# Patent

## Title
Control mechanisms for document-handling apparatus

## Abstract

This application is a .Iadd.reissue application of our original U.S. Pat. No. 3,950,406, dated Apr. 13, 1976, Serial No. 480,989, filed June 19, 1974; which is a .Iaddend.continuation-in-part of our copending application Ser. No. 274,769, filed July 24, 1972, now abandoned.

## Background
This invention relates to novel hydroxy substituted 15-deoxy prostanoic acids and derivatives as well as to intermediates and methods for their preparation. The novel compounds of this invention may be represented by the following general formulae: wherein formula A has the absolute configuration of the naturally-occurring mammalian prostaglandins. ##STR1## wherein R.sub.1 is selected from the group consisting of hydrogen, hydroxy, lower alkoxy, tetrahydropyranyloxy, lower alkanoyloxy, .omega.-hydroxy substituted lower alkoxy and .omega.-tetrahydropyranyloxy substituted lower alkoxy; R.sub.2 is a moiety selected from the group consisting of those of the formulae: ##STR2## wherein P is an hydroxy or triphenylmethoxy group, R' is a straight chain alkyl group having from 2 to 10 carbon atoms, or a straight chain alkyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms, and R" is a straight chain alkyl group having from 2 to 10 carbon atoms and substituted with an hydroxy or triphenylmethoxy group, or a straight chain alkyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms and substituted with an hydroxy or triphenylmethoxy group or a straight chain alkenyl group having from 2 to 10 carbon atoms and substituted with a hydroxy or triphenylmethoxy group, or a straight chain alkenyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms and substituted with a hydroxy or triphenylmethoxy group; R.sub.3 is selected from the group consisting of hydroxy, an alkoxy group having from 1 to 12 carbon atoms and tetrahydropranyloxy; R'" is a straight chain alkyl group having from 2 to 10 carbon atoms and substituted with an hydroxy or triphenylmethoxy group, or a straight chain alkyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms and substituted with an hydroxy or triphenylmethoxy group; Y is a divalent radical selected from the group consisting of those of the formulae: ##STR3## and Z is a divalent radical selected from the group consisting of those of the formulae: ##STR4## wherein n is an integer from 3 to 8 inclusive, R.sub.4 is an alkyl group having up to 3 carbon atoms and R.sub.5 is an alkyl group having up to 3 carbon atoms, a fluorine atom or a phenyl group; and the moiety of the formula: ##STR5## may be the divalent radical of the formula: ##STR6## when R.sub.3 is hydroxy or an alkoxy group having from 1 to 12 carbon atoms; and the moiety of the formula: ##STR7## may be the divalent moiety of the formula: ##STR8## when R.sub.3 is hydroxy or an alkoxy group having from 1 to 12 carbon atoms. Suitable lower alkoxy and lower alkanoyl groups contemplated by the present invention are those having up to four carbon atoms such as, for example, methoxy, ethoxy, isopropoxy, sec-butoxy, formyl, acetyl, propionyl, isobutyryl, etc.

Also embraced within the scope of the present invention are the non-toxic, pharmaceutically acceptable salts of the novel compounds of the present invention when R.sub.3 is hydroxy. The cations comprised in these salts include, for example, the non-toxic metal cations such as the sodium ion, potassium ion, calcium ion, and magnesium ion as well as the organic amine cations such as the tri(lower alkyl)amine cations (e.g., triethylamine), procaine, and the like.

The novel compounds of the present invention are obtainable as yellow oils having characteristic absorption spectra. They are relatively insoluble in water but are relatively soluble in common organic solvents such as ethanol, ethyl acetate, dimethylformamide, and the like. The cationic salts of the compounds when R.sub.3 is hydrogen are, in general, white to yellow crystalline solids having characteristic melting points and absorption spectra. They are relatively soluble in water, methanol and ethanol but are relatively insoluble in benzene, diethyl ether, and petroleum ether.

The prostaglandins are a family of closely related compounds which have been obtained from various animal tissues, and which stimulate smooth muscle, lower arterial blood pressure, antagonize epinephrine-induced mobilization of free fatty acids, and have other pharmacological and autopharmacological effects in mammals. See Bergstom et al., J. Biol. Chem. 238, 3555 (1963) and Horton, Experienta 21, 113 (1965) and references cited therein. All of the so-called natural prostaglandins are derivatives of prostanoic acid. ##STR9## The hydrogen atoms attached to C-8 and C-12 are in trans-configuration. The natural prostaglandins represent only one of the possible optical isomers. The compounds of this convention include all possible optical isomers.

The novel compounds of the present invention may be readily prepared from certain 4-substituted cyclopentenone intermediates which may be represented by the following general formulae: ##STR10## wherein R.sub.1 ' is hydrogen, lower alkoxy, tetrahydropyranyloxy, lower alkanoyloxy or .omega.-tetrahydropyranyloxy lower alkoxy; and R.sub.3 ' is tetrahydropyranyloxy or an alkoxy group having from 1 to 12 carbon atoms.

The 4-oxycyclopentenone intermediates may be readily prepared from 2-carbethoxycyclopentanone in accordance with the reaction schemes set forth in Flowsheets A through D. In particular, the requisite 2-(.omega.-carbethoxyalkyl)cyclopent-2-en-1-one intermediates (VIII) may be prepared in accordance with the following reaction scheme: ##STR11## wherein n is as hereinabove defined .[.ans.]. .Iadd.and .Iaddend.X is iodo or bromo. In accordance with this reaction scheme, the cyclopent-2-en-1-ones (VIII) are developed by first converting 2-carbethoxycyclopentanone (I) to the sodium enolate thereof by means of sodium hydride in dimethoxyethane and then treating the sodium enolate with an ethyl .omega.-haloalkanoate (II). There is thus obtained the corresponding 2-carbethoxy-2-(.omega.-carbethoxyalkyl)cyclopentanone (III) which is then hydrolyzed and decarboxylated to afford the 2-(.omega.-carboxyalkyl)cyclopentanone (IV). This acid is then esterified with ethanol whereby the 2-(.omega.-carbethoxyalkyl)cyclopentanone (V) is obtained. The reaction conditions for carrying out the above sequence of reactions are well known in the art. The conversion of the cyclopentanone (V) to the enol acetate (VI) is effected by heating with acetic anhydride in the presence of p-toluenesulfonic acid. Preparation of the enol acetate (VI) usually requires heating for a period of from about 8 to 36 hours. During this period, it is preferable to allow by-product acetic acid to distill out in order to force the reaction to completion. The bromination of the enol acetates (VI) to the 2 -bromocyclopentanones (VII) is preferably carried out in a two phase system as follows. A solution of bromine in chloroform is added to a rapidly stirred mixture of a solution of the enol acetate (VI) in chloroform and an aqueous solution of an acid acceptor such as calcium carbonate or soda ash. This addition is carried out at 0.degree.-5.degree. C. over a period of about 90 minutes stirring is continued for an additional period of about half an hour to a few hours, and the product (VII) is then isolated by standard procedures. The dehydrobromination of the 2-bromocyclopentanones (VII) is preferably carried out in dimethylformamide with a mixture of lithium bromide and lithium carbonate at the reflux temperature for a period of about 30 minutes to an hour or so. The so formed cyclopent-2-en-1-ones (VIII) are also isolated by standard procedures well known in the art. Substitution of X--(CH.sub.2).sub.n --C(R.sub.4).sub.2 -- --CH.sub.2 --CO.sub.2 C.sub.2 H.sub.5 for (II) in Flowsheet A and carrying through the sequence of transformations illustrated therein is productive of the following cyclopent-2-en-1-ones (VIIIa): ##STR12## wherein X, n, and R.sub.4 are as hereinabove defined.

The required cyclopent-2-en-1-one intermediates of general structure (XVI), wherein the side-chain has a lower alkyl group, fluorine atom or phenyl group alpha to the carbethoxy function, may be prepared in accordance with the following reaction scheme: ##STR13## wherein n and R.sub.5 are as hereinabove defined, and Y is a methyl or p-tolylradical. In accordance with this reaction scheme, the 2-(.omega.-carbethoxyalkyl)cyclopent-2-en-1-ones (IX), prepared as described in Flowsheet A for the preparation of (VIII) where n is 2- 7, inclusive,  are converted to the corresponding 1-methoximino-2-(.omega.-carbethoxyalkyl)-2-cyclopentenes (X) by treatment with methoxyamine. With the ring carbonyl function thus blocked it is possible to effect a preferential reduction of the ester group by treatment with diisobutylaluminum hydride. The resulting alcohol (XI) is converted to a mesylate or tosylate derivative (XII), which undergoes displacement on treatment with the sodium salt of a diethyl substituted malonate (XIII) to provide the disubstituted malonate derivatives (XIV). Hydrolysis and decarboxylation as well as concomittant cleavage of the methoximino blocking group provides the desired 2-(.omega.-carboxy-.omega.-substituted alkyl)cyclopent-2-en-1-ones (XV), which are readily converted to the corresponding ester (XVI) by the usual Fisher procedure.

The requisite 2-(.omega.-carbethoxy-3-oxa-alkyl)cyclopen-2-en-1-ones (XXII) may be prepared in the procedure the reaction scheme of Flowsheet C, wherein n is as hereinbefore defined. ##STR14##

In accordance with the reaction scheme shown in Flowsheet C, for the preparation of the oxa derivatives (XXII), an appropriate 2-(.omega.-carbethoxyalkyl)cyclopent-2-en-1-one (XVII) is converted to the corresponding methoxime (XVIII), the ester function of which is then preferentially reduced with diisobutylaluminum hydride to afford the methoxime alcohol (XIX). The alcohol (XIX) is converted on treatment with n-butyl lithium to the lithio alcoholate, which then is O-alkylated by reaction with ethyl bromoacetate to provide (XX). Hydrolysis with acetone-aqueous hydrochloric acid furnishes the deblocked keto-acid (XXI), which is then re-esterified with ethanol in the presence of p-toluenesulfonic acid to give the required 2-(.omega.-carbethoxy-3-oxa-alkyl)cyclopent-2-en-1-one (XXII). O-Alkylation can also be accomplished by treatment of the lithio alcoholate of (XIX) with sodium or other metal salt of bromoacetic acid, in which case the free carboxylic acid corresponding to ester (XX) is obtained. Hydrolysis as for (XX) provides the keto acid (XXI).

Some of the transformations involved in the preparation of the 4-oxycyclopentenone intermediates are set forth in the following reaction scheme: ##STR15## wherein R.sub.8 is hydrogen or lower alkyl, R.sub.9 is lower alkyl, and Z' is as hereinabove defined for Z except that it does not include the moiety: --(CH.sub.2).sub.n --S--CH.sub.2 --, and m is an integer from 2 to 5, inclusive. Introduction of the 4-oxy-function into the 4-unsubstituted cyclopentenones (XXIII) is accomplished by first halogenating the 4-position with an allylic halogenating reagent, preferably N-bromosuccinimide. The resulting 4-bromocyclopentenone (XXIV) is then solvolyzed for the introduction of the oxy function. This step is preferably carried out in the presence of a silver salt to facilitate the displacement of the halide ion. The particular 4-oxy derivative that is formed is determined by the nature of the solvent system. Treatment of the 4-bromocyclopentenone with silver fluoroborate in water-acetone (for solubility) provides the 4-hydroxycyclopentenone (XXV). When the cyclopentenone is a carboxylic acid (i.e. R.sub.8 = hydrogen), then this procedure provides (XXXI). When the solvent system is water-tetrahydrofuran, in addition to the 4-hydroxy derivative there is also obtained the  4'-hydroxybutyloxy derivative (XXVI), formed by solvolysis with tetrahydrofuran. When the solvent is only tetrahydrofuran then only the latter compound is formed. Substitution of tetrahydrofuran with alcohols, e.g., methanol, ethanol, isopropyl, butanol and the like, provides the 4-alkoxycyclopentenones (XXVII). With ethylene glycol or propylene glycol etc. the corresponding 4-(.omega.-substituted hydroxy alkoxy) cyclopentenone (XXVIII) is obtained. In the latter three procedures it is preferable to add a proton acceptor which will not react with (XXIV), for example, sym. collidine. When solvolysis is carried out with a silver lower alkanoate in the corresponding lower alkanoic acid, such as the silver acetateacetic acid system, the 4-acetoxy derivative (XXIX) is obtained. Careful alkaline hydrolysis of this product with potassium carbonate in aqueous methanol provides the free 4-hydroxy derivative (XXX); further hydrolysis with barium hydroxide gives the free carboxylic acid (XXXI).

In general these procedures are operable with either the free carboxylic acid or alkyl carboxylate, as desired. A particular alkyl carboxylate not provided by formula (XXIII) can be obtained by hydrolysis to the acid and esterification in the usual way, for example with the appropriate alcohol, or for a t-butyl ester with isobutylene. However, for the subsequent alanate conjugate addition process it is necessary to utilize a cyclopentenone wherein the carboxylic acid as well as all free hydroxyl groups are blocked. A particularly useful blocking group for both functions is the tetrahydropyranyl group (see for example XXXI.fwdarw.XXXII) since this group can easily be cleaved with weak acid under conditions which do not disrupt the subsequently-prepared, relativey-unstable 11-oxy-9-keto system (.beta.-hydroxy-ketone). Thus, it is not possible to effect a satisfactory chemical hydrolysis of an alkyl ester or of an 11-O-alkanoyl group in an 11-oxy-9-keto prostanoic acid derivative under conditions to which this system is stable (enzymatic hydrolysis, for example with baker's yeast is possible). Of course these stability considerations do not apply in the F (9-hydroxy) series.

The 9-keto-15-deoxy-13-trans-prostenoic acids and esters of this invention, as defined in the general formula on page 1 above may be prepared from cyclopentenone (XXXVII) and the triphenylmethoxy substituted 1-alkyne (XXXIII), as depicted in Flowsheet E. In Flowsheet E, R'.sub.1, R'.sub.3, and Z are as hereinabove defined and R.sub.6 is a moiety of the formulae: ##STR16## wherein R' is as hereinabove defined and R" is a straight chain alkyl group having from 2 to 10 carbon atoms and substituted with a triphenylmethoxy group, or a straight chain alkyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms and substituted with a triphenylmethoxy group, or a straight chain alkenyl group having from 2 to 10 carbon atoms and substituted with a triphenylmethoxy group, or a straight chain alkenyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms and substituted with a triphenylmethoxy group; and R'.sub.6 has all the possibilities of R.sub.6 except that triphenylmethoxy is replaced by hydroxy. Also, R is a lower alkyl group of up to 4 carbon atoms, R".sub.1 is as defined above for R.sub.1 except that it is not tetrahydropyranyloxy or .omega.-tetrahydropyranyloxy substituted lower alkoxy, and R".sub. 3 is as defined above for R.sub.3 except that it is not tetrahydropyranloxy. ##STR17##

In accordance with the reaction scheme of Flowsheet E, the triphenylmethoxy substituted 1-alkyne (XXXIII) is treated with diisobutylaluminum hydride (XXXIV), This reaction of the 1-alkyne (XXXIII) with diisobutylaluminum hydride (XXIV) provides the alane (XXXV) containing the trans-double bond and is carried out in an inert solvent such as benzene, toluene, and the like at temperatures in the range of 40.degree.-60.degree. C. for several hours. It can also be carried out in a solvent such as tetrahydrofuran, usually in an approximate 2:1 mixture with benzene or hexane; in which case the reaction requires somewhat more vigorous conditions, usually treating at about 70.degree.-75.degree. C. for about eighteen hours. The subsequent reaction with methyl or n-butyl lithium (R-Li) is preferably carried out in a mixture of the above solvents with an ether-type solvent such as diethyl ether, dibutyl ether, tetrahydrofuran, and the like. This reaction is rapid and is preferably carried out at 0.degree.-10.degree. C. with cooling. The conjugate 1,4-addition of the resulting alanate salt (XXXVI) to the cyclopent-2-en-1-one (XXXVII) is preferably carried out at ambient temperatures for a period of 12 to 24 hours. This reaction is also best carried out in an ether-type solvent such as diethyl ether, dibutyl ether, and the like. The intermediate alanate-enolate adduct is then carefully hydrolyzed in situ with dilute hydrochloric acid with cooling, and the products (XXXVIII) are isolated in the usual manner well known in the art. Removal of tetrahydropyranyl blocking groups and of the triphenylmethyl blocking group can then be accomplished by treating with weak acid. A preferred procedure involves heating at 45.degree. C. for 3.5 hours in a solvent system consisting of acetic acid:tetrahydrofuran:water in the proportion of 4:2:1. If (XXXVIII) is a tetrahydropyranyl ester, there is then obtained the prostenoic acid (XXXIX, R".sub.3 =hydroxy).

All available evidence leads us to believe that the --CH=CH--R.sub.6 function introduced by the alanate process (see XXXVIII) occupies a position trans to the 11-oxy function (when R'.sub.1 is not hydrogen). Similarly, we are led to the conclusion that in the product (XXXIX) the two side-chains attached to C.sub.8 and C.sub.12 are trans to each other. However, we are not certain of this configurational relationship in product (XXXVIII) as it is obtained directly from the alanate process. These products may have the side-chains in a trans- or cis-relationships or they may be a mixture containing both the trans- and cis-isomers. This is indicated in the nomenclature of the compounds involved by the designation 8 .xi.. In order to ensure a trans-relationship in both (XXXVIII) and XXIX) these products can be submitted to conditions known in the literature to equilibrate the cis-8-iso-PGE.sub.1 to a mixture containing about 90% of the trans product. These conditions involve treatment with potassium acetate in aqueous methanol for 96 hours at room temperature.

