Prostaglandin derivatives of the formula ##STR1## in which R.sup.4, R.sup.5, R.sup.6 and R.sup.7 each are hydrogen or lower alkyl, X is hydroxy and Y is hydrogen or X and Y together are oxo, Z is CH.sub.2 CH.sub.2 or trans CH.dbd.CH, m is an integer from one to three and n is an integer from two to five, with the proviso that at least one of R.sup.4, R.sup.5 or R.sup.6 is hydrogen, are disclosed together with a process for their preparation. The compounds in which Z is CH.sub.2 CH.sub.2 and the process are new. The new derivatives possess hypotensive, antihypertensive, bronchospasmolytic, gastric acid secretion inhibiting, abortifacient, estrus synchronizing and ovulation regulating properties. These compounds also inhibit the aggregation of platelets and promote the disaggregation of aggregated platelets. Methods for their use are also disclosed.

BACKGROUND OF THE INVENTION 
(a) Field of Invention 
This invention relates to prostaglandin derivatives. More specifically this 
invention relates to 9,15-dioxygenated derivatives of prost-5-enoic and 
prosta-5,13-dienoic acid having optional alkyl substituents, to lower 
alkyl esters thereof and to homologs thereof. Also encompassed within this 
invention are processes for preparing these compounds and intermediates 
used therein. 
(B) Description of the Prior Art 
The chemistry and pharmacological effects of the prostaglandins have been 
the subject of several recent reviews; for example, see E. W. Horton, 
Physiol. Rev., 49, 122 (1969), J. F. Bagli in "Annual Reports in Medicinal 
Chemistry, 1969", C. K. Cain, Ed., Academic Press, New York and London, 
1970, p. 170, and J. E. Pike in "Progress in the Chemistry of Organic 
Natural Products", Vol. 28, W. Herz, et al. Eds., Springer Verlag, New 
York, 1970, p. 313. 
Due to the increasing interest in these natural products a rather extensive 
effort has been given recently to the synthesis of prostaglandins and 
their analogs. Included among these syntheses are several synthetic 
methods for the preparation of 9,15-dioxygenated derivatives of prostanoic 
or prost-13-enoic acid. For example, the synthesis of the first 
pharmacologically active 9,15-dioxygenated prostanoic acid derivative, 
9.beta.,15.xi.-dihydroxyprost-13-enoic acid (11-desoxyprostaglandin 
F.sub.1.beta.) was reported in detail by J. F. Bagli, T. Bogri and R. 
Deghenghi, Tetrahedron Letters, 465 (1966). A significant simplification 
and modification of that process was described by Bagli and Bogri in U.S. 
Pat. No. 3,455,992, issued July 15, 1969, whereby 
9.beta.,15.xi.-dihydroxyprost-13-enoic acid as well as homologs thereof 
were obtained, see also Bagli and Bogri, Tetrahedron Letters, 5 (1967). 
Further improvements in the synthesis of 9,15-dioxygenated derivatives of 
prostanoic acid have been described by Bagli and Bogri in Tetrahedron 
Letters, 1639 (1969) and German Offenlegungsschrift No. 1,953,232, 
published Apr. 30, 1970, and in British Pat. Specification No. 1,097,533, 
published Jan. 3, 1968. 
More recently, Bagli and Bogri have extended the scope of their processes 
for preparing 9,15-dioxygenated derivatives of prostanoic acid to include 
the preparation of 9-oxo-15-hydroxy prostanoic acid derivatives having an 
alkyl substituent at position 15, U.S. Pat. No. 3,671,570, issued June 20, 
1972. These 15-alkyl derivatives possess hypotensive, antihypertensive, 
bronchospasmolytic and gastric acid secretion inhibiting properties, as 
well as inhibiting the aggregation of platelets and promoting the 
disaggregation of aggregated platelets. 
Still further improvements in the synthesis of such 9,15-dioxygenated 
derivatives are described in U.S. Pat. No. 3,773,795, issued Nov. 20, 
1973, U.S. Pat. application Ser. No. 351,381, filed Apr. 16, 1973 and the 
publication by N. A. Abraham, Tetrahedron Letters, 451 (1973). 
Other recent syntheses of 9,15-dioxygenated derivatives are reported in 
Belgian Pat. No. 766,521, published Nov. 3, 1971, P. Crabbe and A. Guzman, 
Tetrahedron Letters, 115 (1972), M. P. L. Caron, et al., Tetrahedron 
Letters, 773 (1972), C. J. Sih, et al., Tetrahedron Letters, 2435 (1972), 
F. S. Alverez, et al., J. Amer. Chem. Soc., 94, 7823 (1972), A. F. Kluge, 
et al. and J. Amer. Chem. Soc., 94, 9256 (1972). 
It is noteworthy that the synthetic 9,15-dioxygenated prostanoic acid 
derivatives described above possess a number of the biological activities 
of the natural compounds although they lack the 11-hydroxyl of the latter. 
In addition it should be noted that the natural PGE.sub.1, PGE.sub.2, 
PGF.sub.1.alpha. and PGF.sub.2.alpha. do have the disadvantage of being 
relatively unstable, see T. O. Oesterling, et al., J. Pharm. Sci., 61, 
1861 (1972). For example, it is well known that the 11-hydroxy group of 
PGE.sub.1 and PGE.sub.2 participates readily in dehydration reactions 
under both basic and acidic conditions, see S. Bergstrom et al., J. Biol. 
Chem. 238, 3555 (1963), E. J. Corey et al., J. Amer. Chem. Soc., 90, 3245 
(1968), J. E. Pike et al., J. Org. Chem. 34, 3552 (1969) and "The 
Prostaglandins, Progress in Research", S. M. M. Karim, Ed., 
Wiley-Interscience, New York, 1972, p. 10. 
As realized by those skilled in the art this inherent disadvantage of the 
natural compounds must always be taken into account when considering the 
practical aspects of preparation, formulation or storage of these 
compounds. In contrast, the compounds of the present invention are free 
from this disadvantage. 
It is the purpose of the present disclosure to describe certain 
9,15-dioxygenated prostanoic acid derivatives possessing useful 
pharmacologic properties coupled with a relatively low order of toxicity. 
Furthermore, there is disclosed a process for preparing the derivatives 
which starts from readily available starting materials, avoids noxious 
agents, is executed facilely and is adaptable to large scale preparation 
of the derivatives. 
For example, the present process utilizes as one of its starting materials 
a dialkyl 2-(carboalkoxymethyl)malonate (formula 3, see below), which is 
readily prepared by condensing a dialkyl malonate with the appropriate 
readily available lower alkyl haloacetic acid. The ready availability of 
this starting material represents an improvement over our earlier process 
of U.S. Patent application Ser. No. 238,650, filed Mar. 27, 1973 (see also 
corresponding West German Offenlegungsschrift No. 2,313,686, published 
Apr. 10, 1973). The earlier process utilizes a substituted malonate 
derivative which in some cases takes a seven or eight step synthesis to 
prepare. 
Other advantages of the present process are that it yields directly 
prostaglandin derivatives having the hydroxy group of the cyclopentane 
ring in the most desirable configuration. In other words the more active 
epimer with respect to the configuration of the cyclopentane hydroxy group 
is obtained. Furthermore, this desirable result can be achieved with 
simple and non-hazardous reagents, for example by reducing the appropriate 
precursor ketone with sodium borohydride, thereby eliminating the 
necessity of using noxious or expensive reagents; cf. E. J. Corey, et al., 
J. Amer. Chem. Soc., 93, 1491 (1971). 
Still another advantage of the present process features the preparation of 
an entirely new class of prostaglandin derivatives in which the acid side 
chain is unsaturated and the side chain bearing the hydroxy group is fully 
saturated. 
The foregoing advantages render the prostaglandin derivatives of this 
invention particularly desirable as pharmacologic agents. 
SUMMARY OF THE INVENTION 
One aspect of this invention is a process for the preparation of the key 
intermediates, the hydroxylactone 6 and the ketolactone of formula 7. The 
process is represented by the following flow diagram: 
##STR2## 
in which R.sup.1 and R.sup.3 each are lower alkyl, R.sup.2 is hydrogen or 
a hydroxy protecting radical, R.sup.4, R.sup.5 and R.sup.6 each are 
hydrogen or lower alkyl, and n is an integer from two to five with the 
provisos that at least one of R.sup.4, R.sup.5 or R.sup.6 is hydrogen and 
that R.sup.2 is hydrogen when R.sup.6 is lower alkyl. 
With reference to the above flow diagram a lower alkyl 
cyclopropanedicarboxylate of formula 1 in which R.sup.1, R.sup.2, R.sup.4, 
R.sup.5, R.sup.6 and n are as defined herein is condensed with a triester 
of formula 2 in which R.sup.3 is lower alkyl in the presence of a base to 
give the corresponding cyclopentanonetriester of formula 3. When R.sup.2 
of the latter compound is a hydroxy protecting radical, the radical is 
removed by treating the cyclopentanonetriester with a deprotecting agent 
to give the corresponding cyclopentanonetriester of formula 3 in which 
R.sup.2 is hydrogen. The instant compound of formula 3 in which R.sup.2 is 
hydrogen is now subjected to base treatment in the presence of water, 
followed by acidification of the basic reaction mixture to give the 
corresponding .gamma.-ketoacid of formula 4. In the case where R.sup.6 is 
hydrogen the latter compound is transformed to its corresponding hydroxy 
protected derivative (4, R.sup.2 = hydroxy protecting radical). The 
compound of formula 4 in which R.sup.6 is hydrogen or lower alkyl is 
reduced with a complex borohydride to give a mixture of the corresponding 
acid of formula 5 and the corresponding hydroxylactone 6. Transformation 
of the acid 5 to the hydroxylactone 6, thereby increasing the yield of the 
hydroxylactone 6, is effected by subjecting the acid 5, or the mixture of 
the acid 5 and the hydroxylactone 6, obtained as above, to treatment with 
methanesulfonyl or p-toluenesulfonyl chloride or bromide in the presence 
of a suitable proton acceptor. In the case where the hydroxylactone of 
formula 6 is obtained in the form of its corresponding hydroxy protected 
derivative (6, R.sup.2 = hydroxy protecting group and R.sup.6 = H), the 
protected derivative is converted readily to its corresponding free 
hydroxy derivative (6, R.sup.2 = H) by treatment with a deprotecting 
agent. 
On subjecting the latter free hydroxy derivative of formula 6 in which 
R.sup.6 is hydrogen to oxidation with an agent known to be effective for 
oxidizing allylic alcohols to .alpha.,.beta.-unsaturated ketones, the 
corresponding desired ketolactone of formula 7 in which R.sup.4 and 
R.sup.5 each are hydrogen or lower alkyl and n is an integer from two to 
five is obtained. One of these ketolactones has been reported previously; 
i.e., the compound of formula 7 in which R.sup.4 and R.sup.5 each are 
hydrogen and n = 3, see E. J. Corey and R. Ravindranathan, Tetrahedron 
Letters, 4755 (1971). 
The ketolactone of formula 7 is transformed to prost-5-enoic and 
prosta-5,13-dienoic acid derivatives and related homologs according to one 
of the following three methods A, B, or C: 
In method A the ketolactone of formula 7 is reduced catalytically to give 
the corresponding dihydroketolactone of formula 8 
##STR3## 
in which R.sup.4, R.sup.5 and n are as defined herein. Subsequent 
reduction of the latter compound with a metal borohydride yields the 
corresponding dihydrohydroxylactone of formula 9 in which R.sup.2 and 
R.sup.6 are hydrogen and R.sup.4, R.sup.5 and n are as defined herein. 
Thereafter, the latter dihydrohydroxylactone of formula 9, or preferably 
its hydroxy protected derivative, is reduced with a mono- or dialkyl 
aluminum hydride to give the corresponding hemiacetal of formula 10 
##STR4## 
in which R.sup.2 is hydrogen or a hydroxy protecting group, R.sup.6 is 
hydrogen, and R.sup.4, R.sup.5 and n are as defined herein. Condensation 
of the latter compound with a Wittig reagent of the formula 
##STR5## 
in which Hal is bromine, chlorine or iodine, m is an integer from one to 
three and R.sup.7 is hydrogen or lower alkyl yields the corresponding 
novel prostaglandin derivative of formula 11 
##STR6## 
in which R.sup.2 is hydrogen or a hydroxy protecting group, R.sup.6 is 
hydrogen, X is hydroxy, Y is hydrogen, Z is CH.sub.2 CH.sub.2 and R.sup.4, 
R.sup.5, R.sup.7, m and n are as defined herein; and when R.sup.2 of the 
latter compound is a hydroxy protecting group, subsequent reaction of the 
latter compound with a deprotecting agent for removing the protecting 
group yields the corresponding compound of formula 11 in which R.sup.2 is 
hydrogen. 
In method B the ketolactone of formula 7 in which R.sup.4 is hydrogen and 
R.sup.5 and n are as defined herein is reduced catalytically in the same 
manner as described in the method A and the resulting corresponding 
dihydroketolactone of formula 8 (R.sup.4 = H and R.sup.5 = H or lower 
alkyl) is reacted with substantially one equivalent of a lower alkyl 
magnesium halide (i.e. a Grignard type reaction) to yield the 
corresponding dihydrohydroxylactone of formula 9 in which R.sup.2 is 
hydrogen, R.sup.6 is lower alkyl, R.sup.4 is hydrogen and R.sup.5 and n 
are as defined herein. Subsequent reduction of the latter compound with a 
mono- or dialkyl aluminum hydride gives the corresponding hemiacetal of 
formula 10 in which R.sup.2 is hydrogen, R.sup.6 is lower alkyl and 
R.sup.4 is hydrogen and R.sup.5 and n are as defined herein which is 
condensed in a like manner with the appropriate Wittig reagent as 
described in the first method to yield the corresponding novel 
prostaglandin derivative of formula 11 in which R.sup.2 and R.sup.4 each 
are hydrogen, R.sup.6 is lower alkyl, X is hydroxy, Y is hydrogen, Z is 
CH.sub.2 CH.sub.2 and R.sup.5, R.sup.7, m and n are as defined herein. 
In method C the ketolactone of formula 7 in which R.sup.4 is hydrogen and 
R.sup.5 and n are as defined herein is reacted with a lower alkyl 
magnesium halide to produce the corresponding hydroxylactone of formula 12 
##STR7## 
in which R.sup.2 is hydrogen, R.sup.4 is hydrogen, R.sup.6 is lower alkyl, 
and R.sup.5 and n are as defined herein. The latter compound is reduced 
with a monoalkyl or dialkyl aluminum hydride to give the corresponding 
hemiacetal of formula 13 
##STR8## 
in which R.sup.2 is hydrogen, R.sup.4 is hydrogen, R.sup.6 is lower alkyl, 
and R.sup.5 and n are as defined herein. Subsequent condensation of the 
hemiacetal of formula 13 with the appropriate Wittig reagent as described 
in the first method gives the prostaglandin derivatives of formula 11 in 
which R.sup.2 and R.sup.4 each are hydrogen, R.sup.6 is lower alkyl, X is 
hydroxy, Y is hydrogen, Z is trans CH.dbd.CH, and R.sup.5, R.sup.7, m and 
n are as defined herein. 
These prostaglandin derivatives, prepared by a different process, are part 
of the subject matter of our U.S. Pat. No. 3,773,795, issued Nov. 20, 1973 
and Ser. No. 351,381, filed Apr. 16, 1973. 
