Bicyclo[3.3.0]octenylaldehyde derivatives represented by the formula: ##STR1## wherein R.sup.1 is a substituent selected from the group consisting of a hydrogen atom and a protective group of a hydroxy group; PA1 R.sup.2 is a substituent selected from the group consisting of --CH.sub.2 OR.sup.5, ##STR2## where R.sup.5 is a substituent selected from the group consisting of a hydrogen atom and a protective group of a hydroxy group, PA1 R.sup.6 is a substituent selected from the group consisting of an alkyl group, an alkenyl group and an alkynyl group, said substituent being straight, branched or cyclic and having 5 to 10 carbon atoms, PA1 X is a substituent selected from the group consisting of a vinylene group and an acetylene group, and PA1 R.sup.7 is a substituent selected from the group consisting of an alkyl, an alkenyl group, and an alkynyl group, said substituent being straight, branched or cyclic and having 5 to 10 carbon atoms; and PA1 R.sup.4 is a hydrogen atom, and a process for producing the derivatives are available for producing a 9(0)-methano-.DELTA..sup.6(9..alpha.) -PGI.sub.1.

BACKGROUND OF THE INVENTION 
This invention relates to a bicyclo[3.3.0]octane derivative and a process 
for producing the same. 
9(0)-methano-.DELTA..sup.6(9.alpha.) -PGI.sub.1 has a potent platelet 
aggregation inhibiting action. For example, its action is comparable to 
chemically unstable PGI.sub.2, when human platelet is employed, and it is 
a compound which can be utilized as a therapeutic or preventive for 
various diseases of circulatory organs (see the test examples shown 
below). 
In the prior art, as the process for producing 
9(0)-methano-.DELTA..sup.6(9.alpha.) -PGI.sub.1, there have been known (a) 
the process in which it is produced through the 14 steps using PGE.sub.2 
as the starting material [Preliminary Text for Lectures in 103rd Annual 
Meeting in Pharmaceutical Society of Japan, p. 156, (1983)] and (b) the 
process in which it is produced from 1,3-cyclooctadiene through 19 steps 
[Preliminary Text for Lectures in 103rd Annual Meeting in Pharmaceutical 
Society of Japan, p. 157, (1983)]. The former process has the drawback 
that the starting material is expensive, while the latter process that the 
desired product is formed as a racemic mixture. Further, both processes 
(a) and (b) are also disadvantageously very low in the overall yield. 
On the other hand, (4'-alkoxycarbonyl-1'-alkenyl)-cis-bicyclo[3.3.0]octene 
derivative can be led to 9(0)-methano-.DELTA..sup.6(9.alpha.) -PGI.sub.1 
and its various derivatives by highly selective reduction of the double 
bonds of the .alpha.-chains, elimination of the protective group for 
hydroxyl group and hydrolysis of the ester. 
Further, (4'-alkoxycarbonyl-1'-alkenyl)-cis-bicyclo[3.3.0]octene derivative 
can easily be led to various carbacyclines stereospecifically by 
1,4-reduction of conjugated diene. 
The above carbacyclines are synthesized according to any of the processes 
by the Wittig reaction to cis-bicyclo[3.3.0]octane-3-one derivatives [e.g. 
W. Skuballa and H. Vorbruggen, Angew. Chem. Int. Ed. Engl., 20, 1046 
(1981); W. Skuballa et al. (Schering AG), Eur. Pat. 11, 591; Ger. Offen. 
2,845,770.7; '83 Inflammation Seminar-Prostaglandin Program Preliminary 
Text, Shinsaku Kobayashi, at p. 37]. 
However, according to this process, a mixture of 5-E derivative [a] and 5-Z 
derivative [b] is obtained, and separation of the 5-E derivative [a] which 
is useful as pharmaceutical remains as the great problem in the synthetic 
process. 
##STR3## 
SUMMARY OF THE INVENTION 
The present inventors have studied extensively to produce 
9(0)-methano-.DELTA..sup.6(9.alpha.) -PGI.sub.1 carbacyclines from a cheap 
starting material at good yield and with optical activity as well as 
steric configuration specificity, and consequently found that the compound 
of the present invention and the process for producing the same can be an 
important intermediate and a process for achieving the object to 
accomplish the present invention. 