An alternative procedure for the conversion of substituted 1-alkyne (XXXIII) to the 9-keto-15-deoxy-13-trans-prostenoic acids and esters of this invention entails reduction of 1-alkyne (XXXIII) with disiamylborane in an ether solvent, in accordance with Flowsheet F. The intermediate dialkyl-alkenyl borane (XXXIXa) is not isolated but is sequentially treated with trimethylamine oxide, iodine, and aqueous sodium hydroxide solution in a manner known in the art [A. F. Kluge, K. G. Untch, and J. H. Fried, Journal Amer. Chem. Soc., 94, 7827 (1972)]. This treatment provides trans-vinyl iodide (XXXIXb), a novel and useful intermediate for preparation of certain of the compounds of this invention.

Submission of the substituted vinyl iodide (XXXIXb) to metal interchange with an alkyl lithium, e.g., n-butyl lithium, at very low temperatures, e.g. -78.degree. C., provides the vinyl lithium derivative (XXXIXc), the trans-configuration of the double bond being retained. After 1 to 4 hours, addition of a trialkyl aluminum, to the solution of the lithio derivative (XXXIXc) furnishes the lithio alanate intermediate (XXXIXd), also with retention of the trans-configuration of the double bond. The reaction of alanate (XXXIXd) with cyclopent-2-en-1-one (XXXVII) is carried out as described hereinabove (see Flowsheet E). ##STR18##

The triphenylmethoxy substituted 1-alkynes (A) and the alanes (B) derived from it are novel and useful intermediates for the synthesis of the compounds of this invention and are to be considered a part of this invention. In formulae (A) and (B), R.sub.6 and R are as hereinabove defined. ##STR19##

When the 11-oxy derivatives (XXXVIII or XXXIX, R'.sub.1 or R'.sub.1 is not hydrogen), preferably the 11-hydroxy derivative such as (XL), are treated with dilute acid it is possible to effect elimination and the formation of the corresponding .DELTA..sup.10 derivative (XLI, prostaglandins of the A type). A preferred procedure involves treatment in tetrahydrofuran: water (2:1) solvent 0.5N in hydrochloric acid for about seventy hours at ambient temperatures as set forth in the following reaction scheme. Under these conditions a tetrahydropyranyl ester will undergo hydrolysis.

When the 11-oxy derivatives (XXXVIII) or (XXXIX) or (XL) or the .DELTA..sup.10 derivative (XLI) are treated with an aqueous base system, e.g., sodium carbonate in aqueous methanol, it is possible to prepare the corresponding .DELTA..sup.8(12) derivative (XLII), prostaglandins of the B type). The formation of the .DELTA..sup.8(12) compound (XLII) is conveniently observed by the appearance of the ultraviolet absorption maximum due to (XLII) at about 280 m.mu.. This is a procedure well-known in the art. See Flowsheet G below, wherein Z, R.sub.2, R.sub.3 and R".sub.3  are as hereinabove defined. ##STR20##

Those compounds of this invention embodying the --CH.sub.2 --CH.sub.2 -- linkage at --C.sub.13 --C.sub.14 -- may be prepared from the corresponding .DELTA..sup.13 derivatives, obtained via the alanate process, by catalytic reduction, preferably at low pressure with a noble metal catalyst in an inert solvent at ambient temperatures.

The 11 -oxy-9-keto derivatives of this invention can be converted to the corresponding 9-hydroxy derivatives. If this conversion is effected with sodium borohydride, the product is a mixture of 9.alpha.- and 9.beta.-hydroxy derivatives (XLIII) and (XLIV) as set forth in the following reaction scheme of Flowsheet H, wherein R.sub.1, R.sub.2, R.sub.3 and Z are as hereinabove defined. ##STR21## When the reaction is carried out with lithium perhydro-9b-boraphenylyl hydride [H. C. Brown and W. C. Dickason, Journ. Amer. Chem. Soc., 92,709 (1970)] or with lithium tri(sec-butyl)-borohydride [H. C. Brown and S. Krishnamerthy ibid. 94, 7159 (1972)], the product is at least predominantly the 9.alpha.-hydroxy derivative (XLIII), wherein the 9-hydroxy group is cis to the side-chain attached to C.sub.8 and to the 11-oxy function. In accordance with accepted convention, an .alpha.-substituent at the 8-, 9-, 11- or 12-positions is behind the plane of the paper whereas a .beta.-substituent at these positions is in front of the plane of the paper. This is usually represented by a - - - bond for an .alpha.-substituent, a -- bond for a .beta.-substituent, and a   bond which both are indicated. Thus, the 9-hydroxy derivatives may be variously represented as follows: ##STR22##

The preparation of the thia intermediates (XLVIII) and (IL), proceeds from the intermediate (XLV) (XIX in Flowsheet C) which after conversion to the tosylate intermediate (XLVI) and reaction with the sodium salt of ethyl mercaptoacetate furnishes intermediate (XLVII). Deblocking of (XLVII) with acetone-aqueous hydrochloric acid provides the keto-acid (XLVIII), which on re-esterification with ethanol gives the required 2-(.omega.-carbethoxy-3-thia-alkyl)cycloalk-2-en-1-ones (IL). ##STR23##

When the compounds of this invention are prepared from racemic starting compounds two racemates are obtained. In appropriate instances these racemates can be separated from each other by careful application of the usual chromatographic procedures. In the more difficult instances it may be necessary to apply high pressure liquid chromatography including recycling techniques. [See G. Fallick, American Laboratory, 19-27 (Aug., 1973) as well as references cited therein. Additional information concerning high speed liquid chromatography and the instruments necessary for its application is available from Waters Associate, Inc. Maple St., Milford, Mass.]

It is also possible to prepare the individual enantiomers via the conjugate addition procedure discussed above by starting with a resolved 4-oxycyclopentenone (see XXXVII) and a resolved .beta.-chain precursor (see XXXIII or XXXIXb).

The 4-hydroxycyclopentenone racemates may be resolved into their component enantiomers (L) and (LI) by derivatizing the ketone function with a reagent having an optically active center. The resulting diastereoisomeric mixture can then be separated by fractional crystallization, or by chromatography, or by hidh speed liquid chromatography involving, if necessary, recycling techniques. Among the useful optically active ketone derivatizing reagents are 1-.alpha.-aminoxy-.gamma.-methylpentanoic acid hydrochloride (to give LII), (R)2-aminoxy-3,3-dimethylbutyric acid hydrochloride, and 4-.alpha.-methylbenzyl semicarbazide. After separation of the diastereomeric derivatives, reconstitution of the keto function provides the individual 4-hydroxycyclopentenone enantiomers (L) and (LI). A useful procedure for the resolution of a 4-hydroxycyclopentenone racemate via an oxime such as (LII) is described in the art [R. Pappo, P. Collins and C. Jung, Tetrahedron Letters, 973 (1973)]. ##STR24##

An alternative procedure for the preparation of the 4(R)-hydroxycyclopentenone enantiomers such as (L) involves as a key stop the selective microbiological or chemical reduction of trione (LIII) to the 4(R)-hydroxycyclopentanedione (LIV). A wide variety of microorganisms are capable of accomplishing this asymmetric reduction, one of the most useful being Dipodascus unincleatus. This step also can be achieved chemically by catalytic hydrogenation in the usual manner (for example, under about one atmosphere of hydrogen in methanol) using a soluble rhodium catalyst with chiral phosphine ligands, such as (1,5-cyclooctadiene)-bis(o-anisylcyclohexylmethylphosphine)rhodium (I) tetrafluoroborate in the presence of one equivalent of organic base, such as triethylamine.

Conversion of hydroxycyclopentanedione (LIV) to an enol ether or enol ester, (LV, E = alkyl, preferably isopropyl; aroyl such as benzoyl; or arylsulfonyl such as 2-mesitylenesulfonyl), is accomplished by treatment, for example, with isopropyl iodide and a base such as potassium carbonate in refluxing acetone for from 15 to 20 hours, or with a base such as triethylamine and 0.95 equivalents of benzoyl chloride or a slight excess of 2-mesitylenesulfonyl chloride, in a non-prototropic solvent at a temperature of about -10.degree. to -15.degree. C. Reduction of (LV) with excess sodium bis(2-methoxyethoxy)aluminum hydride in a solvent such as tetrahydrofuran or toluene at low temperatures, such as -60.degree. to -78.degree. C., followed by mild acid hydrolysis (representative conditions: aqueous dilute hydrochloric acid, pH 2.5; or oxalic acid, sodium oxalate in chloroform) at ambient temperatures from 1 to 3 hours provides the 4(R)-hydroxycyclopentenone ester (LVI). The ester (LVI), after blocking the hydroxy function as described hereinabove, can be subjected to conjugate addition reactions also as described hereinabove. The conjugate addition product, after deblocking the 11- and 15-hydroxy groups, will then be a methyl ester which can be hydrolyzed to the corresponding carboxylic acid by enzymatic or microbiological procedures, for example with baker's yeast or by exposure to Rhizopus oryzae.

For a description of these procedures in the art see: C. J. Sih et al., Journ. Amer. Chem. Soc., 95 1676 (1973); J. B. Heather et al., Tetrahedron Letters, 2213 (1973); R. Pappo and P. W. Collins, Tetrahedron Letters, 2627 (1972) and R. Pappo, P. Collins and C. Jung, Ann. N.Y. Acad. Sci., 180, 64 (1971). For a descriptive of the baker's yeast procedure see C. J. Sih et al., Journ. Amer. Chem. Soc., 94 3643 (1972). ##STR25##

Procedures for the preparation of the requisite cyclopentanetriones (LII) are well-established in the art and generally involve the treatment of an .omega.-1 oxo long chain ester (LVII) with methyl or ethyl oxalate and a base such as sodium methoxide in methanol, followed by treatment with dilute hydrochloric acid in aqueous methanol to effect the dealkoxalylation of the intermediate (LXVIII). See J. Kutsube and M. Matsui, Agr. Biol. Chem., 33, 1078 (1969); P. Collins, C. J. Jung and R. Pappo, Israel Journal of Chemistry, 6, 839 (1968); R. Pappo, P. Collins and C. Jung, Ann. N.Y. Acad. Sci. 180, 64 (1971); C. J. Sih et al., Journ. Amer. Chem. Soc., 95, 1676 (1973) (see reference 7); and J. B. Heather et al., Tetrahedron Letters, 2313 (1973) for pertinent background literature. ##STR26##

The intermediate keto esters (LVII) may be prepared by a variety of methods known to the art. One useful procedure is outlined below and involves alkylation of ethyl acetoacetate sodium salt (LIX) in the usual manner with the appropriate side-chain precursor (LX, X=Cl, Br, I, preferably Br or I) followed by decarbethoxylation and reesterification, all in the usual manner. ##STR27##

The side-chain precursors (LX) are commercially available where Z is --(CH.sub.2).sub.n --, and can be prepared as described in Belgian Pat. No. 786,215 (granted and opened to inspection Jan. 15, 1973) where Z is ##STR28## precursor (LX) can be prepared as indicated below by mono-tetrahydropyranylation of the diol (LXIII) to (LXIV), followed by mesylation, treatment of the resulting mesylate (LXVI) with the appropriate substituted sodio malonate to give (LXV), decarbethoxylation and reesterification to (LXVII), mesylation of the second hydroxy function to (LXIX) and displacement with lithium bromide (or iodide) to (LXXI). Alternatively, the .omega.-bromo alcohol (LXX) after blocking as the tetrahydropyranyl derivative (LXVIII), on treatment with the substitued sodio malonate provides (LXV). ##STR29##

Those precursors wherein Z is --(CH.sub.2).sub.n --O--CH.sub.2 -- can be prepared by the transformation shown directly below starting with the mono-tetrahydropyranyl derivative (LXIV). Thus, (LXIV) is converted to the lithium alcoholate by treatment with butyl lithium, the alcoholate is then O-alkylated with ethyl bromoacetate to provide (LXXII), which on de-tetrahydropyranylation, mesylation and reaction with lithium bromide gives the required (LXXV). (These and all the above-described transformation can be effected in the usual manner, well-established in the art; pertinent examples for most of the reactions can be found in the above-cited Belgian Pat. No. 786,215.) ##STR30##

It is also possible to resolve the 4-hydroxycyclopentenone racemate (LXXVI) by microbiological means. Thus, treatment of the 4-O-alkanoyl or aroyl derivatives (LXXVII), R.sub.12 = aryl (or alkyl) of racemate (LXXVI) (preferably the 4-O-acetyl and 4-O-propionyl derivatives) with an appropriate microorganism preferably a Saccharomyces species, e.g. 1375-143, affords preferential de-O-acylation of the 4(R)-enantiomer to give (LXXVIII), which is then separated from the unreacted 4(S)-O-acyl enantiomer (LXXIX) by chromatographic procedures. After separation, mild hydrolysis of the 4(S) derivative (LXXIX) provides the 4(S)-hydroxycyclopentenone (LXXX) [See N.J. Marsheck and M. Miyano, Biochimica et Biophysica Acta, 316, 363 (1973) for related examples.] ##STR31##

It is also possible to prepare the individual 4-hydroxycyclopentenones (LXXVIII) and (LXXX) directly by selective microbial hydroxylations of the corresponding 4-unsubstituted cyclopentenone (LXXXI). For example, with Aspergillus niger ATCC 9142; a selective 4(R)-hydroxylation of (LXXXI) [Z = (CH.sub.2).sub.6 ] has been reported; for a literature example, see S. Kurozumi, T. Tora and S. Ishimoto Tetrahedron Letters, 4959 (1973). Other organisms can also accomplish this hydroxylation. ##STR32##

An alternate resolution procedure involves derivatization of the alcohol function of the racemic hydroxycyclopentenone to give ester-acid derivatives such as (LXXXII) wherein R".sub.3 is hydrogen or an alkoxy group, n' is zero or two and Z is as hereinabove defined. ##STR33##

Such derivatives may be obtained from the corresponding free hydroxycyclopentenone by treatment in the usual manner with oxalyl chloride, succinyl chloride, succinic anhydride and the like. Treatment of the resulting acid or diacid (D".sub.3 = hydrogen) with optically active amines e.g., 1-(- )-.alpha.-methylbenzylamine, d-(+)-.alpha.-methylbenzylamine, brucine, dehydroabietylamine, strychnine, quinine, cinchonine, quinidine, ephedrine, (+)-.alpha.-amino-1-butanol and the like, and fractional recrystallization of the resulting diasteromeric mixtures, followed by cleavage of the 4-oxy ester function in each of the individually isolated diastereomers provides the individual 4(S)- and 4(R)-hydroxycyclopentenone enantiomers (L) and (LI) or their respective esters. Cleavage of the oxalate acid ester (LXXXII, n = 0) can be accomplished by treatment with lead tetraacetate in pyridine solution. For an example of a similar use of oxalate acid-esters see J. G. Molotkovsky and L. D. Bergelson, Tetrahedron Letters 4791 (No. 50, 1971); for an example of the use of the succinate acid-ester see B. Goffinet, Ger. Offen. No. 2,263,880; Chem. Abstracts, 79, 78215.sub.z (1973).

The racemic .beta.-chain precursors can be resolved at either the acetylenic alcohol stage (XXXIII, Flowsheet E) or the trans-vinyl iodide state (XXXIXb, Flowsheet F) by a variety of methods well-known in the art. These methods will be illustrated below with the acetylenic alcohol (LXXXIII), but they apply equally well to the trans-vinyl iodide (LXXXIV). Furthermore, the resolved acetylenic alcohols corresponding to (LXXXIII) can be converted to the trans-vinyl iodides corresponding to (LXXXIV) or its derivatives as described hereinabove without racemization [see for an example, A. F. Kluge, K. G. Untch and J. H. Fried, Journ. Amer. Chem. Soc., 94, 7827 (1972)]. ##STR34##

Racemates (LXXXIII) or (LXXXIV) can be resolved by reverse phase and absorption chromatography on an optically active support system or by selective transformation of one isomer by microbiological or enzymatic procedures.

A more generally applicable procedure involves conversion of the racemic alcohol to a mixture of diastereomers by derivatization of the hydroxy function with an optically active reagent, followed by separation of the diastereomers by fractional crystallization or chromatographic procedures, as discussed hereinabove. Regeneration of the alcohol function from the individual diasteromer then provides the individual enantiomeric alcohols, e.g. (LXXXV) and (LXXXVI). ##STR35##

Useful derivatives for resolution purposes include the salts of the phthalate half acid ester (LXXVII) with an optically active amine (e.g., 1-(-)-.alpha.-methylbenzylamine, d-(+)-.alpha.-methylbenzylamine, brucine, dehydroabietylamine, strychnine, quinine, cinchonine, cinchonidine, quinidine, ephedrine, deoxyephedrine amphetamine, (+)-2-amino-1-butanol, (-)-2-amino-1-butanol and the like). ##STR36##

For the resolution in the art of the related 3-hydroxy-1-octyne by this procedure see J. Fried et al., Annals of the N.Y. Acad. of Sci., 180, 38 (1971), and of the related 1-iodo-trans-1-octen-3-ol see A. F. Kluge, K. G. Untch and J. H. Fried, Jour. Amer. Chem. Soc., 94, 7827 (1972).

Other useful derivatives are the diastereomeric carbamates (LXXXVIII) obtained by treatment of racemate (LXXXIII) with an optically active isocyanate (e.g., (+)-1-phenylethylisocyanate and (-)-1-phenylethylisocyanate). ##STR37##

Various esters of racemate (LXXXIII) with optically active acids are also useful for resolution purposes. Among the optically active acids which can be used in this connection are .omega.-camphoric acid, methoxyacetic acid, 3.alpha.-acetoxy-.DELTA..sup.5 -etianic acid, 3.alpha.-acetoxy-5,16-etiadienoic acid, (-)-.alpha.-methoxy-.alpha.-trifluoromethylphenylacetic acid (see LXXXIX), (+)-.alpha.-methoxy-.alpha.-trifluoromethylphenylacetic acid, and the like. ##STR38##

The resolution of the related 1-octyne-3-ol with 3.beta.-acetoxy-.DELTA..sup.5 -etianic acid and 3.beta.-acetoxy-5,16-etiadienoic acid has been described in the art [see R. Pappo, P. Collins, and C. Jung, Annals of the N.Y. Acad. of Sci., 180, 64 (1971)].