In another aspect of this invention the hydroxylactone of formula 6 in 
which R.sup.2, R.sup.4, R.sup.5 and n are as defined in the first instance 
is utilized to prepare prostaglandin derivatives by one of the following 
two methods, D or E: 
In method D the hydroxylactone of formula 6 in which R.sup.6 is hydrogen, 
preferably in its protected hydroxyl form (i.e., R.sup.2 is a hydroxy 
protecting group), is reduced catalytically to give the corresponding 
dihydrohydroxylactone of formula 9 in which R.sup.2 is hydrogen or a 
hydroxy protecting group, R.sup.6 is hydrogen and R.sup.4, R.sup.5 and n 
are as defined in the first instance. Thereafter, the latter 
dihydrohydroxylactone, preferably in its protected hydroxyl form, is 
transformed to the corresponding novel prostaglandin derivative of formula 
11, through the hemiacetal (10; R.sup.2 being hydrogen or a hydroxy 
protecting group, R.sup.6 being hydrogen and R.sup.4, R.sup.5 and n being 
as defined in the first instance) by reduction with a mono- or 
dialkylaluminum hydride to the corresponding hemiacetal followed by 
condensation with the appropriate Wittig reagent in the manner described 
previously. In this manner the same prostaglandin derivatives are obtained 
as those obtained by transforming the ketolactone of formula 7 according 
to the method A described hereinbefore, i.e., the derivatives of formula 
11 in which R.sup.2 is hydrogen or a hydroxy protecting group, R.sup.6 is 
hydrogen, X is hydroxy, Y is hydrogen, Z is CH.sub.2 CH.sub.2 and R.sup.4, 
R.sup.5, R.sup.7, m and n are as defined in the first instance. 
In method E for transforming the hydroxylactone of formula 6 in which 
R.sup.2, R.sup.4, R.sup.5, R.sup.6 and n are as defined in the first 
instance to prostaglandin derivatives, the hydroxylacetone of formula 6, 
preferably in its protected hydroxyl form when R.sup.6 is hydrogen, is 
reduced to its corresponding hemiacetal of formula 13 in which R.sup.2, 
R.sup.4, R.sup.5, R.sup.6 and n are as defined in the first instance by 
treatment with a monoalkyl or dialkyl aluminum hydride. Thereafter, the 
latter hemiacetal, preferably in its protected hydroxyl form when R.sup.2 
is hydrogen, is condensed with a Wittig reagent in the manner described 
above to yield the corresponding prostaglandin derivatives of formula 11 
in which R.sup.2 is hydrogen or a hydroxy protecting group and R.sup.6 is 
hydrogen or R.sup.2 is hydrogen and R.sup.6 is lower alkyl, X is hydroxy, 
Y is hydrogen, Z is trans CH.dbd.CH, and R.sup.4, R.sup.5, R.sup.7, m and 
n are as defined in the first instance; and when R.sup.2 of the latter 
compound is a hydroxy protecting radical, treating said latter compound 
with a deprotecting agent for removing the radical to obtain the 
corresponding compound of formula 11 in which R.sup.2 is hydrogen. These 
latter prostaglandin derivatives, prepared by another process, are part of 
the subject matter of our copending U.S. application, Ser. No. 351,381, 
filed Apr. 16, 1973. 
Thereafter, if desired, the aforementioned compounds of formula 11 in which 
R.sup.2 is a hydroxy protecting group, R.sup.4 is hydrogen or lower alkyl 
and R.sup.6 is hydrogen, or R.sup.2 and R.sup.4 each are hydrogen and 
R.sup.6 is a lower alkyl; R.sup.7 is hydrogen, X is hydroxy, Y is hydrogen 
and Z is CH.sub.2 CH.sub.2 or trans CH.dbd.CH and R.sup.5, m and n are as 
defined in the first instance, are treated with an agent capable of 
oxidizing the hydroxy function to its corresponding keto function to 
obtain the corresponding compound of formula 11 in which X and Y together 
are oxo, followed, when R.sup.2 of the latter compound is a hydroxy 
protecting group, by reacting the latter compound with a deprotecting 
agent to obtain the corresponding compound of formula 11 in which R.sup.2 
is hydrogen. 
Furthermore, if desired, the aforementioned compound of formula 11 in which 
R.sup.2 and R.sup.7 are hydrogen, X is hydroxy and Y is hydrogen or X and 
Y together are oxo and Z is CH.sub.2 CH.sub.2 or CH.dbd.CH and R.sup.4, 
R.sup.5, R.sup.6, m and n are as defined in the first instance, are 
treated with a lower alkanol containing one to three carbons in the 
presence of an acid catalyst to obtain its corresponding ester derivative 
of formula 11 in which R.sup.7 is lower alkyl.

DETAILS OF THE INVENTION 
The numbering system applied to the compounds of this invention, as used 
hereinafter, refers to the .omega.-cyclopentyl(lower)alkanoic acid 
nucleus. 
A feature of this invention is that the process described herein leads to 
the compounds of formula 11 in which the two side chains are in the trans 
configuration characteristic for the natural prostaglandins. Also, like 
the natural prostaglandins a double bond in the acid side chain of the 
compounds of this invention has the cis configuration and the double bond 
in the side chain bearing the hydroxy group has the trans configuration. 
Notwithstanding the preceding considerations the compounds of this 
invention having one or more asymmetric carbon atoms can exist in the form 
of various stereochemical isomers. More specifically, the compounds are 
produced as a mixture of racemates. These mixtures result from the 
asymmetric centers, for example the carbon bearing a hydroxyl group, and 
can be separated into pure racemates at appropriate stages by methods well 
known in the art, for example, see below. If desired, the racemates can be 
resolved into enantiomorphs also be known methods. It is to be understood 
that such racemates and enantiomorphs are included within the scope of 
this invention. 
Furthermore, it is to be understood that the pictorial representations used 
herein illustrating the compounds of this invention, are to be construed 
as including such racemates and enantiomorphs. For example, in formula 11 
the dotted line joining the acid side chain to the cyclopentane ring and 
the solid line joining the side chain bearing the hydroxy group are used 
for the purpose of illustrating the trans relationship of these two side 
chains and should not be construed as limiting the compounds to one 
enantiomorph but rather as including all possible enantiomorphs having 
this trans relationship. 
Also included within this invention are the pharmaceutically acceptable 
salts of the acids of formula 11 in which R.sup.7 is hydrogen. The latter 
compounds are transformed in excellent yield into the corresponding 
pharmaceutically acceptable salts by neutralization of said latter 
compounds with the appropriate inorganic or organic base. The relative 
stability of the acid facilitates this transformation. The salts possess 
the same activities as the parent acid compounds when administered to 
animals and may be utilized in the same manner. Suitable inorganic bases 
to form these salts include, for example, the hydroxides, carbonates, 
bicarbonates or alkoxides of the alkali metals or alkaline earth metals, 
for example, sodium, potassium, magnesium, calcium and the like. Suitable 
organic bases include the following amines: lower mono-, di- and 
trialkylamines, the alkyl radicals of which contain up to 3 carbon atoms, 
such as methylamine, dimethylamine, trimethylamine, ethylamine, di- and 
triethylamine, methylethylamine, and the like; mono-, di- and 
trialkanolamines, the alkanol radicals of which contain up to 3 carbon 
atoms, such as mono-, di- and triethanolamine; alkylene-diamines which 
contain up to 6 carbon atoms, such as hexamethylenediamine; cyclic 
saturated or unsaturated bases containing up to 6 carbon atoms, such as 
pyrrolidine, piperidine, morpholine, piperazine and their N-alkyl and 
N-hydroxyalkyl derivatives, such as N-methyl-morpholine and 
N-(2-hydroxyethyl)-piperidine, as well as pyridine. Furthermore, there may 
be mentioned the corresponding quaternary salts, such as the tetraalkyl 
(for example tetramethyl), alkyl-alkanol (for example methyl-triethanol 
and trimethyl-monoethanol) and cyclic ammonium salts, for example the 
N-methyl-pyridinium, N-methyl-N-(2-hydroxyethyl)-pyrrolidinium, 
N,N-dimethylmorpholinium, N-methyl-N-(2-hydroxyethyl)morpholinium, 
N,N-dimethyl-piperidinium and N-methyl-N-(2-hydroxyethyl)piperidinium 
salts, which are characterized by an especially good water-solubility. In 
principle, however, there can be used all ammonium salts which are 
physiologically compatible. 
The transformations to the salts can be carried out by a variety of methods 
known in the art. For example, in the case of the inorganic salts, it is 
preferred to dissolve the selected acid in water containing at least an 
equivalent amount of a hydroxide, carbonate, or bicarbonate corresponding 
to the inorganic salt desired. Advantageously, the reaction is performed 
in an inert organic solvent, for example, methanol, ethanol, dioxane, and 
the like. For example, such use of sodium hydroxide, sodium carbonate or 
sodium bicarbonate gives a solution of the sodium salt. Evaporation of the 
water or addition of a water-miscible solvent of moderate polarity, for 
example, a lower alkanol or a lower alkanone gives the solid inorganic 
salt if that form is desired. 
To produce an amine salt, the selected acid is dissolved in a suitable 
solvent of either moderate or lower polarity, for example, ethanol, 
acetone, ethyl acetate, diethyl ether and benzene. At least an equivalent 
amount of the amine corresponding to the desired cation is then added to 
that solution. If the resulting salt does not precipitate, it can usually 
be obtained in solid form by addition of a miscible diluent of low 
polarity, for example, benzene or diethyl ether or by evaporation. If the 
amine is relatively volatile, any excess can easily be removed by 
evaporation. It is preferred to use equivalent amounts of the less 
volatile amines. 
Salts wherein the cation is quaternary ammonium are produced by mixing the 
selected acid with an equivalent amount of the corresponding quaternary 
ammonium hydroxide in water solution, followed by evaporation of the 
water. 
The term "lower alkyl" as used herein contemplates straight chain alkyl 
groups containing from one to three carbon atoms and includes methyl, 
ethyl and propyl. 
The term "complex borohydride" as used herein contemplates the metal 
borohydrides, including sodium borohydride, potassium borohydride, lithium 
borohydride, zinc borohydride and the like, and metal 
trihydrocarbylborohydrides including lithium 
9-alkyl-9-borabicyclo[3,3,1]nonylhydride, in which the alkyl contains one 
to seven carbon atoms, preferably lithium 
9-tert-butyl-9-borabicyclo[3,3,1]nonylhydride, prepared according to the 
procedure described in German Offenlegungsschrift 2,207,987, published 
Aug. 31, 1972, lithium diisopinocamphenyl-tert-butylborohydride and 
lithium 2-thexyl-4,8-dimethyl-2-borobicyclo[3,3,1]nonylhydride, described 
by E. J. Corey et al., J. Amer. Chem. Soc., 93, 1491 (1971), lithium 
perhydro-9b-borophenalylhydride, described by H. C. Brown and W. C. 
Dickason, J. Amer. Chem. Soc., 92, 709 (1970) and the like. 
The compounds of formula 11 possess interesting pharmacological properties 
when tested in standard pharmacological tests. In particular, they have 
been found to possess hypotensive, antihypertensive, bronchospasmolytic, 
gastric acid secretion inhibiting, abortifacient and estrus synchronizing 
and ovulation regulating properties, which make them useful in the 
treatment of conditions associated with high blood pressure, in the 
treatment of asthmatic conditions, in the treatment of pathological 
conditions associated with excessive secretion of gastric acid such as, 
for example, peptic ulcer, in population control, and in animal husbandry. 
In addition, the compounds of this invention inhibit the aggregation of 
platelets and promote the disaggregation of aggregated platelets, and are 
useful as agents for the prevention and treatment of thrombosis. 
More particularly, these compounds, when tested in a modification of the 
tests for determining hypotensive activities described in "Screening 
Methods in Pharmacology", Academic Press, New York and London 1965, page 
146, using the cat in urethane-chloralose anaesthesia as the test animal 
and measuring mean arterial blood pressure before and after intravenous 
administration of the compounds, have exhibited utility as hypotensive 
agents. When tested in the renal hypertensive rat, prepared by the method 
of A. Grollman described in Proc. Soc. Exp. Biol. Med., 7, 102 (1954), and 
measuring blood pressure by the method described by H. Kersten, J. Lab. 
Clin. Med., 32, 1090 (1947), they have exhibited utility as 
antihypertensive agents. 
Moreover, the compounds of this invention, when tested in a modification of 
the test method described by A. K. Armitage, et al., Brit. J. Pharmacol., 
16, 59 (1961), have been found to alleviate bronchospasms, and are useful 
as bronchospasmolytic agents. 
Furthermore, the compounds of this invention, when administered to rats in 
the test method described by H. Shay, et al., Gastroenterol., 26, 906 
(1954), have been found to inhibit the secretion of gastric acid, and are 
useful as agents inhibiting the secretion of gastric acid. 
In addition, the compounds of this invention, when tested in a modification 
of the test method described by G. V. R. Born, Nature, 194, 927 (1962), 
using the aggregometer manufactured by Bryston Manufacturing Limited, 
Rexdale, Ontario, Canada, have been shown to inhibit the aggregation of 
platelets and to promote the disaggregation of aggregated platelets, and 
are useful as agents for the prevention and treatment of thrombosis. 
When the compounds of this invention are employed as hypotensive or 
anti-hypertensive agents, as agents inhibiting gastric acid secretion in 
warm-blooded animals, for example, in cats or rats, as agents for the 
prevention or treatment of thrombosis, or as bronchospasmolytic agents, 
alone or in combination with pharmacologically acceptable carriers, their 
proportions are determined by their solubilities, by the chosen route of 
administration, and by standard biological practice. The compounds of this 
invention may be administered orally in solid form containing such 
excipients as starch, lactose, sucrose, certain types of clay, and 
flavouring and coating agents. However, they are preferably administered 
parenterally in the form of sterile solutions thereof which may also 
contain other solutes, for example, sufficient sodium chloride or glucose 
to make the solution isotonic. For use as bronchospasmolytic agents, the 
compounds of this invention are preferably administered as aerosols. 
The dosage of the present hypotensive, antihypertensive, gastric acid 
secretion inhibiting, or bronchospasmolytic agents, or agents for the 
prevention and treatment of thrombosis will vary with the forms of 
administration and the particular hosts under treatment. Generally, 
treatments are initiated with small dosages substantially less than the 
optimum doses of the compounds. Thereafter, the dosages are increased by 
small increments until the optimum effects under the circumstances are 
reached. In general, the compounds of this invention are most desirably 
administered at a concentration level that will generally afford effective 
results without causing any harmful or deleterious side effects and 
preferably at a level that is in a range of from about 0.1 mg to about 
10.0 mg per kilo, although as aforementioned variations will occur. 
However, a dosage level that is in the range of from about 0.5 mg to about 
5 mg per kilo is most desirably employed in order to achieve effective 
results. When administering the compounds of this invention as aerosols 
the liquid to be nebulized, for example, water, ethyl alcohol, 
dichlorotetrafluoroethane and dichlorodifluoromethane, contains preferably 
from 0.005-0.05 percent of the acid, or a non-toxic alkali metal, ammonium 
or amine salt thereof, or ester of formula 11. 
Furthermore, when the compounds of this invention are tested by the method 
of A. P. Labhsetwar, Nature, 230, 528 (1971) whereby the compound is given 
subcutaneously on a daily basis to mated hamsters on days 4, 5 and 6 of 
pregnancy, thereafter the animals being sacrificed on day 7 of pregnancy 
and the number of abortions counted, the compounds are shown to have 
abortifacient properties. 
For example, complete abortion resulted in all animals when the following 
compounds of formula 11 were tested according to this method at doses 
noted below: 
trans,cis-7-[2.alpha.-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl] 
-5-heptenoic acid (Example 175), 0.5 mg/kg/day, 
cis-7-[2.alpha.-hydroxy-5-(3-hydroxyoctyl)cyclopentyl]-5-heptenoic acid 
(Example 175), 2.5 mg/kg/day, and 
cis-7-[2.alpha.-hydroxy-5-(3-hydroxy-3-methyloctyl)cyclopentyl]-5-heptenoi 
c acid (Example 175), 5.0 mg/kg/day. 
The potency of the above unsaturated compounds is especially noteworthy in 
light of the fact that the completely saturated 15-methyl analog, 
2-(3-hydroxy-3-methyloctyl)-5-oxocyclopentaneheptanoic acid, described in 
U.S. Pat. No. 3,671,570, cited above, does not cause complete abortion in 
the above test at doses less than 30 mg/kg/day. 
Furthermore, the compounds of this invention are useful for inducing labor 
in pregnant animals at or near term. When the compounds of this invention 
are employed as agnets for abortion or for inducing labor, the compounds 
are infused intravenously at a dose of 0.01 to 100 mg/kg per minute until 
the desired effect is obtained. 
Still furthermore, the compounds of formula 11 are useful for the 
synchronization of estrus and the regulation of ovulation in animals. 