This invention concerns a compound of the formula: 
##STR4## 
wherein R.sup.1 : a hydrogen atom or a protective group of a hydroxy 
group; 
R.sup.2 : --CH.sub.2 OR.sup.5, 
##STR5## 
(R.sup.5 : a hydrogen atom or a protective group of a hydroxy group, 
R.sup.6 : straight, branched or cyclic alkyl group, alkenyl group or 
alkynyl group each having 5 to 10 carbon atoms, 
X: a vinylene group or an acetylene group, 
R.sup.7 : a straight, branched or cyclic alkyl group, alkenyl group or 
alkynyl group each having 5 to 10 carbon atoms); 
R.sup.3 : a formyl group or --Y--(CH.sub.2).sub.2 --COOR.sup.8 
(R.sup.8 : a hydrogen atom or an alkyl group, and 
Y: a vinylene group or an alkylene group); 
R.sup.4 : a hydroxy group when the compound is an octane derivative, or a 
hydrogen atom when the compound is an octene derivative; 
dotted line: optional presence of a double bond; 
provided that where R.sup.2 is 
##STR6## 
R.sup.3 being --(CH.sub.2).sub.4 --COOR.sup.8 is excluded, and a process 
for producing the same. 
DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The bicyclo[3.3.0]octane derivative represented by the above formula [I] of 
this invention can be led to (3-oxo-1-alkenyl)-cis-bicyclo[3.3.0]octene 
derivative by subjecting the bicyclo[3.3.0]octenylaldehyde to the reaction 
step as hereinafter described or oxidizing the bicyclo[3.3.0]octene 
derivative and then subjecting the oxidized product to Wittig reaction. 
The (3-oxo-1-alkenyl)-cis-bicyclo[3.3.0]octene derivative can be led to 
9(0)-methano-.DELTA..sup.6(9.alpha.) -PGI.sub.1 by reducing the ketone, 
carrying out the deprotection reaction of the hydroxy group and subjecting 
the ester to hydrolysis (see Reference example shown below). 
The bicyclo[3.3.0]octane derivative represented by the above formula [I] of 
this invention can be stated to be a very useful intermediate in that it 
can be led to not only the natural type .omega.-chain of prostaglandin 
skelton but also to a prostaglandin derivative having a nonnatural type 
.omega.-chain having higher activity as disclosed in a literature 
[Casals-Stenzel, J. et al., Protaglandins, Leukotrienes Med. 1983, 10 (2), 
pp. 197-212]. 
The bicyclo[3.3.0]octane derivative represented by the above formula [I] 
can be produced according to the reaction schemes as shown below. 
The protective group of hydroxy group in this invention may include, for 
R.sup.1, tetrahydropyranyl group, methoxymethyl group, 
4-methoxytetrahydropyranyl group, 1-ethoxyethyl group, 
1-methyl-1-methoxyethyl group, t-butyldimethylsilyl group, 
diphenyl-t-butylsilyl group, benzoyl group, acetyl group, triethylsilyl 
group, etc. and, for R.sup.5, t-butyldimethylsilyl group, benzoyl group, 
acetyl group, tetrahydropyranyl group, methoxymethyl group, 
4-methoxytetrahydropyranyl group, 1-ethoxyethyl group, 
1-methyl-1-methoxyethyl group, diphenyl-t-butylsilyl group, triethylsilyl 
group, etc. 
The substituent Y in the substituent R.sup.3 may preferably include a 
vinylene group and an ethylene group. 
In the compounds of the present invention, bicyclo[3.3.0]octenylaldehyde 
derivatives [I'] can be prepared following the reaction schemes shown 
below: 
##STR7## 
wherein R.sup.1 and R.sup.5 are the same as defined above. 
[The first step] 
This step produces a hydroxymethyl cyclopentane derivative represented by 
the above formula [III] by hydration of a cyclopentylidene derivative 
represented by the above formula [II]. 
The cyclopentylidene derivative represented by the above formula [II] is a 
compound which can easily be obtained by reducing a Corey's lactone 
derivative to lactol, which is then subjected to the Wittig reaction to 
oxidation of the hydroxyl group, followed by the methylenation reaction 
(see Reference example shown below). 
