US3922289A

US3922289A - Trans-prostaglandin-like compounds and methods

Info

Publication number: US3922289A
Application number: US335432A
Authority: US
Inventors: John W Patterson; John H Fried
Original assignee: Syntex USA LLC
Current assignee: Syntex USA LLC
Priority date: 1973-02-23
Filing date: 1973-02-23
Publication date: 1975-11-25
Anticipated expiration: 1992-11-25

Abstract

Trans-prostaglandin-like compounds wherein the chain attached to the C-3 carbon atom of the cyclopentane ring is of various lengths and the chain attached to the C-2 carbon atom of the cyclopentane ring contains a furan ring, a thiophene ring or sulfur.

Description

United States Patent 1w:

Patterson et al.

TRANS-PROSTAGLANDIN-LIKE COMPOUNDS AND METHODS Inventors: John W. Patterson, Mountain View;

John H. Fried. Palo Alto. both of Calif.

Assignee: Synte x (U.S.A.) Inc.. Palo Alto v Calif.

Filed: Feb. 23, 1973 Appl. No.: 335,432

U.S. Cl. 260/347.3; 424/275; 424/285: 260/332.2 A: 260/3322 C: 260/3322 R; 260/347.4. 260/468 D: 260/468 J; 260/5l4 D; 260/514 J Int. Cl.'......... C07D 307/34 Fleld of Search 260/3473. 347.4

[ Nov. 25, 1975 [56] Reierences Cited OTHER PUBLICATIONS Apsimon. The Total Synthesis of Natural Products. Vol. I. pp. l32-l34. Wiley-lntersciencc NY (1973).

Primary Examiner-John D. Randolph Attorney, Agent or Firm-Gerard A. Blaularh; William B. Walker 21 Claims. No Drawings 1 TRANS-PROSTAG LAN DIN-LIKE COM POUN DS AND METHODS SUMMARY OF THE INVENTION Amongst the novel (dl) mixtures of compounds, disomeric and l-isomeric compounds of our invention are those represented by the formulas:

'/ (CH ClI on on (I) (II) wherein R is -H or CH,; m is a whole integer from zero through eight;

Ais

O l -cn D (cs co a BACKGROUND OF THE INVENTION l. The Invention This invention relates to prostaglandin-Iike compounds.

More particularly, it relates to trans-prostaglandinlike compounds of Formulas (l) and (II) above wherein the chain attached to the C-3 carbon atom ofthe cyclopentane ring is of various length and the chain attached to the C-2 carbon atom of the cyclopentane ring contains a furan ring, a thiophene ring or sulfur. The nomenclature used for the compounds of Formulas (I) and (II) is discussed more fully below.

2. The Prior Art Prostaglandins have clasically been described as chemically related -carbon chair hydroxy fatty acids having the basic skeleton of prostanoie acid:

9 8,. e 4 I 2 coon IOOVV I 12 1 16\ ia\/2o Prostanoic Acid The prostaglandins. as described immediately above. havinga hydroxy group at the G] 1 position and a keto group at the C-9 position are known as the POE series, those having a hydroxy! group in place of the keto group are known as the PGF series and are further designated by an or or B suffix to indicate the configuration of the hydroxyl group at said position. The natural compounds are the a-hydroxy substituted compounds. They may contain different degrees of unsaturation in the molecule, particularly at C-5. C-l3 and 017. the unsaturation is also indicated by a suffix. Thus, for example, PGE refers to a prostanoic acid having a trans olefin bond at the l3-position. For a review on prostaglandins and the definition of primary prostaglandins. see, for example, S. Bergstrom, Recent Progress in Hormone Research. 22, pp. 153-175 (I966) and Science, I57. p. 382 (I967) by the same author.

Prostaglandins are widely distributed in mammalian tissues and have been isolatedfrom natural sources in very small amounts. In addition, a number of the natural occurring prostaglandins have been prepared by chemical synthesis; note, for example, J. Am. Chem. Soc., 91, p. 5675 (I969), J. Am. Chem. Soc., 92, p. 2586 (I970) and J. Am. Chem. Soc., 93, pp. l489-l493 (I971) and references cited therein, W. P. Schneider et al., J. Am. Chem. Soc.. 90, p. 5895 (I968), U. Axen et al., Chem. Commun., p. 303

(I969), and W. P. Schneider, Chem. Commun., p. 304 (1969).

Because of the remarkable range of biological and pharmacological properties exhibited by this family of compounds, a great deal of interest has focused upon such compounds and, accordingly, we have discovered novel trans-prostaglandin-like compounds wherein the chain attached to the C-3 carbon atom of the cyclopentane ring is of various lengths and the chain attached to the C-2 carbon atom of the cyclopentane ring contains a furan ring. a thiophene ring or sulfur.

FURTHER DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS As discussed above, prostaglandins have for the most part classically been named using as the base for such nomenclature the 20-carbon chain hydroxy fatty acids having the basic skeleton of prostanoic acid. For the naturally occurring prostaglandis this nomenclature has sufficed.

However, in view of the lengthening and shortening of the side chains (and the increased complexity of the side chains) attached at the C-2 and 03 carbon atoms of the cyclopentane nucleus. as well as other substituents attached to the cyclopentane nucleus. it is readily apparent that a more systematic nomenclature must be pairs, i.e.. a mixture of the d and I isomers, or the indiuscd. vidual d-isomers and l-isomers. Thus, the (dl) pairs are Therefore, in the description which follows. the coma mixture of the d and I isomers. For examp e. the pounds will be named as substituted cyclopentanes in pounds of For u are ly a mixture Of which the cyclopentane nucleus will be numbered as 5 follows:

0 R )g; A a 10. .(cu ctt Thus (dl)-PGF. having the structure H and its mirror image, I 2 4 3 OH 1 (A) O B A would be systematically named (dl)-2a-(6-carboxy- (CH CH hex-l-yl)-3B-(3a-hydroxy-trans-l-octenyl)-4a- 2 3 hydroxy-l-oxocyclopentane.

According to already established convention in the art. the chain attached to the C-3 carbon atom of the (I cyclopentane ring of naturally occurring prostaglandins 1 having a trans double bond nearest to said C-3 carbon atom is depicted by structural configuration formula thusly The individual isomers are, of course, represented by Formulas (l) and (ll) individually.

@ To avoid undue prolixity, only one isomer. namely (CH CH that-analogous to that depicted by Formula (I), rather W 2 4 3 than Formula (A,). will be shown, it being understood that in the specification and claims the mirror images 40 for the (dl) mixtures and the individual d-isomers and l-isomers are also encompassed thereby.

It is to be further understood that encompassed (B) within this invention are racemic mixtures and diastereomeric mixtures. It is to be understood and will be apparent to those The novel compounds of our invention and novel skilled in the art that the compounds of Formulas (l) processes for their production are illustratively repreand (II) above and (I) through (7) below exist as (dl) sented by the following reaction sequence:

OAc O R R Chi (CH CH (1) OS1(CH3)2C (CH3) 3 (CH CH osi. (CH3) c (CH3) 3 (CH en OH 3 R 5 (CH Ci-I In the above flow shcct Formula (4) is a composite of 0 2 Formulas (4'). (4') and (4'); and N CO R R is -H or --CH,; 65

m is a whole integer from zero through eight; S I Ac is acetyl; 2 A is 2 H CO R or p is a whole integer from one through six; A is in which R and p are defined as above; A is in which R and p are defined as above; A is --CH,S(O).(CH|),CO|R' in which q is a whole integer from zero through two; and

in which R, n, q and p are defined as above; and the wavy line represents the aor B- configuration or mixtures thereof; and in Steps (d) [(4) (4')] and (e) [(4) (4')] A is --CH,S(CH,),CO,R (in which R and p are defined as above) only.

The term "alityl of from one through ten carbon atoms" includes both straight and branched chain alkyl groups; and the dotted line I represents the a-configuration.