It is often desirable to synchronize estrus in domestic animals, for 
example, horses, cattle, sheep, swine or dogs, in order to be able to 
perform artificial insemination or mating with a male of the desired 
genetic quality under optimum conditions. In the past, this has been done 
by administering to the animals an ovulation-inhibiting agent, withdrawing 
administration of said agent shortly before the data chosen for mating or 
artificial insemination, and relying either upon the natural production of 
LH and FSH to induce ovulation and to produce estrus or by administering 
gonadotrophins. However, this procedure was not entirely satisfactory 
because ovulation at a predetermined time occured only in a certain 
proportion of the animals when gonadotrophins were not used. On the other 
hand, the high cost of gonadotrophins and side effects encountered in 
their administration made this method impractical. It is now possible to 
obtain substantially complete synchronization of ovulation and of estrus, 
by treating the animals in a given group with the compound of formula 11 
before the predetermined period of time for mating or artificial 
insemination, so as to obtain ovulation and estrus within that time 
interval. The delay in the onset of ovulation and estrus following 
administration of the compound of this invention varies with the species 
of animal. For example, in rodents such as rats or hamsters ovulation 
takes place within 18 hours following administration of the compound and 
in the horse ovulation usually takes place within one week after the 
compound is given. 
More specifically, synchronization of estrus and regulation of ovulation in 
the horse is achieved by giving the compound of formula 11 either randomly 
to a group of horses during the life of the corpus luteum (usually day 5 
to day 16 of the cycle) or two to three days prior to the expected onset 
of estrus. The compound for example, trans, 
cis-7-[2.alpha.-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl]-5-hep 
tenoic acid, is given by intrauterine infusion, subcutaneously or 
intramuscularly in sterile solutions. A dosage which is in the range of 
from about 1 to 100 mg/1000 lb, preferably 5 to 25 mg/1000 lb is employed 
and is administered as a single dose or spread over a period of 72 hours. 
Practically speaking it is preferable to give one-half the total dose on 
two consecutive days for the latter form of administration. For example, 
in a group of horses receiving this medication on the second and third day 
before expected estrus, estrus follows within 24 to 48 hours which in turn 
is followed by ovulation occurring in the majority of animals, from the 
forth to the sixth day thereafter as determined by rectal palpation of the 
ovaries. 
In a control group receiving no medication the occurance of ovulation was 
spread rather unevenly over the third to eighth day after the onset of 
estrus. 
PROCESS 
The starting materials of formula 1 are described in U.S. Pat. No. 
3,773,795 and the U.S. Patent application Ser. No. 351,381, cited above; 
see also West German Offenlegungsschrift, No. 2,313,686, published Apr. 
10, 1973 and the publication by N. A. Abraham, cited above. 
Briefly the starting materials are prepared readily by treating an aldehyde 
of formula 14 
##STR9## 
in which R.sup.1 is lower alkyl with a Wittig reagent of formula 
(AlKO).sub.2 POCH.sub.2 COCR.sup.4 R.sup.5 -(CH.sub.2).sub.n CH.sub.3 in 
which Alk is lower alkyl and R.sup.4, R.sup.5 and n are as defined herein 
to obtain the corresponding ketodicarboxylic acid of formula 15 in which 
R.sup.1, R.sup.4, R.sup.5 and n are as defined herein; followed by 
reduction of the latter compound with a metal borohydride, preferably 
sodium borohydride, to obtain the corresponding starting material of 
formula 1 in which R.sup.2 is hydrogen, which in turn is readily 
transformed to its corresponding hydroxy protected derivative. The 
starting material of formula 1 in which R.sup.6 is lower alkyl is obtained 
by reacting the ketodicarboxylic acid of formula 15 with substantially one 
molar equivalent of a lower alkyl magnesium halide in the manner described 
herein. 
The aldehyde of formula 14 in which R.sup.1 is ethyl, required for the 
preceding preparation, has been described by D. T. Warner, J. Org. Chem., 
24, 1536 (1959). By following the process described therein for the 
preparation of that aldehyde and using the appropriate 
di(lower)alkylbromomalonate, the aldehydes of formula 14 in which R.sup.1 
is a lower alkyl other than ethyl are obtained. 
The requisite Wittig reagents are prepared by the method of E. J. Corey and 
G. T. Kwiatkowsky, J. Amer. Chem. Soc., 88, 5654 (1966) using the 
appropriate lower alkyl alkanoate and di(lower)alkyl 
.alpha.-lithiomethanephosphonate. 
The triester of formula 3, the other starting material of this process, is 
readily prepared by condensing a di(lower)alkyl malonate with a lower 
alkyl bromoacetic acid ester in the presence of a base. For example, the 
preparation of the triester of formula 2 in which R.sup.3 is ethyl has 
been described by A. Horeau, Bull. Soc. Chim. Fr., 1959 (1943) and by T. 
R. Kasturi, Indian Inst. Sci., Golden Jubilee Research Vol., 1909-59, 40 
(Publ. 1959); see Chem. Abstr., 55, 23371 h (1961). 
The preferred hydroxy protecting groups for use in the process of this 
invention are tetrahydropyran-2-yl (THP), trimethylsilyl (TMS), 
dimethylisopropylsilyl (DMIS), dimethyl-tert-butylsilyl and tert-butyl. 
The transformation of the free hydroxy derivative to the hydroxy protected 
derivative is effected by treating the hydroxy derivative with a reagent 
known to be effective for converting a hydroxy group of a known compound 
to a protected hydroxy group. Such reagents include an excess of 
dihydropyran and an acid catalyst for example, p-toluenesulfonic acid, 
hydrogen chloride or sulfuric acid for the THP group, 
trimethylchlorosilane with hexamethyldisilazane for the TMS group, 
dimethylisopropylchlorosilane and diisopropyltetramethyldisilazane for the 
DMIS group, dimethyl-tert-butylchlorosilane and imidazole for the 
dimethyl-tert-butylsilyl group or isobutylene for the tert-butyl group. 
For removal of the hydroxy protecting groups various agents known to be 
effective for this purpose are available. These agents are called 
deprotecting agents. For example, the THP group is removed by treating the 
derivative having a THP group as the hydroxy protecting group with an 
acid, for example, hydrochloric acid, aqueous acetic acid or preferably 
p-toluenesulfonic acid, in an inert solvent in the presence of water, 
preferably methanol-water (9:1). The TMS radical is removed by treatment 
with an excess of water-methanol (10:1) for 24 hours or with 
tetrahydrofuran-acetic acid at room temperature for one to two hours. 
Likewise, the DMIS and dimethyl-tert-butylsilyl group are removed by the 
same conditions used for the removal of the TMS radical. 
In practising the process of this invention the starting material of 
formula 1, preferable in the form of its THP derivative, and the triester 
of formula 2, preferably, the triethyl ester, are subjected to a base 
catalyzed condensation to give the corresponding cyclopentanonetriester of 
formula 3. This condensation is preformed in the presence of a suitable 
base, preferably an alkali metal alkoxide, for example, sodium methoxide. 
Other suitable bases include sodium ethoxide, potassium tert-butoxide, and 
sodium hydride. More specifically, this condensation is conveniently 
effected by heating a mixture of about equimolar amounts of the compound 
of formula 1 and the triester 2 at 80.degree. to 150.degree. C., 
preferably 100.degree.-140.degree. C., for 30 minutes to six hours, 
preferably one to three hours. The reaction mixture is then cooled, 
neutralized with an acid, for example, acetic acid, and extracted with a 
water-immiscible solvent, for example, diethyl ether. Evaporation of the 
extract and purification of the residue by chromatography on silica gel 
yields the cyclopentanonetriester of formula 3. 
Thereafter, in the case where the hydroxy group has been protected by a 
suitable protecting group, said group is now removed by a deprotecting 
agent. The compound of formula 3 in its free hydroxy from is now treated 
with an alkali metal hydroxide in the presence of water to give the 
corresponding .gamma.-ketoacid of formula 4 in which R.sup.2, R.sup.4, 
R.sup.5, R.sup.6 and n are as defined in the first instance. Preferably 
this reaction is done by heating a mixture of the cyclopentanonetriester 
with an alkali metal hydroxide, preferably sodium hydroxide or potassium 
hydroxide, in the presence of water at reflux temperature of the mixture 
for a period of 15 minutes to six hours, preferably about one to three 
hours. Neutralization of the reaction mixture with acid, for example, 2N 
HCl, extraction with a water-immiscible solvent, for example, diethyl 
ether, and subsequent work up of the extract yields the desired 
.gamma.-ketoacid of formula 4 as a mixture of stereoisomers, i.e., a 
mixture of trans and cis isomers with respect to the side chains of the 
cyclopentanone ring. The trans isomers, as shown in formula 4, is the 
preponderate isomer of the mixture. 
Thereafter, the latter compound is converted to its corresponding hydroxy 
protected derivative, which is treated with a complex borohydride to give 
a mixture of the corresponding acid 5 and hydroxylactone 6. 
This reduction is carried out preferably by treating the .gamma.-ketoacid 
with sodium borohydride in an inert solvent, for example, methanol, 
ethanol or tetrahydrofuran at -20.degree. to 30.degree. C. from 30 minutes 
to two hours. It is desirable to effect this reduction in the presence of 
about one equivalent of a base, for example, sodium methoxide, or 
potassium .+-.-butoxide, so that effectively the reduction is performed on 
the salt of the .gamma.-ketoacid, for example, the sodium or potassium 
salt, and complex-formation between the acid and the reducing agent, and 
hence the need for an excess of the latter, is eliminated. 
The reduction mixture of compounds 5 and 6 may be separated by conventional 
techniques, such as extraction or chromatography. However, it has been 
found practical to treat the mixture according to a procedure for 
converting the acid 5 to the hydroxylacetone 5. The procedure for this 
latter conversion involves reacting the acid 5 or the mixture of compound 
5 and 6 with methanesulfonyl or p-toluenesulfonyl chloride or bromide, in 
the presence of a proton acceptor, preferably trimethylamine, 
N-methylmorpholine or pyridine. The reaction is conveniently performed in 
an inert organic solvent, for example, methylene chloride or 
tetrahydrofuran. A reaction time of 30 to 180 minutes and a reaction 
temperature of -30.degree. to 20.degree. C. have been found to be 
practical and effective for this conversion. Under these conditions the 
preceding conversion apparently involves the transformation of the ring 
hydroxyl to a mesylate or p-toluenesulfonate, as the case may be, followed 
by a S.sub.n 2 displacement of the latter by the carboxyl to give the 
desired hydroxylactone. Thereafter, if desired, the hydroxylacetone of 
formula 6 in which R.sup.2 is a hydroxy protecting group is reacted with a 
deprotecting agent to give the corresponding hydroxylactone of formula 6 
in which R.sup.2 is hydrogen. 
From the latter key intermediate of formula 6, the key intermediate of 
formula 7 is obtained. More precisely, the compound of formula 6 in which 
R.sup.2 and R.sup.6 are both hydrogen (i.e., a compound of formula 6 in 
which the side chain alcohol is a secondary alcohol) is oxidized with an 
agent known to be effective for oxidizing allylic alcohols to 
.alpha.,.beta.-unsaturated ketones. Suitable agents for this purpose 
include manganese dioxide, selenium dioxide, chloranil and 
2,3-dichloro-5,6-dicyano-1,4-benzoquinone. Manganese dioxide is a 
preferred reagent for this purpose. Treatment of the compound of formula 6 
with manganese dioxide at 20.degree. to 70.degree. C. for about one to 
three hours in an inert organic solvent, for example, chloroform, benzene 
or carbon tetrachloride, readily gives the desired ketolacetone 
intermediate. 
As noted above the key intermediates of formula 6 and 7 are used 
subsequently to prepare the prostaglandin derivatives of formula 11. Also 
as noted hereinbefore these subsequent transformations involve some or all 
of the following types of reaction: catalytic reduction, reduction with a 
monoalkyl or dialkyl aluminum hydride, treatment with a Wittig reagent, 
treatment with a lower alkyl magnesium halide and reduction with a metal 
borohydride. Convienent and effective conditions for effecting these 
reactions are generalized in the following manner. 
The catalytic reduction is accomplished by treating the compound to be 
hydrogenated with hydrogen in the presence of a hydrogenation catalyst in 
a nonreactive solvent medium. Suitable catalysts for this purpose include 
palladium or platinum or a suitable inert carrier or Raney nickel in 
dioxane. The latter catalyst is preferred for catalytic reduction of the 
hydroxylacetone of formula 6. Suitable non-reactive solvents include ethyl 
acetate and ethanol. 
The reduction with a monoalkyl or diethyl aluminum hydride is accomplished 
by subjecting the compound to be reduced to the action of the aluminum 
hydride reduction agent, for example, ethyl aluminum hydride, isopropyl 
aluminum hydride or preferably diisolbutyl aluminum hyride, in an inert 
organic solvent, for example, benzene, ether, hexane or toluene. Although 
the reaction can be practised over a wide range of temperatures from about 
-80.degree. C. to the reflux temperature of the solvent, preferred 
temperatures are from -75.degree. to 0.degree. C. Also the reaction is 
preferably carried out in an atmosphere of an inert gas, for example, 
nitrogen or argon. Under these conditions this reduction is usually 
completed within 0.25 to five hours. 
The Wittig reaction on the hemiacetals of this invention involves the use 
of a triphenylphosphonium halide of formula 
##STR10## 
in which R.sup.7 is hydrogen or lower alkyl, m is an interger from one to 
three, and Hal is bromine, chlorine or iodine. The preferred 
triphenylphosphonium halide is the triphenylphosphonium bromide, i.e. Hal 
is bromine. The latter reagent is prepared readily by treating the 
appropriate .omega.-bromoacid or .omega.-bromester of formula Br-CH.sub.2 
-(CH.sub.2).sub.m COOR.sup.7 in which m and R.sup.7 are as defined 
hereinbefore with triphenylphosphine in an inert solvent, for example, 
benzene, or acetonitrile, at 20.degree.-100.degree. C. for 12 to 24 hours 
and collecting the precipitate. Similarly the corresponding 
triphenylphosphonium chloride or iodide salts are prepared from 
appropriate haloacids or haloesters. 
The Wittig reaction is carried out by treating the appropriate hemiacetal 
with about two to ten molar equivalents of the above triphenylphosphonium 
halide in the presence of four to 20 molar equivalents of a base. For a 
detailed discussion of the Wittig reaction, see A. Maercker in Organic 
Reactions, Vol. 14, A. C. Cope, et. al., Eds. John Wiley and Sons, Inc. 
New York, 1965, page 3. More patticularly, the triphenylphosphonium halide 
is treated with an excess of a hydrogen halide-binding base, for example, 
sodium hydride in an inert organic solvent, for example, dimethoxyethane 
or dimethylformamide, or preferably sodium methylsulfinyl carbanide, 
prepared from sodium hydride and dimethylsulfoxide [see R. Greenwald, et 
al., J. Org. Chem., 28, 1128 (1963)]. In this manner the corresponding 
ylide of the triphenylphosphonium halide is obtained. Subsequent reaction 
of ylide with the appropriate hemiacetal readily gives the corresponding 
compound of formula 11. The preparation of the ylide is accomplished 
readily at 20.degree.-100.degree. C. at 10 to 60 minutes, preferably at 
20.degree. to 40.degree. C. for about 1 to 2 hours when using sodium 
hydride is used as the hydrogen halide-binding base, and at 60.degree. to 
90.degree. C. for about one to two hours when sodio methylsulfinyl 
carbanide is used at the base. Thereafter the solution of the resulting 
ylide is reacted with the appropriate hemiacetal at 20.degree. to 
60.degree. C., conveniently room temperature, for a period of time of from 
2 to 24 hours. Preferably the reaction is performed in nitrogen 
atmosphere. 
The treatment with a lower alkyl magnesium halide, for example, methyl 
magnesium bromide, ethyl magnesium chloride, propyl magnesium iodide and 
the like, is accomplished according to the conditions of the Grignard 
reaction. Convenient and practical conditions for this addition include 
ether or tetrahydrofuran as the solvent for the reaction and a reaction 
temperature of from -80.degree. to 25.degree. C., preferably -10.degree. 
to 10.degree. C. 