The hydration reaction in this step is conducted out by hydroboration and 
oxidation. In carrying out hydroboration, there may be employed a 
hydroborating reagent such as 9-BBN (9-borabicyclo[3.3.1]nonane), 
thexylborane, disiamylborane, etc. The amount of the hydroborating agent 
used may be generally 1 to 1.5 equivalent. 
The reaction is desired to be carried out in a solvent, preferably an ether 
type solvent such as tetrahydrofuran, diglyme, diethylether, etc. 
The reaction proceeds smoothly at -25.degree. C. to room temperature. 
Further, this step carries out oxidation of the product subsequent to the 
hydroboration without isolation thereof. The oxidation may be carried out 
by use of an oxidizing agent such as an alkaline hydrogen peroxide, an 
amine oxide, oxygen, peracid, etc. The amount of the oxidizing agent 
employed may be 5 to 15 equivalents. 
The reaction proceeds smoothly at room temperature to 60.degree. C. 
In this step, the compound formed by hydroboration with the use of, for 
example, 9-BBN may be estimated to have a formula as shown below: 
##STR8## 
[The second step] 
This step produces a .beta.-hydroxyaldehyde derivative represented by the 
above formula [IV] by oxidation of the hydroxymethyl cyclopentane 
derivative represented by the above formula [III]. 
In carrying out oxidation, it is possible to use dimethylsulfoxide-oxalyl 
chloride, dimethylsulfoxide-a pyridine complex of sulfur trioxide, etc. 
The amount of the oxidizing agent employed may be generally 1 to 5 
equivalents. 
The reaction is desired to be carried out in a solvent, for example, a 
halogenated hydrocarbon such as methylene chloride. 
The reaction can proceed smoothly at a temperature, which may differ 
depending on the oxidizing agent employed, but generally at -70.degree. C. 
to room temperature. 
For obtaining the oxidized product in this step, a tertiary amine such as 
triethylamine, diisopropylamine, etc. is added into the reaction product 
and treatment is carried out at -70.degree. C. to room temperature. Under 
this condition where dialdehyde is formed, intramolecular aldol 
condensation occurs rapidly to give a .beta.-hydroxyaldehyde derivative 
represented by the above formula [IV]. 
After completion of this step, the product is subjected to the next third 
step without isolation. 
[The third step] 
This step produces a bicyclo[3.3.0]octenylaldehyde derivative represented 
by the above formula [I'] by dehydrating the .beta.-hydroxyaldehyde 
derivative represented by the above formula [IV] obtained in the second 
step as described above in the presence of an acidic catalyst. 
Dehydration is required to be carried out in the presence of an acidic 
catalyst. As the acidic catalyst, an acid-ammonium salt is available. An 
acid-ammonium salt can be formed from an acid and an amine. The acid 
available may be exemplified by trifluoroacetic acid, toluenesulfonic 
acid, camphorsulfonic acid, acetic acid, etc. The amine available may be 
exemplified by dibenzylamine, diethylamine, dimethylamine, 
diisopropylamine, piperidine, pyrrolidine, piperazine, etc. These acids 
and amines may appropriately be selected and combined to be provided for 
use. Above all, the catalyst comprising a combination of trifluoroacetic 
acid and dibenzylamine is preferred on account of good yield of the 
desired product. The amount of the catalyst employed may be about 0.2 
equivalent, but it is preferred to employ about one equivalent in order to 
proceed rapidly the reaction. 
The reaction is desired to be carried out in a solvent, for example, an 
aromatic hydrocarbon such as benzene, toluene, xylene, etc. 
The reaction temperature may be selected within the range from room 
temperature to 100.degree. C., but preferably within the range from 
50.degree. C. to 70.degree. C. in order to carry out the reaction 
smoothly. 
The bicyclo[3.3.0]octenylaldehyde derivative obtained as described above 
can be subjected to the steps A to D as described below, whereby 
.omega.-chain can be introduced thereinto. 
##STR9## 
wherein R.sup.1 and R.sup.5 are the same as defined above, R.sup.6 is a 
straight, branched or cyclic alkyl, alkenyl or alkynyl group each having 5 
to 10 carbon atoms, R.sup.8 is a hydrogen atom or an alkyl group and 
R.sup.9 is a phenyl group or an alkyl group. 