The preparation of the enantiomeric acetylenic alcohols or 4-hydroxy-trans-vinyl iodides can also be accomplished by microbial techniques, involving a selective deesterification of 4-O-alkanoyl or aroyl derivatives (XL) followed by chromatographic separation to the individual enantiomers and hydrolysis of the non de-esterified ester. Useful microorganisms for this purpose are Rhizopus arrhizus and Rhizopus nigricans (ATCC 6227b). ##STR39##

Alternatively, it is possible to effect selective microbial reduction of the corresponding 4-keto derivatives (XCI) and (XCII) to a single enantiomer, useful microorganisms for this purpose are Penicillium decumbens and Aspergillus ustus. Ketones (XCI) and (XCII) are readily obtainable by oxidation under mild conditions of the corresponding alcohols. For pertinent literature examples see J. B. Heather et al., Tetrahedron Letters, 2313 (1973). It is also possible to effect optically selective reduction of ketones. ##STR40## (XCI) or (XCII) by the use of an optically active reducing agent such as tri(+S-2-methylbutyl)aluminum etherate, lithium aluminum hydride-3-O-benzyl-1,2-O-cyclohexylidene-.alpha.-glucofuranose complex, and lithium hydrodipinan-3.alpha.-ylborate. For pertinent references to this procedure see R. A. Kretchmer, Journ. Org. Chem. 37, 801 (1972); S. A. Landor et al., Journ. Chem. Soc. (C) 1822, 2280 (1966), ibid. 197 (1967); M. F. Grundon et al., ibid., 2557 (1971); and J. D. Morrison and H. S. Mosher, "Assymetric Organic Reactions", pp. 160-218, Prentice-Hall, Englewood Cliffs, N.J. (1971).

It is to be noted that use of only one resolved precursor, either the .beta.-chain or the 4-hydroxycyclopentenone, in the conjugate addition process will lead to the formation of two diastereomers, which, at least in appropriate instances, can then be separated by chromatographic and other procedures (as described above for the corresponding racemate) into the individual component enantiomers.

For the particular case of the preparation of optically active acetylenic alcohols wherein the hydroxy group occupies the 4-position of the chain, advantage may be taken of a well-known and general microbiological reduction process, depicted in Flowsheet J. According to this process, a 1-hydroxy-2-oxoalkene (XCV) is added to the fermenting mixture obtained from sucrose and baker's yeast (see P. A. Levene and A. Walti, Org. Synthesis, Coll. Vol. II, p. 545 and J. P. Anette and N. Spassky, Bull. Soc. Chim. France, 1972, 4217, for appropriate examples). The reductase of this system stereospecifically provides the (R)-1,2 -dihydroxyalkanes (XCVII). The glycol thus prepared is converted stereospecifically to the (R)-1,2-epoxyalkane (XCVI) by one of several procedures known in the art (see B. T. Golding et al., Journal. Chim. Soc. Perkin I, 1973, 1214 and M. S. Newman and C. M. Chen, Journ. Amer. Chem. Soc. 95, 278 (1973), for appropriate examples). The stereospecific conversion of this epoxide to the (R)-4-hydroxy-1-alkyne (XCVIII) may be accomplished by displacement with lithium acetylide-ethylenediamine complex in dimethyl sulfoxide (see E. Casadevall, et al., Compt. Rind. C, 265, 839 for pertinent literature).

The (R)-1,2-dihydroxyalkane (XCVII) obtained from the yeast fermentation may also be used for the preparation of the (S)-4-hydroxy-1-alkyne (CII). Preferential triphenylmethylation of the primary alcohol group provides the monoether (IC) (see L. J. Stegerhoek and P. E. Verkade, Rec. Trav. Chim. 74, 143 (1955) for pertinent literature). The remaining alcohol group is esterified with a sulfonyl halide such p-toluenesulfonyl chloride to provide the sulfonate ester (CI). Catalytic hydrogenolysis of the trityl group followed by treatment of the resulting free primary alcohol with a strong base, e.g. potassium hydroxide in methyl alcohol, provides the epoxide of the opposite configuration, a (S)-1,2-epoxyalkane (CIII) (see J. Fried, et al. Journ. Amer. Chem. Soc., 94, 4343 (1972) and J. W. Cornforth et al. Journ. Chem. Soc., 1959, 112, for pertinent literature). This substance is reacted with lithium acetylide-ethylenediamine complex to provide the (S)-4-hydroxy-1alkyne (CII).

Alternatively the (R)-4-hydroxy-1-alkyne (XCVIII) may be converted to a sulfonate ester (C), and the sulfonate function of the latter may be displaced by hydroxy to provide the (S)-4-hydroxy-1-alkyne (CII) (see R. Baker, et al., Journ. Chem. Soc. C. 1969, 1605 for pertinent literature).

The (R)- or (S)-4-hydroxy-1-alkynes are converted via either the vinyl iodide (XCIII) or the alane (XCIV) to 16-hydroxyprostaglandins of the (16R)- and (16S)-series respectively by the procedure outlined hereinabove. ##STR41##

The starting 1-hydroxy-2-oxoalkanes for this procedure may be prepared in a variety of ways well-known to the literature [see P. A. Levene and M. L. Maller, Journ. Biol. Chem., 79, 475 (1928) and I. Forgo and J. Buchi, Pharm. Acta Helv., 45, 227 (1970)]. In Flowsheet J which follows Ra is an alkyl group. FLOWSHEET J ______________________________________ ##STR42## ##STR43## ##STR44## ##STR45## ##STR46## ##STR47## ##STR48## ##STR49## ##STR50## ##STR51##

Utilization of only a resolved .beta.-chain or only a resolved hydroxycyclopentenone gives a mixture of diastereomers, which depending upon the circumstances, may or may not be separable by the usual procedures of crystallization and chromatography. If necessary, high speed liquid chromatography, including recycling techniques, can be applied. Additional procedures, well-understood in the literature, for effecting the resolution of diasteromeric prostenoic acids and esters (or of two racemates) of this invention are described below.

In these procedures 9-oxo-11.alpha. ,16(S)-dihydroxy-13-trans-prostenoic acid and its 9.alpha.-hydroxy derivative are used for illustrative purposes, it being understood, however, that the procedures are general and have applicability to the other products of this invention, particularly to those derivatives wherein the 11-position is not substituted with an oxy function.

Conversion of a 9.alpha.-hydroxy diasteromeric mixture (the component diastereomers are illustrated by CIV and CV below) wherein the C.sub.11 and C.sub.16 hydroxy functions have been preferentially blocked by tetrahydropyranyl or trialkylsilyl groups, to the corresponding phthalate half acid-ester, deblocking the C.sub.11 and C.sub.16  hydroxy functions and conversion of the diacid (e.g., CVI) to a bis salt (e.g., CVII) with an optically active amine (e.g., 1-(-)-.alpha.-methylbenzylamine, D-(+)-.alpha.-methylbenzylamine, brucine, dehydroaebietylamine, strychnine, quinine, cinchonine, cinchonindine, quindine, ephedrine, deoxyepedrine, amphetamine, (+)-2-amino-1-butanol, (-)-2-amino-1-butanol and the like). The resulting diastereomers are then separated by fractional crystallization and the individual components are then converted by acidification and saponification to the individual optically active parent 9.alpha.-hydroxy diastereomers (CIV) and (CV), oxidation of which, after preferential blocking of the C.sub.11 and C.sub.16 hydroxy functions with tetrahydropyranyl or trialkylsilyl groups, provides the corresponding individual 9-oxo diastereomers (CVIII) and (CIX). (For an appropriate literature procedure see E. W. Yankee, C. H. Lin and J. Fried, Journ. Chem. Soc., 1972, 1120). ##STR52##

Another procedure involves conversion of the 9.alpha.-hydroxy diastereomeric mixtures (as the prostenoic acid ester and with the C.sub.11 and C.sub.16 alcohol functions preferentially blocked as tetrahydropyranyl or trialkylsilyl ethers) to the diastereomeric carbamates with an optically active isocyanate, e.g., (+)-1-phenylethylisocyanate or (-)-1-phenylethylisocyanate, followed by deblocking. Separation of the diastereomers, for example (CX) and (CXI) can be accomplished by fractional crystallization or by the usual chromatographic procedures, or if necessary by high speed liquid chromatography involving, if necessary, recycling techniques. Base-treatment of the individual diastereomeric carbamates affords the individual diasteromeric alcohols, for example (CIV) and (CV). ##STR53##

It is also possible to effect resolution of the 9.alpha.-hydroxy derivative, preferably as the prostenoate esters, by esterification of the 9.alpha.-hydroxy function (prior preferential blocking of C.sub.11 and C.sub.16 hydroxy functions as tetrahydropyranyl or trialkylsilyl ethers) with an optically active acid, via its acid chloride followed by deblocking the C.sub.11 and C.sub.16 alcohol groups. Suitable optically active acids include .omega.-camphoric acid, methoxyacetic acid, 3.alpha.-acetoxy-.DELTA..sup.5 -etianic acid, (-)-.alpha.-methoxy-.alpha.-trifluoromethylphenylacetic acid and (+)-.alpha.-methoxy-.alpha.-trifluoromethylphenylacetic acid, and the like. The resulting diastereomeric esters, for example (CXII) and (CXIII), are then separated by fractional crystallization or by chromatographic techniques including, if necessary, the use of high speed liquid chromatography. Saponification of the individual diastereomers then provides the individual 9.alpha.-hydroxyprostenoic acid diastereomers (CIV) and (CV). ##STR54##

Another resolution procedure, less useful than the methods described above based on the 9.alpha.-hydroxy derivative but particularly applicable to 11-unsubstituted compounds of this invention, involves derivatization of the keto function of the diastereomeric 9-oxo-prostenoic acid or ester illustrated by (CVIII and CIX) with the usual type of ketone derivatizing agents bearing an optically active center. The resulting mixture of diastereomeric derivatives can then be separated by fractional crystallization or by chromatography or, if necessary, by high speed liquid chromatography. The individual diastereomeric keto derivatives, for example (CXIV) and (CXV), are then convertable to the individual 9-oxo diastereomers (CVIII) and (CIX) by any of the usual cleavage techniques, provided that they are sufficiently mild so as not to disturb the sensitive 11-hydroxy-9-keto system. (This latter point is not a problem with 11-unsubstituted derivatives.) Ketone reduction of the 9-oxo-enantiomer as .[.descried.]. .Iadd.described .Iaddend. hereinabove then provides the corresponding 9.alpha.-hydroxy or 9.beta.-hydroxy diastereomer (CIV) or (CV). Among the optically active reagents useful for ketone derivatization are 1-.alpha.-aminoxy-.alpha. -methylpentanoic acid hydrochloride [E. Testa et al., Helv. Chemica Acta, 47 (3), 766 (1973)], methylhydrazine, and 4-.alpha.-methylbenzylsemicarbazide. A useful procedure for the cleavage of oximes such as (CXIV) and (CXV) involves treatment of the oxime at about 60.degree. C. for about 4 hours in 1:2 aqueous-tetrahydrofuran buffered with ammonium acetate and containing titanium trichloride. ##STR55##

Other useful ketone derivatizing agents are optically active 1,2-glycols, e.g., D(-)-2,3-butanediol, or 1,2-dithiols, e.g., L(+)-2,3-butanedithiol. These are used to convert the 9-oxo derivative to 9,9-alkylenedioxa or 9,9-alkylenedithia derivatives, separation of diastereomers by chromatographic procedures followed by regeneration of the individual 9-oxo diastereomer by ketal cleavage all by procedures well-known in the art. Both ketalization and deketalization would have to be accomplished by procedures which would not disrupt the 11-oxo-9-keto system, which of course, is not a problem in the 11-unsubstituted series.

An alternative procedure for the conversion of substituted 1-alkyne (CXVI) to product (CXX) (formulae XXXIII and XXXVIII respectively of Flowsheet E) proceeds via vinyl lithium reagent (CXVII) (formula XXXIXc of Flowsheet F). ##STR56## In this procedure (CXVII) is reacted with the complex of cuprous iodide-tri-n-butylphosphine is an ether solvent at very low temperatures, e.g., -78.degree. C., to provide a divinyl lithio cuprate species (CXIX). This reagent (CXIX) is reacted with cyclopentenone (CXVIII) (XXXVII of Flowsheet E) in ether-hydrocarbon solvent at -78.degree. C. to 0.degree. C. to provide product (CXX), after workup with aqueous ammonium chloride.

The novel compounds of the present invention have potential utility as hypotensive agents, anti-ulcer agents, agents for the treatment of gastric hypersecretion and gastric erosion, agents to provide protection against the ulcerogenic and other gastric difficulties associated with the use of various non-sterodial antiinflammatory agents, e.g. indomethacin, aspirin, and phenylbutazone, bronchodilators, antimicrobial agents, anticonvulsants, abortifacients, agents for the induction of labor, agents for the induction of menses, fertility-controlling agents, central nervous system regulatory agents, salt and water-retention regulatory agents, diuretics, fat metabolic regulatory agents and as serum-cholesterol lowering agents. Certain of the novel compounds of this invention possess utility as intermediates for the preparation of other of the novel compounds of this invention.

Anti-ulcerogenic Effect of Indomethacin

The compounds of this invention also provide protection against the ulcerogenic properties of indomethacin. This assay was carried out in the following manner.

Rats were starved for 48 hours (water was given ad libitum). Indomethacin (20 mg./kg. of body weight) was administered by the subcutaneous route and one-half the dose of the test compound was administered by gavage at the same time. After 3 hours, the second half of the test compound was administered also by gavage. Five hours after the administration of indomethacin the animals were decapitated and the stomachs removed. The stomachs were washed with distilled water, blotted on gauze, cut along the larger curvature, and the contents rinsed with distilled water. The stomachs were spread out, pinned on a cork and visualized under magnifying glass for ulcers. The criteria for scoring of .[.ulers.]. .Iadd.ulcers .Iaddend. was as previously reported. [Abdel-Galil et al. Brit. J. Pharmac. Chemotherapy 33:1-14 (1968)]. SCORE 0-       Normal Stomach 1-       Petechial hemorrhage or pin point ulcers 2-       1 or 2 small ulcers 3-       Many ulcers, a few large 4-       Many ulcers, mainly large ______________________________________

A difference of at least 0.7 unit between the scores for control animals (treated with indomethacin but not test compound) and animals treated with indomethacin and test compound is considered indicative of activity for the test compound. (Control animals treated with neither indomethacin nor test compound give scores of about 0.5-0.8.) The results obtained in this assay with typical compounds of the present invention are set forth in Table I below. ______________________________________ Total oral dose: mg./kg Score Compound       of body weight treated control ______________________________________ 9-oxo-16-hydroxy- 13-trans-pro- stenoic acid   50          1.2      2.3 9-oxo-16-hydroxy- prostenoic acid 50          1.3      2.3 9-oxo-11.alpha.,16-di- 12.5        1.0      3.0 hydroxy-13-trans- 4.4         1.0      3.0 prostenoic acid 1.56        1.0      2.5 0.78        1.5      3.0 0.39        2.0      3.0 0.18        2.5      3.0 9-oxo-11.alpha.,17-di- hydroxy-13-trans- 25          1.3      2.7 prostenoic acid ______________________________________

The novel compounds of the present invention are also effective inhibitors of gastric acid secretion and of ulcer development in experimental animals, and thus are potentially valuable as agents for the control of gastric acid secretion and of gastric erosion and as anti-ulcer agents. Gastric acid secretion inhibitory action is usually measure by the "Shay rat" procedure.sup.(1,2) with some modifications as follows.

The rats (male, CFE strain) were starved for 48 hours (water was given ad libitum) to permit evacuation of stomach contents. On the morning of the experiment, under ether anesthesia, the abdominal region was shaved and a midline incision (1-11/2 inches) was made with a scapel. With the help of a closed curved hemostate the duodenum was picked up. Upon getting the duodenum into view, fingers were used to pull the stomach through the opening, the stomach was then gently manipulated with fingers to rid the stomach of air and residual matter which were pushed through the pylorus. Two-5 inch sutures were drawn under the pyloric-duodenal puncture. A ligature, at the juncture, was formed with one of the threads. The second ligature was also formed but not tightened.

The test compound and the vehicle, usually 1 ml./100 g. body weight, were injected into the duodenum as close as possible to the first ligature. After injection the second ligature was tightened below the injection site to minimize leakage. The stomach was placed back through the opening into the abdominal cavity, the area of incision was washed with saline and the incision was closed with autoclips. (Occasionally, instead of an intraduodenal injection, animals were dosed by the oral or subcutaneous route. In the latter case, dosing was done 30 to 60 minutes before the operation.)

Three hours later, the rats were decapitated and exanguinated, taking care that blood did not drain into the esophagus. The abdominal cavity was exposed by cutting with scissors and the esophagus close to the stomach was clamped off with a hemostat, the stomach was removed by cutting above the hemostat (the .[.espphagus.]. .Iadd.esophagus .Iaddend.was cut) and between the two sutures. Extraneous .[.tisue.]. .Iadd.tissue .Iaddend.was removed, the stomach washed with saline and blotted on gauze. A slit was carefully made in the stomach which was held over a funnel and the contents were collected in a centrifuge tube. The stomach was further cut along the outside edge and turned inside out. Two ml. H.sub.2 O were used to wash the stomach contents into the respective centrifuged tube. The combined stomach contents and wash were then centrifuged out for 10 min. in the International Size 2 Centrifuge (setting at 30). The supernatant was collected, volume measured and recorded, 2 drops of a phenylphthalein indicator (1% in 95% ethanol) were added and the solution was titrated with 0.02N NaOH (or with 0.04N NaOH when large volumes of stomach contents were encountered to pH 8.4 (because of usual coloring of the stomach contents, phenolphthalein was only used to permit visual indication that the end point was near) and the amount of acid present was calculated.