The aforementioned treatment of the compounds of formula 11 with an agent 
capable of oxidizing a hydroxy function to its corresponding keto function 
is effectively and conveniently accomplished by treating the appropriate 
compound of formula 11 in which X is hydroxy and Y is hydrogen with one of 
the agents chromium trioxide-pyridine complex or chromium 
trioxide-sulfuric acid in acetone, with the latter being preferred. 
Finally, reductions with metal borohydride, preferably sodium borohydride, 
are conveniently performed in a lower alkanol solvent, preferably methanol 
or ethanol, at 0.degree. to 40.degree. C. for five to 60 minutes. 
The following examples illustrate further this invention. In the examples 
the temperatures are noted in the Centigrade scale. 
EXAMPLE 1 
Dimethyl 3,3-dimethyl-2-oxoheptyl phosphonate [AlkO).sub.2 POCH.sub.2 
COCR.sup.4 R.sup.5 -(CH.sub.2).sub.n CH.sub.3 in which Alk is CH.sub.3, 
R.sup.4 and R.sup.5 = CH.sub.3 and n = 3] 
The title compound is prepared by treating 2,2-dimethylhexanoic acid methyl 
ester, S. M. McElvain, et al., J. Amer. Chem Soc., 75, 3987 (1953), with 
dimethyl methyl phosphonate according to the procedure of E. J. Corey and 
G. T. Kwiatkowski, J. Amer. Chem. Soc., 88, 5654 (1966). An 
exemplification of this procedure is as follows: 
Dimethyl methphosphonate (14.88 g) is dissolved in dry tetrahydrofuran 
(THF, 34 ml) under a nitrogen atmosphere. The solution is cooled to 
-78.degree.. Butyllithium (7.68 g, 52 ml of 2.3 molar solution, 3 equiv.) 
is added very slowly during one hour. The mixture is stirred at 
-78.degree. for 15 minutes. A solution of 2,2-dimethylhexanoic acid methyl 
ester (6.32 g) in dry THF (16 ml) is added to the cold solution over a 
period of one hour. The mixture is stirred for 30 minutes and then allowed 
to warm up to room temperature. The reaction mixture is diluted with 
ether. Dilute (10%) hydrochloric acid (30 ml) is added and the reaction 
mixture shaken well. The organic phase is separated and washed several 
times with water, dried (MgSO.sub.4) and the solvent removed. The residue 
is distilled under reduced pressure to give the title compound, b.p. 
110.degree.-120.degree./0.1 mm, .nu..sub.max.sup.film 1700, 1250, 1020 
cm.sup.-1. 
Similarly other Wittig reagents of the formula (AlkO).sub.2 POCH.sub.2 
COCR.sup.4 R.sup.5 -(CH.sub.2).sub.n CH.sub.3 in which Alk is an alkyl 
containing one to three carbon atoms, R.sup.4 and R.sup.5 are hydrogen or 
lower alkyl and in is an integer from two to five are prepared by using 
the appropriate lower alkyl alkanoate and di(lower)alkyl 
methanephosphonate. For instance, treatment of 2,2-dipropylpentanoic acid 
methyl ester with dimethyl methylphosphonate gives 2-oxo-3,3-dipropylhexyl 
phosphonate and treatment of 2,2-diethyloctanoic acid ethyl ester with 
diethyl methylphosphonate gives 2-oxo-3,3-diethylnonyl phosphonate. 
EXAMPLE 2 
Dimethyl 2-formylcyclopropane-1,1-dicarboxylate (14; R.sup.1 = CH.sub.3) 
By following the procedure of D. T. Warner, cited above, used for preparing 
diethyl 2-formylcyclopropane-1,1-dicarboxylate from acrolein but using 
equivalent amounts of dimethylbromomalonate and methanol instead of 
diethylbromomalonate and ethanol, respectively, the title compound, nmr 
(CDCl.sub.3) .delta. 1.98 (m, 2H), 2.80 (m, 1H), 3.79 (s, 6H), 8.82 (d, J 
= 4 cps, 1H), is obtained. 
Likewise the use of dipropylbromomalonate and propanol gives dipropyl 
2-formylcyclopropane-1,1-dicarboxylate. 
EXAMPLE 3 
Diethyl 
trans-2-(4,4-dimethyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate (15; 
R.sup.4 and R.sup.5 = CH.sub.3, n = 3 R.sup.1 = C.sub.2 H.sub.5) 
To a suspension of 50% sodium hydride (0.46 g, washed with hexane) in 
dimethylformamide (DMF) is added a solution of dimethyl 
3,3-dimethyl-2-oxoheptyl phosphonate (2.75 g), described in Example 1, in 
DMF (15 ml) over a period of 30 min. The mixture is stirred and cooled in 
ice water during the addition and for an additional period of 45 min. A 
solution of diethyl 2-formylcyclopropane-1,1-dicarboxylate (2.14 g) in DMF 
(15 ml) is added over 20 min. The reaction mixture is heated at 55.degree. 
to 60.degree. and stirred for 45 min. The mixture is now cooled in an ice 
bath and acetic acid is added to render the mixture substantially neutral. 
The reaction mixture is poured into water (4 .times. the volume) and the 
resulting oily precipitate extracted with ether. The extract is washed 
with water, dried (Na.sub.2 SO.sub.4) and concentrated. The residue is 
dissolved in ethyl acetate-benzene (1:9) and the solution poured through a 
column of silica gel (148 g). The eluate is concentrated to yield the 
title compound, .nu..sub.max.sup.film 1725, 1680, 1620 cm.sup.-1, nmr 
(CDCl.sub.3) .delta. 0.88 (-, 3H), 4.27 (4H), 6.5, 6.68 and 7.39 (m, 2H), 
.lambda..sub.max.sup.EtOH 242 nm (.epsilon. = 7500). 
In the same manner but replacing diethyl 
2-formylcyclopropane-1,1-dicarboxylate with dimethyl 
2-formylcyclopropane-1,1-dicarboxylate, dimethyl 
trans-(4,4-dimethyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate, 
.nu..sub.max.sup.film 1728, 1682 cm.sup.-1, is obtained. 
In the same manner but replacing dimethyl 3,3-dimethyl-2-oxoheptyl 
phosphonate with an equivalent amount of dimethyl 3-methyl-2-oxoheptyl 
phosphonate, b.p. 112.degree.-115.degree./0.2 mm, prepared from 
2-methylhexanoic acid methyl ester or the 2-methylhexanoic acid chloride 
according to the procedure of Example 1, diethyl 
trans-2-(4-methyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate, 
.nu..sub.max.sup.film 1725, 1680, 1665, 1620 cm.sup.-1, nmr (CDCl.sub.3) 
.delta. 4.19 (q, J = 7, 4H), 6.32 (d, J = 5, 2H), is obtained. 
In the same manner but replacing dimethyl 3,3-dimethyl-2-oxoheptyl 
phosphonate with an equivalent amount of dimethyl 2-oxoheptyl phosphonate, 
described by E. J. Corey, et al., J. Amer. Chem. Soc., 90, 3247 (1968), 
diethyl trans-2-(3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate, b.p. 
153.degree.-154.degree./0.7 mm, is obtained. 
In the same manner but replacing dimethyl 
3,3-dimethyl-2-oxoheptylphosphonate with an equivalent amount of dimethyl 
3-ethyl-2-oxohexyl phosphonate, dimethyl 3-propyl-2-oxoctyl phosphonate, 
or dimethyl 3-ethyl-2-oxononyl phosphonate, dimethyl 
trans-2-(4-ethyl-3-oxo-1-heptenyl)cyclopropane-1,1-dicarboxylate, dimethyl 
trans-2-(3-oxo-4-propyl-1-nonenyl)cyclopropane-1,1-dicarboxylate and 
dimethyl trans-2-(4-ethyl-3-oxo-1-decenyl)cyclopropane-1,1-dicarboxylate 
are obtained, respectively. 
By following the procedure of Example 3 and utilizing the appropriate 
Wittig reagent and the aldehyde of formula 14 then other compounds of 
formula 15 are obtained. Examples of such compounds of formula 15 are 
listed in Table I together with the appropriate Wittig reagent and 
aldehyde of formula 14 utilized for their preparation. 
TABLE I 
__________________________________________________________________________ 
Wittig Reagent Product: (Prefix Listed 
(AlkO.sub.2)POCH.sub.2 COCR.sup.4 R.sup.5 --(CH.sub.2).sub.n CH.sub.3 
ALDEHYDE 14 
below)-cyclopropane 
Ex. 
Alk R.sup.4 
R.sup.5 
n R.sup.5 1,1-dicarboxylate 
__________________________________________________________________________ 
4 CH.sub.3 
H H 2 CH.sub.3 dimethyl trans-2-(3-oxo- 
l-heptenyl) 
5 CH.sub.3 
H H 4 C.sub.2 H.sub.5 
diethyl trans-2-(3-oxo- 
l-nonenyl) 
6 CH.sub.3 
H H 5 CH.sub.3 dimethyl trans-2-(3-oxo- 
l-decenyl) 
7 CH.sub.3 
CH.sub.3 
H 2 C.sub.2 H.sub.5 
diethyl trans-2-(4- 
methyl-3-oxo-l-heptenyl) 
8 CH.sub.3 
CH.sub.3 
H 4 CH.sub.3 dimethyl trans-2-(4- 
methyl-3-oxo-l-nonenyl) 
9 CH.sub.3 
C.sub.2 H.sub.5 
H 3 C.sub.2 H.sub.5 
diethyl trans-2-(4-ethyl- 
3-oxo-l-octenyl) 
10 CH.sub.3 
C.sub.2 H.sub.5 
H 5 CH.sub.3 dimethyl trans-2-(4- 
methyl-2-oxo-l-decenyl) 
11 CH.sub.3 
n-C.sub.3 H.sub.7 
H 2 C.sub.2 H.sub.5 
diethyl trans-2-(3-oxo- 
4-propyl-l-heptenyl) 
12 CH.sub.3 
n-C.sub.3 H.sub.7 
H 4 CH.sub.3 dimethyl trans-2-(3-oxo- 
4-ethyl-l-nonenyl) 
13 C.sub.2 H.sub.5 
CH.sub.3 
CH.sub.3 
5 n-C.sub.3 H.sub.7 
dipropyl trans-2-(4,4- 
dimethyl-3-oxo-l-decenyl) 
14 C.sub.2 H.sub.5 
C.sub.2 H.sub.5 
CH.sub.3 
5 n-C.sub.3 H.sub.7 
dipropyl trans-2-(4-ethyl- 
4-methyl-3-oxo-l-decenyl) 
15 C.sub.2 H.sub.5 
n-C.sub.3 H.sub.7 
CH.sub.3 
2 CH.sub.3 dimethyl trans-2-(4- 
methyl-3-oxo-4-propyl-l- 
heptenyl) 
16 C.sub.2 H.sub.5 
n-C.sub.3 H.sub.7 
n-C.sub.3 H.sub.7 
4 C.sub.2 H.sub.5 
diethyl trans-2-(3-oxo-4,- 
4-dipropyl-l-nonenyl) 
__________________________________________________________________________ 
EXAMPLE 17 
Diethyl trans-2-(3-hydroxy-4,4-dimethyl-1-octenyl) 
cyclopropane-1,1-dicarboxylate (1; R.sup.1 = C.sub.2 H.sub.5, R.sup.2 and 
R.sup.6 = H. 
Sodium borohydride (0.19 g) is added to a solution of diethyl 
trans-2-(4,4-dimethyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate (1.62 
g), described in Example 3, in ethanol (2.5 ml) at 0.degree. to 5.degree.. 
After the addition the mixture is rendered neutral by the addition of 
acetic acid, diluted with ether and washed with water. The ether phase is 
dried (Na.sub.2 SO.sub.4) and concentrated. The residue is dissolved in 
ethyl acetate-benzene (1:9) and the solution poured through a column of 
silica gel (50 g). The eluate is concentrated to give the title compound, 
.nu..sub.max.sup.film 3500, 1706 cm.sup.-1, nmr (CDCl.sub.3) .delta. 2.6 
m, 1H), 3.78 (m, 1H), 4.21 (q, 4H), 5.28 (q, 1H), 5.9 (q, 1H). 
In the same manner but replacing diethyl 
trans-2-(4,4-dimethyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate with 
an equivalent amount of diethyl 
trans-2-(4-methyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate, 
described in Example 3, diethyl 
trans-2-(3-hydroxy-4-methyl-1-octenyl)cyclopropane-1,1-dicarboxylate, 
.nu..sub.max.sup.film 3500 cm.sup.-1, is obtained. 
By following the procedure of Example 17 utilizing the appropriate compound 
of formula 15 then other compounds of formula 1 (R.sup.2 = H) are 
prepared. Examples of such compounds of formula 1 are listed in Table II. 
In each case the compound of formula 15 used as starting material is noted 
by the Example in which it is prepared. 
TABLE II 
______________________________________ 
No. of Example in which 
Product: (Prefix Listed 
Starting Material of Formula 
Below)-Cyclo- 
Ex. 15 is Prepared Propane-1,1-Dicarboxylate 
______________________________________ 
18 3 dimethyl trans-2-(4-ethyl- 
3-hydroxy-1-heptenyl) 
19 3 diethyl trans-2-(3-hydroxy- 
4-propyl-1-nonenyl) 
20 3 dimethyl trans-2-(4-ethyl- 
3-hydroxy-1-decenyl) 
21 7 diethyl trans-2-(3-hydroxy- 
4-methyl-1-heptenyl) 
22 8 dimethyl trans-2-(3-hydroxy- 
4-methyl-1-nonenyl) 
23 9 diethyl trans-2-(4-ethyl-3- 
jhydroxy-1-octenyl) 
24 10 dimethyl trans-2-(4-methyl- 
hydroxy-1-decenyl) 
25 11 diethyl trans-2-(3-hydroxy- 
propyl-1-heptenyl) 
26 12 dimethyl trans-2-(3-hydroxy- 
4-ethyl-1-nonenyl 
27 13 dipropyl trans-2-(3-hydroxy- 
4,4-dimethyl-1-decenyl) 
28 14 dipropyl trans-2-(4-ethyl- 
3-hydroxy-4-methyl- 
1-decenyl) 
29 15 dimethyl trans-2-(3-hydroxy- 
4-methyl-4-propyl- 
1-heptanyl) 
30 16 diethyl trans-2-(3-hydroxy- 
4-dipropyl-1-nonenyl) 
______________________________________ 
EXAMPLE 31 
Diethyl 
trans-2-(3-hydroxy-3-methyl-1-octenyl)cyclopropane-1,1-dicarboxylate (1; 
R.sup.1 = C.sub.2 H.sub.5 ; R.sup.2, R.sup.4 and R.sup.5 = H, R.sup.6 = 
CH.sub.3 and n = 3) 
A solution of the lower alkyl magnesium halide, methyl magnesium iodide, 
prepared from 24.31 g of magnesium turnings and 157 g of methyl iodide in 
1000 ml of ether, is cooled to -70.degree.. Diethyl 
trans-2-(3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate (124.2 g); 
described in Example 3, in 600 ml ether is added slowly taking care that 
reaction mixture temperature does not exceed -45.degree.. The mixture is 
stirred 75 min. at the temperature range -50.degree. to -45.degree.. 
Aqueous saturated NH.sub.4 Cl solution is added slowly keeping the 
temperature of the reaction mixture below -55.degree.. The mixture is 
diluted with water and extracted with 1500 ml ether. The ether layer is 
washed with saturated NaCl solution twice, then with 10% sodium 
thiosulfate solution twice, again with saturated NaCl solution, dried 
(NaSO.sub.4) and concentrated to give a greenish yellow oil. The oil is 
dissolved in ethyl acetate-benzene (3:17) and poured through a column of 
silica gel. The eluate is concentrated to yield the title compound, nmr 
(CDCl.sub.3) .delta. 0.88 (+, J = 5, 3H), 2.45 (q, 2H), 4.13 (q, 2H), 5.14 
(2xd, J = 16.8, 1H), 5.72 (d, J = 16, 1H). 