[Step A] 
This step produces an alkenylbicyclo[3.3.0]octene derivative represented by 
the above formula [VI] by carrying out the reaction between the 
bicyclo[3.3.0]octenylaldehyde derivative represented by the above formula 
[I'] and 3-carboxypropylphosphonium bromide. 
This step is required to be carried out in the presence of a base. The base 
may include potassium t-butoxide, butyl lithium, sodium salt of 
dimethylsulfoxide, etc. For carrying out the reaction with good 
efficiency, it is preferred to employ potassium t-butoxide. The amount of 
the base employed may be generally 1 to 1.2 equivalent based on the above 
3-carboxypropylphosphonium bromide. 
The reaction may be carried out preferably in an ether solvent such as 
tetrahydrofuran, dimethoxyethane, diethyl ether, etc. The solvent is not 
particularly limited, provided that it does not interfere with the 
reaction. 
The reaction temperature may be selected within the range from 0.degree. C. 
to 50.degree. C., at which the reaction can proceed smoothly. 
The compound obtained in this step is formed generally as a free carboxylic 
acid, but it can be isolated as an ester by use of the condition of 
diazomethane or alkyl halide-diazabicycloundecene-acetonitrile for the 
reactions in the subsequent step et seq. Conversion to ester may be 
conducted according to the method easily done by those skilled in the art. 
[Step B] 
This step produces a bicyclo[3.3.0]octene derivative represented by the 
above formula [VII] in which only one of the olefins is selectively 
reduced by catalytic reduction of the alkenylbicyclo[3.3.0]octene 
derivative represented by the formula [VI] obtained in the previous step 
A. 
The available catalysts include palladium catalysts such as 
palladium-carbon, palladium black, etc., Wilkinson catalysts, platinum, 
nickel, etc. The catalyst may be sufficiently employed in the so-called 
catalytic amount. 
In practicing this step, hydrogen may be allowed to react with the compound 
under normal pressure or under pressurization. 
The reaction may be carried out preferably in a solvent, for example, an 
alcohol solvent such as methanol, ethanol, etc. or an ester solvent such 
as ethyl acetate, etc. 
The reaction can proceed smoothly at a temperature selected within the 
range from -25.degree. C. to room temperature. 
[Step C] 
This step produces a hydroxymethylbicyclo[3.3.0]octene derivative 
represented by the above formula [VIII] by selective deprotection of 
R.sup.5 of the bicyclo[3.3.0]octene derivative represented by the above 
formula [VII] obtained in the previous step B. 
In carrying out deprotection, when R.sup.5 is a silyl group, 
tetra-n-butylammonium fluoride may be used as the deprotecting agent, 
while potassium carbonate may be used, when it is benzoyl group or acetyl 
group. 
The reaction should desirably be conducted in a solvent. When 
tetra-n-butylammonium fluoride is used as the deprotecting agent, an ether 
solvent such as tetrahydrofuran, dimethoxyethane, ethyl ether, etc. may 
preferably be used. On the other hand, when potassium carbonate is used as 
the deprotecting agent, an alcohol solvent such as methanol, ethanol, etc. 
may preferably be used. 
The reaction can proceed smoothly at -25.degree. C. to room temperature. 
[Step D] 
This step produces a (3-oxo-1-alkenyl)-cis-bicyclo[3.3.0]octene derivative 
represented by the above formula [XI] by oxidizing the 
hydroxymethylbicyclo[3.3.0]octene derivative represented by the above 
formula [VIII] obtained in the previous step C and subsequently allowing 
the resultant product to react with a compound represented by the above 
formula [IX] or the above formula [X]. 
The oxidation in this step is required to be carried out in the presence of 
an oxidizing agent. The oxidizing agent may include Collins reagent, 
dimethyl sulfoxide-pyridine complex of sulfur trioxide, pyridinium 
chlorochromate, dimethyl sulfoxide-oxalyl chloride, etc. The amount of the 
oxidizing agent employed may be 7 to 10 equivalents in the case of Collins 
reagent, and 1 to 5 equivalents in the case of other oxidizing agents. 
The reaction should desirably be carried out in a solvent, preferably in a 
halogenated hydrocarbon such as methylene chloride, chloroform, etc. 