The reaction steps and definitions given above represent an overall view of the methods used for the preparation of the novel compounds of this invention. For a more detailed explanation of the reaction step reference can be made to the examples themselves and the formulas and definitions preceding each of the examples.

in carrying out the processes of our invention, the compounds of Formula (I) are, according to step (a), reacted with a freshly prepared copper(l) lithium reagent of Formula 2 (defined more fully in Example i at a temperature of l00 to 20C, preferably -90 to 0C. in ether (diethyl ether), methyl ethyl ether, and the like, for from 5 minutes to 24 hours. preferably from ten minutes to one hour; .followed by the addition of acetic anhydride and maintaining a temperature of -60 to 20C, preferably -40 to r-25C. for from 5 to 60 minutes to yield the compounds of Formula (2) which are then removed from the reaction mixture according to methods known in the art.

The compounds of Formula (2) are, according to step (b). treated with lithium at a temperature of -90 to -33C, preferably -80 to 60C, for from 5 to 30 minutes, followed by treatment with trimethylborate at a temperature of to .*-50C, for from l0 to 50 minutes, and the addition of chloro compounds of Formula A (defined more fully in Example 2) at a temperature of 70 to 40C, preferably -60 to 50C, for from l0 to 60 minutes, to yield the compounds of For mula (3). The conversion of the compounds of Formula (2) to Formula (3) can be carried out in a variety of suitable inert organic solvents, e.g., tetrahydrofuran, l,2-dimethoxy ethane, diglyme, dioxane, preferably tetrahydrofuran, or mixtures thereof.

The compounds of Formula (3) are. according to step (c), treated under mild acidic conditions with an acid, for example, acetic, dichloroacetic, and the like. preferably acetic acid, at a temperature of ID to 50C, preferably 20 to 30C, for from 10 to 30 hours, preferably l2 to 18 hours. to yield the compounds of Formula (4). Advantageously, this reaction is carried out in the presence of an inert organic solvent, e.g.. tetrahydrofuran, dioxane, methanol, and the like, preferably tetrahydrofuran. The isomeric mixtures obtained are separated by column or thin-layer chromatography.

The compounds of Formula (4), wherein A is CH,S(CH,),CO,R only. are, according to step (d), oxidized with one molar equivalent of sodium metaperiodate per mole of compound of Formula (4) to obtain the compounds of Formula (4). Using two molar equivalents of sodium metaperiodate per mole of compounds of Formula (4), wherein A is -CH,S(CH,)- ,CO,R only, according to step (e), there is obtained the compounds of Formula (4). The conversion of the compounds of Fonnula (4) to the compounds of Formulas (4) and (4) is carried out in dioxane, aqueous alcohols and the like, preferably aqueous methanol.

The compounds of Formula (4), i.e., the compounds embraced by Formulas (4'), (4) and (4) are, according to step (f) treated with a reducing agent to convert the l-oxocyclopentanes to the l-hydroxycyclopentanes of Formula (5). Suitable reducing agents are sodium borohydride. zinc borohydride. and the like, preferably sodium borohydrlde. and the reaction is carried out in methanol, ethanol, propanol. and the like. preferably methanol. The temperature for this step can vary from l0 to 25C, however, an initial temperature of 0C is preferred. The thus-obtained compounds of Formula (5) are then separated by column or thin-layer chrom atography.

The thus-obtained compounds of Formulas (4) and (5) are hydrolyzed according to step (g). to obtain their corresponding free acids of Formulas (6) and (7). The ester hydrolysis reaction is carried out biologically, preferably enzymatically, using a pancreatic lipase preparation to cleave the ester group, thus yielding the free acids. The carboxylic acids are purified by column or thin-layer chromatography.

it is to be understood that any of the isomeric mixtures obtained can be separated and/or purified by any suitable separation and/or purification procedure. such as. for exam ple, extraction. filtration. distillation. evaporation. crystallization. column chromatography, thinlayer chromatography. and the like. Specific illustrations of typical separation and/or purification procedures can be had by reference to the preparations and examples described herein below. Other equivalent separation and/or purification procedures could. of course. also be used.

However. as described above it is preferred to separate the isomeric mixtures at a relatively early stage, i.e.. following the conversion of the compounds of Formula (3) to (4). step (c). and also subsequent to the conversion of the compounds of Formula (4) to Formula (5). step (f).

As noted above. the compounds of Formulas (l) and (ii). wherein R is H. can also be administered in the form of their pharmaceutically acceptable salts. i.e.. salts which do not significantly adversely affect the pharmaceutical properties of the parent compounds. Suitable pharmaceutically acceptable salts include. for example. the salts of sodium. potassium. aluminur calcium. iron, magnesium. ammonia. maieate. benz ate. acetate and the like. The salts can be prepared according to conventional procedures and. for example. can be conveniently prepared by treating the corresponding free acids with about one molar equivalent of a pharmaceutically acceptable base per molar equivalent of free acid. Suitable pharmaceutically acceptable bases include. for example, sodium hydroxide, potassium hydroxide, sodium carbonate. potassium carbonate. sodium bicarbonate. ammonium hydroxide. calcium hydroxide, trimethylamine. triethylamine. tripropylamine. fi-(dimethylamino)ethanol. B-(diethylamino)ethanol. arginine, lysine. caffeine. procaine and the like. Typically the reaction is conducted in an aqueous solution, alone or in combination with an inert, water miscible organic solvent, at a temperature of are also useful in controlling or palliating hypertension in mammals and further exhibit central nervous system depressant activity. in mammals. and are useful as sedatives. in addition. the compounds are useful for inducing labor. in pregnancy. and for inducing menses to correct or reduce menstrual abnormalities. The compounds also possess anti-fertility properties. In addition. they exhibit anti-inflammatory activities and are thus useful as anti-inflammatory agents.

These compounds can be administered in a wide variety of dosage forms. either alone or in combination with other phsnnaceutically compatible medicaments. in the form of pharmaceutical compositions suited for oral or parenteral administration or inhalation in the case of bronchodilators. The compounds are typically administered as pharmaceutical compositions consisting essentially ofthc compounds and/or salts. of the invention, and a pharmaceutical carrier. The pharmaceutical carrier can be either a solid material. liquid. or aerosol. in which the compound and/or salt is dissolved. dispersed or suspended. and can optionally contain small amounts of preservatives and/or pH-buffcring agents. Suitable preservatives which can be used include. for example. benzyl alcohol and the like. Suitable buffering agents include. for example. sodium neetate and pharmaceutical phosphate salts and the like.

The liquid compositions can. for example. be in the form of solutions. emulsions. suspension. syrups. or elixirs. The solid compositions can take the form oftablets. powders. capsules. pills or the like. preferably in unit dosage forms for simple administration or precise dosages. Suitable solid carriers include, for example. pharmaceutical grades of starch. lactose. sodium saccharin. talcum. sodium bisulfite and the like.

For inhalation administration. the compounds can. for example. be administered as an aerosol comprising the compounds or salts in an inert propellant together with a cosolvent (e.g.. ethanol) together with optional preservatives and buffering agents. Additional general information concerning the inhalation administration of aerosols can be had by reference to U.S. Pat. Nos. 2.969.691 and 3.095.355.

The compounds are typically administered in dosages of about from 0.1 to 10 mg. per kg. of body weight. The precise effective dosage will. of course. vary depending upon the mode of administration, condition being treated, and host.

A further understanding of the invention can be had from the following non-limiting preparations and examples. Also. where necessary. preparations and examples are repeated to provide starting materials for subsequent preparations and examples. The term ambient or room temperature refers to about 20C.

The symbol (t) appearing above the double bond in the formulas shown in Preparation 1 and Example l denotes the trans configuration.

Preparation l [Q],Cu(l)Li wherein [Q] is in which m is a whole integer from zero through eight; and

the wavy line l represents the aor B-configurations or mixtures thereof.

A. A solution of 210 ml. of hexanoyl chloride in 750 ml. of carbon tetrachloride is cooled in an ice bath. 200 G. of aluminum chloride is added over a 30 minute period. while acetylene is bubbled through the solution. After 30 minutes. the ice bath is removed and the acetylene addition is continued for six hours. The reaction mixture is poured onto 56 kg. of ice. extracted twice with 500 ml. of methylene chloride and the combined organic layers washed successively with 500 ml. of water and 500 ml. of saturated sodium bicarbonate. The solution is then dried over sodium sulfate. concentrated in vacuo. followed by distillation to yield trans-lchlorooct-l-en-S-one.

a. Similarly. substituting other alkanoyl chlorides for example.

butanoyl chloride. octanoyl chloride. or decanoyl chloride,

for hexanoyl chloride. in the procedure of Preparation HA). is productive of the Corresponding trans-lchloroalk-l-en-Lone. for example.

transl -chlorohexi -en-3 on e. trans-l-chlorodec-i-en-3-one. and transl -chlorododec l -e n-3- one.'