In the same manner but replacing methyl magnesium iodide with an equivalent 
amount of ethyl magnesium chloride, or propyl magnesium bromide, diethyl 
trans-2-(3-ethyl-3-hydroxy-1-octenyl)-cyclopropane-1,1-dicarboxylate and 
diethyl 
trans-2-(3-hydroxy-3-propyl-1-octenyl)cyclopropane-1,1-dicarboxylate, are 
obtained, respectively. 
In the same manner but replacing diethyl 
trans-2-(3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate with an equivalent 
amount of diethyl 
trans-2-(4-methyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate, 
described in Example 3 and using methyl magnesium iodide, ethyl magnesium 
chloride or propyl magnesium bromide as the lower alkyl magnesium halide, 
diethyl 
trans-2-(3-hydroxy-3,4-dimethyl-1-octenyl)cyclopropane-1,1-dicarboxylate, 
diethyl 
trans-2-(3-ethyl-3-hydroxy-4-methyl-1-octenyl)cyclopropane-1,1-dicarboxyla 
te and diethyl 
trans-2-(3-hydroxy-4-methyl-3-propyl-1-octenyl)cyclopropane-1,1-dicarboxyl 
ate, are obtained, respectively. 
By following the procedure of Example 31 and utilizing the appropriate 
lower alkyl magnesium halide and compound of formula 15, for example those 
described in Examples 4 to 12, then other compounds of formula 1 in which 
R.sup.6 is lower alkyl are obtained. Examples of such compounds of formula 
1 are listed in Table III together with the requisite lower alkyl 
magnesium halide and the compound of formula 15. 
TABLE III 
__________________________________________________________________________ 
PRODUCT: 
NO. OF EXAMPLE (PREFIX LISTED 
IN WHICH STARTING MATERIAL 
LOWER ALKYL BELOW)-CYCLOPROPANE- 
EXAMPLE 
OF FORMULA 15 IS PREED 
MAGNESIUM HALIDE 
1,1-DICRBOXYLATE 
__________________________________________________________________________ 
32 4 CH.sub.3 MgI dimethyl trans-2-(3- 
hydroxy-3-methyl-l- 
heptenyl) 
33 5 C.sub.2 H.sub.5 MgBr 
diethyl trans-2-(3- 
ethyl-3-hydroxy-l- 
nonenyl) 
34 6 n-C.sub.3 H.sub.7 MgCl 
dimethyl trans-2-(3- 
hydroxy-3-propyl-l- 
decenyl) 
35 7 CH.sub.3 MgBr 
diethyl trans-2-(3- 
hydroxy-3,4-dimethyl- 
l-heptenyl) 
36 8 C.sub.2 H.sub.5 MgCl 
dimethyl trans-2-(3- 
ethyl-3-hydroxy-4- 
methyl-l-nonenyl) 
37 9 n-C.sub.3 H.sub.7 MgCl 
diethyl trans-2-(4- 
ethyl-3-hydroxy-3- 
propyl-l-octenyl) 
38 10 CH.sub.3 MgI dimethyl trans-2-(3- 
hydroxy-3,4-dimethyl- 
l-decenyl) 
39 11 C.sub.2 H.sub.5 MgCl 
diethyl trans-2-(3- 
ethyl-3-hydroxy-4- 
propyl-l-heptenyl) 
40 12 n-C.sub.3 H.sub.7 MgCl 
dimethyl trans-2-(4- 
ethyl-3-hydroxy-3- 
propyl-l-nonenyl) 
__________________________________________________________________________ 
EXAMPLE 41 
Diethyl 
trans-2-{3-[(tetrahydropyran-2-yl)oxy]-3-methyl-1-octenyl}cyclopropane-1,1 
-dicarboxylate (1; R.sup.1 = C.sub.2 H.sub.5, R.sup.2 = 
(tetrahydropyran-2-yl)oxy, R.sup.4 and R.sup.5 = H, R.sup.6 = CH.sub.3 and 
n = 3) 
A solution of diethyl 
trans-2-(3-hydroxy-3-methyl-1-octenyl)cyclopropane-1,1-dicarboxylate (22.4 
g), described in Example 31, dihydropyran (80 ml, distilled over sodium) 
and p-toluenesulfonic acid monohydrate (300 mg) is allowed to stand at 
room temperature for 30 min. After adding a few ml of 10% Na.sub.2 
CO.sub.3 solution the mixture is extracted with ether. The ether extract 
is washed with water, dried (Na.sub.2 SO.sub.4) and evaporated. 
Purification of the residue by chromatography on silica gel gives the 
title compound, nmr (CDCl.sub.3) .delta. 0.87 (t, 3H), 2.48 (m, 1H), 4.6 
(1H), 5.5 (m, 2H). 
In the same manner but using an equivalent amount of one of the compounds 
of formula 1 (R.sup.2 = H), for example, the compounds listed in Examples 
17 to 40, instead of diethyl 
trans-2-(3-hydroxy-3-methyl-1-octenyl)cyclopropane-1,1-dicarboxylate, then 
the corresponding tetrahydropyranyl ether compound of formula 1 (R.sup.2 = 
tetrahydropyranyl) is obtained, for example, the corresponding 
tetrahydropyran ether compounds of Examples 17 to 40, respectively. More 
specifically exemplified, in the same manner diethyl 
trans-2-(3-hydroxy-4-methyl-1-octenyl)cyclopropane-1,1-dicarboxylate, 
described in Example 17 gives diethyl 
trans-2-{3-[(tetrahydropyran-2-yl)oxy]-4-mehyl-1-octenyl}cyclopropane-1,1- 
dicarboxylate, .nu..sub.max.sup.film 1035, 1140, 1220 cm.sup.-1, and 
dimethyl 
trans-2-(4-ethyl-3-hydroxy-1-decenyl)cyclopropane-1,1-dicarboxylate, 
described in Example 24, gives dimethyl 
trans-2-{4-ethyl-3-[(tetrahydropyran-2-yl)oxy]-1-decenyl}cyclopropane-1,1- 
dicarboxylate. 
EXAMPLE 42 
Dimethyl 
trans-1-(Carbomethoxymethyl)-5-(3-hydroxy-1-octenyl)-2-oxo-1,3-cyclopentan 
edicarboxylate (3; R.sup.1 and R.sup.3 = CH.sub.3, R.sup.2, R.sup.4, 
R.sup.5 and R.sup.6 = H and n = 3) 
A solution of sodium methoxide (5 g of sodium dissolved in 150 ml of 
methanol) is added at room temperature to a solution of tiethyl 
1,1,2-ethanetricarboxylate. The mixture is heated to 80.degree. and a 
solution of the compound of formula 1, dimethyl 
trans-2-{3-[(tetrahydropyran-2-yl)oxy]-1-octenyl}cyclopropane-1,1-dicarbox 
ylate, described by Abraham, cited above, is added slowly. The mixture is 
stirred for 1 hr. The methanol is removed under reduced pressure and the 
residue heated at 110.degree. for 1.5 hr. After cooling the mixture is 
acidified with acetic acid-water (25 ml, 1:1) and extracted with ether. 
The ether extract is washed with water, dried (MgSO.sub.4) and 
concentrated to give dimethyl 
trans-1-(carbomethoxymethyl)-5-{3-[(tetrahydropyran-2-yl)oxy]-1-octenyl}-2 
-oxo-1,3-cyclopentanedicarboxylate, .nu..sub.max.sup.EtOH 290 nm (.epsilon. 
= 13,500) in the presence of a base. [Note: Transesterification of the 
ester groups has occurred during the preceding condensation. If desired 
this can be avoided by the substitution of ethanol for methanol.] 
A mixture of the latter hydroxy protected derivative (95.1 g) in 375 ml of 
methanol-water (9:1) and p-toluenesulfonic acid monohydrate (2.85 g) is 
stirred for 1 hr at room temperature. The mixture is rendered neutral by 
the addition of 10% Na.sub.2 CO.sub.3. The methanol is removed by 
distillation. The residue is extracted with ether. The organic extract is 
washed with water until neutral, dried (MgSO.sub.4) and concentrated. The 
residue is subjected to chromatography on SiO.sub.2 using 20% ethyl 
acetate as eluant. Evaporation of the eluate gives the title compound 
.nu..sub.max.sup.EtOH 289 nm (14,500) in the presence of base. 
EXAMPLE 43 
Dimethyl 
trans-1-(Carboethoxymethyl)-5-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyc 
lopentanedicarboxylate (3; R.sup.1, R.sup.3 and R.sup.6 = CH.sub.3, 
R.sup.2, R.sup.4 and R.sup.5 = H and n = 3) 
To a solution of triethyl 1,1,2-ethanetricarboxylate (1.36 g) in 3 ml of 
methanol, a freshly prepared solution of sodium methoxide (from 0.126 g of 
sodium and 6 ml of absolute methanol) is added. The mixture is heated to 
80.degree.. A solution of dimethyl 
trans-(3-methyl-3-hydroxy-1-octenyl)cyclopropane-1-1-dicarboxylate (1.7 g) 
is gradually added and the resulting mixture stirred for an additional 15 
min. The methanol is removed by distillation at reduced pressure. The 
residue is then heated at 100.degree. for 45 min. Thereafter the mixture 
is cooled in an ice bath and rendered neutral with acetic acid. The 
mixture is extracted with ether. The extract is dried (Na.sub.2 SO.sub.4) 
and concentrated. Chromatography of the residue on silica gel using ethyl 
acetate/benzene (1:4) as eluant gives the title compound, 
.nu..sub.max.sup.film 3350, 1727 cm.sup.-1. 
By following the procedures of Examples 42 and 43 an using the appropriate 
compounds of formulae 1 and formula 2 as starting materials, other 
cyclopentanonetriesters of formula 3 are obtained. 
For example, the use of the compound of formula 1, diethyl 
trans-2-{3-[(tetrahydropyran-2-yl)oxy]-3-methyl-1-octenyl}-cyclopropane-1, 
1-dicarboxylate, described in Example 41, and the compound of formula 2, 
triethyl ethane-1,1,2-tricarboxylate, in the procedure of Example 42 gives 
dimethyl 
trans-1-(carboethoxymethyl)-5-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyc 
lopentanedicarboxylate, identical to the product of Example 43, via the 
intermediate dimethyl 
trans-1-(carboethoxymethyl)-5-{3-[(tetrahydropyran-2-yl)oxy]-3-methyl-1-oc 
tenyl}-2-oxo-1,3-cyclopentanedicarboxylate, .nu..sub.max.sup.film 1730 
cm.sup.-1. 
Likewise, the use of diethyl 
trans-2-{3-[(tetrahydropyran-2-yl)oxy]-4,4-dimethyl-1-octenyl}cyclopropane 
-1,1-dicarboxylate and triethyl ethane-1,1,2-tricarboxylate gives dimethyl 
trans-1-(carbomethoxymethyl)-5-(3-hydroxy-4,4-dimethyl-1-octenyl)-2-oxo-1, 
3-cyclopentanedicarboxylate, .nu..sub.max.sup.film 3500 cm.sup.-1, 
.nu..sub.max.sup.EtOH 291 nm (.epsilon. = 13,600) in the presence of base 
(NaOH). 
Additional examples of compounds of formula 3 are listed in Table III 
together with the requisite starting materials. It is to be noted that 
when the procedure of Example 42 is used the requisite starting material 
of formula I is the corresponding tetrahydropyran-2-yl ether derivative of 
the compound of formula 4 noted therein; the tetrahydropyran-2-yl ether 
being prepared by following the procedure described in Example 41. 
TABLE III 
__________________________________________________________________________ 
NO. OF THE EXAMPLE 
IN WHICH STARTING 
STARTING MATERIAL OF 
PRODUCT: (PREFIX LISTED 
MATERIAL OF FORMULA 1 
FORMULA 2 BELOW)-2-OXO-2,3-CYCLE- 
EX. 
IS DESCRIBED R.sup.3 PENTANEDICARBOXYLATE 
__________________________________________________________________________ 
44 18 CH.sub.3 dimethyl trans-1-(carbo- 
methoxymethyl)-5-(4-ethyl-3- 
hydroxy-1-heptenyl) 
45 19 C.sub.2 H.sub.5 
diethyl trans-1-(carbo- 
ethoxymethyl-5-(3-hydroxy- 
4-propyl-1-nonenyl) 
46 20 CH.sub.3 dimethyl trans-1-(carbo- 
methoxymethyl)-5-(4-ethyl-3- 
hydroxy-1-decenyl) 
47 21 C.sub.2 H.sub.5 
diethyl trans-1-(carbo- 
ethoxymethyl)-5-(3-hydroxy- 
4-methyl-1-heptenyl) 
48 22 CH.sub.3 dimethyl trans-1-(carbo- 
methoxymethyl)-5- 
(3-hydroxy-4-methyl-1- 
nonenyl) 
49 23 C.sub.2 H.sub.5 
diethyl trans-1-(carbo- 
ethoxymethyl)-5-(4-ethyl- 
3-hydroxy-1-octenyl) 
50 24 CH.sub.3 dimethyl trans-1-(carbon- 
methoxymethyl)-5-(4-methyl- 
3-hydroxy-1-decenyl) 
51 25 C.sub.2 H.sub.5 
diethyl trans-1-(carbo- 
ethoxymethyl)-5-(3-hydroxy- 
4-propyl-1-heptenyl) 
52 26 CH.sub.3 dimethyl trans-1-(carbo- 
methoxymethyl)-5-(3-hydroxy- 
4-ethyl-1-nonenyl) 
53 27 n-C.sub.3 H.sub.7 
dipropyl trans-1-(carbo- 
propoxymethyl)-5-(3-hydroxy- 
4,4-dimethyl-1-decenyl) 
54 28 n-C.sub.3 H.sub.7 
dipropyl trans-1-(carbo- 
propoxymethyl)-5-(4- 
ethyl-3-hydroxy-4-methyl- 
1-decenyl) 
55 29 CH.sub.3 dimethyl trans-1-(carbo- 
methoxymethyl)-5-(3-hydroxy- 
4-methyl-4-propyl-1- 
heptenyl) 
56 30 C.sub.2 H.sub.5 
diethyl trans-1-(carbo- 
ethoxymethyl)-5-(3-hydroxy- 
4,4-dipropyl-1-nonenyl) 
57 32 CH.sub.3 dimethyl trans-1-(carbo- 
methoxymethyl)-5-(3-hydroxy- 
3-methyl-1-heptenyl) 
58 33 C.sub.2 H.sub.5 
diethyl trans-1-(carbo- 
ethoxymethyl)-5-(3-ethyl-3- 
hydroxy-1-nonenyl) 
59 34 CH.sub.3 dimethyl trans-1-(carbo- 
methoxymethyl)-5-(3-hydroxy- 
3-propyl-1-decenyl) 
60 35 C.sub.2 H.sub.5 
diethyl trans-1-(carbo- 
ethoxymethyl)-5-(3-hydrocy- 
3,4-dimethyl-1-heptenyl) 
61 36 CH.sub.3 dimethyl trans-1-(carbo- 
methoxymethyl)-5-(3-ethyl- 
3-hydroxy-4-methyl-1-nonenyl) 
62 37 C.sub.2 H.sub.5 
diethyl trans-1-(carbo- 
ethoxymethyl)-5-(4-ethyl-3- 
hydroxy-3-propyl-1-octenyl) 
63 38 CH.sub.3 dimethyl trans-1-(carbo- 
methoxymethyl)-5-(3-hydroxy 
3,4-dimethyl-1-decenyl) 
64 39 C.sub.2 H.sub.5 
diethyl trans-1-(carbo- 
ethoxymethyl)-5-(3-ethyl-3- 
hydroxy-4-propyl-1-heptenyl) 
65 40 CH.sub.3 dimethyl trans-1-(carbo- 
methoxymethyl)-5-(4-ethyl-3- 
hydroxy-3-propyl-1-nonenyl) 
__________________________________________________________________________ 
EXAMPLE 66 
trans-2-(3-Hydroxy-1-octenyl)-5-oxocyclopentaneacetic acid 
(4; R.sup.2, R.sup.4, R.sup.5 and R.sup.6 = H and n = 3) 
A suspension of dimethyl 
trans-1-(carbomethoxymethyl)-5-(3-hydroxy-1-octenyl)-2-oxo-1,3-cyclopentan 
edicarboxylate (26.24 g), described in Example 42, in a solution of sodium 
hydroxide (12 g) in 70 ml of water and 80 ml of methanol is heated at 
reflux for 2 hr. The reaction mixture is cooled, acidified to pH 6 with 2N 
HCl. The resulting oil is extracted with ether. The ether extract is 
washed with water, dried (MgSO.sub.4) and the solvent removed. The residue 
is subjected to chromatography on silica gel (850 g). Elution with 
methanol-chloroform (1:9) yields the title compound, .nu..sub.max.sup.film 
3350, 1727 cm.sup.-1. The corresponding methyl ester of the title 
compound, prepared by treatment with diazomethane, has 
.nu..sub.max.sup.film 3412, 1737 cm.sup.-1. 