The reaction can proceed smoothly at a temperature within the range from 
-70.degree. C. to room temperature. 
In this step, the product obtained by oxidation is not isolated but 
subsequently subjected to the reaction with a compound represented by the 
above formula [IX] or the above formula [X]. The compounds represented by 
the above formula [IX] include, for example, 
dimethyl(2-oxoheptyl)phosphonate, 
dimethyl(2-oxo-3-methylheptyl)phosphonate, 
dimethyl(2-oxo-3,3-dimethylheptyl)phosphonate, 
dimethyl(2-oxo-4,8-dimethyl-7-nonenyl)phosphonate, 
dimethyl(2-oxo-4,4,8-trimethyl-7-nonenyl)phosphonate, 
dimethyl(2-oxo-2-cyclopentylethyl)phosphonate and the like. The compounds 
represented by the above formula [X] include 
tributylphosphine-2-oxoheptylidene, 
tributylphosphine-2-oxo-3-methylheptylidene, 
tributylphosphine-2-oxo-3,3-dimethylheptylidene, 
tributylphosphine-2-oxo-4,8-dimethyl-7-nonenylidene, 
tributylphosphine-2-oxo-4,4,8-trimethyl-7-nonenylidene, 
tributylphosphine-2-oxo-2-cyclopentylethylidene and the like. When the 
compound represented by the above formula [X] is selected as the starting 
material, it is preferred to carry out the reaction in the presence of a 
base, such as sodium hydride, butyl lithium, potassium t-butoxide, etc. in 
order to obtain the desired product at good yield. 
The reaction should desirably be conducted in a solvent, e.g. an ether 
solvent such as tetrahydrofuran, dimethoxyethane, diethyl ether, etc. or 
an aromatic solvent such as benzene, toluene, xylene, etc. 
The reaction temperature may be within the range from -25.degree. C. to 
50.degree. C. when employing a compound represented by the formula [IX] or 
within the range from 20.degree. C. to 150.degree. C. when employing a 
compound represented by the formula [X]. 
The compound obtained by oxidation in this step may be estimated to be a 
compound represented by the formula: 
##STR10## 
wherein R.sup.1 is a protective group for hydroxy group and R.sup.8 is a 
hydrogen atom or an alkyl group. 
In the present invention, the (1-alkenyl)-bicyclo[3.3.0]octenyl derivative 
represented by the following formula [I-a]: 
##STR11## 
can be produced as follows. 
That is, in the presence of a base, bicyclo[3.3.0]octenylaldehyde 
represented by the formula [I']: 
##STR12## 
wherein R.sup.1 and R.sup.5 are a hydrogen atom or protective groups a 
hydroxy group, 
is allowed to react with a 3-carboxypropylphosphonium halilde represented 
by the formula [XII]: 
##STR13## 
wherein R.sup.10 is an alkyl group or an aryl group, and 
X is a halogen atom, 
followed by esterification if desired, to produce a 
(1-alkenyl)-bicyclo[3.3.0]octene derivative. 
The bicyclo[3.3.0]octenylaldehyde derivative represented by the formula 
[I'] can be synthesized easily from Coley lactone which the typical 
intermediate for various prostaglandins (see Reference example shown 
below). In the above formula [I'], R.sup.1 and R.sup.5 may include 
hydrogen atom, tetrahydropyranyl group, t-butyldimethylsilyl group, 
1-ethoxyethyl group, diphenyl-t-butylsilyl group, methoxymethyl group, 
1-methyl-1-methoxyethyl group, 4-methoxytetrahydropyranyl group, methyl 
group, benzyl group, benzoyl group, acetyl group, 
.beta.-methoxyethoxymethyl group, triethylsilyl group, etc. 
The 3-carboxypropylphosphonium halide represented by the above formula 
[XII] can be prepared from, for example, 4-bromobutanoic acid and 
triphenylphosphine [W. Seidel, J. Knolle, and H. J. Schafer, Chem. Ber., 
110, 3544 (1977)]. R.sup.10 in the above formula [XII] may be, for 
example, an alkyl group such as butyl or an aryl group such as a phenyl, 
and X may be chlorine atom, bromine atom or iodine atom. 