(B) A mixture containing l9 gJoftrans-l -chloroocttransl -chlorohexl -en-3-one. trans-l -chlorodecl -en-3-one, or transl -chlorododecl -en-3 one,

for trans-l-chlorooct l-en-3-one. in the procedureof Preparation 1(8), is productive of the corresponding trans-l-iodoalk l-en-li ones. for example.

trans-'1-iodohex-l-en-3-one. trans-l-iododec-l -en-3-one, and transl -iodododeci -en-3-one.

C. The residue consisting oftrans-l-iodooct-l-en- 3-one. obtained in Preparation -l(B). is then dissolved in 150 ml. of diethyl ether and slowly added over a 30 minute period to a suspension containing 2.5 g. of lithium aluminum hydride in 200 ml. of diethyl ether, and the resulting'mixture is stirred at room temperature under nitrogen for 12 hours. The reaction mixture is then worked up by the sequential dropwise addition of 3 ml. of water. 3 ml. of 15% aqueous sodium hydroxide and 9 ml. of water. The mixture is then filtered and the resulting filtered cake is washed with t'wo 50 ml. portions of diethyl ether. The combined filtrate and diethyl ether washings-- are dried over potassium-"carbonate. then filtered. and the resulting filtrate evaporated to yield a residue of (dl)-trans-l iodooct-l-en-3-ol.

a. Similarly, substituting other trans-l-iodo-allt-l-en- 3-ones, for example,

trans-l-iodohexl-en-3one, v transl -iododec l en-3-one, and transi -iodododecl -en-3-one.-

for transl -iodooct-l -en-3 -one. 1 in I the procedure of Preparation NC). is productive of the corresponding dl)-trans-l-iodoallt l-en-5-ols. for example.

(dl)-trans-l-iodohex-i-en-3-ol. I (dl)-trans-l-iododec-l-en-3-ol. and (dl)-transl iodod'odec-l '-en-3-ol.

D. A mixture of 26.2 g. of (dl)-trans-l-iodooct-l-cn- 3-ol. l4.8 g. of phthalic anhydride and ml. of pyridine are heated at 50C for six hours. The resulting solution is poured into 200 ml. of ice-cold 6N hydrochloric acid'and extracted four times with lOO ml. of ether. The ethereal solution is extracted with 300 ml. of icecold two percent sodium hydroxide. The aqueous solution is washed once with 300 ml. of ether. then acidified with dilute hydrochloric acid and extracted four times with I00 ml. of ether. The ethereal solution is concentrated at reduced pressure to give 20.5 g. of phthalate half ester. This ester is dissolved in 100 ml. of methylene chloride. cooled on an ice bath and treated with a solution of 6 g. of (--)-a-phenethylamine in 50 ml. of methylene chloride. The methylene chloride is evaporated in vacuo and the resulting amine salt is recrystallized repeatedly from acetonitrile. The thusobtained amine salt is hydrolyzed with I00 ml. of l5% sodium hydroxide in methanol at room temperature for 12 hours. The reaction mixture is diluted with 500 ml. of waterand extracted twice with 300 ml. of ether. The ethereal solution is washed with five percent hydrochloric acid. dried over anhydrous sodium sulfate. and the ether removed in vacuo. The residue is then chromatog raphed on 200 g. of silica gel using ether-hexane. and those fractions eluted with 10 to 12% ether-hexane yield 3 g. of 3-(S)-trans-l-iodooct-l-en-3-ol.

a.. Similarly. substituting other (dl)-trans-l-iodoalkl-en-3-ols, for example, i

( dl)- trans i -iodohex-i -en-3-ol. (dl)- trans-l-iododec-l -en-3-ol, and (dl)-transl -iodododec-l -en-3-ol,

for (dl)-trans-l-iodooct l-en-3-ol. in the procedure of Preparation l(D), is productive of the corresponding 3-(S)-trans-l-iodoalk-l-en-3-o|s. for example,

3-(S)-trans-l iodohex-l-en-li-ol, 3(S)-trans-l-iododec-l-en-Zl-ol. and 3-( S )-transl -iodododecl -en3-ol.

E. A mixture of 26.2 g. of (dl)-trans-l-iodooct-l-en- 3-ols, 14.8 g. of phthalic anhydride and 100 ml. of pyridine are heated at 50C. for six hours. The resulting solution is poured into 200 ml. of ice-cold 6N hydrochloric acid and extracted four times with lOO ml. of ether. The ethereal solution is extracted with 300 ml. of icecold two percent sodium hydroxide. The aqueous solution is washed once with 300 ml. of ether. then aciditied with dilute hydrochloric acid and extracted four times with 100 ml. of ether. The ethereal solution is concentrated at reduced pressure to give 20.5 g. of

sodium hydroxide in methanol at room temperature for l2 hours. The reaction mixture is diluted with'300 ml. of ether. The ethereal solution is washed with five percent hydrochlorlc acid. dried over anhydrous sodium sulfate. and the ether removed in vacuo. The residue is then chromatographed on 200 g. of silica gelusing ether-hexane.and those fractions eluted with 10 to l2% ether-hexane yield 3 g. of 3-(R)-trans-l-iodo-octl-en-3-ol.

a. Similarly, substituting other (dl)-trans-l-iodoalkl-en-3-ols, for example.

(dl )-trans-l -iodohex-l-en-3-ols. (dl )-transl -iododecl -en-3-ols. and (dl )-transl -iodododecl -en-3-ols,

for (dl)-trans-l-iodooet-l-en- L], in the procedure of Preparation HE). is productive of the corresponding 3-(R)-trttns-l-lodoalk-l-en-3-ols. for example.

3-( R )-transl -iodohexl -en-3-ol, 3-(R )-transl -iododecl -en-3-ol. and 3-( R )-transl -iodododec-l -ert-3-ol.

F. To a solution of 300 g. of (dl)-trans-l-iodooct-len-3-ol. obtained in Preparation l(C), and 25 g. of imidazole in 50 ml. of N,N-dimethyltormamide is added 18.5 g. of t-butyldimethylchlorosilane and the resulting reaction mixture is stirred under a nitrogen atmosphere for one hour at room temperature. The reaction mixture is then poured into 300 ml. of ether and 200 g. of ice. The ethereal solution is separated and washed twice with 200 ml. of water and 100 ml. of saturated sodium bicarbonate. After drying over sodium sulfate, the ethereal solution is concentrated in vacuo, followed by distillation to yield (dl)-trans-l-iodo-3-t-butyldimethylsiloxyoct-l-ene.

a. Similarly, substituting other (dl)-trans-l-iodoalkl-en-3-ols, prepared in Preparation l(C)(a), for example,

(dl)-trans-l -iodohexl -en-3-ol, (dl)-trans-l-iododec-l-en-3-ol, and (dl)-transl -iodododecl -en-3-ol.

for (dl)-trans-l-iodooct-l-en 3-ol, in the procedure of Preparation HP), is productive of the corresponding dl )-transl -iodo-3-t-butyldimethylsiloxyalkl -enes,

for example,

(dl)-trans-l -iodo-3-t-butyldimethylsiloxyhexl -ene,

( dl )-transl -iodo-3-t-butyldimethylsiloxydecl -ene,

and

(dl )-transl -iod0-3-t-butyldimethylsiloxydodecl -ene.

b. Similarly, substituting the 3-(S)-trans-l-iodoalk-l- 14 c. Similarly, substituting the 3-(R )-transl -iodoalkl en-3-ols, obtained in Preparation HE) and l(E)(a). for example.