By following the procedure of Example 66 and using the appropriate 
cyclopentanonetriester of formula 3, for example those described in 
Examples 43 to 65, other compounds of formula 4 are obtained. 
For example, the use of the cyclopentanonetriester of formula 3, dimethyl 
trans-1-(carboethoxymethyl)-5-(3-hydroxy-3-methyl-1-octenyl)-2-oxo-1,3-cyc 
lopentanedicarboxylate, described in Example 43, in the procedure of 
Example 66, gives 
trans-2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentaneacetic acid, 
.nu..sub.max.sup.film 3350, 1727 cm.sup.-1. 
Likewise, the use of dimethyl 
trans-1-(2-carbomethoxymethyl)-5-(3-hydroxy-4,4-dimethyl-1-octenyl)-2-oxo- 
1,3-cyclopentanedicarboxylate, described in Example 43, gives 
trans-2-(3-hydroxy-4,4-dimethyl-1-octenyl)-5-oxocyclopentaneacetic acid, 
.nu..sub.max.sup.film 3355, 1729 cm.sup.-1. 
Further examples of such components of formula 4 are listed in Table IV 
together with the requisite cyclopentanonetriesters starting material, the 
latter compound being noted by the example describing its preparation. 
TABLE IV 
__________________________________________________________________________ 
NO. OF EXAMPLE IN WHICH 
CYCLOPENTANONETRIESTER 
EXAMPLE 
OF FORMULA 3 IS PREED 
PRODUCT: 
__________________________________________________________________________ 
67 44 trans-2-(4-ethyl-3-hydroxy-1- 
heptenyl)-5-oxocyclopentaneacetic 
acid 
68 45 trans-2-(3-hydroxy-4-propyl-1- 
nonenyl)-5-oxocyclopentaneacetic 
acid 
69 46 trans-2-(4-ethyl-3-hydroxy-1-decen- 
yl)-5-oxocyclopentaneacetic acid 
70 47 trans-2-(3-hydroxy-4-methyl-1-hepten- 
yl)-5-oxocyclopentaneacetic acid 
71 48 trans-2-(3-hydroxy-4-methyl-1-nonen- 
yl)-5-oxocyclopentaneacetic acid 
72 49 trans-2-(4-ethyl-3-hydroxy-1-octen- 
yl)-5-oxocyclopentaneacetic acid 
73 50 trans-2-(4-methyl-3-hydroxy-1-decen- 
yl)-5-oxocyclopentaneacetic acid 
74 51 trans-2-(3-hydroxy-4-propyl-1-hepten- 
yl)-5-oxocyclopentaneacetic acid 
75 52 trans-2-(3-hydroxy-4-ethyl-1-nonen- 
yl)-5-oxocyclopentaneacetic acid 
76 53 trans-2-(4,4-dimethyl-3-hydroxy-1- 
decenyl)-5-oxocyclopentaneacetic acid 
77 54 trans-2-(4-ethyl-4-methyl-3-hydroxy- 
1-decenyl)-5-oxocyclopentaneacetic 
acid 
78 55 trans-2-(4-methyl-3-hydroxy-4-propyl)- 
1-heptenyl)-5-oxocyclopentaneacetic 
acid 
79 56 trans-2-(3-hydroxy-4,4-dipropyl-1- 
nonenyl)-5-oxocyclopentaneacetic acid 
80 57 trans-2-(3-hydroxy-3-methyl-1- 
heptenyl)-5-oxocyclopentaneacetic 
acid 
81 58 trans-2-(3-ethyl-3-hydroxy-1-nonenyl)- 
5-oxocyclopentaneacetic acid 
82 59 trans-2-(3-hydroxy-3-propyl-1-decenyl)- 
5-oxocyclopentaneacetic acid 
83 60 trans-2-(3-hydroxy-3,4-dimethyl-1- 
heptenyl)-5-oxocyclopentaneacetic acid 
84 61 trans-2-(3-ethyl-3-hydroxy-4-methyl-1- 
nonenyl)-5-oxocyclopentaneacetic acid 
85 62 trans-2-(4-ethyl-3-hydroxy-3-propyl-1- 
octenyl)-5-oxocyclopentaneacetic acid 
86 63 trans-2-(3-hydroxy-3,4-dimethyl-1- 
decenyl)-5-oxocyclopentaneacetic acid 
87 64 trans-2-(3-ethyl-3-hydroxy-4-propyl-1- 
heptenyl)-5-oxocyclopentaneacetic acid 
88 65 trans-2-(4-ethyl-3-hydroxy-3-propyl-1- 
nonenyl)-5-oxocyclopentaneacetic 
__________________________________________________________________________ 
acid 
EXAMPLE 89 
trans-2-{3-[(Tetrahydropyran-2-yl)oxy]-1-octenyl}-5-oxocyclopentaneacetic 
acid (4; R.sup.2 = tetrahydropyran-2-yloxy, R.sup.4, R.sup.5 and R.sup.6 = 
H and n = 3) 
To a solution of trans-2-(3-hydroxy-1-octenyl)-5-oxocyclopentaneacetic acid 
(4.7 g), described in Example 66, in methylene chloride (20 ml) at 
-20.degree. is added dihydropyran (1.61 g) and p-toluenesulfonic acid 
(0.04 g). The mixture is stirred at that temperature for 30 minutes. A 
further qunatity of p-toluenesulfonic acid (0.07 g) is added and the 
mixture maintained at the same temperature for 1 hr. The reaction mixture 
is diluted with ether, washed with water, dried (MgSO.sub.4) and the 
solvent removed. The residue is passed through a column of silica gel (300 
g) in a solution of 5% methanol-chloroform. The eluate is concentrated to 
give the title compound, .nu..sub.max.sup.film 1727 cm.sup.-1, nmr 
(CDCl.sub.3) .delta. 0.88 (t, 3H), 4.69 (m, 1H), 5.5 (m, 2H). 
In the same manner but using an equivalent amount of one of the other 
compounds of formula 4 (R.sup.2 = H), for example the compound listed in 
Examples 67 to 81, instead of 
trans-2-(3-hydroxy-1-octenyl)-5-oxocyclopentaneacetic acid, then the 
corresponding tetrahydropyranyl ether compound of formula 4 (R.sup.2 = 
tetrahydropyran-2-yl) is obtained; for example, the use of 
trans-2-(3-hydroxy-4,4-dimethyl-1-octenyl)-5-oxocyclopentaneacetic acid, 
described in Example 66, gives 
trans-2-{4,4-dimethyl-3-[(tetrahydropyran-2-yl)oxy]-1-octenyl}-5-oxocyclop 
entaneacetic acid, .nu..sub.max.sup.film 1727 cm.sup.-1. 
EXAMPLE 90 
trans-2.beta.-Hydroxy-5-{3-[(tetrahydropyran-2-yl)oxy]-1-octenyl}cyclopenta 
neacetic acid (5; R.sup.2 = tetrahydropyran-2-yloxy, R.sup.4, R.sup.5 and 
R.sup.6 = H and n = 3) and 
trans-2.alpha.-hydroxy-5-{3-[(tetrahydropyran-2-yl)oxy]-1-octenyl}cyclopen 
taneacetic acid .gamma.-lactone (6; R.sup.2 = tetrahydropyran-2-yloxy, 
R.sup.4, R.sup.5 and R.sup.6 = H and n = 3) 
To a solution of 
trans-2-{3-[(tetrahydropyran-2-yl)oxy]-1-octenyl}-5-oxocyclopentaneacetic 
acid (5.1 g), described in Example 89, in methanol (10 ml), cooled to 
-10.degree., is added a solution of sodium (0.354 g) in methanol (5 ml). 
Thereafter, sodium borohydride (0.152 g) is added to the mixture. The 
mixture is stirred for 1 hr, diluted with ether and rendered acidic wick 
cone. HCl to pH 4.5. The ether layer is separated. The aqueous phase is 
extracted with fresh ether. The combined ether layers are washed quickly 
with water, dried (MgSO.sub.4) and concentrated to yield a mixture of the 
title compounds in about a 7:3 ratio by weight. 
The two compounds can be separated by dissolving the preceding mixture in 
methylene chloride extracting the acid 5 into an aqueous alkaline 
solution, for example, 5% Na.sub.2 CO.sub.3, and subsequent acidification 
thereof gives the title compound of formula 5, .nu..sub.max.sup.film 3200, 
1700 cm.sup.-1, nmr (CDCl.sub.3) .delta. 0.88 (t, 3H), 4.7 (m, 1H), 5.6 
(m, 2H). The corresponding .gamma.-lactone 6 is described below. 
The preceding mixture of the title compounds (4.0 g) in methylene 
dichloride (35 ml) and triethylamine (2.339 g) is cooled to -5.degree. to 
-10.degree.. A solution of methanesulfonyl chloride (1.44 g), in methylene 
chloride (15 ml) is added dropwise. The mixture is stirred at that 
temperature for 45 minutes. The mixture is diluted with methylene 
chloride, washer with water (5X), dried (MgSO.sub.4) and the solvent 
removed to yield a crude product which is poured through on a column of 
silica gel (250 g) in ethylacetate-benzene. Evaporation of the eluate 
gives the title compound of formula 6, .nu..sub.max.sup.film 1762, 1030, 
1012 cm.sup.-1, nmr (CDCl.sub.3) .delta. 4.68 (s, 1H), 5.01 (s, 1H), 5.5 
(m, 2H). 
By following the procedure of Example 90 and using the appropriate compound 
of formula 4, for example those described in Examples 66 to 89, other 
compounds of formulae 5 and 6 are obtained. 
For example, the use of the compound of formula 4, 
trans-2-(3-hydroxy-3-methyl-1-octenyl)-5-oxocyclopentaneacetic acid, 
described in Example 66, gives 
trans-2.alpha.-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentaneacetic 
acid, and its corresponding .gamma.-lactone, .nu..sub.max.sup.film 3400, 
1765 cm.sup.-1. 
Likewise, the use of 
trans-2-(3-hydroxy-4,4-dimethyl-1-octenyl)-5-oxocyclopentaneacetic acid, 
described in Example 66, gives 
trans-2.alpha.-hydroxy-5-(3-hydroxy-4,4-dimethyl-1-octenyl)cyclopentaneace 
tic acid, and its corresponding .gamma.-lactone, .nu..sub.max.sup.film 
3450, 1765 cm.sup.-1. 
Further examples of the compounds of formula 5 and their corresponding 
.gamma.-lactones of formula 6, which may be prepared by the procedure of 
Example 90, are listed in Table V. In each case the requisite starting 
material of formula 4 are noted by the example describing its preparation 
also in each case the corresponding tetrahydropyranyl ether of the 
starting material of formula 4 may replace the designated starting 
material. 
TABLE V 
__________________________________________________________________________ 
NO. OF EXAMPLE IN WHICH 
PRODUCT: (PREFIX LISTED BELOW)- 
STARTING MATERIAL OF 
CYCLOPENTANEACETIC ACID, 5 
EXAMPLE 
FORMULA 4 IS PREED 
(AND CORRESPONDING .gamma.-LACTONE, 
__________________________________________________________________________ 
6) 
91 67 trans-2.alpha.-hydroxy-5-(4-ethyl-3-hydroxy-1- 
heptenyl) 
92 68 trans-2.alpha.-hydroxy-5-(3-hydroxy-4-propyl-1- 
nonenyl) 
93 69 trans-2.alpha.-hydroxy-4-(4-ethyl-3-hydroxy-1- 
decenyl) 
94 70 trans-2.alpha.-hydroxy-5-(3-hydroxy-4-methyl-1- 
heptenyl) 
95 71 trans-2.alpha.-hydroxy-5-(3-hydroxy-4-methyl-1- 
nonenyl) 
96 72 trans-2.alpha.-hydroxy-5-(4-ethyl-3-hydroxy-1- 
octenyl) 
97 73 trans-2.alpha.-hydroxy-5-(4-methyl-3-hydroxy-1- 
decenyl) 
98 74 trans-2.alpha.-hydroxy-5-(3-hydroxy-4-propyl-1- 
heptenyl) 
99 75 trans-2.alpha.-hydroxy-5-(3-hydroxy-4-ethyl-1- 
nonenyl) 
100 76 trans-2.alpha.-hydroxy-5-(4,4-dimethyl-3-hydroxy- 
. 
1-decenyl) 
101 77 trans-2.alpha.-hydroxy-5-(4-ethyl-4-methyl-3- 
hydroxy-1-decenyl) 
102 78 trans-2.alpha.-hydroxy-5-(4-methyl-3-hydroxy-4- 
propyl-1-heptenyl) 
103 79 trans-2.alpha.-hydroxy-5-(3-hydroxy-4,4-dipropyl- 
1-nonenyl) 
104 80 trans-2.alpha.-hydroxy-5-(3-hydroxy-3-methyl-1- 
heptenyl) 
105 81 trans-2.alpha.-hydroxy-5-(3-ethyl-3-hydroxy-1- 
nonenyl) 
106 82 trans-2.alpha.-hydroxy-5-(3-hydroxy-3-propyl- 
1-decenyl) 
107 83 trans-2.alpha.-hydroxy-5-(3-hydroxy-3,4- 
dimethyl-1-heptenyl) 
108 84 trans-2.alpha.-hydroxy-5-(3-ethyl-3-hydroxy- 
4-methyl-1-nonenyl) 
109 85 trans-2.alpha.-hydroxy-5-(4-ethyl-3-hydroxy- 
3-propyl-1-octenyl) 
110 86 trans-2.alpha.-hydroxy-5-(3-hydroxy-3,4-di- 
methyl-1-decenyl) 
111 87 trans-2.alpha.-hydroxy-5-(3-ethyl-3-hydroxy- 
4-propyl-1-heptenyl) 
112 88 trans-2.alpha.-hydroxy-5-(4-ethyl-3-hydroxy-3- 
propyl-1-nonenyl) 
__________________________________________________________________________ 
EXAMPLE 113 
trans-2.alpha.-Hydroxy-5-(3-hydroxy-1-octenyl)cyclopentaneacetic acid 
.gamma.-lactone (6; R.sup.2, R.sup.4, R.sup.5 and R.sup.6 = H and n = 3) 
trans-2.alpha.-Hydroxy-5-{3-[(tetrahydropyran-2-yloxy]-1-octenyl}-cyclopent 
aneacetic acid .gamma.-lactone (2.0 g), described in Example 90, is 
dissolved in methanol (10 ml) and water (3.5 ml) containing 
p-toluenesulfonic acid (0.4 g). The mixture is stirred at room temperature 
for 30 minutes. The solvent is removed under reduced pressure. The residue 
is shaken between water and ether. The ether layer is dried (MgSO.sub.4) 
and evaporated to give the title compound, .nu..sub.max.sup.film 3450, 
1765 cm.sup.-1. 
The corresponding DMIS ether of the title compound has 
.nu..sub.max.sup.film 1765 cm.sup.-1. 
EXAMPLE 114 
trans-2.alpha.-Hydroxy-5-(3-oxo-1-octenyl)cyclopentaneacetic acid 
.gamma.-lactone (7; R.sup.4 and R.sup.5 = H and n = 3) 
A solution of 
trans-2.alpha.-hydroxy-5-(3-hydroxy-1-octenyl)-cyclopentaneacetic acid 
.gamma.-lactone (1.9 g), described in Example 113, in chloroform in (60 
ml) is stirred with activated magnanise dioxide (14.9 g) at 40.degree. 