The present invention is required to be carried out in the presence of a 
base. Examples of the base may be organic bases such as potassium 
t-butoxide, sodium t-amyloxide, sodium methoxide, sodium ethoxide, sodium 
salt of dimethyl sulfoxide (DMSO), potassium salt of DMSO, butyl lithium, 
sec-butyl lithium, t-butyl lithium, phenyl lithium, sodium hydride, 
potassium hydride, lithium diisopropylamide, lithium diethylamide, sodium 
amide and the like, and inorganic bases such as sodium hydroxide, 
potassium hydroxide, potassium carbonate and the like. The amount of the 
base employed may be sufficiently be 2 to 3 mole equivalents based on the 
bicyclo[3.3.0]octenylaldehyde derivative represented by the above formula 
[I']. 
The present invention should desirably be carried out in a solvent. The 
solvent may be an ether solvent such as tetrahydrofuran, dimethoxyethane, 
ether, 2-methoxyethyl ether, etc., an aromatic solvent such as toluene, 
benzene, etc., or a polar solvent such as DMSO, HMPT, DMF, etc., when 
employing an organic base; or alternatively a halogenic solvent such as 
methylene chloride, chloroform, etc. or a solvent mixture of an aromatic 
solvent such as toluene, benzene, etc. with water, when employing an 
inorganic base. 
When an inorganic base is employed, the reaction system consists of two 
layers. For the purpose of effective action of these bases, it is 
preferred to carry out the reaction in the presence of a catalyst for 
inter-phase migration generally employed for two-layer system reaction 
such as tetramethylammonium bromide, tetrabutylammonium iodide, etc., 
whereby the desired product can be obtained with good efficiency. The 
reaction can proceed smoothly by selecting a temperature within the range 
from -78.degree. C. to 100.degree. C. In the present invention, 
esterification may be conducted, if desired. 
It is possible to derive an alkyl ester of the compound represented by the 
above formula [I-a] wherein R.sup.8 represents a hydrogen atom. That is, 
the compound obtained by the above reaction may be allowed to react with 
diazomethane in an ether solvent to be quantitatively converted into a 
methyl ester derivative, which can in turn be allowed to react with 
various alkyl halides such as ethyl bromide, propyl bromide, butyl 
bromide, etc. in acetonitrile in the presence of 
1,8-diazabicyclo[5,4,0]undecene (DBU) to be converted to corresponding 
ethyl ester, propyl ester and butyl ester derivatives, respectively. The 
reaction can proceed smoothly by selecting a temperature within the range 
from -25.degree. C. to 100.degree. C. 
In the present invention, the 
(4'-alkoxycarbonyl-1'-alkenyl)-cis-bicyclo[3.3.0]octene derivative 
represented by the following formula [I-b]: 
##STR14## 
can be produced according to the following steps: 
##STR15## 
wherein R.sup.1, R.sup.5, R.sup.7, and R.sup.8 are the same as defined 
above. 
[The first step] 
This step produces a hydroxymethyl derivative [VIII] by selective 
elimination of the protective group for the primary hydroxy group of a 
conjugated diene derivative represented by the above formula [VI']. 
Deprotection of this step is carried out with fluoride ions when the silyl 
group is protected, and tetrabutylammonium fluoride, potassium fluoride, 
etc. may be used. This step should desirably be conducted in a solvent, 
preferably an ether solvent such as tetrahydrofuran. In this step, the 
reaction can proceed smoothly at a temperature within the range from 
-25.degree. C. to 100.degree. C. 
[The second step] 
This step produces an .alpha.,.beta.-unsaturated ketone by oxidizing the 
hydroxymethyl derivative represented by the formula [VIII] obtained in the 
first step, and then allowing the resultant product with a compound 
represented by the above formula ]IX]. 
This step can be carried out under the same conditions in the step D for 
introducing .omega.-chain into the bicyclo[3.3.0]octenylaldehyde 
derivative as described above. The compounds represented by the above 
formula [IX] may include, for example, 
dimethyl(2-oxo-3-methyl-5-heptynyl)phosphonate, 
dimethyl(2-oxo-4(R)-methyl-8-methyl-7-nonenyl)phosphonate and the like. 
This step may preferably be conducted in the presence of a base for 
obtaining the desired compound with good efficiency. For example, a base 
such as sodium hydride, potassium hydride, butyl lithium, potassium 
t-butoxide, etc. may be employed. 