Compounds inducing inhibition of gastric acid secretion of 20% or more were considered active. In a representative operation, and merely by way of illustration, the results obtained with this assay with typical compounds of the present invention are given in Table II below. ______________________________________ Intraduodenal dose, mg./kg Percent Compound         of body weight Inhibition ______________________________________ 9-oxo-16-hydroxy-13- trans-prostenoic acid             50           67 9-oxo-16-hydroxy prostanoic acid  50           58 9-oxo-20-hydroxy 13-trans-prostenoic acid             100          56 9-oxo-18/19-hydroxy- 13-trans-prostenoic acid             100          28 9-oxo-18-hydroxy-19, 20-dinor-13-trans- prostenoic acid  50           21 Ethyl 9-oxo-18-hy- droxy-19,20-dinor- 13-trans-prostenoate 100          49 9-oxo-11.alpha.,16-dihy- 1.6*         79 droxy-13-trans-pro- 0.8*         53 stenoic acid     0.4*         27 9-oxo-11.alpha.,17-dihy- droxy-13-trans-pro- stenoic acid     50           73 9-oxo-20-hydroxy-10, 13-trans-prosta- 50           91 dienoic acid ______________________________________

Bronchodilator activity was determined in guinea pigs against bronchospasms elicited by intravenous injections of 5-hydroxytryptamine, histamine or acetylcholine by the Konzett procedure, [See J. Lulling, P. Lievens, F. El Sayed and J. Prignot, Arzneimittel-Forschung, 18, 995 (1968).]

In the Table which follows bronchodilator activity for representative compounds of this invention against one or more of the three spasmogenic agents is expressed as an ED.sub.50 determined from the results obtained with three logarithemic cumulative intravenous dose. __________________________________________________________________________ Bronchodilator Activity (Konzett Assays) __________________________________________________________________________ ED.sub.50 mg./kg. Spasmorgenic Agent 5-hydroxy- Compound tryptamine  histamine  choline __________________________________________________________________________ 9-oxo-20-hydroxy-13- trans-prostenoic 117 .times. 10.sup.-3 30 .times. 10.sup.-3 2.16 acid 9-oxo-18-hydroxy- 19,20-dinor-13- 2.85       2.22   10.0 trans-prostenoic acid 9-oxo-16-hydroxy- 13-trans-prostenoic 277 .times. 10.sup.-a 34.6 .times. 10.sup.-3 455 .times. 10.sup.-3 acid 9-oxo-16-hydroxy- prostanoic acid 92.7 .times. 10.sup.-3 477 .times. 10.sup.-a 1.13 9-oxo-18/19-hydroxy- 13-trans-prostenoic 1.19       1.04 acid 9-oxo-11.alpha.,16-dihy- droxy-13-trans- .607 .times. 10.sup.-3 166 .times. 10.sup.-3 .420 .times. 10.sup.-3 prostenoic acid 9-oxo-11.alpha.,17-dihy- droxy-13-trans-pro- 0.235      0.45   0.518 stenoic acid 9-oxo-11.alpha.,20-dihy- droxy-13-trans- 0.377      0.077  2.34 prostenoic acid 9-oxo-20-hydroxy-10, 13-trans-prosta- 1.32       2.28 dienoic acid __________________________________________________________________________

This invention will be described in greater detail in conjunction with the following specific examples. 2-carbalkoxy(methyl/ethyl)-2-(4-carbethoxybutyl)cyclopentan-1-one

To a stirred solution of the sodium cyclopentanone carboxylate enolate in dimethoxyethane, prepared from 187 g. (1.248 moles) of 2-cyclopentanone carboxylate (mixed methyl and ethyl esters), 52.4 g. (1.248 moles) sodium hydride (57.2% in mineral oil) and 1.6 l. of dimethoxyethane, is added dropwise 309 g. (1.212 moles) of ethyl 5-iodovalerate. The reaction mixture is stirred and heated at reflux for 18 hours. The mixture is cooled and filtered. The solvent is removed from the filtrate by evaporation and the residue is poured into dilute hydrochloric acid and extracted with ether. The combined extracts are washed with water and saline, dried over magnesium sulfate and evaporated to give an oil. The oil is distilled under reduced pressure to give 274 g. of a light yellow oil, b.p. 140.degree.-143.degree. C. (0.17 mm).

A stirred mixture of 274 g. of 2-carbalkoxy(mixed methyl and ethyl esters)-2-(4-carbethoxybutyl)cyclopentan-1-one (Example 1), 600 ml. of 20% hydrochloric acid and 325 ml. of acetic acid is heated at reflux for 20 hours. Solution occurs in approximately one-half hour. The solution is cooled and diluted with water and extracted with ether. The combined extracts are washed with .[.salline.]. .Iadd.saline .Iaddend.and dried over magnesium sulfate and evaporated. The residue is evaporated twice with toluene to give 144 g. of an oil.

A stirred solution of 124 g. (0.673 mole) of 2-(4-carboxybutyl)cyclopentan-1-one (Example 2), 800 ml. of ethanol and 1 g. of p-toluenesulfonic acid monohydrate is heated at reflux for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The ether solution is washed with saline, dilute sodium bicarbonate solution and again with saline, dried over magnesium sulfate and evaporated. The oil is distilled under reduced pressure to give 149 g. of a colorless oil, b.p. 106.degree.-109.degree. C. (0.23 mm). 2-carbalkoxy(methyl/ethyl)-2-(3-carbethoxypropyl)cyclopentan-1-one

In the manner described in Example 1, treatment of 2-cyclopentanone carboxylate (mixed methyl and ethyl esters) with sodium hydride in dimethoxyethane followed by ethyl 4-iodobutyrate gives a yellow oil, b.p. 136.degree.-137.degree. C. (0.16 mm).

In the manner described in Example 2, treatment of 2-carbalkoxy(mixed methyl and ethyl esters)-2-(3-carbethoxypropyl)cyclopentan-1-one (Example 4) with a 20% hydrochloric acid and acetic acid mixture gives a yellow oil.

In the manner described in Example 3, treatment of 2-(3-carboxypropyl)cyclopentan-1-one (Example 5) with p-toluenesulfonic acid monohydrate in ethanol gives a colorless oil, b.p. 93.degree. C. (0.10 mm). 2-(6-carbethoxyhexyl)-1-cyclopentanon-2-carboxylate

In the manner described in Example 1, ethyl and methyl 2-cyclopentanone carboxylate is reacted with ethyl 7-bromoheptanoate to furnish the subject product, b.p. 147.degree. C. (0.09 mm).

In the manner described in Example 2, ethyl and methyl 2-(6-carbethoxyhexyl)-1-cyclopentanone-2-carboxylate (Example 7) is hydrolyzed to furnish the subject product, b.p. 143.degree. C. (0.05 mm).

In the manner described in Example 3, 2-(6-carboxyhexyl)cyclopentan-1-one (Example 8) is esterified to furnish the subject product, b.p. 110.degree. C. (0.03 mm).

A stirred solution of 100 g. of 2-(6-carbethoxyhexyl)cyclopentan-1-one (Example 9) in 250 ml. of acetic anhydride containing 0.940 g. of p-toluenesulfonic acid monohydrate is heated to boiling under partial reflux allowing distillate at 118.degree. C. or less (i.e., acetic acid) to escape through a Vigreux column equipped with a condenser to collect the distillate. After 16 hours, during which period acetic anhydride is added in portions in order to keep the solvent level at at least 100 ml., the solution is cooled and poured cautiously into a stirred cold mixture of saturated sodium bicarbonate solution (400 ml.) and hexane (250 ml.). The resulting mixture is stirred for an additional 30 minutes during which period solid sodium bicarbonate is added periodically to insure a basic solution. The hexane layer is separated and washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation of the residual oil gives 102 g. (87%) of pale yellow oil, b.p. 118.degree. C. (0.07  mm).

In the manner described in Example 10, treatment of 2-(3-carbethoxypropyl)cyclopentan-1-one (Example 6) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 98.degree. -103.degree. C. (0.35 mm).

In the manner described in Example 10, treatment of 2-(4-carbethoxybutyl)cyclopentan-1-one (Example 3) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 109.degree.-110.degree. C. (0.37 mm).

To a rapidly stirred mixture of 50 g. of 1-acetoxy-2-(6-carbethoxyhexyl)cyclopent-1-ene (Example 10) in 150 ml. of chloroform, 200 ml. of water and 18.8 g. of calcium carbonate, cooled in an ice bath, is added dropwise over a period of about 30 minutes, a solution of 30 g. of bromine in 50 ml. of carbon tetrachloride. After stirring for an additional 45 minutes the chloroform layer is separated and washed successively with dilute sodium thiosulfate solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure.

The residual oil is dissolved in 50 ml. of N,N-dimethylformamide and added to a mixture of 33 g. of lithium bromide and 32 g. of lithium carbonate in 375 ml. of N,N-dimethylformamide, previously dried by refluxing with 375 ml. of benzene under a Dean-Stark apparatus followed by distillation of the benzene. The mixture is stirred at the reflux temperature for 30 minutes, then cooled and poured into 850 ml. of ice-cold water. The resulting mixture is acidified (cautiously) with 4N hydrochloric acid and extracted with ether three times. The combined ether extracts are washed with saturated sodium chloride solution dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure to afford 41.5 g. of an amber oil. In order to convert any isomeric material to the desired product, 41.5 g. of the above material is treated with 0.500 g. of p-toluenesulfonic acid monohydrate in 450 ml. of absolute alcohol at the reflux temperature for 18 hours. The solution is taken to dryness under reduced pressure. The resulting gum is dissolved in ether and washed with saturated sodium bicarbonate solution, saturatd sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure. The residual oil is distilled to give 30.2 g. of product; b.p. 118.degree. C. (0.05 mm); .lambda..sub.max.sup.MeOH 229 m.mu. (.epsilon.9950); .lambda..sub.max 5.75, 5.85, 6.15, 8.45 .mu.; vapor phase chromatography shows 99% product, containing 1% 2-(6-carbethoxyhexyl)cyclopentan-1-one.

This product can be purified by the following procedure. A mixture of 120 g. of 2-(6-carbethoxyhexyl)-2-cyclopentenone, containing approximately 5% of the saturated analogue, and 7.67 g (10 mole percent) of p-carboxyphenylhydrazine in 400 ml. of absolute ethanol is stirred at ambient temperatures for 18 hours and is then refluxed for 1 hour. The mixture is cooled, the solvent is evaporated, and the residue is taken up into 150 ml. of chloroform and passed through a column of 450 g. of aluminum oxide (Merck). The .[.fltrate.]. .Iadd.filtrate .Iaddend.is evaporated to yield a colorless oil containing <0.5% of the saturated impurity.

In the manner described in Example 13, bromination of 1-acetoxy-2-(3-carbethoxypropyl)cyclopent-1-ene (Example 11) followed by dehydrobromination with lithium bromide and lithium carbonate is productive of the subject compound.

In the manner described in Example 13, treatment of 1-acetoxy-2-(4-carbethoxybutyl)cyclopent-1-ene (Example 12) with bromine and subsequent treatment of the brominated product with a mixture of lithium bromide and lithium carbonate in N,N-dimethylformamide is productive of the subject compound. Treatment of this product with p-carboxyphenylhydrazine by the procedure of Example 13 furnishes a product which contains less than 0.5% of the corresponding saturated ketone.

To a mixture of 35.97 g. (0.151 mole) or of 2-(6-carbethoxyhexyl)-2-cycopentenone (Example 13) and 15.0 g. (0.180 mole) of methoxyamine hydrochloride in 300 ml. of absolute ethanol is added 25 ml. of pyridine and the resulting solution is stirred for 20 hours at ambient temperatures. The solvent is evaporated and the residue is partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (Na.sub.2 SO.sub.4), and the solvent is evaporated to yeild an oil. Distillation yields 38.7 g. of a colorless oil, b.p. 115.degree.-118.degree. C. (0.075 mm). IR (film): 1740, 1627, 1053, 890 cm.sup.-1. .lambda..sub.max (MeOH) 243 (13,000). NMR.delta.(CDCl.sub.3): 3.89.

To an ice cooled solution of 34.10 g. (0.128 mole) of 1-methoximino-2-(6-carbethoxyhexyl)-2-cyclopentene (Example 16) in 200 ml. of benzene under nitrogen is added dropwise 225 ml. of a 25% solution of diisobutyl aluminum hydride in hexane. The resulting solution is stirred for 2 hours at 0.degree.-5.degree. C., poured onto ice and dilute hydrochloric acid, and the aqueous phase is saturated with sodium chloride. The organic phase is separated, washed with saturated brine, dried (Na.sub.2 SO.sub.4), and evaporated to yield an oil. The latter is dissolved in 100 ml. of hot hexane and cooled to yield 24.3 g. of crystals, m.p. 62.degree.-64.degree. C. IR (KBr) 3260, 1630, 1059, 893 cm.sup.-1. .lambda..sub.max 243 (14,200). NMR (CDCl.sub.3).delta.: 2.37. 1-methoximino-2-(7-p-toluenesulfonyloxyheptyl)-2-cyclopentene

To a solution of 5.00 g. (0.222 mole) of 1-methoximino-2-(7-hydroxyheptyl)-2-cyclopentene (Example 17) in 50 ml. of dry pyridine at 0.degree. C. is added 8.45 g. (0.0444 mole) of p-toluenesulfonyl chloride and the resulting solution is chilled at 5.degree. C. overnight. The mixture is partitioned between 300 ml. of ice water and diethyl ether. The organic phase is washed with 1:1 ice cold hydrochloric acid, cold water, and cold saturated brine, dried (NaSO.sub.4 /K.sub.2 CO.sub.3), and evaporated under reduced pressure at room temperature to yield an oil. The latter is dissolved in 600 ml. of hexane, treated with 0.5 g. of Darco, filtered and evaporated to yeild 7.7 g. of colorless oil. IR (film) 1600, 1192, 1182, 1053, 890 cm.sup.-1. .lambda..sub.max (MeOH) 228 and 243.

To an alcoholic solution of sodiodiethyl malonate, prepared from 0.847 g. (0.0368 g. atoms) of sodium, 100 ml. of absolute ethanol, and 7.05 g. (0.0440 mole) of diethyl malonate is added 7.7 g. of the tosylate of Example 18 and the mixture is refluxed for 2 hours under a nitrogen atmosphere. The mixture is partitioned between cold dilute hydrochloric acid and diethyl ether, and the organic phase is washed with water and saturated brine, dried (Na.sub.2 SO.sub.4), and evaporated to yield an oil. The excess diethyl malonate is distilled off under reduced pressure to yield 6.45 g. of a yellowish oil. IR (film) 1755, 1728, 1625, 1054, 890 cm.sup.-1.

A mixture of 6.45 g. of the diester of Example 19 and 6.72 g. of potassium hydroxide in 150 ml. of 1:1 aqueous methanol is refluxed for 1 hour, cooled, and is partitioned between water and diethyl ether. The aqueous phase is acidified with hydrochloric acid, extracted with ether, and the organic phase is washed with water and saturated brine, dried (Na.sub.2 SO.sub.4) and evaporated to yield a solid. The solid is crystallized from benzene to yield 4.15 g. of tan crystals, m.p. 135.degree.-137.degree. C. (--CO.sub.2).

A solution of 3.926 g. (0.0126 mole) of the diacid of Example 20 in 20 ml. of xylene is refluxed for 1.5 hours, cooled and evaporated to yield a tan solid. IR (KBr) 1720, 1618, 1179, .[.1050,,.].  .Iadd.1050, .Iaddend.986 cm.sup.-1.

The acid methoxime from Example 21 is refluxed for 5 hours with 55 ml. of acetone and 20 ml. of 2N hydrochloric acid. The mixture is cooled, the solvent is evaporated, and the residue is partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (Na.sub.2 SO.sub.4), and evaporated to yield a tan solid. IR (KBr) 1745, 1665 cm.sup.-1. .lambda..sub.max (MeOH) 228 (12,600).

The acid ketone from Example 22 is Fisher esterfied with 100 ml. of absolute ethanol, 100 ml. of benzene, and 20 mg. of p-toluenesulfonic acid for 6 hours, cooled, and the solvent is evaporated. The resulting oil is dissolved in 3:1 benzene-ether and the solution is passed through a column of 100 g. of Florisil. The filtrate is evaporated and the residue is distilled to yield 2.97 g. of a colorless oil, b.p. 137.degree.-139.degree. C. (0.05 Torr).

Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenone (Example 15) with methoxyamine hydrochloride in the manner described in Example 16 gives an oil, b.p. 107.degree.-109.degree. C. (0.05 mm). IR (film): 1740, 1628, 1050, 885 cm.sup.-1. .lambda..sub.max (MeOH) 243 (13,600).

Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenomethoxime (Example 24) with diisobutyl aluminum hydride in the manner described in Example 17 gives crystals, m.p. 33.degree.-35.degree. C. IR (KBr) 3420, 1630, 1050, 886 cm.sup.-1. .lambda..sub.max.sup.MeOH 243 (12,020).

Treatment of 2-(5-hydroxypentyl)-2-cyclopentenone methoxime (Example 25) with p-toluenesulfonyl chloride in pyridine in the manner described in Example 18 gives a colorless oil. IR (film) 1600, 1190, 1180, 1050, 885 cm.sup.-1.