(bath temperature) for 15 hr. The reaction mixture is filtered and the 
precipitate washed with hot chloroform. The combined chloroform solutions 
are evaporated. The residue is subjected to chromatography on silica gel 
using ethyl acetate-benzene (3:7) as eluant. Evaporation of the eluant 
gives the title compound, mp 36.degree.-36.5.degree. C., 
.nu..sub.max.sup.CHCl 3 1755, 1685, 1625 cm.sup.-1. 
By following the procedure of Example 114 and using the appropriate 
hydroxylactone of formula 6; for example, those of Examples 91 to 103, 
other compounds of formula 7 are obtained. 
For example, the use of the compound of formula 6, 
trans-2.alpha.-hydroxy-5-(3-hydroxy-4,4-dimethyl-1-octenyl)cyclopentaneace 
tic acid .gamma.-lactone, described in Example 90, gives 
trans-2.alpha.-hydroxy-5-(4,4-dimethyl-3-oxo-1-octenyl)cyclopentaneacetic 
acid .gamma.-lactone, .nu..sub.max.sup.film 1765, 1680, 1620 cm.sup.-1. 
Further examples of the compounds of formula 7 are listed in Table VI. In 
each case the requisite starting material of formula 6 is noted by the 
example describing its preparation. 
TABLE VI 
______________________________________ 
No. of Ex. in 
which Starting 
Material of 
Formula 6 is Product: (Prefix Listed Below)- 
Ex. Prepared Cyclopentaneacetic Acid .gamma.-Lactone 
______________________________________ 
115 91 trans-2.alpha.-hydroxy-5-(4-ethyl-3-oxo-1- 
heptenyl) 
116 92 trans-2.alpha.-hydroxy-5-(3-oxo-4-propyl-1- 
nonenyl) 
117 93 trans-2.alpha.-hydroxy-5-(4-ethyl-3-oxo-1- 
decenyl) 
118 94 trans-2.alpha.-hydroxy-5-(4-methyl-3-oxo-1- 
heptenyl) 
119 95 trans-2.alpha.-hydroxy-5-(3-oxo-4-methyl-1- 
nonenyl) 
120 96 trans-2.alpha.-hydroxy-5-(4-ethyl-3-oxo-1- 
octenyl) 
121 97 trans-2.alpha.-hydroxy-5-(4-methyl-3-oxo-1- 
decenyl) 
122 98 trans-2.alpha.-hydroxy-5-(3-oxo-4-propyl-1- 
heptenyl) 
123 99 trans-2.alpha.-hydroxy-5-(4-ethyl-3-oxo-1- 
nonenyl) 
124 100 trans-2.alpha.-hydroxy-5-(4,4-dimethyl-3- 
oxo-1-decenyl) 
125 101 trans-2.alpha.-hydroxy-5-(4-ethyl-4-methyl- 
3-oxo-1-decenyl) 
126 102 trans-2.alpha.-hydroxy-5-(4-methyl-3-oxa- 
4-propyl-1-heptenyl) 
127 103 trans-2.alpha.-hydroxy-5-(3-oxo-4,4-dipropyl- 
1-nonenyl) 
______________________________________ 
EXAMPLE 128 
2.alpha.-Hydroxy-5-(3-oxooctyl)cyclopentaneacetic acid .gamma.-lactone (8; 
R.sup.4 and R.sup.5 = H and n = 3) 
A solution of trans-2.alpha.-hydroxy-5-(3-oxo-1-octenyl)cyclopentaneacetic 
acid .gamma.-lactone (5.0 g), described in Example 114, in methanol (100 
ml) is hydrogenated in the presence of 10% palladium-charcoal (1.0 g) at 
25.degree.. After the uptake of the theoretical amount of hydrogen, the 
catalyst is collected on a filter and the filtrate is concentrated to 
yield the title compound, .nu..sub.max.sup.film 1765, 1710 cm.sup.-1. 
By following the procedure of Example 128 and using the appropriate 
hydroxylactone of formula 7; other compounds of formula 8 are obtained. 
For example the use of the compound of formula 7, 
trans-2.alpha.-hydroxy-5-(4,4-dimethyl-3-oxo-1-octenyl)cyclopentaneacetic 
acid .gamma.-lactone, described in Example 114, gives 
2.alpha.-hydroxy-5-(4,4-dimethyl-3-oxooctyl)cyclopentaneacetic acid 
.gamma.-lactone, .nu..sub.max.sup.film 1770, 1700 cm.sup.-1. 
Further examples of the compound of formula 8 are listed in Table VIII. In 
each case the requisite starting material of formula 7 is noted by the 
example in which is prepared. 
TABLE VII 
______________________________________ 
No. of Ex. in which 
starting material of 
Product: (Prefix Listed Below)- 
Ex. Formula 7 is prepared 
Cyclopentaneacetic Acid .gamma.-Lactone 
______________________________________ 
129 115 2.alpha.-hydroxy-5-(4-ethyl-3- 
oxoheptyl) 
130 116 2.alpha.-hydroxy-5-(3-oxo-4- 
propylnonyl) 
131 117 2.alpha.-hydroxy-5-(4-ethyl-3- 
oxodecyl) 
132 118 2.alpha.-hydroxy-5-(4-methyl-3- 
oxoheptyl) 
133 119 2.alpha.-hydroxy-5-(4-methyl-3- 
oxononyl) 
134 120 2.alpha.-hydroxy-5-(4-ethyl-3- 
oxooctyl) 
135 121 2.alpha.-hydroxy-5-(4-methyl-3- 
oxodecyl) 
136 122 2.alpha.-hydroxy-5-(3-oxo-4- 
propylheptyl) 
137 123 2.alpha.-hydroxy-5-(4-ethyl-3- 
oxononyl) 
138 124 2.alpha.-hydroxy-5-(4,4-dimethyl- 
3-oxo-1-decyl) 
139 125 2.alpha.-hydroxy-5-(4-ethyl-4- 
methyl-3-oxodecyl) 
140 126 2.alpha.-hydroxy-5-(4-methyl-3- 
oxo-4-propylheptyl) 
141 127 2.alpha.-hydroxy-5-(3-oxo-4,4- 
dipropylnonyl) 
______________________________________ 
EXAMPLE 142 
2.alpha.-Hydroxy-5-(3-hydroxyoctyl)cyclopentaneacetic acid .gamma.-lactone 
(9; R.sup.2, R.sup.4, R.sup.5 and R.sup.6 = H and n = 3) 
By following the procedure of Example 17 but replacing diethyl 
trans-2-(4,4-dimethyl-3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate with 
an equivalent amount of 2.alpha.-hydroxy-5-(3-oxooctyl)cyclopentane-acetic 
acid .gamma.-lactone, described in Example 128, the latter compound is 
reduced to give the title compound, .nu..sub.max.sup.film 3400, 1770 
cm.sup.-1. 
The title compound is also obtained by the procedure of Example 165. 
By following the procedure of Example 142 and using the appropriate 
compound of formula 8, for example those in Examples 129 to 141, other 
compounds of formula 9 in which R.sup.6 is hydrogen are obtained. 
For example, the use of the compound of formula 8, 
2.alpha.-hydroxy-5-(4,4-dimethyl-3-oxooctyl)cyclopentaneacetic acid 
.gamma.-lactone, described in Example 128, gives 
2.alpha.-hydroxy-5-(3-hydroxy-4,4-dimethyloctyl)cyclopentaneacetic acid 
.gamma.-lactone. 
Further examples of the compound of formula 9 in which R.sup.6 is hydrogen 
are listed in Table VIII. In each case the requisite starting material of 
formula is noted by the example in which it is prepared. 
TABLE VIII 
______________________________________ 
No. of Ex. in Which 
Product: (Prefix Listed Below)- 
Starting Material of 
Cyclopentaneacetic Acid, 5 
Ex. Formula 4 is Prepared 
(and Corresponding .gamma.-Lactone, 
______________________________________ 
6) 
143 136 2.alpha.-hydroxy-5-(3-hydroxy-4-propyl- 
heptyl) 
144 137 2.alpha.-hydroxy-5-(4-ethyl-3-hydroxy- 
nonyl) 
145 138 2.alpha.-hydroxy-5-(4,4-dimethyl-3- 
hydroxy-1-decyl) 
146 139 2.alpha.-hydroxy-5-(4-ethyl-3-hydroxy- 
4-methyldecyl) 
147 140 2.alpha.-hydroxy-5-(3-hydroxy-4-methyl- 
4-propylheptyl) 
148 141 2.alpha.-hydroxy-5-(3-hydroxy-4,4- 
dipropylnonyl) 
______________________________________ 
EXAMPLE 149 
2.alpha.-Hydroxy-5-(3-hydroxy-3-methyloctyl)cyclopentaneacetic acid 
.gamma.-lactone (9; R.sup.2, R.sup.4 and R.sup.5 = H, R.sup.6 = CH.sub.3 
and n = 3) 
A solution of 2.alpha.-hydroxy-5-(3-oxooctyl)cyclopentaneacetic acid 
.gamma.-lactone (6.66 g), described in Example 128, in ether (100 ml) is 
treated dropwise with the lower alkyl magnesium halide, methyl magnesium 
iodide (1.5 molar in ether, 33 ml) while keeping the reaction temperature 
at 0.degree.. The Grignard complex is then decomposed with 10% ammonium 
chloride solution. The reaction mixture is extracted with ether, washed 
with brine, dried (Na.sub.2 SO.sub.4) and concentrated. The residue in 
ethyl acetate-benzene (2:8) is poured through a column of silica gel. 
Evaporation of the eluate gives the title compound, nmr (CDCl.sub.3) 
.delta. 0.9 (t, J = 5, 3H), 1.13 (s, 3H), 1.67 (b, 1H), 2.33 and 2.71 (m, 
2H), 500 (m, 1H). 
By following the procedure of Example 149 and using the appropriate 
compound of formula 8, for example, those described in Examples 129 to 
137, together with the appropriate lower alkyl magnesium halide, other 
compounds of formula 9 are obtained. 
Further examples of the compound of formula 9 are listed in Table IX. In 
each case the requisite starting material of formula 8 is noted by the 
example in which it is prepared. 
TABLE IX 
__________________________________________________________________________ 
PRODUCT: (PREFIX LISTED 
NO. OF EXAMPLE IN WHICH BELOW)-CYCLOPENTANEACETIC 
STARTING MATERIAL OF 
LOWER ALKYL ACID, 5 (AND CORRESPONDING) 
EXAMPLE 
FORMULA 8 IS PREED 
MAGNESIUM HALIDE 
.gamma.-LACTONE, 6 
__________________________________________________________________________ 
150 129 CH.sub.3 Mgl 2.alpha.-hydroxy-5-(4-ethyl-3- 
hydroxy-3-methylheptyl) 
151 130 C.sub.2 H.sub.5 MgBr 
2.alpha.-hydroxy-5-(3-ethyl-3- 
hydroxy-4-propylnonyl) 
152 131 n-C.sub.3 H.sub.7 MgCl 
2.alpha.-hydroxy-5-(4-ethyl-3- 
hydroxy-3-propyldecyl) 
153 132 C.sub.2 H.sub.5 MgCl 
2.alpha.-hydroxy-5-(3-ethyl-3- 
hydroxy-4-methylheptyl) 
154 133 CH.sub.3 Mgl 2.alpha.-hydroxy-5-(3-hydroxy- 
3,4-dimethylnonyl) 
155 134 C.sub.2 H.sub.5 Mgl 
2.alpha.-hydroxy-5-(3,4- 
diethyl-3-hydroxyoctyl) 
156 135 n-C.sub.3 H.sub.7 Mgl 
2.alpha.-hydroxy-5-(3-hydroxy- 
4-methyldecyl) 
__________________________________________________________________________ 
EXAMPLE 157 
trans-2.alpha.-Hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentaneacetic 
acid .gamma.-lactone (12; R.sup.2, R.sup.4 and R.sup.5 = H, R.sup.6 = 
CH.sub.3 and n = 3) 
By following the procedure of Example 149, but replacing 
2.alpha.-hydroxy-5-(3-oxooctyl)cyclopentaneacetic acid .gamma.-lactone, 
with an equivalent amount of 
trans-2.alpha.-hydroxy-5-(3-oxo-1-octenyl)cyclopentaneacetic acid 
.gamma.-lactone, described in Example 114, the title compound is obtained, 
.nu..sub.max.sup.film 3420, 1770 cm.sup.-1, nmr (CDCl.sub.3) .delta. 0.9 
(t, J = 5, 3H), 1.26 (3H), 1.7 (1H), 5.05 (m, 1H), 5.65 (m, 2H). 
By following the procedure of Example 157 and using the appropriate 
compound of formula 7, for example, those described in Examples 115-123, 
together with the appropriate lower alkyl magnesium halide, other 
compounds of formula 12 are obtained. 
Further examples of the compound of formula 12 are listed in Table X. In 
each case the requisite starting material of formula is noted by the 
example in which it is prepared. 
TABLE X 
______________________________________ 
No. of Ex. in 
which starting Product. (Prefix Listed 
material of Lower Below)-Cyclopentaneacetic 
Formula 7 is 
Magnesium Acid, 5 (and corresponding 
Ex. prepared Halide .gamma.-Lactone, 6 
______________________________________ 
158 115 CH.sub.3 MgBr 
trans-2.alpha.-hydroxy-5-(4- 
ethyl-3-hydroxy-4- 
propyl-1-nonenyl) 
159 116 C.sub.2 H.sub.5 MgBr 
trans-2.alpha.-hydroxy-5-(3- 
ethyl-3-hydroxy-4- 
propyl-1-nonenyl) 
160 117 n-C.sub.3 H.sub.7 MgCl 
trans-2.alpha.-hydroxy-5-(4- 
ethyl-3-hydroxy-3- 
propyl-1-decenyl) 
161 118 C.sub.2 H.sub.5 MgCl 
trans-2.alpha.-hydroxy-5-(3- 
ethyl-3-hydroxy-4- 
methyl-1-heptenyl) 
162 119 CH.sub.3 Mgl 
trans-2.alpha.-hydroxy-5-(3- 
hydroxy-3,4-dimethyl-1- 
nonenyl) 
163 120 C.sub.2 H.sub.5 Mgl 
trans-2.alpha.-hydroxy-5-(3,4- 
diethyl-3-hydroxy-1- 
octenyl) 
164 121 CH.sub.3 Mgl 
trans-2.alpha.-hydroxy-5-(3- 
hydroxy-3,4-dimethyl-1- 
decenyl) 
______________________________________ 
EXAMPLE 165 
2.alpha.-Hydroxy-5-(3-hydroxyoctyl)cyclopentaneacetic acid .gamma.-lactone 
(9, R.sup.2, R.sup.4, R.sup.5 and R.sup.6 = H and n = 3) 
The title compound is obtained, in a addition to the procedure of Example 
142, by hydrogenation of the compound of formula 6 (R.sup.6 = H), 
trans-2.alpha.-hydroxy-5-(3-hydroxy-1-octenyl)cyclopentaneacetic acid 
.gamma.-lactone, described in Example 113, by the procedure of R. D. 
Hoffsommer, et al., Tetrahedron Letters, 4085 (1971), using Raney nickel 
in dioxane. 
By following the procedure of Example 165 and using the appropriate 
compound of formula 6 (R.sup.6 = H), for Example those described in 
Examples 90 to 112, other corresponding compounds of formula 9 (R.sup.6 = 
H) are obtained. 
Further examples of the compounds of formula 9 are listed in Table XI. In 
each case the requisite starting material of formula 6 is noted by the 
example in which it is prepared. 