The compound obtained by oxidation in this step may be estimated to be a 
compound represented by the formula: 
##STR16## 
[The third step] 
This step produces an allyl alcohol derivative by reduction of the carbonyl 
group of the .alpha.,.beta.-unsatuated ketone represented by the above 
formula [XI'] obtained in the second step. Reduction in this step is 
required to be carried out in the presence of a reducing agent. The 
reducing agent may include sodium borohydride, 
diisobutylaluminum-2,6-di-t-butyl-4-methyl-phenoxide, etc. The amount of 
the reducing agent used may be 1 to 15 equivalents. The reaction should 
desirably be carried out in a solvent, e.g. an alcohol solvent such as 
methanol, ethanol and the like, an aromatic hydrocarbon solvent such as 
benzene, toluene, etc. The reaction can proceed smoothly at a temperature 
in the range from -78.degree. C. to room temperature. The allyl alcohol 
derivative obtained in this step is a mixture of .alpha.-isomer and 
.beta.-isomer. 
[The fourth step] 
This step produces a diol derivative by elimination of the protective group 
of the secondary hydroxyl group of the allyl alcohol derivative 
represented by the formula [I-c] obtained in the third step. Deprotection 
in this step is carried out in the presence of an acid. The acid to be 
employed may be acetic acid, pyridinium salt of p-toluene sulfonic acid, 
etc. The reaction should desirably be conducted in a solvent such as 
THF-water, ethanol-water, etc. The reaction can proceed smoothly at room 
temperature to 100.degree. C. The diol derivative obtained in this step 
can be easily separated into isomers at the 15-position (prostaglandin 
numbering) into a highly polar isomer 15.alpha. and a lowly polar isomer 
15.beta.. 
[The fifth step] 
This step protects the two hydroxy groups of the diol derivative 
represented by the above formula [I-d] obtained in the fourth step, if 
desired. The protective group to be employed may be, for example, 
t-butyldimethylsilyl group, triethylsilyl group, tetrahydropyranyl group, 
1-ethoxyethyl group, diphenyl-t-butylsilyl group, 1-methyl-1-methoxyethyl 
group, etc. It is desired to employ the condition of 
t-butyldimethylsilylchloride-imidazole-DMF in the case of 
t-butyldimethylsilyl group; of triethylsilyl chloride-pyridine in the case 
of triethylsilyl group; of dihydropyrane-catalytic amount of p-toluene 
sulfonic acid-methylene chloride in the case of tetrahydropyranyl group; 
of ethyl vinyl ether-catalytic amount of p-toluene sulfonic acid-methylene 
chloride in the case of 1-ethoxyethyl group; etc. 
The reaction can proceed readily at 0.degree. C. to 100.degree. C. 
The (4'-alkoxycarbonyl-1'-alkenyl)-cis-bicyclo[3.3.0]octene derivative of 
the present invention has an asymmetric carbon in the molecule, and the 
present invention is inclusive of the R-configuration or the 
S-configuration or a mixture of those at any desired ratio. 
In the present invention, a bicyclo[3.3.0]octane derivative represented by 
the following formula [I-e]: 
##STR17## 
can be further produced according to the following steps: 
##STR18## 
wherein R.sup.1, R.sup.5 and R.sup.8 are the same as defined above. 
[The first step] 
This step produces a cyclopentylidene derivative represented by the formula 
[XIV] by methylenation of the cyclopentanone derivative represented by the 
above formula [XIII]. 
The cyclopentanone derivative represented by the above formula [XIII] is a 
compound which can be obtained easily by reducing a Coley lactone 
derivative into a lactol, subjecting the lactol to the Wittig reaction, 
converting the carboxyl group into ester group and oxidizing the hydroxy 
group (see Reference examples shown below). 
The group R.sup.8 in the formula [XIII] may be, for example, an alkyl group 
such as methyl, ethyl, etc. 