To a solution of sodio diethyl ethylmalonate, prepared from 1.63 g. (0.0387 mole) of sodium hydride in mineral oil (57.2%), 100 ml. of ethylene glycol dimethyl ether and 8.5 g. (0.0452 mole) of ethyl diethyl malonate, is added 7.5 g. of tosylate from Example 26 in 20 ml. of ethylene glycol dimethyl ether and the mixture is refluxed for 3 hours and then allowed to stand at room temperature for 18 hours under nitrogen atmosphere. The reaction mixture is filtered and most of the solvent is removed. The mixture is partitioned between cold dilute hydrochloric acid and diethyl ether, and the organic phase is washed with water and saturated brine, dried (MgSO.sub.4), and evaporated to yield an oil. The excess ethyl diethyl malonate is distilled off under reduced pressure to yield 6.7 g. of a yellow oil. IR (film) 1755, 1728, 1627, 1050, 885 cm.sup.-1.

Treatment of 2-(6,6-dicarbethoxyoctyl)-2-cyclopentene methoxime (Example 26) with potassium hydroxide, and 1:1 aqueous methanol in the manner described in Example 20 gives a light yellow oil.

In the manner described in Example 21, treatment of 2-(6,6-dicarboxyoctyl)-2-cyclopentenone methoxime (Example 28) with xylene at reflux for 18 hours gives a yellow oil.

Treatment of 2-(6-carboxyoctyl)-2-cyclopentenone methoxime (Example 29) with acetone and 2N hydrochloric acid in the manner described in Example 22 gives a light yellow oil.

Treatment of 2-(6-carboxyoctyl)-2-cyclopentenone (Example 30) with thionyl chloride and then treatment of the acid chloride with ethanol in the usual manner gives an amber oil. The oil is placed on a magnesia-silica gel column and eluted with 3:1 benzene:ether. The solvent is removed and the residue is distilled, b.p. 122.degree. C. (0.06 mm).

To 486 mg. (0.02  g.-atoms) of magnesium in 5 ml. of toluene containing one molar equivalent of tetrahydrofuran per equivalent of magnesium and one percent iodine (calculated in weight of magnesium) is added dropwise 3.86 g. (0.02 mole) of 4-chloro-1-tetrahydropyranyloxybutane over a period of one hour with stirring, under nitrogen at 70.degree. C. The reaction mixture is stirred at 70.degree. C. for four hours. This reagent is then added dropwise to 3 g. (0.015 mole) of ethyl isopropylidenemalonate in 40 ml. of tetrahydrofuran containing 392 mg. of tetrakis [iodo(tri-n-butylphosphine)copper (I)] and stirred at room temperature for 2 hours. The reaction mixture is poured into cold dilute hydrochloric acid and extracted with ether. The ether extract is dried over magnesium sulfate and concentrated to give 5.92 g. of subject product as an oil.

A solution of 3.5 g. (0.01 mole) of diethyl 1,1-dimethyl-5-tetrahydrofuranyloxypentylamalonate in 70 ml. of ethanol containing 3 ml. of hydrochloric acid is allowed to stir at room temperature for 18 hours. The solution is concentrated, diluted with water and extracted with ether. The ether extract is washed with water, dried over magnesium sulfate and concentrated to give 3.262 g. of a light yellow oil. The oil is purified by distillation, b.p. 116.degree.- 117.degree. C. (0.05 mm).

A mixture of 32 g. (0.117 mole) of diethyl 1,1-dimethyl-5-hydroxypentylmalonate, 25 g. of potassium hydroxide and 600 ml. of methanol-water (1:1) is heated at reflux for 8 hours and then allowed to stand at room temperature for 18 hours. The methanol is removed, diluted with water and the reaction mixture is acidified with concentrated hydrochloric acid. The mixture is extracted with ether. The extract is washed with water and saline, dried over anhydrous magnesium sulfate and concentrated to give 27 g. of 1,1-dimethyl-5-hydroxypentylmalonic acid. This crude oil is dissolved in 200 ml. of bis-(2-methoxyethyl)ether and is heated at reflux for 4 hours and then allowed to stand at room temperature overnight. The solvent is removed and the reaction mixture is diluted with water and extracted with ether. The organic solution is washed with saline, dried over magnesium sulfate and concentrated to give 18 g. of product as an oil.

To a solution of 3.484 g. (0.02 mole) of 3,3-dimethyl-7-hydroxyheptanoic acid in 25 ml. of chloroform containing 3 drops of dimethylformamide is added 5.8 ml. (0.08 mole) of thionyl chloride and the solution is then heated at reflux for 3-4 hours. The solution is concentated to give the intermediate 3,3-dimethyl-7-chloro-1-heptanoyl chloride. The acid chloride is dissolved in a minimum amount of benzene and added slowly to 20 ml. benzene, 10 ml. of ethanol and 2.65 ml. of collidine. The solution is heated at reflux for one hour and then concentrated. The residue is dissolved in ether, washed with water, dilute sodium bicarbonate solution and saline. The organic solution is dried over magnesium sulfate and concentrated to give 3.57 g. of product as a yellow oil.

To a solution of 3.57 g. (0.0162 mole) of ethyl 3,3-dimethyl-7-chloroheptanoate in 100 ml. of methyl ethyl ketone is added 4 g. of sodium iodide and the mixture heated at reflux for 18 hours. The reaction mixture is cooled, filtered and concentrated. The residue is partitioned between ether and water. The aqueous phase is extracted several times with ether. The extract is washed with sodium bisulfite solution, water and saline. The organic solution is dried over magnesium sulfate and concentrated to give 4.182 g. of a yellow oil. The material is purified by distillation, b.p. 86.degree.-87.degree. C. (0.18 Torr). 2-carbalkoxy(methyl/ethyl)-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1 -one

This compound is prepared by treatment of sodiocyclopentanone carboxylate enolate with ethyl 3,3-dimethyl-7-iodoheptanoate by the procedure described in Example 1.

This compound is prepared by decarbalkoxylation of 2-carbalkoxy (mixed methyl and ethyl ester)-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one by the procedure described in Example 2.

Esterification of 2-(6-carboxy-5,5-dimethylhexyl)cyclopentan-1-one with ethanol by the procedure described in Example 3 is productive of the subject compound.

This compound is prepared from 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one and acetic anhydride by the process described in Example 10.

This compound is prepared from 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene via bromination and dehydrobromination according to the procedure described in Example 13.

In the manner described for the preparation of the compound of Example 16, 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene is prepared from 2-(3-carbethoxypropyl)-2-cyclopentenone (Example 14) and methoxyamine hydrochloride.

In the manner described for the preparation of the compound of Example 17, 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene is prepared from 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene and diisobutylaluminum hydride.

To an ice cold solution of 4.833 g. (0.0266 mole) of 2-(4-hydroxypentane)-1-methoximino-2-cyclopentene in 50 ml. of dry tetrahydrofuran under nitrogen is added 16.7 ml. of 1.6 molar n-butyl lithium in hexane, dropwise. The reaction mixture is stirred for 0.5 hour and then 4.85 g. (0.029 mole) of ethyl bromoacetate is added dropwise. The reaction mixture is stirred overnight at room temperature and then refluxed for 1.5 hours. The reaction is cooled and poured into water and extracted several times with ether. The ether extracts are washed with saline, dried over magnesium sulfate, and concentrated. The residue is placed on an alumina column, chloroform being used as a wash solvent. The combined washings are concentrated to dryness to give 4.903 g. of product an a yellow oil.

In the manner described in Example 22, treatment of 2-(6-carbethoxy-5-oxahexyl)-1-methoximino-2-cyclopentene with acetone and 2N hydrochloric acid at reflux gives the subject compound as a yellow oil.

In the manner described in Example 23, treatment of 2-(6-carboxy-5-oxahexyl)-2-cyclopentenone with p-toluenesulfonic acid in ethanol produces the subject product as a light yellow oil.

To an ice cold solution of 3.66 g. (0.02 mole) of 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene (Example 43) in 50 ml. of 1,2-dimethoxyethane under nitrogen is added dropwise 17 ml. of 1.6 M n-butyl lithium in hexane. The reaction mixture is stirred for half an hour and then the lithium salt of chloroacetic acid, prepared from 1.89 g. (0.02 mole) of chloroacetic acid and 16 ml. of 1.6M n-butyl lithium in 20 ml. of dimethoxyethane, is added and the reaction mixture is heated at reflux for 48 hours. The solvent is evaporated and the residue is partitioned between ether and water. The aqueous phase is acidified with hydrochloric acid and extracted with ether. The organic phase is washed with water and saturated saline solution, dried (MgSO.sub.4), and evaporated to give 3.35 g. of a yellow oil.

In the manner described in Example 22, treatment of 2-(6-carboxy-5-oxahexyl)-1-methoximino-2-cyclopentene (Example 47) with acetone and 2N hydrochloric acid at reflux gives the subject compound as a yellow oil.

To a solution of 1.83 g. (0.01 mole) of 1-methoximino-2-(4-hydroxybutyl)-2-cyclopentene (Example 43) in 10 ml. of methylene chloride containing 1.52 g. (0.015 mole) of triethylamine is added 1.265 g. (0.011 mole) of methanesulfonyl chloride over a period of 5-10 minutes at -10.degree.-0.degree. C. Stirring is continued for 15 minutes and the solution is then washed with cold water cold 10% hydrochloric acid, cold sodium bicarbonate solution, and cold saline solution. The organic phase is dried (MgSO.sub.4) and concentrated to give an oil which solidifies upon cooling. Crystallization from ether-petroleum ether (30.degree.-60.degree. C.) gives 1.797 g. of white crystals, m.p. 67.degree.-68.degree. C.

A mixture of 2.75 g. (0.01 mole) of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene (Example 60) and 1.47 g. (0.03 mole) of sodium cyanide in 20 ml. of dry N,N-dimethylformamide is heated at 65.degree.-70.degree. C. for 3 hours. The cooled reaction mixture is poured into water and extracted with diethyl ether. The organic phase is washed with water and saturated saline solution, dried (MgSO.sub.4), and evaporated to give 1.89 g. of a light yellow oil.

A mixture of 1.89 g. (0.0092 mole) of 1-methoximino-2-(5-cyanopentyl)-2-cyclopentene (Example 50) and 1 g. (0.025 mole) of sodium hydroxide in 50 ml. of 1:1 aqueous-ethanol is refluxed for 48 hours, coled, and partitioned between water and diethyl ether. The aqueous phase is acidified with hydrochloric acid, extracted with diethyl ether, and the organic phase is washed with water and saturated saline solution, dried (MgSO.sub.4), and evaporated to give 1.86 g. of a yellow oil.

A solution of 1.86 g. (0.00825 mole) 1-methoximino-2-(5-carboxypentyl)-2-cyclopentene (Example 51) in 44 ml. of acetone and 13.1 ml. of 2N hydrochloric acid is refluxed for 5 hours. The solvent is partially evaporated and a solid precipitates and is collected. The residue is extracted with diethyl ether and the organic phase is washed with saturated saline solution, dried (MgSO.sub.4), and evaporated to yield additional solid. The combined solid material is crystallized from ether/pet ether (30.degree.-60.degree. C) to yield crystalline material, m.p. 70.degree.-72.degree. C.

A solution of 1.309 g. (0.00668 mole) of 2-(5-carboxypentyl)-2-cyclopentenone (Example 52) and 90 mg. of p-toluenesulfonic acid in 150 ml. of ethanol is refluxed for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The organic phase is washed with water, sodium bicarbonate solution, and saturated saline solution, dried (MgSO.sub.4), and evaporated to give 1.371 g. of light yellow oil.

A mixture of sodiocyclopentanone carboxylate, prepared from 1200 g. (8.0 moles) of cyclopentanone carboxylate (methyl and ethyl esters) and 200 g. (8.3 moles) of mineral oil free sodium hydride in 10 l. of 1,2-dimethoxyethane, 1320 g. (8.0 moles) of 5-chloro-1-amyl acetate [M.E. Synerholm, Journ. Amer. Chem. Soc., 69, 2681 (1947)], and 1200 g. (8.0 moles) of sodium iodide is refluxed under nitrogen for 18 hours. The mixture is cooled, connected to 4 l. and partitioned between dilute hydrochloric acid and diethyl ether. The organic phase is washed with water and saturated brine, dried (MgSO.sub.4), and evaporated to yield 1920 g. of an oil. 2-(5-hydroxypentyl)cyclopentanone/2-(5-acetoxypentyl)-cyclopentanone

A mixture of 4,500 g. (16.2 moles) of 2-(5-acetoxypentyl)-2-carbomethoxy/carboethoxy-cyclopentanone (Example 54), 2.2 l. of glacial acetic acid, 1 l. of concentrated hydrochloric acid, and 1 l. of water is refluxed for 18 hours, cooled, and partitioned between saturated brine and benzene. The organic phase is washed with saturated brine, dried (MgSO.sub.4), and evaporated in vacuo to yield 3155 g. of an oil.

A solution of 400 g. (2.04 moles) of a mixture of 2-(5-hydroxypentyl)cyclopentanone and 2-(5-acetoxypentyl)cyclopentanone (Example 55) and 4.0 g. of p-toluenesulfonic acid monohydrate in 11 l. of acetic anhydride is refluxed acetic a rate to maintain a steady distillation of acetic acid from the reaction through a relix-packed fractionation column. The reaction is continued with the addition of acetic anhydride to maintain a constant volume until complete conversion of starting materials to product is evident. The mixture is cooled and partitioned between 2 l. of hexane and 3 l. of cold water containing solid sodium bicarbonate to maintain a neutral pH. The organic phase is washed with saturated brine, dried (MgSO.sub.4), and evaporated to yield 452 g. of an oil.

To a well stirred mixture of 405 g. (4.05 moles) of calcium carbonate, 3 l. of water, and 2.5 l. of chloroform cooled to 5.degree. C. is added simultaneously 1016 g. (4.0 moles) of 1-acetoxy-2-(5-acetoxy-pentyl)-1-cyclopentene (Example 56) and a solution of 648 g. (4.05 moles) of bromine in 500 ml. of carbon tetrachloride at a rate to maintain a temperature below 10.degree. C. The mixture is stirred for half an hour after addition of the reagents and the phases are then separated. The organic phase is washed with 2% sodium thiosulfate solution, water, and saturated brine, dried (MgSO.sub.4), and evaporated in vacuo to an oil. The oil is immediately added to a refluxing slurry of 500 g. (5.0 moles) of calcium carbonate in 2.5 l. of N,N-dimethylacetamide under nitrogen and the mixture is then refluxed for 30 minutes. The mixture is cooled, filtered, and partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (MgSO.sub.4), and evaporated to yield 757 g. of an oil, b.p. 116.degree.-118.degree. C. (0.25 mm.).

In the manner described for Example 16, 2-(5-acetoxypentyl)-2-cyclopentenone (Example 57) is treated with methoxyamine hydrochloride in pyridine and ethanol to yield the subject compound, b.p. 101.degree.-103.degree. C. (0.20 mm.).

A mixture of 74 g. (0.22 mole) of 1-methoximino-2-(5-acetoxypentyl)-2-cyclopentene (Example 58) and 56 g. (1.0 mole) of potassium hydroxide in 300 ml. of 1:1 aqueous methanol is refluxed for 2 hours and then cooled. The solvent is partially removed in vacuo and the residue is partitioned between saturated brine and diethyl ether. The organic phase is washed with saturated brine, dried (MgSO.sub.4), and evaporated to yield an oil which crystallized, m.p. 35.degree.-36.degree. C.

To a cold solution of 9.85 g. (0.05 mole) of 1-methoximino-2-(5-hydroxypentyl)-2-cyclopentene (Example 59) and 7.6 g. (0.075 mole) of triethylamine in 100 ml. of methylene chloride at -10.degree. C. is added 6.3 g. (0.055 mole) of methanesulfonyl chloride at a rate to maintain a temperature of -10.degree. C. The mixture is then stirred for 15 minutes and then poured into ice water. The organic phase is washed with cold 10% hydrochloric acid, cold saturated sodium bicarbonate solution, and cold saturated brine, dried (MgSO.sub.4), and evaporated to yield a solid, m.p. 78.degree.-80.degree. C.

To a suspension of sodiodiethylmalonate in 1,2-dimethoxyethane, prepared from 248 g. (1.55 moles) of diethyl malonate and 17.2 g. (0.95 mole) of mineral oil free sodium hydride in 1 l. of 1,2-dimethoxyethane under nitrogen, is added 170 g. (0.62 mole) of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene (Example 60) in 1.5 l. of 1,2-dimethoxyethane and the mixture is refluxed for 5 hours. The mixture is cooled, filtered, and the solvent is evaporated. The residue is partitioned between cold dilute hydrochloric acid and water, and the organic phase is washed with saturated brine, dried (MgSO.sub.4), and evaporated to remove solvent and excess diethyl malonate to yield 209 g. of an oil.

In the manner described in Example 20, 1-methoximino-2-(6,6-dicarbethoxyhexyl)-2-cyclopentene is treated with potassium hydroxide in 1:1 aqueous methanol and then hydrochloric acid to yield the desired compound as crystals from diethyl ether, m.p. 110.degree.-115.degree. C.

A solution of 141 g. (0.50 mole) of 1-methoximino-2-(6,6-dicarboxyhexyl)-2-cyclopentene in 500 ml. of bis-(2-methoxyethyl) ether is refluxed for 2 hours, cooled, and evaporated to yeild an oil. The latter is crystallized from hexane to yield 92 g. of solid, m.p. 70.degree.-72.degree. C.

In the manner described in Example 22, treatment of 1-methoximino-2-(6-carboxyhexyl)-2-cyclopentene (Example 63) with acetone and 2N hydrochloric acid at reflux provides the subject compound.