3-( R )-transl -iodooetl en-3-ol. 3-(R)-transl -iodohexl -en-3-ol, 3-(R)-trans-l-iododec--en-3-ol. and 3-( R )-transl -iodododecl -en-3-ol.

for (dl)-trans-l-iodooct-l-en-3-ol in the procedure of Preparation l(F) is productive of the corresponding 3-(R)-truns-l-iodo-3-t-butyldimethylsiloxyulk-I-enes. for example,

3-( R )-transl -iodo-3-t-butyldimethylsiloxyoctl -ene,

3-(R )-transl -iodo-3-t-butyldimethylsiloxyhexl -cnc,

3-(R)-transl -iodo-3-t-butyldimethylsiloxydecl -ene,

and

3-(R )-transl -iodo-3-t-butyldimethylsiloxydodecl-ene.

G. 15 Ml. ofa l.5 M n-butyl lithium in hexane solution is admixed to a mixture containing 7.36 g. of (dl) t-rans-l-iodo-3-t-butyldimethylsiloxyoetl -enes, prepared in Preparation l(F), in 8 ml. of hexane at 78C. under an argon atmosphere. The resulting mixture is stirred and maintained at -78C., under argon, for 30 minutes. During this time a second mixture containing 4.4 g. of bistrimethylphosphite copper(l) iodide in 60 ml. of diethyl ether is prepared and maintained under argon and cooled to i78C. At the end of the 30 min utes period, previously referred to, the first mixture is admixed to the second mixture and the temperature of the resulting mixture is brought to -50C. The formation of the (dl) copper(l) lithium reagent having the octene moiety is periodically monitored by a Gilman test [notez Gilman and Sculze,J. Am. Chem. Soc, v. 47,

en-3-ols, obtained in Preparation 1(0) and l(D)(a),

for example,

3-( S )-transl -iodooctl -en-3-ol,

3-( S )-transl -iodohex-l -en-3-ol, 3-(S)-trans-l-iododec-l-en-3-ol, and 3-(S )-transl -iodododeel -en-3-ol,

3-( S )-transl -iod0-3-t-butyldimethylsiloxyoetl -ene, 3 S )-transl -iodo-3-t-butyldimethylsiloyxhexl -ene, 3-( S )-transl -iodo-3-t-butyldimethylsiloxydecl -ene, 3-( S )-transl -iodo-3-t-butyldimethylsiloxydodecl -ene 2002 (l925)], and maintained at 50C. until a negative Gilman test is obtained (about 45 minutes).

a. Similarly, substituting other (dl)-trans-l-iodo-3-tbutyldimethylsiloxyalk-l-enes, prepared in Preparation .1(F)(a), for example,

(dl)-trans-l-iodo-3-t-butyldimethylsiloxyhex-l -ene,

(dl)-transl -iodo-3-t-butyldimethylsiloxydecl -ene,

and

(dl)-transl -iodo-3-t-butyldimethylsiloxydodecl -ene,

for (dl)-trans-l-iodo-3-t-butyldimethylsiloxyoct-l-ene in the procedure of Preparation l(G) is productive of (dl) copper(l) lithium reagents having the respective alkene moieties, for example, hexene, decene and dodecene.

b. Similarly, substituting the 3-(S)-trans-l-iodo-3-tbutyldimethylsiloxyalk-l-enes, obtained in Preparation l(F)(b), for example,

3-(S)-transl -i0do-3-t-butyldimethylsiloxyocz:- l -ene.

3-(S)-transl -iodo-3-t-butyldimethylsiloxyhexl -ene,

3-(S)-transl -iodo-3-t-butyldimethylsiloxydecl -ene,

and

3-(S)-transl -iodo-3-t-butyldimethy lsiloxydodecl-ene,

for (dl)-trans-l -iodo-3-t-butyldimethylsiloxyoctl -enes in the procedure of Preparation H6) is productive of 3-(S) copper(l) lithium reagents having the respective 15 alkenc moieties, for example, octene, hexene, decene and dodecene.

c. Similarly, substituting the 3-(R)-trans-l-iodo-3-tbutyldimethylsiloxyallt-l-enes, obtained in Preparation 1(F)(e), for example,

3 R )-transi -iodo-3-t-butyldimethylsiloxyoetl -ene, 3 R )-transl -iodo3-t-butyldimethylsiloxyhex-i -ene,

3 R )-trans-l -iodo-3-t-butyldimethylsiloxydecl-ene, and 3 R )-trans i -iodo-3-t-butyldimethylsiloxydodecl -ene,

i or (dl )-transl -iodo-3-3-t-butyldimethylsiloxyoctl-enes in the procedure of Example 1(0) is productive of 3-(R) copper(l) lithium reagents having the respective alkene moieties, for example, octene, hexene, decone and dodecene Preparation 2 ClCH 2 2 U C R wherein R is alkyl of from one through ten carbon atoms; and

n is a whole integer from zero through four.

A. 11.2 G. of 3-(fur-2-yl)propanoic acid is added, with stirring, to 93 ml. of a solution of tetramethylammonium hydroxide. The water is then evaporated under reduced pressure from the resulting solution to give a semi-solid residue which is then suspended in 75 ml. of anhydrous N,N-dimethylformamide and stirred vigorously while 9.0 ml. of methyl iodide is added over a five minute period. The reaction mixture is stirred overnight and poured into 300 ml. of water. The thusobtained aqueous solution is extracted with four 100 ml. portions of ether. The ether extracts are combined and washed successively with 200 ml. of water and 200 ml. of saturated sodium chloride, and dried over anhydrous sodium carbonate. The ether is removed in vacuo and the thus-produced oil distilled to yield 13.37 g. of 45 methyl 3-(fur-2-yl)propanoate.

a. Similarly, substituting 2-furoic acid, 2-(fur-2-yl)acetie acid. 4-(fur-2-yl)butanolc acid, and 5-(fur-2-yl)pentanoic acid,

for 3-(fur-2-yl)propanoic acid, in the procedure of Preparation 2(A), is productive of methyl (fur-Z-ylJcarboxylate,

methyl 2-(fur-2-yl)scetate,

methyl 4-(fur-2-yl)butanoate, and

methyl 5-(fur-2-yl)pentanoate, respectively.

B. 3.68 Ml. of N,N-dimethylformamide is cooled on an ice bath and treated with 4.6 ml. of phosphorous oxychloride. The resulting solution is stirred at 5C for 20 minutes under a nitrogen atmosphere. 7.3 G. oi'methyl 3-(fur-2-yl)propanoate is then added and the resulting solution is stirred for one hour at 5C and then for two hours at room temperature. The reaction mixture is poured onto 200 g. of ice, 4 g. of potassium carbonate is added and the resulting solution is then extracted twice with l00 ml. of ether. The combined ethereal solutions are dried over anhydrous sodium sulfate and the solvents removed in vacuo to yield 4.7l g. of methyl 3- (5-formyliur-2-yl)propanoate.

a. Similarly, substituting methyl (fur-2-yl)carboxylate, methyl 2-(fur-2-yl)acetate, methyl 4-(fur-2-yl)butanoate, and methyl S-(fur-Z-yDpentanoate,

for methyl 3-(fur-2-yl)propanoate, in the procedure of Preparation 2(8), is productive of methyl (S-formylfur-Z-yl)carboxylate,

methyl 2-(5-formylfur-2-yl)acetate,

methyl 4-(5-formylfur-2-yl)butanoate, and

methyl 5-(5-formylfur-2-yl)pentanoate, respectively.

b. In like manner, substitution of other alkanotes of the w-(fur-Z-yl) compounds, prepared in Preparation 2(A) (b), in the procedure of Preparation 2(8) is productive of the corresponding alkyl esters having from two to ten carbon atoms, e.g. ethyl, propyl, isopropyl. octyl, and the like, of the respective w-(S-formylfur- 2-yl) compounds.