The methylenation in this step may be carried out by use of a mixed reagent 
of methylene bromide-titanium tetrachloride-zinc [L. Lombardo, Tetrahedron 
Lett., 23, 4293 (1982)] or Johnson reagent [C. R. Johnson, J. R. Shanklin, 
R. A. Kirchoff, J. Am. Chem. Soc., 95, 6462 (1973)]. The reaction should 
desirably be carried out in a solvent, for example, a solvent mixture such 
as a halogenic solvent (e.g. methylene chloride)--an ether solvent (e.g. 
tetrahydrofuran) in the case of using the former reagent, while an ether 
solvent in the case of the latter reagent. The reaction can proceed 
smoothly at -80.degree. C. to 60.degree. C., but room temperature is 
preferred because the reaction can be carried out without heating or 
cooling. 
When the protective group R.sup.1 in the cyclopentylidene derivative is 
subjected to subsequent steps, particularly the fourth step, it is 
preferably converted to a protective group which is high in thermal 
stability, such as t-butyldimethylsilyl group, diphenyl-t-butylsilyl 
group, methyl group, etc. 
[The second step] 
This step can be carried out according to the same procedure as in the 
first step in preparation of the bicyclo[3.3.0]octenylaldehyde derivative 
as described above. 
Further, as described above, this step oxidizes the product without 
isolation subsequent to hydroboration. In oxidation, an oxidizing agent 
selected from peroxides of hydrogen peroxide, peracetic acid, perbenzoic 
acid, etc. may be employed. When a peroxide is employed as the oxidizing 
agent, the peroxide is desired to be in a basic state and a base such as 
caustic soda may be employed for this purpose. The amount of the oxidizing 
agent to be employed may be generally 5 to 15 equivalents. The reaction 
can proceed smoothly at -20.degree. to 60.degree. C., but the reaction at 
room temperature is preferable because of simple operation. 
[The third step] 
This step produces a formylcyclopentane derivative represented by the above 
formula [XVI] by oxidation of the hydroxymethylcyclopentane derivative 
represented by the above formula [XV] obtained in the second step. 
In carrying out oxidation, it is possible to use an oxidizing agent such as 
pyridinium chlorochromate (PCC) in the presence of sodium acetate, Collins 
reagent, pyridinium dichromate (PDC), dimethyl sulfoxide (DMSO)-pyridinium 
complex of sulfur trioxide, DMSO-oxalyl chloride, etc. The amount of the 
oxidizing agent employed is different depending on the oxidizing agent, 
but generally 1 to 8 equivalent. 
The reaction should desirably be conducted in a solvent, for example, a 
halogenic solvent such as methylene chloride, chloroform, etc. The 
reaction temperature is different depending on the oxidizing agent 
employed. When PCC, Collins reagent, PDC or DMSO-pyridinium complex of 
sulfur trioxide is employed, the reaction can proceed readily at 
-20.degree. C. to 30.degree. C. In the case of DMSO-oxalyl chloride, the 
reaction can proceed smoothly at -70.degree. C. to room temperature. 
[The fourth step] 
This step produces an alkenylbicyclo[3.3.0]octane derivative represented by 
the above formula [I-a] by treating the formylcyclopentane derivative 
represented by the above formula [XVI] obtained in the third step under 
heating. 
This step is the so-called thermal heteroene reaction and the heating 
condition may be selected within the range of from 120.degree. to 
300.degree. C. However, for carrying out the reaction efficiently, the 
range from 150.degree. to 250.degree. C. is preferred. 
The reaction should desirably be conducted in a solvent, for example, an 
aromatic hydrocarbon such as benzene, toluene, xylene and the like. 
[The fifth step] 
This step produces an alkylbicyclo[3.3.0]octane derivative represented by 
the above formula [I-g] by catalytic reduction of the 
alkenylbicyclo[3.3.0]octane derivative represented by the above formula 
[I-f] obtained in the fourth step. 
The catalysts available include palladium catalysts such as 
palladium-carbon, palladium black, etc., Wilkinson catalyst, platinum, 
nickel, etc. It is sufficient to employ the catalyst in the so-called 
catalytic amount. 
In practicing this step, hydrogen may be allowed to react with the compound 
either at normal pressure or under pressurization. 
The reaction should desirably be conducted in a solvent, for example, an 
alcohol solvent such as methanol, ethanol, etc. or an ester solvent such 
as ethyl acetate. 
The reaction can proceed smoothly at a temperature which may be selected 
within the range from -25.degree. C. to room temperature.