Fischer estification of 2-(6-carboxyhexyl)-2-cyclopentenone (Example 64) in the manner of Example 23 provides the subject compound. 1-methoximino-2-(6-fluoro-6,6-dicarbethoxyhexyl)-2-cyclopentene

To a solution of sodiodiethyl fluoromalonate, prepared from 2.062 g. (0.0491 mole) of sodium hydride in mineral oil (57.2%), 40 ml. of dry N,N-dimethylformamide and 8.174 g. (0.0458 mole) of diethyl fluoromalonate is added dropwise 11.32 g. (0.0413 mole) of 1-methoximino-2-(5-methylsulfonyloxypentyl)-2-cyclopentene (Example 60) in 60 ml. of N,N-dimethylformamide. The mixture is refluxed for 2 hours under a nitrogen atmosphere. The mixture is concentrated and partitioned between cold dilute hydrochloric acid and diethyl ether, and the organic phase is washed with saturated brine, dried (MgSO.sub.4), and evaporated to yield 13.631 g. (92%) of a yellow oil.

A mixture of 13.631 g. of the diester of Example 66 and 16 g. of potassium hydroxide in 364 ml. of 1:1 aqueous methanol is refluxed for 5 hours, cooled, concentrated, and is partitioned between water and diethyl ether. The aqueous phase is acidified with hydrochloric acid, extracted with ether, and the organic phase is washed with saturated brine, dried (MgSO.sub.4), and evaporated to yield a solid. The solid is crystallized free diethyl ether petroleum ether (30.degree.-60.degree. C.) to give 10 g. (90%) of white crystals, m.p. 143.degree.-145.degree. C. (--CO.sub.2).

A solution of 10 g. of the diacid of Example 67 in 60 ml. of 2-methoxyethyl ether is refluxed for 7 hours, cooled, and evaporated to yield 8.5 g. (95%) of a tan solid. A sample is crystallized from diethyl ether-petroleum ether (30.degree.-60.degree. C.) to give white crystals, m.p. 98.degree.-100.degree. C.

The acid methoxime (8.5 g.) from Example 68 is refluxed for 5 hours with 180 ml. of acetone and 64 ml. of 2N hydrochloric acid. The mixture is cooled, the solvent is evaporated, and the residue is partitioned between water and diethyl ether. The organic phase is washed with saturated brine, dried (MgSO.sub.4), and evaporated to yield 7.4 g. (98%) of a light yellow oil.

The acid ketone (7.4 g.) from Example 69 is Fisher esterified with 300 ml. of absolute ethanol and 400 mg. of p-toluenesulfonic acid for 18 hours, cooled and the solvent is evaporated. The resulting oil is dissolved in ether, washed with dilute sodium bicarbonate solution, and saline, dried (MgSO.sub.4) and evaporated to give 7.306 g. (86%) of a light yellow oil.

Treatment of 1-methoximino-2-(7-p-toluenesulfonyloxy)-2-cyclopentene (Example 18) with sodium cyanide in the manner of Example 50 is productive of the subject compound.

Alkaline hydroylsis of 2-(7-cyanoheptyl)-1-methoximino-2-cyclopentene (Example 71) of th eprocedure of Example 51 is productive of the subject compound.

Hydrolysis of the methoxime of Example 72 with acetone-hydrochloric acid by the procedure of Example 52 is productive of the subject compound.

Fisher esterification of the carboxylic acid of Example 73 by the procedure of Example 53 is productive of the subject compound. 2-(6,6-dicarbethoxy-6-phenylhexyl)-1-methoximino-2-cyclopentene

Treatment of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene (Example 60) with sodio diethyl phenylmalonate by the procedure of Example 61 is productive of the subject compound.

Alkaline hydrolysis of 2-(6,6-dicarbethoxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 75) by the procedure of Example 20 is productive of the subject diacid. 2-(6-carboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene-dicarbethoxy

Decarboxylation of 2-(6,6-dicarboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 76) by the procedure of Example 63 is productive of the subject compound.

Methoxime cleavage of 2-(6-carboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 77) in the manner of Example 69 is productive of the subject ketone.

Fisher esterification of the carboxylic acid of Example 78 in the manner of Example 70 is productive of the subject keto-ester. 2-(6-fluoro-6,6-dicarbethoxyhexyl)-1-methoximino-2-cyclopentene

An ethanolic solution of sodium ethoxide, prepared from 0.389 g. of sodium and 40 ml. of absolute ethanol, is treated at ambient temperatures with 5.05 g. of 2-(6,6-dicarbethoxyhexyl)-1-methoximino-2-cyclopentene (Example 61). The resulting solution is cooled to -20.degree. C. and then treated with a stream of perchloryl fluoride until the mixture becomes neutral. The excess perchloryl fluoride is removed with a stream of nitrogen and the mixture is retreated with 10 ml. of an ethanol solution of sodium ethoxide (from 0.350 g. of sodium) and then with perchloryl fluoride until the mixture becomes neutral. The excess perchloryl fluoride is removed with a stream of nitrogen and the mixture is filtered an evaporated to an oil. The latter is partitioned between ether and water and the organic phase is washed with saturated saline, dried (Na.sub.2 SO.sub.4) and evaporated to afford the subject compound.

A solution of 50 g. of 2-(6-carboxyhexyl)cyclopent-2-en-1-one [Bagli et al., Tertrahedron Letters, No. 5, 465 (1966)] in 400 ml. of n-butanol containing 2.7 g. of p-toluenesulfonic acid monohydrate is allowed to stand at room temperature in a stoppered flask for about 24 hours. The solution is taken to dryness. The residue is taken up in ether and the ethereal solution is washed several times with saline solution, dried with anhydrous magnesium sulfate, and taken to dryness to afford the subject butyl ester.

Treatment of 2-(6-carboxyhexyl)cyclopent-2-en-1-one by the procedure of Example 81 with the appropriate alcohol affords the esters of the following table. ______________________________________ Example Alcohol   Product Ester ______________________________________ 82     isopropanol 2-(6-carboisopropoxyhexyl)cyclopent-2- en-1-one 83     methanol  2-(6-carbomethyoxyhexyl)cyclopent-2-en- 1-one 84     1-hydroxy- 2-(6-carbo-n-decyloxyhexyl)cyclopent-2- n-decane  en-1-one ______________________________________

To magnesium (71 g. 2.92 moles) under 1 l. of ether containing a few crystals of iodine is added dropwise 1-chloro-4-bromobutane (500 g., 2.92 moles) over a period of 30 minutes with stirring under nitrogen. The reaction is maintained at a temperature of 0.degree. C. to 5.degree. C. by immersing in an acetone-Dry Ice bath periodically. After stirring for 30 minutes at room temperature, the solution is chilled to below 0.degree. C. and is then transferred to a dropping funnel from which it is added dropwise to diethyl isopropylidene malonate (440 g., 2.19 moles) [A.C. Cope and E. M. Hancock, J.A.C.S. 60, 2644  (1938)] dissolved in 1000 ml. of ether containing the tri(n-butyl)phosphine complex of copper (I) iodide (57 g.) [G. B. Kaufman and L. A. Teter, Inorganic Synthesis, 7, 9(1963)] at -10.degree. C. with stirring under nitrogen over a period of 2 hours. After stirring at room temperature for 4 hours, the reaction mixture is poured into cold dilute hydrochloric acid and is extracted with ether. The combined ether extracts are washed with saline solution, dried over magnesium sulfate, and concentrated in vacuo to give 700 g. of crude amber oil, which is distilled under vacuum to yield two fractions: 212.4 g. with b.p. at 110.degree. - 135.degree. C. at 0.3 mm. and 100.0 g. with b.p. at 135.degree. -145.degree. C. at 0.3 mm. The total yield is 312.4 g. (49%).

A mixture containing diethyl 5-(5-chloro-1,1-dimethylpentyl)malonate (648 g., 2.22 moles) potassium hydroxide (460 g. and eight liters of 1:1 isopropanol:water is stirred at room temperature overnight. Most of the isopropanol is distilled and the residue is diluted with water, and then carefully acidified with conc. hydrochloric acid. The mixture is extracted with ether and the extracts are washed with water and saline, dried over magnesium sulfate and concentrated in vacuo to give 548 g. of crude oil. The oil is dissolved in three liters of diglyme which is heated under reflux for sixteen hours. About 2.7 l. of solvent is distilled, and the remainder is diluted with water and extracted with ether. The extracts are washed with saline, dried over magnesium sulfate and concentrated in vacuo to give 428 g. of crude oil (99%).

To a solution of 3,3-dimethyl-7-chloroheptanoic acid (428 g., 2.21 moles) in 3 l. of chloroform containing 3 ml. of N,N-dimethylformamide is added 500 ml. of thionyl chloride and the resulting solution is tested under reflux for 3 hours. The reaction solution then is concentrated in vacuo and the residual acid chloride is dissolved in a minimum amount of benzene and added slowly to a solution containing 1260 ml. of 95% ethanol and 2520 ml. of benzene and 390 ml. of collidine. After heating under reflux for one hour, the solution is concentrated and the residue is dissolved in ether washed with water, dilute sodium bicarbonate solution and saline solution, dried over magnesium sulfate and concentrated to give 415 g. of crude oil, which is distilled under vacuum to yield two fraction 46.6 g. boiling at 75.degree. C. (0.3 mm.) and 236.7 g. boiling at 75.degree. -80.degree. C. (0.3 mm). The total yield is 283.3 g. (60%) and the product is indicated to be 95% pure by g.l.c. cyclopentanone-2-carboxylate

Sodium hydride (67 g., 1.55 moles) is placed in a three l. round-bottom flask and to this is added 1.1 liters of glyme from a dropping funnel under nitrogen flow and with stirring. To the resulting grayish mixture is added the 2-carbalkoxycyclopentanone (mixed methyl and ethyl esters) dropwise over a period of 45 minutes with nitrogen flow whilst the temperature is maintained in the range of 40.degree.-55.degree. . Ethyl 3,3-dimethyl-7-chloroheptanoate (283 g., 1.28 moles) and potassium iodide (195 g., 1.32 moles) are added and the mixture is heated at reflux overnight. After most of the solvent is distilled, the residue is made acidic with dilute hydrochloric acid and is then extracted with ether. The ether extracts are washed with water and saline solution, dried over magnesium sulfate, and concentrated in vacuo to 500 g. of crude yellow oil, which is distilled to give 405 g. (94% yield) of oil with b.p. 140.degree.-180.degree. (0.8 mm).

Methyl/Ethyl 2-(6-carbethoxy-5,5-dimethylhexyl) cyclopentanone-2-carboxylate (200 g., 0.6 moles), glacial acetic acid (180 ml) and 240 ml. of diluted hydrochloric acid, prepared from 100 ml. of conc. hydrochloric acid and 300 ml. of water, are placed in a 2 l. flask, containing a reflux condenser and a magnetic stirrer. The mixture then is stirred at reflux for 24 hours. The reaction mixture is cooled, 1 l. of water is added and the mixture is extracted several times with benzene. The organic extracts are combind, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to an oil (173.5 g.). The oil is rendered basic with sodium hydroxide solution, extracted with benzene and made acidic with hydrochloric acid and reextracted with benzene several times. The benzene layers are combined and washed with water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to yield 109.8 g. (78%) of crude oil, which was used without further purification in the next step.

To a solution of 7-(2-cyclopentanone)-3,3-dimethylheptanoic acid (45 g., 0.22 mol.) in 285 ml. of chloroform containing three drops of N,N-dimethylformamide is added dropwise 25 ml. of thionyl chloride. The solution is stirred at room temperature for 20 minutes, the solvent is removed at reduced pressure and the residual acid chloride is dissolved in a minimum amount of benzene and added slowly to a solution containing 115 ml. of ethanol, 230 ml. benzene and 30 ml. of collodine. This solution is heated under reflux for 15 minutes and then concentrated. The residue is dissolved in ether, washed with water, diluted sodium bicarbonate solution and saline solution, dried over magnesium sulfate and concentrated to give 51 g. of crude oil. Distillation gives 40 g. (67%) b.p. 135-145 (0.1 mm.) of oil.

A solution of ethyl 7-(2-cyclopentanone)-3,3-dimethylheptanoate (90g., 0.336 mol.) and p-toluenesulfonic acid (0.94 g.) in 250 ml. of acetic anhydride is heated to boiling under partial reflux, allowing distillate at 118.degree. or less (i.e. acetic acid) to escape thru a Vigreux column equipped with a condenser to collect the distillate. After ten hours 130 ml. of distillate is collected. Another 50 ml. of acetic anhydride is added and the reaction is heated for 5 more hours; an additional 125 ml. of acetic anhydride is added, the reaction is heated for 7 more hours; finally another 50 ml. of acetic anhydride is added and heating is continued for 4 more hours. The solution is cooled and poured (cautiously) into a cold (0.degree.-5.degree.) mixture of saturated aqueous sodium bicarbonate (400 ml.) and hexane (250 ml.). The resulting cold mixture is stirred for 30 minutes during which time portions of solid sodium bicarbonate are added periodically until carbon dioxide evalution ceases. The hexane layer is separated and washed with saturated sodium chloride solution until the washings are neutral, dried over magnesium sulfate and treated with Darco decolorizing charcoal for clarification and then evaporated to dryness leaving an amber colored oil (87.5 g., 84%).

To a rapidly stirred mixture of 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene (35 g., 0.113 mole) chloroform (95 ml.), water (125 ml.) and calcium carbonate (11.8 g.) cooled in an ice-bath is added dropwise over a period of thirty minutes a solution of bromine (18.8 g.) in carbon tetrachloride (31 ml.). After stirring in the cold for an additional 45 minutes the orange colored chloroform layer is separated and washed with dilute sodium bisulfite and saturated saline solution, dried over magnesium sulfate and taken to dryness in vacuo (bath temperature: 35.degree.-40.degree.) leaving an amber colored oil. A slurry of 100 ml. of N,N-dimethylacetamide and 16.5 g. of CaCO.sub.3 is stirred and heated to reflux under nitrogen flow. The above dried oil is added from a dropping funnel rapidly, maintaining reflux and nitrogen flow for 30 minutes. The cooled reaction mixture is filtered, and the precipitate is washed with ether. The filtrate is poured into two liters ice-cold water and is extracted with ether. The combined extracts and washing is washed with water, saturated saline, treated with decolorizing charcoal, filtered. The solvent evaporated in vacuo to give 24 g. (77%) of subject product.

A stirred mixture of 35.9 g. (0.171 moles) of 2-(6-carboxyhexyl)cyclopent-2-en-1-one [Bagli et al., Tetrahedron Letters, No. 5, 465 (1966)], 35.0 g. (0.197 moles) of N-bromosuccinimide, and 600 ml. of carbon tetrachloride is refluxed for 35 minutes. The mixture is cooled to 5.degree. C. and filtered. The filtrate is washed with cold water, dried over magnesium sulfate, and taken to dryness to give an oil, .lambda. max..sup.MeOH =  225 m.mu. (8850); .nu. max. = 1705 (carbonyl groups) and 1625. cm.sup.-1 (olefin group).

In the manner of the preceding Example 93, the various cyclopentenones of Table V, which follows, are converted to the corresponding 4-bromo derivatives. ______________________________________ Starting Cyclopentenone Ex.   of Example  Product 4-Bromocyclopentenone ______________________________________ 94   13          4-bromo-2-(6-carbethoxyhexyl)- cyclopent-2-en-1-one 95   83          4-bromo-2-(6-carbomethoxyhexyl)- cyclopent-2-en-1-one 96   15          4-bromo-2-(4-carbethoxybutyl)- cyclopent-2-en-1-one 97   14          4-bromo-2-(3-carbethoxypropyl)- cyclopent-2-en-1-one 98   2           4-bromo-2-(4-carboxybutyl)cyclo- pent-2-en-1-one 99   5           4-bromo-2-(3-carboxypropyl)cyclo- pent-2-en-1-one 100   22          4-bromo-2-(8-carboxyoctyl)cyclo- pent-2-en-1-one 101   23          4-bromo-2-(8-carbethoxyoctyl)cyclo- pent-2-en-1-one 102   30          4-bromo-2-(6-carboxyoctyl)cyclo- pent-2-en-1-one 103   31          4-bromo-2-(6-carbethoxyoctyl)cy- clopent-2-en-1-one 104   92          4-bromo-2-(6-carboxy-5,5-dimethyl- hexyl)cyclopent-2-en-1-one 105   41          4-bromo-2-(6-carbethoxy-5,5-di- methylhexyl)cyclopent-2-en-1-one 106   45          4-bromo-2-(6-carboxy-5-oxahexyl)- cyclopent-2-en-1-one 107   46          4-bromo-2-(6-carbethoxy-5-oxahexyl)- cyclopent-2-en-1-one 108   69          4-bromo-2-(6-carboxy-6-fluorohexyl)- cyclopent-2-en-1-one 109   70          4-bromo-2-(6-carbethoxy-6-fluoro- hexyl)cyclopent-2-en-1-one 110   52          4-bromo-2-(5-carboxypentyl)cyclo- pent-2-en-1-one 111   53          4-bromo-2-(5-carbethoxypentyl)cy- clopent-2-en-1-one 112   73          4-bromo-2-(7-carboxyheptyl)cyclo- pent-2-en-1-one 113   74          4-bromo-2-(7-carbethoxyheptyl)- cyclopent-2-en-1-one 114   78          4-bromo-2-(6-carboxy-6-phenyl- hexyl)cyclopent-2-en-1-one 115   79          4-bromo-2-(6-carbethoxy-6-phenyl- hexyl)cyclopent-2-en-1-one 116   81          4-bromo-2-(6-carbo-n-butoxyhexyl)- cyclopent-2-en-1-one 117   82          4-bromo-2-(6-carbo-isopropoxy- hexyl)-cyclopent-2-en-1-one 118   84          4-bromo-2-(6-carbo-n-decyloxy- hexyl)cyclopent-2-en-1-one 118a 272         4-bromo-2-(6-carboxyheptyl)-cyclo- pent-2-en-1-one ______________________________________

To a stirred solution of 57.2 g. of crude 4-bromo-2-(8-carboxyoctyl)cyclopent-2-en-1-one (Example 100) in 500 ml. of acetone and 325 ml. of water at 3.degree. C. is added 44.1 g. (0.226 moles) of silver fluoborate during a 15 minute period. The mixture is stirred at 0.degree.-3.degree. C. for 2 hours and filtered. The filtrate is diluted with water, saturated with solid sodium chloride, and extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Partition chromatography of the residue on Celite gives white crystals, m.p. 58.degree.-66.degree. C., .lambda. max..sup.MeOH =  223 m.mu. (7800); .nu. max (KBR) = 3340 (hydroxyl groups), 1705 (carbonyl groups), and 1625 cm.sup.-1 (olefin group).