C. A solution of 4.l0 g. methyl 3-(5-formylfur-2- yl)propanoate in 25 ml. of methanol is cooled on an ice bath and treated with 258 mg. of sodium borohydride. After ten minutes the solution is poured into ice water and extracted twice with ml. of ether. The combined ethereal layers are dried over sodium sulfate and concehtrated in vacuo to yield 3.08 g. of methyl 3-(5- hydroxymethylfur-2-yl)propanoate.

a. Similarly, substituting methyl (5-formylfur-2-yl)carboxylate, methyl 2-(5-fonnylfur-2-yl)acetate, methyl 4-(S-formylfur-2-yl)butanoate, and methyl 5-(5-forrnylfur-2-yl)pentanoate,

for methyl B-(S-t'ormylfur-Z-yl)propanoate, in the procedure of Preparation 2(C), is productive of methyl (5-hydroxymethylfur-2-yl)carboxylate,

methyl 2-(S-hydroxymethylfur-Z-yl)acetate,

methyl 4-(S-hydroxymethylfur-Z-yl)butanoate, and

methyl 5-(5-hydroxymethylfur-2-yl)pentanoate,

spectively.

b. In like manner, substitution of other alltyl esters of the w-(5-formylfur-2-yl) compounds, prepared in Prep- 17 ride and 2.75 g. of triphenylphosphene in i ml. of N,N-dimethylformamide is stirred at room temperature for three hours. The N,N-dimethylformamide is then removed in vacuo and the resulting residue chromatographed on 200 g. of silica gel, eluting with ether-hexane. Those fractions eluted with l0% ether-hexane are combined and the solvent evaporated to yield methyl 3-(5-chloromethylfur-2-yl)propanoate. -thiaalka. Similarly, substituting methyl (-hydroxymethylfur-2-yl)carboxylate,

methyl 2-(5-hydroxymethylfur-2-yl)acetate,

methyl 4-(S-hydroxymethylfur-Z-yl)butanoate, and

and

methyl 5-(S-hydroxymethyifur-Z-yl)pentanoate.

for methyl 3-(S-hydroxymethylfur-Z-yl)propanoate, in the procedure of Preparation 2(D), is productive of methyl (S-chloromethylfur-Z-yl)carboxylate,

methyl 2-(S-chloromethylfur-Z-yl)acetate.

methyl 4-(S-chloromethylfur-Z-yl)butanoate, and

methyl $-(5-chloromethylfur-2-yl)pentanoate, respectively.

b. in like manner, substitution of other alkyl esters of the m-(5-hydroxymethylfur-2-yl) compounds, prepared in Preparation 2(C) (b), in the procedure of Preparation 2(D) is productive of the corresponding alkyl esters having from two to ten carbon atoms, e.g. ethyl, propyl, isopropyl, octyl, and the like, of the respective ce-($-chloromethyifur-2-yl) compounds.

Preparation 3 2 clca OM1 co a wherein three 100 ml. portions of ether. The ether extracts are combined and washed successively with 300 ml. of water and 300 ml. of saturated sodium chloride and dried over anhydrous sodium carbonate. The ether is removed in vacuo and the resulting oil distilled to yield 13.24 g. of methyl 3-(thien-2-yl)propanoate.

a. Similarly, substituting 2-thiophene carboxylic acid. 2-(thien-2-yl)acetic acid, 4-(thien-2-yi)butanoic acid. and 5-(thien-2-yl)pentanoic acid,

for 3-(thien-2-yl)propanoic acid, in the procedure of Preparation 3(A), is productive of 18 methyl (thien-2-yl)carboxylate, methyl 2-(thien-2-yl)acetate, methyl 4-(thien-2-yl)butanoate. and methyl S-(thien-Z-yl)pentanoate.

b. in like manner, substitution of other alkyl iodides for methyl iodide, and using the appropriate starting acid [of Preparation 3, parts (A) and (A) (a)] in the procedure of Preparation 3( A) is productive of the corresponding alkyl esters having from two to ten carbon atoms, e.g. ethyl, propyl, isopropyl, octyl, and the like, of the respective ai-(thien-2-yl) compounds.

B. I g. of methyl 3-(thien-2-yl)propanoate and 50 ml. of concentrated hydrochloric acid are placed in a 600 ml. beaker andcooled to -l0C in a dry-ice/acetone bath. A stream ofhydrogen chloride gas is passed into the reaction mixture with vigorous stirring and when the temperature reaches 0C, l25 ml. of 37% formaldehyde is added at rate such that the temperature remains below 5C. After the addition of the formaldehyde, the rcaction mixture is extracted with three 200 ml. portions of ether. The ether extracts are combined, washed successively with 200 ml. of water, 200 ml. of saturated sodium bicarbonate and dried over anhydrous sodium sulfate. The ether is evaporated under reduced pressure and the residue remaining is distilled to give 42 g. of methyl 3-(S-chloromethylthien-Z- yl)propanoate.

a. Similarly, substituting methyl (thien-2-yi)carboxylate, methyl 2-(thien-2-yl)acetate, methyl 4-(thien-2-yl)butanoate, and methyl 5-(thicn-2-yl)pentanoate,

for methyl 3-(thien-2-yl)propanoate, in the procedure of Preparation 3(8), is productive of methyl (5-chloromethylthien-2-yl)carboxylate, methyl 2-(S-chloromethyithien-Z-yl)acetate, methyl 4-(5-chloromethylthien-2-yl)butanoate, and methyl 5-(5-chloromethylthien-2-yl)pentanoate.

b. in like manner, substitution of other alkyl esters of the (thien-Z-yl) compounds, prepared in Preparation 3(A) (b), in the procedure of Preparation 3(8) is productive of the corresponding alkyl esters having from two to ten carbon atoms, e.g. ethyl propyl, isopropyl, octyl and the like, of the respective m-(S-chloromethylthien-Z-yl) compounds.

Preparation 4 CICH,S(CH,),CO,R' wherein R, is alkyl of from one through ten carbon atoms; and

p is a whole integer of one through six.

(A) A mixture of I00 ml. of methanol, l25 ml. of chloroform, 10 drops of concentrated sulfuric acid and i0 g. of 4,4'-dithiadibutanoic acid is heated on an oil bath while lOO ml. of chloroform-methanol-water azeotrope is allowed to distill out over a 2 hour period. The reaction mixture is cooled to room temperature, washed with ml. of saturated sodium bicarbonate, dried over sodium sulfate and concentrated, followed by distillation at reduced pressure to yield dimethyl 4,4'-dithiadibutanoate.

a. Similarly, substituting 2.2'-dithiadiacene acid. 3.3'-tlithiadipropionie acid, 5.5'-dithiadipentanoie acid. 6,6'-dithiadihexanoic acid. and 7,7-dithiadiheptanoic acid. for 4.4'-dithiadibutanoic acid, in the procedure of Preparation 4(A). is productive of. dimethyl 2,2'-dithiadiacetatc. dimethyl 3.3'-dithiadipropunoate, dimethyl 5.5'-dithiadipentanoate. dimethyl 6,6'-dithiadihexanoate. and dimethyl 7.7'-dithiadiheptanoate.

b. In like manner. substitution of other alkanols for methanol, and using the appropriate starting acid [of Preparation 4. parts (A) and (A) (a)] in the procedure of Preparation 4(A) is productive of the corresponding dialkyl esters having from two to ten carbon atoms. e.g.. ethyl, propyl, isopropyl. octyl, and the like. of the respective w,w'-dithiodialkanoates.

B. A solution of 26.7 g. of dimethyl 4,4- dithiadibutanoate. prepared in Preparr." 4(A). in ml. of dry carbon tetrachloride is cooled to 35C and treated with 7.l g. of chlorine. The reaction mixture is stirred at -35C for 30 minutes to yield an orange solution of methyl 4-ehlorosulfenylbutanoate, which is maintained at -35C, while a solution of approximately 0.1 1 moles of diazomethane in 200 ml. of dry ether is added. The reaction mixture is then allowed to warm to room temperature for 30 minutes and the solvent removed in vacuo. The resulting residue is distilled at reduced pressure to yield methyl 6-chloro-5-thiahexanoate.

a. Similarly, substituting, dimethyl 2,2'-dithiadiaeetate,, dimethyl 3,3'-dithiadipropanoate, dimethyl 5,5dithiadipentanoate, dimethyl 6,6'-dithiadihexanoate, and dimethyl 7,7-dithiadiheptanoate.

for dimethyl 4.4'-dithiadibut'anoate. in the procedure of Preparation 4(8), is productive of.

methyl 4-ehloro-3-thiabutanoate. methyl 5-chloro-4-thiapentanoate, methyl 7-ehloro--thiaheptanoate. methyl 8-chloro-7-thiaoctanoate, and methyl 9-chlero-8-thianonanoate.

b. In like manner, substitution of other dialkyl esters of the w,w'-dithladialltanoatc compounds, prepared in Preparation 4(A) (b) in the procedure of Preparation 4(8) is productive of the corresponding alkyl esters having from two to ten carbonatoms, e.g.. ethyl, propyl. isopropyl, oetyl. and the like. of the respective ai-thiachloroalkanoates.