TABLE XI 
______________________________________ 
No. of Ex. in 
which starting 
material of Product: (Prefix Listed Below)- 
Formula 4 is Cyclopentaneacetic Acid, 5 
Ex. prepared (and corresponding .gamma.-Lactone, 6) 
______________________________________ 
166 99 2.alpha.-hydroxy-5-(3-hydroxy-4- 
ethylnonyl) 
167 100 2.alpha.-hydroxy-5-(4,4-dimethyl-3- 
hydroxydecyl) 
168 101 2.alpha.-hydroxy-5-(4-ethyl-4-methyl-3- 
hydroxydecyl) 
169 102 2.alpha.-hydroxy-5-(4-methyl-3-hydroxy-4- 
propylheptyl) 
170 103 2.alpha.-hydroxy-5-(3-hydroxy-4,4-dipropyl- 
nonyl) 
171 104 2.alpha.-hydroxy-5-(3-hydroxy-3- 
methylheptyl) 
172 108 2.alpha.-hydroxy-5-(3-ethyl-3-hydroxy-4- 
methylnonyl) 
173 109 2.alpha.-hydroxy-5-(4-ethyl-3-hydroxy-3- 
propyloctyl) 
______________________________________ 
EXAMPLE 174 
Hexahydro-2-hydroxy-4-[3-(dimethyl-tert-butylsilyloxy)-1-octenyl]-2H-cyclop 
enta[b]furan (13; R.sup.2, R.sup.4, R.sup.5 and R.sup.6 = H and n = 3) 
A solution of the compound of formula 6, 
trans-2.alpha.-hydroxy-5-(3-hydroxy-1-octenyl)cyclopentaneacetic acid 
.gamma.-lactone, in the form of its dimethyl-tert-butylsilyl ether, (6.66 
g), described in Example 113, in dry toluene (40 ml) is cooled to 
-75.degree. C. As solution of diisobutyl aluminum hydride (3.9 g in 10.8 
ml. of hexane) is added by syringe under a nitrogen atmosphere. The 
mixture is stirred afor 15 minutes at that temperature and then diluted 
with ether, washed with water. The gelantinous aluminum salts are removed 
by filtration. The filtrate is washed with water (2X), dried (MgSO.sub.4) 
and the solvent is removed to give the title compound, .gamma. 3360 
cm.sup.-1, nmr (CDCl.sub.3) .delta. 4.02 (m, 1H), 4.63 (m, 1H), 5.42 (m, 
2H). 
EXAMPLE 175 
trans, 
cis-7-[2.alpha.-Hydroxy-5-(3-hydroxy-1-octenyl)cyclopentyl]-5-heptenoic 
acid (11; R.sup.2, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 = H, X = OH, Y = 
H, Z = trans CH = CH, m = 3 and n = 3) 
To a suspension of sodium hydride (7.42 g, 57% in oil) washed with hexane, 
is added dry dimethyl sulfoxide (45 ml). The mixture is heated to 
75.degree.-80.degree. (bath temperature) for one hour. By this all the 
sodium hydride has reacted. The mixture is cooled. A solution of the 
phosphonium bromide, (39.0 g) derived from triphenylphosphine and 
.omega.-bromo pentanoic acid, in dry DMSO (90 ml) is added gradually to 
the solution of sodio methylsulfinyl carbinide; followed by the addition 
of a solution of the hemiacetal of formula 13, 
hexahydro-2.alpha.-hydroxy-4-[3-(dimethyl-tert-butylsilyloxy)-1-octenyl]-2 
H-cyclopenta[b]furan (5.42 g), described in Example 174, in dry 
dimethylsulfoxide (15 ml). The mixture is stirred overnight at room 
temperature. The reaction mixture is diluted with water, acidified with 
acetic acid (5 ml), and extracted with ether. The ether extract is washed 
with water, dried (Na.sub.2 SO.sub.4) and the solvent is removed. The 
residue is passed through a column of silica gel (400 g) using 
ether-hexane (1:1) as eluant. Evaporation of the eluate gives the 
corresponding dimethylisopropylsilyl ether of the title compound, 
.nu..sub.max.sup.film 3470, 1710 cm.sup.-1. 
Removal of the hydroxy protecting group 
The latter compound (4.1) g is dissolved in methanol (20 ml) and water (7 
ml) containing p-toluene sulfonic acid (0.4 g). The reaction mixture is 
stirred for 30 minutes, the solvent is removed under reduced pressure. The 
residue is extracted with ether. The extract is washed with water, dried 
(MgSO.sub.4) the solvent is evaporated. Purification by chromatography of 
the residue [SiO.sub.2, benzene-ethyl acetate (9:1)] gives the title 
compound as a mixture of stereochemical isomers with respect to the 
asymmetric carbon atom in the side chain to which the hydroxyl is 
attached. The mixture has .nu..sub.max.sup.film 3480, 1700 cm.sup.-1, nmr 
(CDCl.sub.3) .delta. 0.87 (m, 3H), 4.18 (m, 2H), 5.45 (m, 4H), identical 
to the mixture of the same name described in copending U.S. application 
Ser. No. 238,650, filed Mar. 27, 1972. 
By following sequentically the procedure of Examples 174 and 175, and using 
the appropriate compound of formula 6 or 9, for example, those of Examples 
90 to 112 other prostaglandin derivatives of formula 11 are obtained. 
For example the use of the compound of formula 6, 
trans-2.alpha.-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentaneacetic 
acid .gamma.-lactone, described in Example 90, gives 
trans,cis-7-[2.alpha.-hydroxy-5-(3-hydroxy-3-methyl-1-octenyl)cyclopentyl] 
-5-heptenoic acid, described in the copending U.S. application, Ser. No. 
351,381, filed Apr. 16, 1973, via the intermediate hemiacetal of formula 
13, 
hexahydro-2-hydroxy-4-{3-[(tetrahydropyran-2-yl)oxy]-1-octenyl}-2H-cyclope 
nta[b]furan, .nu..sub.max.sup.film 3350 cm.sup.-1. 
Likewise, the use of 
2.alpha.-hydroxy-5-{3-[(tetrahydropyran-2-yl)-oxy]octyl}cyclopentaneacetic 
acid .gamma.-lactone, described in Example 142, gives 
cis-7-[2.alpha.-hydroxy-5-(3-hydroxyoctyl)cyclopentyl]-5-heptenoic acid, 
nmr (CDCl.sub.3) .delta. 9.0 (t, J = 5, 3H), 3.65 (m, 1H), 4.25 (m, 1H), 
4.9 (s, 3H), 5.5 (m, 2H), via the intermediate hemiacetal of formula 10, 
hexahydro-2-hydroxy-4-[3-(dimethyl-tert-butyl)octyl]-2H-cyclopenta[b]furan 
, .nu..sub.max.sup.film 3360 cm.sup.-1. 
Likewise, the use of 
2.alpha.-hydroxy-5-(3-hydroxy-3-methyloctyl)cyclopentaneacetic acid 
.gamma.-lactone, described in Example 149, gives 
cis-7-[2.alpha.-hydroxy-5-(3-hydroxy-3-methyloctyl)cyclopentyl]-5-heptenoi 
c acid, nmr (CDCl.sub.3) .delta. 0.9 (t, J = 5, 3H), 1.2 (s, 3H), 1.5 (s, 
2H), 4.2 (m, 1H), 5.5 (m, 2H), via the intermediate hemiacetal of formula 
10, hexahydro-2-hydroxy-4-[3-hydroxy-3-methyloctyl]-2H-cyclopenta[b]furan, 
.nu..sub.max.sup.film 3355 cm.sup.-1. 
Likewise, the use of 
2.alpha.-hydroxy-5-(3-hydroxy-4,4-dimethyloctyl)cyclopentaneacetic acid 
.gamma.-lactone, described in Example 142, gives 
cis-7-[2.alpha.-hydroxy-5-(3-hydroxy-4,4-dimethyloctyl)cyclopentyl]-5-hept 
enoic acid, via the intermediate hemiacetal of formula 10, 
hexahydro-2-hydroxy-4-{3-(dimethyl-tert-butylsilyloxy)-4,4-dimethyloctyl}- 
2H-cyclopenta[b]furan, .nu..sub.max.sup.film 3350 cm.sup.-1 and the 
corresponding dimethyl tert-butyl ether of 
cis-7-[2.alpha.-hydroxy-5-(3-hydroxy-4,4-dimethyloctyl)cyclopentyl]-5-hept 
enoic acid has .nu..sub.max.sup.film 3350, 3260 cm.sup.-1. 
Further examples of the compound of formula 11 are listed in Table XII. In 
each case the requisite starting material of formula 9 is noted by the 
example in which it is prepared. 
TABLE XII 
__________________________________________________________________________ 
Wittig Reagent of 
Formula 
No. of Example in Which 
##STR11## 
Starting Material of 
(CH.sub.2).sub.m COOR.sup.7 Br.sup.- 
Example 
Formula 9 is Prepared 
m R.sup.7 Product: 
__________________________________________________________________________ 
176 143 3 H cis-7-[2.alpha.-hydroxy-5-(3- 
hydroxy-4-propylheptyl)- 
cyclopentyl]-5-heptenoic 
acid 
177 144 2 H cis-6-[2.alpha.-hydroxy-5-(4- 
ethyl-3-hydroxynonyl)- 
cyclopentyl]-4-hexenoic 
acid 
178 145 1 H cis-5-[2.alpha.-hydroxy-5-(4,4- 
dimethyl-3-hydroxy-1- 
decyl)cyclopentyl]-3- 
pentenoic acid 
179 146 2 CH.sub.3 
cis-6-[2.alpha.-hydroxy-5-(4- 
ethyl-3-hydroxy-4-methyl- 
decyl)cyclopentyl]-4- 
hexenoic acid methyl ester 
180 147 3 H cis-7-[2.alpha.-hydroxy-5-(3- 
hydroxy-4-methyl-4- 
propylheptyl)cyclopentyl]- 
5-heptenoic acid 
181 148 2 C.sub.2 H.sub.5 
cis-6-[2.alpha.-hydroxy-5-(3- 
hydroxy-4,4-dipropylnonyl)- 
cyclopentyl]-4-hexenoic 
acid ethyl ester 
182 150 3 H cis-7-[2.alpha.-hydroxy-5-(4- 
ethyl-3-hydroxy-3-methyl- 
heptyl)cyclopentyl]-5- 
heptenoic acid 
183 151 2 n-C.sub.3 H.sub.7 
cis-6-[2.alpha.-hydroxy-5-(3- 
ethyl-3-hydroxy-4-pro- 
pylnonyl)cyclopentyl]-4- 
hexenoic acid propyl ester 
184 152 1 H cis-5-[2.alpha.-hydroxy-5-(4- 
ethyl-3-hydroxy-3-propyl- 
decyl)cyclopentyl]-3-pente- 
noic acid 
185 153 2 CH.sub.3 
cis-6-[2.alpha.-hydroxy-5-(3- 
ethyl-3-hydroxy-4-methyl- 
heptyl)cyclopentyl]-4- 
hexenoic acid methyl 
ester 
186 154 3 H cis-7-[2.alpha.-hydroxy-5-(3- 
hydroxy-3,4-dimethylnon- 
yl)cyclopentyl]-5-hexenoic 
acid 
187 155 2 H cis-6-[2.alpha.-hydroxy-5-(3,4- 
diethyl-3-hydroxyoctyl)- 
cyclopentyl]-4-hexenoic 
acid 
188 156 1 CH.sub.3 
cis-5-[2.alpha.-hydroxy-5-(3- 
hydroxy-4-methyldecyl)- 
cyclopentyl]-3-pentenoic 
acid methyl ester 
__________________________________________________________________________ 
EXAMPLE 189 
cis-7-[2-(3-hydroxy-4,4-dimethyloctyl)-5-oxocyclopentyl]-5-heptenoic acid 
(11; R.sup.2, R.sup.6 and R.sup.7 = H, R.sup.4 and R.sup.5 = CH.sub.3, X 
and Y = O, Z = CH.sub.2 CH.sub.2, m = 3 and n = 3) 
To a solution of 
cis-7-{2.alpha.-hydroxy-5-[3-(dimethyl-tert-butylsilyloxy)-4,4-dimethyloct 
yl]cyclopentyl}-5-heptenoic acid (0.817 g), described in Example 175, in 
acetone (10 ml), cooled to -10.degree., 0.75 ml of Jones' reagent [chromic 
acid in acetone containing a trace of sulphuric acid, see E. R. H. Jones 
et al., J. Chem. Soc., 2548 (1953)] is added. After stirring for 10 
minutes the excess reagent is destroyed with methanol. The reaction 
mixture is diluted with water and extracted with ether. The extract is 
washed with water, dried (Na.sub.2 SO.sub.4) and the solvent removed to 
yield 
cis-7-{2-[3-(dimethyl-tert-butylsilyloxy)-4,4-dimethyloctyl]-5-oxocyclopen 
tyl}-5-heptenoic acid, .nu..sub.max.sup.film 1730, 1710 cm.sup.-1. 
The latter compound is deprotected by treatment with p-toluenesulfonic acid 
in aqueous methanol according to the procedure of Example 175 to give the 
title compound .nu..sub.max.sup.film 3470, 1730, 1710 cm.sup.-1. 
In the same manner but replacing 
cis-7-{2.alpha.-hydroxy-5-[3-(dimethylisopropylsilyloxy)-4,4-dimethyloctyl 
]cyclopentyl}-5-heptenoic acid by the appropriate compound of formula 11 in 
which X and Y are hydroxy and hydrogen, respectively, other corresponding 
compounds of formula 11 in which X and Y are oxo are obtained. Note 
protection of the hydroxyl on the side chain is not required when it is a 
tertiary alcohol (i.e., R.sup.6 = lower alkyl). 
For example, in the same manner, but replacing 
cis-7-{2.alpha.-hydroxy-5-[3-(dimethylisopropylsilyloxy)-4,4-dimethyloctyl 
]cyclopentyl}-5-heptenoic acid, with 
cis-7-{2.alpha.-hydroxy-5-[3-(dimethylisopropylsilyloxy)octyl]cyclopentyl} 
-5-heptenoic acid, described in Example 175, 
cis-7-[2-(3-hydroxyoctyl)-5-oxocyclopentyl]-5-heptenoic acid, nmr 
(CDCl.sub.3) .delta. 0.9 (t, J = 5, 3H), 3.7 (m, 1H), 5.42 (m, 2H), 6.6 
(s, 2H), is obtained. 
Likewise, replacement with 
cis-7-[2.alpha.-hydroxy-5-(3-hydroxy-3-methyloctyl)cyclopentyl]-5-heptenoi 
c acid, described in Example 175 gives 
cis-7-[2-(3-hydroxy-3-methyloctyl)-5-oxocyclopentyl]-5-heptenoic acid, nmr 
(CDCl.sub.3) .delta. 0.9 (t, J = 5, 3H), 5.42 (m, 2H), 6.5 (s, 2H). 
Furthermore if desired a compound of formula 11 (R.sup.6 = H) may be 
separated into its two epimers with respect to the asymmetric carbon atom 
bearing the hydroxy group. This separation is effected preferably by 
converting the aforementioned compound to its corresponding methyl ester 
using methanol in the presence of a acid catalyst, for example, 2% 
perchloric acid, and subjecting the ester to chromatography on S.O.sub.2 
use benzene-ethyl acetate (9:1) as eluant. In this manner the epimers are 
separated. These isomers are arbitrarily designated as isomers A (least 
polar isomer) and isomer B (more polar isomer); the polarity being 
determined by the order in which they are eluted. Thereafter the epimers 
may be hydrolyzed with 5% sodium hydroxide in aqueous methanol for 15 
minutes at 30.degree. to 40.degree. to give the corresponding acid. 
For example, by the preceding method the epimers of the title compound are 
obtained, 
Isomer A has .nu..sub.max.sup.film broad hydroxyl, 1725-1730 cm.sup.-1, and 
Isomer B has .nu..sub.max.sup.film broad hydroxyl, 1725-1730 cm.sup.-1. 
The corresponding methyl esters of the preceding Isomers A and B have the 
following characteristics: 
Isomer A, a racemate of methyl 
cis-7-[2-(3-hydroxy-4,4-dimethyloctyl)-5-oxocyclopentyl]-5-heptenoate, has 
Rf of about 0.47 on thin layer plates of silica gel when using ethyl 
acetate-benzene (1:4) as the mobile phase. 
Isomer B, a second racemate of methyl 
cis-7-[2-(3-hydroxy-4,4-dimethyloctyl)-5-oxocyclopentyl]-5-heptenoate, has 
Rf of about 0.37 on thin layer plates of silica gel when using ethyl 
acetate-benzene (1:4) as the mobile phase.