A mixture of 51.6 g. (0.137 moles) of crude 4-bromo-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one (Example 94), 27 g. (0.162 moles) of silver acetate, and 200 ml. of glacial acetic acid is stirred at reflux for 4.5 hours. The mixture is cooled, and solids are removed by filtration. The filtrate is concentrated and extracted with hot hexane. The extract is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated to give an oil. The crude product is distilled at reduced pressure to give a liquid, b.p. 152.degree.-163.degree. C. (0.01 mm); .lambda. max..sup.MeOH =  223 m.mu. (10700); .nu. max. = 1745 (ester carbonyl groups), 1725 (ketone carbonyl groups), and 1235 cm.sup.-1 (acetoxy group).

To a stirred solution of 6.91 g. (50 mmoles) of potassium carbonate in 1400 ml. of methanol and 1400 ml. of water containing 100 mg. of hydroquinone is added 14.8 g. (50 mmoles) of 4-acetoxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one (Example 120) during one minute at room temperature under nitrogen. The solution is stirred for 90 minutes and at this stage it contains 4-hydroxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one. It is then treated with 23.6 g. (75 mmoles) of barium hydroxide octahydrate during one minute. The mixture is stirred for 60 minutes and then is concentrated at reduced pressure to a volume of 1800 ml. during one hour. The solution is diluted with 300 ml. of water, saturated with sodium chloride, and stirred with 400 ml. of ether while 70 ml. of 4N hydrochloric acid is added. The aqueous phase is extracted with additional ether, and the combined organic phases are washed with saturated sodium chloride solution. The extract is dried over magnesium sulfate. The crude product obtained after evaporation of the solvents is purified by chromatography on silica gel to give an oil, .lambda. max..sup.MeOH =  223 m.mu. (7360); .nu. max. = 3380 (hydroxyl groups), 1710 (carbonyl groups), and 1632 cm.sup.-1 (olefin group).

To a stirred solution of 10.6 g. (ca. 34 mmoles) of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 100 ml. of acetone and 65 ml. of water is added 8.80 g. (45.2 mmoles) of silver fluoborate during 2 minutes. The temperature is maintained at 25.degree.-30.degree. C. by external cooling. The mixture is stirred for 90 minutes, filtered, saturated with sodium chloride, and extracted with ether. The extract is extracted with half saturated sodium bicarbonate solutions. The basic solutions is reacidified with dilute hydrochloric acid, saturated with sodium chloride, and extracted with ether. The extract is washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by partition chromatography on Celite to give an oil with the properties described in Example 121.

By the procedure of the preceding Example 122 the various 4-bromocyclopentenones of the following Table VI are solvolyzed in acetone-water in the presence of silver fluoborate to provide the 4-hydroxycyclopentenones of the Table. ______________________________________ Starting cyclopentenones Product Example of Example   4-hydroxycyclopente-2-en-ones ______________________________________ 123     94          4-hydroxy-2-(6-carbethoxyhexyl)- cyclopent-2-en-1-one 124     95          4-hydroxy-2(6-carbomethoxyhexyl)- cyclopent-2-en-1-one 125     96          4-hydroxy-2-(4-carbethoxybutyl)- cyclopent-2-en-1-one 126     97          4-hydroxy-2-(3-carbethoxypropyl)- cyclopent-2-en-1-one 127     98          4-hydroxy-2-(4-carboxybutyl)- cyclopent-2-en-1-one 128     99          4-hydroxy-2-(3-carboxypropyl)- cyclopent-2-en-1-one 129    101          4-hydroxy-2-(8-carbethoxyoctyl)- cyclopent-2-en-1-one 130    102          4-hydroxy-2-(6-carboxyoctyl)- cyclopent-2-en-1-one 131    103          4-hydroxy-2-(6-carbethoxyoctyl)- cyclopent-2-en-1-one 132    104          4-hydroxy-2-(6-carboxy-5,5-di- methylhexyl)cyclopent-2-en-1-one 133    105          4-hydroxy-2-(6-carbethoxy-5,5- dimethylhexyl)cyclopent-2-en-1- one 134    106          4-hydroxy-2-(6-carboxy-5-oxa- hexyl)cyclopent-2-en-1-one 135    107          4-hydroxy-2-(6-carbethoxy-5-oxa- hexyl)cyclopent-2-en-1-one 136    108          4-hydroxy-2-(6-carboxy-6-fluoro- hexyl)cyclopent-2-en-1-one 137    109          4-hydroxy-2-(6-carbethoxy-6- fluorohexyl)cyclopent-2-en-1-one 138    110          4-hydroxy-2-(5-carboxypentyl)- cyclopent-2-en-1-one 139    111          4-hydroxy-2-(5-carbethoxypentyl)- cyclopent-2-en-1-one 140    112          4-hydroxy-2-(7-carboxyheptyl)- cyclopent-2-en-1-one 141    113          4-hydroxy-2-(7-carbethoxyheptyl)- cyclopent-2-en-1-one 142    114          4-hydroxy-2-(6-carboxy-6-phenyl- hexyl)cyclopent-2-en-1-one 143    115          4-hydroxy-2-(6-carbethoxy-6- phenylhexyl)cyclopent-2-en-1- one 144    116          4-hydroxy-2-(6-carbo-n-butoxy- hexyl)cyclopent-2-en-1-one 145    117          4-hydroxy-2-(6-carbo-isopropoxy- hexyl)cyclopent-2-en-1-one 146    118          4-hydroxy-2-(6-carbo-n-decyloxy- hexyl)cyclopent-2-en-1-one 146a   118a        4-hydroxy-2-(6-carboxyheptyl)- cyclopent-2-en-1-one ______________________________________ 4-tetrahydropyranyloxy-2-(6-tetrahydropyranylcarboxyhexyl)cylopent-2-en-1- one

To a stirred solution of 5.59 g. (24.6 mmoles) of 4-hydroxy-2-(6-carboxyhexyl)cyclopent- 2-en-1one (Example 122) and 20.7 g. (246 mmoles) of dihydropyran in 100 ml. of methylene chloride at 20.degree. C. is added 47 mg. (0.246 mmoles) of p-toluenesulfonic acid monohydrate in one portion. The temperature is maintained at 20.degree.-25.degree. C. by cooling and is stirred for one hour at that temperature. The solution is diluted with 200 ml. of ether and poured into a mixture of 40 ml. of saturated sodium bicarbonate solution, 40 ml. of saturated sodium chloride solution, and 80 ml. of water. The phases are .[.seaparated.]. .Iadd.separated.Iaddend. , and the aqueous phase is extracted with additional ether. The total extract is washed successively with water and saturated sodium chloride solution, dried over potassium carbonate, and freed of volatile matter by concentration at reduced pressure to give an oil, .lambda. max..sup.MeOH =  223 m.mu. (9500); .nu. max. 1730 (ester carbonyl group), 1705 (ketone carbonyl group), and 1030 cm.sup.-1 (tetrahydropyranyloxy groups).

By the procedure of Example 147, the various 4-hydroxycyclopentenones of Table VII, which follows, are converted to the tetrahydropyranyl 4-tetrahydropyranyloxycyclopentenone esters of the table. ______________________________________ Starting      Product Tetrahydropyran-2'- 4-hydroxycyclopent- yl 4-tetrahydropyran-2'-yl'- Example enone of Example oxycyclopent-2-en-1-ones ______________________________________ 148    127           4-tetrahydropyran-2'-yloxy- 2-(4-carbotetrahydropyran- 2-'-yloxybutyl)cyclopent-2- en-1-one 149    128           4-tetrahydropyran-2'-yloxy- 2-(3-carbotetrahydropyran- 2'-yloxypropyl)cyclopent- 2-en-1-one 150    119           4-tetrahydropyran-2'-yloxy- 2-(8-carbotetrahydropyran- 2'-yloxyoctyl)cyclopent-2- en-1-one 151    130           4-tetrahydropyran-2'-yloxy- 2-(6-carbotetrahydropyran- 2'-yloxyoctyl)cyclopent-2- en-1-one 152    132           4-tetrahydropyran-2'-yloxy- 2-(6-carbotetrahydropyran- 2'-yloxy-5,5-dimethyl)- cyclopent-2-en-1-one 153    134           4-tetrahydropyran-2'-yloxy- 2-(6-carbotetrahydropyran- 2'-yloxy-5-oxahexyl)cyclo- pent-2-en-1-one 154    136           4-tetrahydropyran-2'-yloxy- 2-(6-carbotetrahydropyran- 2'-yloxy-6-fluorohexyl)cy- clopent-2-en-1-one 155    138           4-tetrahydropyran-2'-yloxy- 2-(5-carbotetrahydropyran- 2'-yloxypentyl)cyclopent- 2-en-1-one 156    140           4-tetrahydropyran-2'-yloxy- 2-(7-carbotetrahydropyran- 2'-yloxyheptyl)cyclopent- 2-en-1-one 157    142           4-tetrahydropyran-2'-yloxy- 2-(6-carbotetrahydropyran- 2'-yloxy-6-phenylhexyl)- cyclopent-2-en-1-one 157a   146a         4-tetrahydropyran-2'-yloxy- 2-(6-carbotetrahydropyran- 2'-yloxyheptyl)-cyclopent- 2-en-1-one ______________________________________ 4-tetrahydropyranyloxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one

To a stirred solution of 674 mg. (2.64 mmoles) of 4-hydroxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one (Example 123) and 2.22 g. (26.4 mmoles) of dihydropyran in 2.6 ml. of methylene chloride is added 5.0 mg. (0.026 mmoles) of p-toluenesulfonic acid monohydrate. After stirring for 20 minutes at room temperature the solution is diluted with ether and poured into saturated sodium chloride solution containing a little sodium bicarbonate. The organic phase is separated and washed with saturated sodium chloride solution. The extract is dried over magnesium sulfate, and volatile matter is evaporated at reduced pressure to give an oil, .lambda. max..sup.MeOH =  224 m.mu. (7950); .nu. max. = 1735 (ester carbonyl group), 1710 (ketone carbonyl group), and 1030 cm.sup.-1 (tetrahydropyranyloxy group).

In the manner of Example 158 the alkyl 4-hydroxycyclopentenone esters of Table VIII, which follows, are converted to the corresponding 4-tetrahydropyranyloxy alkyl esters of the table. ______________________________________ Starting 4- hydroxycyclo- Product pentenone Esters 4-tetrahydropyran-2'-yloxy- Example of Example   cyclopent-2-en-1-one esters ______________________________________ 159    124          4-tetrahydropyran-2'-yloxy-2- (6-carbomethoxyhexyl)cyclopent- 2-en-1-one 160    125          4-tetrahydropyran-2'-yloxy-2- (4-carbethoxybutyl)cyclopent- 2-en-1-one 161    126          4-tetrahydropyran-2'-yloxy-2- (3-carbethoxypropyl)cyclo- pent-2-en-1-one 162    129          4-tetrahydropyran-2'-yloxy-2- (8-carbethoxyoctyl)cyclopent- 2-en-1-one 163    131          4-tetrahydropyran-2'-yloxy-2- (6-carbethoxyoctyl)cyclopent- 2-en-1-one 164    133          4-tetrahydropyran-2'-yloxy-2- (6-carbethoxy-5,5-dimethyl- hexyl)cyclopent-2-en-1-one 165    135          4-tetrahydropyran-2'-yloxy-2- (6-carbethoxy-5-oxahexyl)- cyclopent-2-en-1-one 166    137          4-tetrahydropyran-2'-yloxy-2- (6-carbethoxy-6-fluorohexyl)- cyclopent-2-en-1-one 167    139          4-tetrahydropyran-2'-yloxy-2- (5-carbethoxypentyl)cyclo- pent-2-en-1-one 168    141          4-tetrahydropyran-2'-yloxy-2- (7-carbethoxyheptyl)cyclopent- 2-en-1-one 169    143          4-tetrahydropyran-2'-yloxy-2- (6-carbethoxy-6-phenylhexyl)- cyclopent-2-en-1-one 170    144          4-tetrahydropyran-2'-yloxy-2- (6-carbo-n-butoxyhexyl)cyclo- pent-2-en-1-one 171    145          4-tetrahydropyran-2'-yloxy-2- (6-carbo-isopropxyhexyl)cyclo- pent-2-en-1-one 172    146          4-tetrahydropyran-2'-yloxy-2- (6-carbo-n-decyloxyhexyl)-cyclo pent-2-en-1-one ______________________________________

(Example 93) in 85 ml. of methanol at 0.degree.-3.degree. C. is added  4.40 g. (22.6 mmole) of silver fluoborate in one portion. After 2 minutes, the mixture is treated with 2.66 g. (24.8 mmoles) of 2,6-lutidine. After stirring for 30 minutes at 0.degree.-3.degree. C. the mixture is stirred at ambient temperature for 45 minutes. Silver bromide is removed by filtration, and the filtrate is concentrated to a volume of 40 ml. The solution is treated with saturated sodium chloride solution and extracted with ether. The extract is washed successively with 0.5N hydrochloric acid solution, water, and saturated sodium chloride solution; dried over magnesium sulfate; and concentrated. Partition chromatography of the residue on Celite gives an oil, .lambda. max..sup.MeOH =  220 m.mu. (7450); .nu. max. = 1715 (carbonyl groups) and 1095 cm.sup.-1 (methoxy group).

Alcoholysis with the appropriate alcohol of the 4-bromocyclopentenones listed in Table IX, directly following, in the manner of Example 173 provides the 4-alkoxycyclopentenones of the Table. ______________________________________ Starting bromo- cyclopentenone Product Example of example  4-alkoxycyclopent-2-en-ones ______________________________________ 174     94         4-ethoxy-2-(6-carbethoxyhexyl)- cyclopent-2-en-1-one 175     95         4-methoxy-2-(6-carbomethoxyhexyl)- cyclopent-2-en-1-one 176     96         4-propoxy-2-(4-carbethoxybutyl)- cyclopent-2-en-1-one 177     97         4-isopropoxy-2-(3-carbethoxypro- pyl)cyclopent-2-en-1-one 178     98         4-methoxy-2-(4-carboxybutyl)cyclo- pent-2-en-1-one 179     99         4-ethoxy-2-(3-carboxypropyl)cyclo- pent-2-en-1-one 180    100         4-methoxy-2-(8-carboxyoctyl)cyclo- pent-2-en-1-one 181    101         4-isopropoxy-2-(8-carbethoxyoctyl)- cyclopent-2-en-1-one 182    102         4-methoxy-2-(6-carboxyoctyl)cyclo- pent-2-en-1-one 183    103         4-n-butoxy-2-(6-carbethoxyoctyl)- cyclopent-2-en-1-one 184    104         4-methoxy-2-(6-carboxy-5,5-di- methylhexyl)cyclopent-2-en-1-one 185    105         4-methoxy-2-(6-carbethoxy-5,5-di- methylhexyl)cyclopent-2-en-1-one 186    106         4-methoxy-2-(6-carboxy-5-oxahexyl)- cyclopent-2-en-1-one 187    107         4-ethoxy-2-(6-carbethoxy-5-oxa- hexyl)cyclopent-2-en-1-one 188    108         4-methoxy-2-(6-carboxy-6-fluoro- hexyl)cyclopent-2-en-1-one 189    109         4-propoxy-2-(6-carbethoxy-6-fluoro- hexyl)cyclopent-2-en-1-one 190    110         4-methoxy-2-(5-carboxypentyl)cy- clopent-2-en-1-one 191    111         4-sec-butoxy-2-(5-carbethoxypentyl)- cyclopent-2-en-1-one 192    112         4-methoxy-2-(7-carboxyheptyl)- cyclopent-2-en-1-one 193    113         4-methoxy-2-(7-carbethoxyheptyl)- cyclopent-2-en-1-one 194    114         4-methoxy-2-(6-carboxy-6-phenyl- hexyl)cyclopent-2-en-1-one 195    115         4-ethoxy-2-(6-carbethoxy-6-phenyl- hexyl)cyclopent-2-en-1-one 196    116         4-methoxy-2-(6-carbo-n-butoxy- hexyl)cyclopent-2-en-1-one 197    117         4-methoxy-2-(6-carbo-isopropoxy- hexyl)cyclopent-2-en-1-one 198    118         1-methoxy-2-(6-carbo-n-decyloxy- hexyl)cyclopent-2-en-1-one 199     93         4-ethoxy-2-(6-carboxyhexyl)cyclo- pent-2-en-1-one 200     93         4-propoxy-2-(6-carboxyhexyl)cyclo- pent-2-en-1-one 201    93          4-isopropoxy-2-(6-carboxyhexyl)- cyclopent-2-en-1-one 202    93          4-n-butoxy-2-(6-carboxyhexyl)- cyclopent-2-en-1-one ______________________________________

A stirred mixture of 6.35 g. (20 mmoles) of 4-bromo-2-(carbethoxyhexyl)cyclopent-2-en-1-one (Example 94), 3.01 g. (11 moles) of silver carbonate, and 40 ml. of t-butanol is heated at 70.degree. C. for 17 hours. The mixture is cooled and filtered. After evaporation of t-butanol the residue is treated with aq. sodium chloride and extracted with 3:1 ether-hexane. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by chromatography on silica gel to give, in order of elution; the subject compound as an oil; .lambda. max..sup.MeOH = 219 m.mu. (8860); .nu. max. = 1735 (ester carbonyl group), 1725 ketone carbonyl group), and 1365 cm.sup.-1 (tert.-butyl group); and 4-hydroxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one also as an oil.