Preparation 5 This preparation illustrates methods of preparing a pancreatic lipase preparation which can be used to cleave ester groups from carboalkoxy cyclopentanes. In this preparation, l0 g. of crude pancreatic lipase lnote: Bioehem. Biophysics Aclm, v. 23, p. 264 l957)] is suspended in 65 ml. of water at 0C. The suspension is stirred for one hour at 0C. and then centrifuged for 20 minutes at 10,000 X g. The supernatant liquid is separated and maintained at 0C. for later use. The precipitate is again suspended in 65 ml. of water at 0C. and centrifuged as before. The supernatant liquid is separated and combined with the previously obtained supernatant liquid and then added to l30 ml. of saturated aqueous ammonium sulfate solution at 0C.. with stirring, and then allowed to stand for five minutes. The resulting mixture is then centrifuged at 10,000 X g. for 20 minutes. The supernatant liquid is decanted and the precipitate is collected, then dissolved in sufficient water to yield I25 ml. of solution. 15 ml. of saturated aqueous ammonium sulfate solution is then added to the water solution yielding a suspension which is then centrifuged at 10,000 X g. for 20 minutes. The supernatant liquid is collected and treated with l00 ml. of saturated ammonium sulfate affording a second suspension, which is divided into two equal portions. Each portion is again centrifuged for 20 minutes at l0,000 X g., and in each instance the supernatant liquid is discarded (decantation) and the precipitate collected. Each pre cipitate is stored at 40C. prior to use.

The pancreatic lipase ester cleaving preparation is then prepared immediately prior to use by dissolving one of the above precipitates in 25 ml. of an aqueous 0.lM sodium chloride solution and 0.05M calcium chloride solution and then adjusting the pH to 7.2 by the careful addition (i.e., titration) of a 0.1M aqueous sodium hydroxide solution.

EXAMPLE I Step (a) OAC / (CH CH 0Si(CH ctcn i 3 wherein R isH or CH,; 2 is [Q], Cu(l) Li in which [0] is (i) CH-CHCH(CHs)-CHs OSl(CHsls (CH,),

m is a whole integer from zero through eight; Ac is acetyl; and

the wavy line l represents the aor B- configuradodecenyl)-l-acetoxycyclopent-l-encs.

tron or mixtures thereof; D. Likewise. substituting 2-methyleyclopent-2-en- A. l Mmoles of freshly prepared (dl) octent copl-one. for cyclopent-Z-en-l-one. in the procedure of per(l) lithium reagent [Preparation l(G)] is cooled to Example HA). is productive of (dl)-SB-(3a-and Bfl-t- 78C and treated with 0.82g. of cyclopent-Z-en-l-one 5 butyldimethylsiloxy-trans-l-octenyl)-2-mcthyll in 5 ml. of ether. After l5 minutes at --78, 50 ml. of anacetoxycyclopent-l -cnc. hydrous tetrahydrofuran and 5 ml. of acetic anyhdrid a. Likewise. substituting Z-mcthylcyclopcnt-Z-cnis added. The reaction mixture is then stirred 20 mi l-one. for cyclopent-Z-en-l-one. and other freshly preutes at --30C and then allowed to warm to room tempared (dl) alkenyl copper(l) lithium reagents. prepared pcrature for 30 minutes. The resulting mixture is in Preparation [(6) (a). for (dl) octenyl copper(l) lithpoured into 300 ml. of ice water and extracted twice i r a ent. in the procedure of Example HA). is prowith 120 ml. ofether. The combined ethereal solutions ductive f h respective .3 3 are washed with 200 ml. of water. dried over sodium dimethylsiloxy-trans-l-alkcnyl)-2-mclhyl-l-ztcetoxy sulfate and concentrated in vacuo. The resulting rcsil pp f example. due is chromamgmphed on 8- of silica gel and (dl)-3B-(3a-and Bfi-t-butyldimethylsiloxy-trnns-lthose fractions eluted with to ethyl acetate in hcxcnyn-zqnclhyl-l-agc[gxycycl0pcnl-I-cnc. hexane yield (dl)- B-( B- y y (dl)-3B-(3a-and 3B-t-butyldimethylsiloxy-trans-lsiloxy'tl'ans' l yn l y y l decenyl )-2-methyll -acetoxycyclopent- I -ene. and

a. Similarly. substituting other freshly prepared (dl) (d1).3B.(3 -t-butyldimethylsiloxy-trans-lalkenyl copper(l) lithium reagents. prepared in Prcpa- 20 d d ny])-2-methyl l-acetoxycyclopent-l-ene. for octenyl pp lithium E. Likewise. substituting 2-methylcyclopent-2-en- 8 in the Procedurc of Examplc HA) is Producfive l-one. for cyclopcnt-2-cn-l-one. and freshly prepared of respecfivc 54 l y y 3-(S) alkenyl copper (l) lithium reagents. prepared in siloxy-transl-alkenyl)-l-acetoxycyclopent-l-enes. for preparation 1 b for dl) uctcnyl coppcrfl) lithcxample- 25 ium reagent, in the procedure of Example HA). is pro- B( B" y y ductive of the respective 3a-and 3fl-(3a-t-butyldimehsxcnyll-lacetoxyeyclopsnslsns. thylsiloxy-transl -alkenyl )-2-methyll -acetoxyeyclo- (dl)-3B-(3a-and 3B-t-butyldimethylsiloxy-trans-l penbpenes' f example yh-loxycy l pcnt-l-cne. and Sa-and 3fl-(Ba-t-butyldimethylsiloxy-transl p-l fiy y 3o octenyl)-2-methyl-l-acetoxycyclopent-l-enes.

yn"' y 3a-and 3B-(3a-t-butyldimethylsil0xy-trans-hexenyl 8. Similarly. substituting freshly prepared 3-(S) alke- 2-mcthyl-l-acctoxycyclopent-l-enes. nyl copper(l) lithium reagents, prepared in Preparation Isa-and 3fi-(3a-t-butyldimethyl5iloxy-trang-d l). 1(0) (b). for (dl) octenyl copper (l) lithium reagent. in Z-methyl-l-acetoxycycl0pent-l-enes. and the procedure of Example l(A). is productive of the 35 Ba-and 3B-(3a-t-butyldimethylsiloxy-transrespective 3G-8lld 3B-( 3a-t-butyldimethylsiloxy-transdodecenyl)-2-methyll -acet0xycycl0pcntl -enes. yl-l-a t y y p ntfor mpl F. Likewise. substituting Z-methylcyclopcnt-Z-en- 30l-8nd 3B-(3a-ty i et ylsiloxy-tra -ll-one. for cyclopent-Z-en-l-one. and freshly prepared yn- Y Y W 40 3-(R) alkenyl copper (l) lithium reagents. prepared in 3a-and 3B-(3a-t-butyldimethylsiloxy-trans-l-hex- Preparation 1(6) (c), for (dl) octenyl copper(l) lithnyD-l-acetoxyeyclopent-l-enes. ium reagent. in the procedure for Example HA). is B4 y y y-" productive of the respective 3a-and 3B-(3Bt-butyldc nynl -a t0xy y l p n an dimethylsiloxy-transl -alkenyl )-2-methyll -acetoxycy- Zia-and 3B-(Sa-t-butyldimethylsiloxy-trans-ll npl for l yhyy i Zia-and 3 34 3B-t-butyldimethylsiloxy-transl- C. Similarly. substituting freshly prepared 3-(R) alkeoctenyl)-2-methyll -acetoxycyclopentl -enc nyl copper(l) lithium reagents. prepared in Preparation Lia-and 3B-(BB-t-butyldimethylsiloxy-trans-l-hcx- 1(0) (c). for (dl) octenyl copperfl) lithium reagent. in enyl)-2-methyl-l-acetoxycyclopent-l-enes. the procedure of Example HA). is productive of the so Bot-and 3B-(3B-t-butyldimethylsiloxy-trans-lrespective Zia-and 3/343B-t-butyldimethylsiloxy-transdecenyl)-2-methyl-l-acetoxycyclopent-l-enes. and l-alkenyl)l-aeetoxycyclopent-l-enes. for example. 3a-and 3B-(3fl-t-butyldimethylsiloxy-trans-l- Sa-and 3fl-(BB-t-butyldimethylsiloxy-transl dodecenyl)-2-methyll -acetoxycyclopentl -enes.

octenyl l -acetoxycyclopentl -enes. Sui-and 3B-(SB-t-butyldimethylsiloxy-trans-l-hex- EXAMPLE 2 enyl)-l-acetoxycyclopent-l-enes. Step (b) la A CH ca (CH CH osilca C(CH osi(cn c(cn 3 Ba-and 3;3-( JB-t-butyldimethylsiloxy-transl wherein dcceny|)-l-acetoxycyclopent-l-enes. and is Sol-and 3B-( 3B-t-butyldimethylsiloxy-transl A is -ca ten co R2 s 2 wa -J- (H co R or:

in which in A" and A, R is alkyl of from one through ten carbon atoms;

n is a whole integer from zero through four; and

p is a whole integer from one through six; and

Ac, R. m and the wavy line( I are defined as in Example l.

