyl-silyloxy-2-[(3S,4RS) 
(1E)-4-methyl-3-hydroxy-oct-1-en-6-inyl]bicyclo[3.3.0]octane 
4.5 g of 
(1S,2S,3R,5R)-7,7-(2,2-dimethyl-trimethylenedioxy)-3-(2,3-dimethyl-but-2-y 
l)-dimethyl-silyloxy-2[(4RS) 
(1E)-4-methyl-3-oxo-oct-1-en-6-inyl]bicyclo[3.3.0]octane is reduced 
according to example 3a). 3.16 g of nonpolar 15alpha-hydroxy isomer 
[alpha].sub.D +3.0.sup.o (chloroform, c=1), 0.65 g of polar 15beta-hydroxy 
isomer and 0.57 g of mixed fractions are obtained. 
HLPC measurements after cleavage of the protecting groups shows that the 
methyl isomers are present in a ratio of alpha:beta=54:46. 
EXAMPLE 6 
(1S,2S,3R,5R)-7,7-(2,2-dimethyl-trimethylenedioxy)-3-tertbutyldiphenylsilyl 
oxy-2-[(3S,4RS) 
(1E)-(4-methyl-3-hydroxy-oct-1-en-6-inyl]bicyclo[3.3.0]octane 
3.0 g of 
(1S,2S,3R,5R)-7,7-(2,2-dimethyl-trimethylenedioxy)-3-tert-butyldiphenylsil 
yloxy-2-[(4RS) (1E)-4-methyl-3-oxo-oct-1-en-6-inyl]bicyclo[3.3.0]octane is 
reduced according to example 3a. 2.60 g of the nonpolar 15alpha-hydroxy 
isomer [alpha].sub.D 21.1.sup.o (chloroform, c=1) and 0.35 g of the polar 
15beta-hydroxy isomer, which still contains some 15alpha-hydroxy isomer, 
are obtained. 
HPLC measurements following cleavage of the protecting groups show that the 
methyl isomers are present in the ratio of alpha:beta=53:47. 
EXAMPLE 7 
(1S,2S,3R,5R)-7,7-(2,2-dimethyl-trimethylenedioxy)-3-tertbutyldimethylsilyl 
oxy-2-[(1E) (3S)-3-hydroxy-oct-1-enyl]bicyclo[3.3.0]octane 
10.0 g of the ketone obtained in example A 4 are reduced according to 
example 3a). 8.05 g of the nonpolar 15alpha-hydroxy compound with 
[alpha].sub.D -3.5.sup.o (chloroform, c=1), besides 1.30 g of polar 
15beta-hydroxy isomer, is obtained.