A. O.l90 g. of lithium is dissolved in I20 ml. of anhydrous ammonia and the resulting blue solution cooled to 78C., and a solution of 3.66 g. of (dl)-3fl-(3aand 3 B-t-butyldimethylsiloxy-transl -octenyl i -acetoxycyclopent-l-ene. prepared in Example NA). in 30 mi. of tetrahydrofuran is added over a five minute period. After another five minutes, 3 ml. of trimethyiborate in 4 ml. of tetrahydrofuran is added and the solution warmed to -5 SC for minutes. A solution of 10 g. of methyl 3-(5-chloromethylfur-2-yl)propanoate, prepared in Preparation 2(0), in 10 ml. of tetrahydroturan is added over three minutes and the reaction allowed to stir at --55C. for 30 minutes. 3 O. of ammonium chloride is added and the ammonia removed by a stream of nitrogen at a temperature below -l5C. The thus produeted residue is poured into 500 g. of ice. 200 ml. of ether and 50 ml. ofaeetic acid. The ethereal layer is separated and the aqueous layer washed with another 200 ml. portion of ether. The combined ethereal solutions are washed with saturated sodium chloride. dried over sodium sulfate and concentrated in vacuo to yield (dl)-2a-[(2.2'-earbomethoxyethylfur-5-yi)methyl1-33 -(3a-and 3B-t-butyldimethylsiioxy-trans-l-oetenyl)- cyclopentan-l-one.

a. Similarly, substituting other (di)-3p-(3a-and Sfl-tbutyldimethylsiloxy-transi -aikenyl l -aeetoxycyclopent-l-enes, prepared in Example l(A) (a), for exampie (dl )-3p-( 3pand 3p-t-butyldimethylsiloxy-transl hexenyl)-l-acetoxycyelopent-l-ene,

(dl)-3B-(3aand Bfl-t-butyldimethylsiloxy-trans-ldecenyl)-l-acetoxycyelopent-l-ene, and

(dl)-3B-(3aand SB-t-butyldimethylsiloxy-trans-ldodeeenyl)-l-acetoxyeyclopent-l-ene. for (dl)-3B-(3aand Sfl-t-butyldimethylsiloxy-trans-loctcnyU-l-aeetoxycyeiopent-l-ene. in the procedure of Example 2(A), is productive oi the respective (dl)- 2a-[(2,2-earbomethoxyethylfur-S-yl)methyll-Jfi-(Saand 3/94-butyldimethylsiloxy-trans-i-alitenyl)-cyelopentan-l-ones, for example.

38-(301- and 3B-t-butyldimethylsiloxy-trans-l-hexenyl)-cyclopentan-l-one,

3B-(3aand 3B-t-butyldimethylsiloxy-trans-ldecenyl)-cyelopentan-l-one, and

(dl)-2a-[(2,2'-carbomethoxyethylfur-S-yl)methyl]- 3(3-(301- and fifl-t-hutyldimethylsiloxy-trans-ldodecenyl )-cyclopentani -one.

b. Similarly, substituting the 3aand 3fl-(3a-t-butyldimethylsiloxy-trans-l-alkenyli-l-acetoxycyclopentl-enes, prepared in Example 1(8). for example.

Baand 3,8--(3a-tbutyldimethylsiloxy-truns-loctcnyl)- l -acet0xycyelopcntl -cne.

3c:- and 3,8-(Sa-t-butyldimethylsiloxy-trans-l-hexenyl)-i-aectoxycyclopent-l-ene.

3aand 3/3(Ser-t-butyldimethylsiloxy-trans-ldecenyl)-l-aeetoxycyclopent-l-ene. and

3aand 3B-(Bert-butyldimethylsiloxy-trans-ldodecenyl)-l-acetoxycyclopent-l-ene, for (dl)-3B-(3aand IiB-t-bulyldimethyisiloxy-truns-loctenyl)-l-acetoxyeyclopent-l-enc. in the procedure of Example 2(A). is productive of the respective 2a- [(2,2-carbomethoxyethylfur-S-yl)methyll-3B-(3a-tbutyldimethylsiloxy-trunsi -alkenyl)-eyclopentanl-ones and 2[3-[(2,2'-carbomethoxyethylfur-5-yl)methyl]-3a-(3a-t-butyldimethylsiloxy-trans-l-alkenyl)- eyclopentan-l-ones, for example,

Za-i(2,2'-carbomethoxyethylfur-5-yl)methylidli- (3a-t-butyldimethysiloxy-trans-l-octenyltcyclopentan-l-one. 2a-[(2,2'-curbomethoxyethylfur-5-yl)methyl1-38- (3a-t-butyldimethylsiloxy-trans-l-hexenyl)-cyclopentan-l-one, 2a-[(2,2-carbomethoxyethyltur-S-yl)methyl1-3/3 (3a-t-butyldimethylsiloxy-trans-l-decenyl)-cyclopentani -one. 2ol-[(2,2'-carbomethoxyethylfur-5-yl)methyl1-38- (3a-t-butyldimethyisiloxy-trans-l-dodecenyl)- cyclopentan-l-one, 2B-[(2,2'-carbomethoxyethylfur-S-yl)methyl]-3a- (3a-t-butyldimethylsiloxy-trans-l -octenyl )-cyclopentan-l-one.

ZB-l(2,2-carbomethoxyethylfur-5-yl)methyll-Ba- (3a-t-butyidimethylsiloxy-transl -hexcnyl )-cyclopentan-l-one, Zfl-i(2.2'-carbomethoxyethylfur-5-yl)methyl1-301- (3a-t-butyldimethylsiloxy-transl -decenyl )-cyclopentan-l -one, and

2B-[(2,2'-carbomethoxyethylfur-5-yl)methyl1-301- (3a-t-butyldimethylsiloxy-trans-l-dodecenyl)- cyeopentan-l-one. c. Similarly, substituting the 301- and 3fi-(3E-t-butyldimethyisiloxy-trans-l-alkenyl)- l-acetoxycyclopent-l-enes. prepared in Example l(C). for example.

3aand 3fl-(3a-t-butyldimethylsiloxy-trans-loctenyl l -acetoxycyclopentl -ene,

30:- and 3B-(3a-t-butyldimethylsiloxy-trans-l-hexenyl)-l-acetoxycyclopent-l-ene.

3aand 3B-(Zia-t-butyldimethylsiloxy-trans-ldecenyi)-i-acetoxycyclopent-l-ene. and

301- and dodeeonyi)-l-ucctoxycycl0pent-l-ene. for (dl)-3B-(3a and 3l:i-t-butyldimcthylsiloxy-truns-loctenyl)-l-acetoxycyclopent-bane. in the procedure of Example 2(A). is productive of the respective 2a- [(2,2'-carbomethoxyethylfur-5-yl)methyl]-3fl-(3/34- butyldimethylsiloxy-transl 'alkenylh l -acetoxycyclo- 3B-(Sa-t-butyldimcthylsiloxy-trans-l- I

Claims

1. THE (DL) MIXTURES, D-ISOMERS, AND 3-ISOMERS OF THE COMPOUNDS OF THE FORMULAS

2. The compounds of Formula (I) of claim 1.

3. The (dl) mixture of claim 2 wherein R and R1 are both -H, n is two and m is four, (dl)-2 Alpha -((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta -(3 Alpha - and 3 Beta -hydroxy-trans-1-octenyl)-cyclopentan-1-one, and the pharmaceutically acceptable salts thereof.

4. The compound of claim 2 wherein R and R1 are both -H, n is two, the side chain attached at the C-2 carbon atom of the cyclopentane ring is Alpha and the side chain attached at the C-3 carbon of the cyclopentane ring is 3 Beta -(3 Alpha -hydroxy-trans-1-octenyl), 2 Alpha -((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta -(3 Alpha -hydroxy-trans-1-octenyl)-cyclopentan-1-one, and the pharmaceutically acceptable salts thereof.

5. The compound of claim 2 wherein R and R1 are both -H, n is two, the side chain attached at the C-2 carbon atom of the cyclopentane ring is Beta and the side chain attached at the C-3 carbon atom of the cyclopentane ring is 3 Alpha -(3 Alpha -hydroxy-trans-1-octenyl), 2 Beta -((2,2''-carboxyethylfur-5-yl)methyl)-3 Alpha -(3 Alpha -hydroxy-trans-1-octenyl)-cyclopentan-1-one, and the pharmaceutically acceptable salts thereof.

6. The compound of claim 2 wherein R and R1 are both -H, n is two, the side chain attached at the C-2 carbon atom of the cyclopentane ring is Alpha and the side chain attached at the C-3 carbon atom of the cyclopentane ring is 3 Beta -(3 Beta -hydroxy-trans-1-octenyl), 2 Alpha -((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta -(3 Beta -hydroXy-trans-1-octenyl)-cyclopentan-1-one, and the pharmaceutically acceptable salts thereof.

7. The compound of claim 2 wherein R and R1 are both -H, n is two, the side chain attached at the C-2 carbon atom of the cyclopentane ring is Beta and the side chain attached at the C-3 carbon atom of the cyclopentane ring is 3 Alpha -(3 Beta -hydroxy-trans-1-octenyl), 2 Beta -((2,2''-carboxyethylfur-5-yl)methyl)-3 Alpha -(3 Beta -hydroxy-trans-1-octenyl)-cyclopentan-1-one, and the pharmceutically acceptable salts thereof.

8. The compounds of Formula (II) of claim 1.

9. The (dl) mixture of claim 8 wherein R and R1 are both -H, n is two, m is four and the hydroxyl group at the C-1 carbon atom of the cyclopentane ring is Alpha , (dl)-2 Alpha -((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta (3 Alpha - and 3 Beta -hydroxy-trans-1-octenyl)-cyclopentan-1 Alpha -ol, and the pharmaceutically acceptable salts thereof.

10. The compound of claim 8 wherein R and R1 are both -H, n is two, the hydroxyl group at the C-1 carbon atom of the cyclopentane ring is Alpha , the side chain attached at the C-2 carbon atom of the cyclopentane ring is Alpha and the side chain attached at the C-3 carbon of the cyclopentane ring is 3 Beta -(3 Alpha -hydroxy-trans-1-octenyl), 2 Alpha -((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta -(3 Alpha -hydroxy-trans-1-octenyl)-cyclopentan-1 Alpha -ol, and the pharmaceutically acceptable salts thereof.

11. The compound of claim 8 wherein R and R1 are both -H, n is two, the hydroxyl group at the C-1 carbon atom of the cyclopentane ring is Alpha , the side chain attached at the C-2 carbon atom of the cyclopentane ring is Beta and the side chain attached at the C-3 carbon atom of the cyclopentane ring is 3 Alpha -(3 Alpha -hydroxy-trans-1-octenyl), 2 Beta -((2,2''-carboxyethylfur-5-yl)methyl)-3 Alpha -(3 Alpha -hydroxy-trans-1-octenyl)-cyclopentan-1 Alpha -ol, and the pharmaceutically acceptable salts thereof.

12. The compound of claim 8 wherein R and R1 are both -H, n is two, the hydroxyl group at the C-1 carbon atom of the cyclopentane ring is Alpha , the side chain attached at the C-2 carbon atom of the cyclopentane ring is Alpha and the side chain attached at the C-3 carbon atom of the cyclopentane ring is 3 Beta -(3 Beta -hydroxy-trans-1-octenyl), 2 Alpha -((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta -(3 Beta -hydroxy-trans-1-octenyl)-cyclopentan-1 Alpha -ol, and the pharmaceutically acceptable salts thereof.

13. The compound of claim 8 wherein R and R1 are both -H, n is two, the hydroxyl group at the C-1 carbon atom of the cyclopentane ring is Alpha , the side chain attached at the C-2 carbon atom of the cyclopentane ring is Beta and the side chain attached at the C-3 carbon atom of the cyclopentane ring is 3 Alpha -(3 Beta -hydroxy-trans-1-octenyl), 2 Beta -((2,2''-carboxyethylfur-5-yl)methyl)-3 Alpha -(3 Beta -hydroxy-trans-1-octenyl)-cyclopentan-1 Alpha -ol, and the pharmaceutically acceptable salts thereof.

14. The compound of claim 8 wherein R and R1 are both -H, q is two, p is three, the hydroxyl group at the C-1 carbon atom of the cyclopentane ring is Alpha , the side chain attached at the C-2 carbon atom of the cyclopentane ring is Beta and the side chain attached at the C-3 carbon atom of the cyclopentane ring is 3 Alpha -(3 Beta -hydroxy-trans-1-octenyl), 2 Beta -(5-carboxy-2,2-dioxido-2-tHiapent-1-yl)-3 Alpha -(3 Beta -hydroxy-trans-1-octenyl)-cyclopentan-1 Alpha -ol, and the pharmaceutically acceptable salts thereof.

15. The (dl) mixture of claim 8 wherein R and R1 are both -H, n is two m is four, and the hydroxyl group at the C-1 carbon atom of the cyclopentane ring is Beta , (dl)-2 Alpha ((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta -(3 Alpha - and 3 Beta -hydroxy-trans-1-octenyl)-cyclopentan-1 Beta -ol, and the pharmaceutically acceptable salts thereof.

16. The compound of claim 8 wherein R and R1 are both -H, n is two, the hydroxyl group at the C-1 carbon atom of the cyclopentane ring is Beta , the side chain attached at the C-2 carbon atom of the cyclopentane ring is Alpha and the side chain attached at the C-3 carbon of the cyclopentane ring is 3 Beta -(3 Alpha -hydroxy-trans-1-octenyl), 2 Alpha ((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta -(3 Alpha -hydroxy-trans-1-octenyl)-cyclopentan-1 Beta -ol, and the pharmaceutically acceptable salts thereof.

17. The compound of claim 8 wherein R and R1 are both -H, n is two, the hydroxyl group at the C-1 carbon atom of the cyclopentane ring is Beta , the side chain attached at the C-2 carbon atom of the cyclopentane ring is Beta and the side chain attached at the C-3 carbon atom of the cyclopentane ring is 3 Alpha -(3 Alpha -hydroxy-trans-1-octenyl), 2 Beta -((2,2''-carboxyethylfur-5-yl)methyl)-3 Alpha -(3 Alpha -hydroxy-trans-1-octenyl)-cyclopentan-1 Beta -ol, and the pharmaceutically acceptable salts thereof.

18. The compound of claim 8 wherein R and R1 are both -H, n is two, the hydroxyl group at the C-1 carbon atom of the cyclopentane ring is Beta , the side chain attached at the C-2 carbon atom of the cyclopentane ring is Alpha and the side chain attached at the C-3 carbon atom of the cyclopentane ring is 3 Beta -(3 Beta -hydroxy-trans-1-octenyl), 2 Alpha -((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta -(3 Beta -hydroxy-trans-1-octenyl)-cyclopentan-1 Beta -ol, and the pharmaceutically acceptable salts thereof.

19. The compounds of the Formula (I) of claim 1 wherein R is -CH3.

20. The compounds of Formula (II) of claim 1 wherein R is -CH3.

21. Process for the production of a compound selected from the (dl) mixtures, d-isomers and l-isomers of the compounds of the formulas