To a stirred solution of 19.1 g. of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 310 ml. of ethylene glycol is added 15.6 g. (80 mmole) of silver fluoborate during 2 minutes. The exothermic reaction is controlled to give a temperature of 29.degree. C., and after 1 minute the mixture is treated during 1 minute with 8.6 g. (80 mmole) of 2,6-lutidine. The mixture is stirred at ambient temperature for 2 hours, diluted with water, and filtered. The filtrate is diluted with saturated sodium chloride solution and extracted with ether. The extract is washed with half-saturated sodium chloride solution containing a little hydrochloric acid and saturated sodium chloride solution. The extract is dried over magnesium sulfate and concentrated. Column chromatograph of the residue on silica gel gives an oil, .lambda. max.sup.MeOH =  216 m.mu. (8350); .nu. max = 3340 (hydroxyl groups), 1700 (carbonyl groups), and 1620 cm.sup. -1 (olefin group).

By the procedure described in Example 204 the various 4-bromocyclopentenones listed in Table X, which follows, are converted, to the corresponding 4(.omega.-hydroxyalkyl)cyclopentenones of the table. ______________________________________ Starting 4-bromo- Product cyclopentenene 4-(.omega.-hydroxyalkoxy)cyclopent- Example of example   2-en-1-ones ______________________________________ 205     94          4-.beta.-hydroxyethoxy-2-(6-car- bethoxyhexyl)cyclopent-2-en- 1-one 206     95          4-.beta.-hydroxyethoxy-2-(6-carbo- methoxyhexyl)cyclopent-2-en- 1-one 207     96          4-.mu.-hydroxypropoxy-2-(4-oar- bethoxybutyl(cyclopent-2-en- 1-one 208     97          4-.beta.-hydroxyethoxy-2-(3-car- bethoxypropyl(cyclopent-2-en- 1-one 209     98          4-.beta.-hydroxyethoxy-2-(4-car- boxybutyl(cyclopent-2-en-1- one 210     99          4-.beta.-hydroxyethoxy-2-(3-car- boxypropyl)cyclopent-2-en-1-one 211    100          4-.beta.hydroxyethoxy-2-(8-car- boxyoctyl)cyclopent-2-en-1-one 212    101          4-.beta.-hydroxyethoxy-2-(8-oar- bethoxyoctyl)cyclopent-2-en- 1-one 213    102          4-.beta.-hydroxyethoxy-2-(6-oar- boxyoctyl)cyclopent-2-en-1-one 214    103          4-.gamma.-hydroxypropoxy-2-(6-car- bethoxyoctyl)cyclopent-2-en- 1-one 215    104          4-.beta.-hydroxyethoxy-2-(6-car- boxy-5,5-dimethylhexyl)cyclo- pent-2-en-1-one 216    105          4-.beta.-hydroxyethoxy-2-(6-car- bethoxy-5,5,-dimethylhexyl)- cyclopent-2-en-1-one 217    106          4-.beta.-hydroxyethoxy-2-(6-car- boxy-5-oxahexyl)cyclopent-2- en-1-one 218    107          4.gamma.-hydroxypropoxy-2-(6-car- bethoxy-5-oxahexyl)cyclopent- 2-en-1-one 219    108          4-.beta.-hydroxyethoxy-2-(6-car- boxy-6-fluorohexyl)cyclo- pent-2-en-1-one 230    109          4-.beta.-hydroxyethoxy-2-(6-car- bethoxy-6-fluorohexyl)cyclo- pent-2-en-1-one 221    110          4-.beta.-hydroxyethoxy-2-(5-car- boxypentyl)cyclopent-2-en- 1-one 222    112          4-.beta.-hydroxyethoxy-2-(7-car- boxyheptyl)cyclopent-2-en-1- one 223    114          4-.beta.-hydroxyethoxy-2-(6-car- boxy-6-phenylhexyl)cyclo- pent-2-en-1-one 224    115          4-.beta.-hydroxyethoxy-2-(6-car- bethoxy-6-phenylhexyl)cyclo- pent-2-en-1-one 225    116          4-.beta.-hydroxyethoxy-2-(6-carbo- n-butoxyhexyl)cyclopent-2- en-1-one 236    117          4-.beta.-hydroxyethoxy-2-(carbo- isopropoxyhexyl)cyclopent-2- en-1-one 227    118          4-.beta.-hydroxyethoxy-2-(6-carbo- n-decyloxyhexyl)cyclopent-2- en-1-one 228     93          4-.beta.-hydroxypropoxy-2-(6-car- boxyhexyl)cyclopent-2-en-1- one ______________________________________

By the procedure described in Example 147 the 4-alkoxycyclopentenone carboxylic .[.acis.]. .Iadd.acids .Iaddend.listed in Table XI were converted to the corresponding tetrahydropyran-2'-yl esters of the table. ______________________________________ Starting 4 alkoxy- cyclopentenone Product Ex-   carboxylic acid Tetrahydropyran-2'yl ester ample of example   4-alkocycyclopent-1-ones ______________________________________ 229   178          4-methoxy-2-(4-carbotetra- hydropyran-2'yloxybutyl)- cyclopent-2-en-1-one 230   179          4-ethoxy-2-(3-carbotetra- hydropyran-2'yloxypropyl)- cyclopent-2-en-1-one 231   180          4-methoxy-2-(8-carbotetra- hydropyran-2'yloxyoctyl)- cyclopent-2-en-1-one 232   182          4-methoxy-2-(6-carbotetra- hydropyran-2'-yloxyoctyl)- cyclopent-2-en-1-one 233   184          4-methoxy-2-(6-carbotetra- hydropyran-2'-yloxy-5,5- dimethylhexyl)cyclopent-2- en-1-one 234   186          4-methoxy-2-(6-carbotetra- hydroxypyran-2'-yloxy-5-oxa- hexyl)cyclopent-2-en-1-one 235   188          4-methoxy-2-(6-carbotetra- hydropyran-2'-yloxy-6-fluoro- hexyl)-cyclopent-2-en-1-one 236   190          4-methoxy-2-(5-carbotetra- hydropyran-2'-yloxy-pentyl)- cyclopent-2-en-1-one 237   192          4-methoxy-2-(7-carbotetra- hydropyran-2'-yloxyheptyl)- cyclopent-2-en-1-one 238   194          4-methoxy-2-(6-carbotetrahydro- pyran-2'-yloxy-6-phenylhexyl)- cyclopent-2-en-1-one 239   199          4-ethoxy-2-(6-carbotetrahydro- pyran-2'-yloxyhexyl)cyclopent- 2-en-1-one 240   200          4-propoxy-2-(6-carbotetrahydro- pyran-2'-yloxyhexyl)cyclopent- 2-en-1-one 241   201          4-isopropoxy-2-(6-carbotetra- hydropyran-2'-yloxyhexyl)cyclo- pent-2-en-1-one 242   202          4-n-butoxy-2-(6-carbotetra- hydropyran-2'-yloxyhexyl)cyclo- pent-2-en-1-one 242a 173          4-methoxy-2-(6-carbotetrahydro- pyran-2'-yloxyhexyl)cyclopent- 2-en-1-one ______________________________________

Treatment of the 4-(.omega.-hydroxyalkoxy)cyclopentenones of Table XII below with dihydropyran in the manner of Example 147 provides the 4-(.omega.-tetrahydropyranyloxyalkoxy)-cyclopentenone esters listed in the table. ______________________________________ Starting 4-(.omega.- Product hydroxyalkoxy)- 4-(.omega.-tetrahydropyran-2'-yloxy- cyclopentenone alkoxy)-cyclopent-2-en-1-one Example of example  esters ______________________________________ 243    205         4-.beta.-tetrahydropyrany-2'-yloxy- ethoxy-2-(6-carbethoxyhexyl)- cyclopent-2-en-1-one 244    206         4-.beta.-tetrahydropyrany-2'-yloxy- ethoxy-2-(6-carbomethoxyhexyl)- cyclopent-2-en-1-one 245    207         4-.gamma.-tetrahydropyran-2'-yloxy- propoxy-2-(4-carbethoxybutyl)- cyclopent-2-en-1-one 246    208         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(3-carbethoxypropyl)- cyclopent-2-en-1-one 247    204         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(6-carbotetrahydro- pyran-2'-yloxyhexyl)cyclopent- 2-en-1-one 248    209         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(4-carbotetrahydro- pyran-2'-yloxybutyl)cyclopent- 2-en-1-one 249    210         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(3-carbotetrahydro- pyran-2'-yloxypropyl)cyclopent- 2-en-1-one 250    212         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(8-carbethoxyoctyl)- cyclopent-2-en-1-one 251    211         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(8-carbotetrahydro- pyran-2'-yloxyoctyl)cyclopent- 2-en-1-one 252    213         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(6-carbotetrahydro- pyran-2'-yloxyoctyl)cyclopent- 2-en-1-one 253    214         4-.gamma.-tetrahydropyran-2'-yloxy- propoxy-2-(6-carbethoxyoctyl)- cyclopent-2-en-1-one 254    215         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(6-carbotetrahydro- pyran-2'-yloxy-5,5-dimethyl- hexyl)cyclopent-2-en-1-one 255    216         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(6-carbethoxy-5,5-d- methylhexyl)cyclopent-2-en-1-one 256    217         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(6-carbotetrahydro- pyran-2-yloxy-5-oxahexyl)cy- clopent-2-en-1-one 257    218         4-.gamma.-tetrahydropyran-2'-yloxy- propoxy-2-(6-carbethoxy-5- oxahexyl(cyclopent-2-en-1-one 258    219         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(6-carbotetrahydro- pyran-2'-yloxy-6-fluorohexyl)- cyclopent-2-en-1-one 259    220         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(6-carbethoxy-6-fluoro- hexyl)cyclopent-2-en-1-one 260    221         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(5-carbotetrahydro- pyran-2'-yloxpentyl(cyclopent- 2-en-1-one 261    222         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(7-carbotetrahydro- pyran-2'-yloxheptyl)cyclopent- 2-en-1-one 262    223         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(6-carbotetrahydro- pyran-2'-yloxy-6-phenylhexyl)- cyclopent-2-en-1-one 263    224         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(6-carbethoxy-6-phenyl- hexyl)cyclopent-2-en-1-one 264    225         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(6-carbo-n-butoxy- hexyl)cyclopent-2-en-1-one 265    226         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(6-carbo-isopropoxy- hexyl)cyclopent-2-en-1-one 266    227         4-.beta.-tetrahydropyran-2'-yloxy- ethoxy-2-(6-carbo-n-decyloxy- hexyl)cyclopent-2-en-1-one 267    228         4-.beta.-tetrahydropyran-2'-yloxy- propoxy-2-(6-carbotetrahydro- pyran-2'-yloxhexyl)cyclopent- 2-en-1-one ______________________________________

To a stirred solution of 56.0 g. of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 400 ml. of tetrahydrofuran and 133 ml. of water at 3.degree. C. is added 44.1 g. (0.226 moles) of silver fluoborate during 25 minutes. The mixture is stirred at 0.degree.-5.degree. C. for 60 minutes, diluted with water and ether, and filtered. The aqueous portion of the filtrate is saturated with solid sodium chloride and extracted with additional ether. The combined organic phases and washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue gives the subject compound as a mixture with 4-hydroxy-2-(6-carboxyhexyl)cyclopent-2-en-1-one. NMR (CDCl.sub.3) 3.60 (multiplet, O-methylene hydrogens) and 4.60 f (multiplet, O-methine hydrogen). 4-(4-tetrahydropyranyloxybutoxy)-2-(6-tetrahydropyranylcarboxyhexyl)cyclop ent-2-en-1-one

In the manner of Example 147 the mixture of 4-hydroxy-2-(6-carboxyhexyl)cyclopent-2-en-1-one and 4-(4-hydroxybutoxy)-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 268) is converted to a mixture of the subject compound and 4-tetrahydropyranyloxy-2-(6-tetrahydropyranylcarboxyhexyl)cyclopent-2-en-1 -one with dihydropyran and p-toluenesulfonic acid monohydrate in methylene chloride.

The subject compound is prepared from sodio diethyl methylmalonate and 2-(5-methanesulfonyloxypentyl)-2-cyclopentenone methoxime (Example 60) by the procedure described in Example 61.

Saponification of 2-(6,6-dicarbethoxyheptyl)-2-cyclopentenone methoxime (Example 270) with potassium hydroxide by the method of Example 20 is productive of 2-(6,6-dicarboxyheptyl)-2-cyclopentenone methoxime, decarboxylation of which in the manner of Example 63 provides the subject compound.

Methoxime cleavage of 2-(6-carboxyheptyl)-2 (Example 271) in the manner of Example 22 provides the subject ketone.

Esterification with ethanol of the acid chloride derived from 2-(6-carboxyheptyl)-2-cyclopentenone in the manner of Example 31 is productive of the subject compound.

To a stirred mixture of 1.465 g. (0.0348 mole) of sodium hydride (57.2% in mineral oil) in 50 ml. of dimethoxyethane, under nitrogen, is added slowly 4.8 g. (0.0347 mole) of ethyl-2-mercaptoacetate. The reaction mixture is stirred at room temperature for one hour and then a solution of 7.8 g. (0.0231 mole) of 2-(4p-toluenesulfonyloxybutyl)-1-methoximino-2-cyclopentene in 30 ml. of dimethoxyethane is added dropwise and stirred at room temperature for 18 hours. The solution is heated at reflux for 1 hour, cooled and poured into cold dilute hydrochloric acid and then extracted with ether. The combined ether extracts are washed with saline, dried over magnesium sulfate and evaporated to give 7.6 g. of subject product as a yellow oil.

In the manner described in Example 22, treatment of 2-(6-carbethoxy-5-thiahexyl)-1-methoximino-2-cyclopentene with acetone and 2N hydrochloric acid at reflux gives the subject product as a yellow oil.

In the manner described in Example 23, treatment of 2-(6-carboxy-5-thiahexyl)-2-cyclopentenone with p-toluenesulfonic acid in ethanol gives the subject ester as a yellow oil.

A stirred mixture of 9.81 g. (0.10 moles) of 5-hexyn-1-ol, 33.5 g. (0.12 moles) of triphenylmethyl chloride, and 200 ml. of dry pyridine is refluxed for 60 minutes. The cooled mixture is poured into water and extracted with ether. The extract is washed successively with water, ice-cold N hydrochloric acid, water, saturated sodium bicarbonate solution, and saturated sodium chloride solution. The extract is dried with magnesium sulfate. The crude product obtained after evaporation of the solvent is purified by chromatography on Florisil to give an oil, .nu. max. 3290 (acetylenic hydrogen), 1600, 1072, and 705 cm.sup.-1 (triphenylmethoxy group).

A mixture of 10 g. (0.08 moles) of 4-hydroxy-1-octyne [L. Crombie and A. G. Jacklin, J. Chem. Soc., 1632 (1957)] and 30.75 g. (0.09 moles) of triphenylmethyl bromide in 85 ml. of dry pyridine is heated on the steam bath for 2 hours. The cooled mixture is treated with water and extracted with ether. The extract is washed successively with ice cold 2% hydrochloric acid, saturated sodium chloride solution, dried with magnesium sulfate, and taken to dryness. Column chromatography of the residue on Florisil affords an oil; .lambda. max 3.01, 4.72 (acetylenic hydrogen), 6.28, 9.65 and 14.25 m.mu. (triphenylmethoxy group).

A stirred solution of 9.81 g. (0.10 moles) of 4-hydroxy-1hexyne and 33.5 g. (0.12 moles) of triphenylmethyl chloride in 100 ml. of dry pyridine is heated at reflux for 2 hours. The cooled mixture is treated with water and extracted with a hexane-ether mixture. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue on Florisil gives an oil, .nu. max. 3290 (acetylenic hydrogen), 1600, 1030, and 705 cm.sup.-1 (triphenylmethoxy group). Tetrahydropyran-2-yl-9-oxo-11.alpha.-tetrahydropyranyloxy-20-triphenylmeth oxy-8.xi.-13-trans-prostenoate

In the manner described in Example 281, 36.8 g. (100 mmoles) of 8-triphenylmethoxy-1-octyne (Example 304) contained in 50 ml. of benzene is converted to an alanate reagent by treatment with 83.5 ml. of 1.2 M diisobutylaluminum hydride in hexane and 45 ml. of 2.2 M methyl lithium in ether. To the stirred reagent is added 80 mmoles of crude 2-(6-tetrahydropyranylcarboxyhexyl)-4-tetrahydropyranyloxycyclopent-2-en-1 -one (Example 147) in 40 ml. of ether at 5.degree.-10.degree. during 10 minutes. The mixture is stirred at ice temperature for 1 hour and at ambient temperature for 15 hours. The mixture is diluted with ether and poured into a stirred mixture of ice and hydrochloric acid. The organic phase is separated, and the aqueous phase is extracted with ether. The combined extracts are washed with cold N HCl, water, and saturated sodium chloride solution. The extract is dried over magnesium sulfate, and the solvents are evaporated at reduced pressure to give the crude product as an oil, .nu. max, 1730 (carbonyl groups), 1035 (tetrahydropyranyloxy groups), 975 (trans vinyl group), and 705 cm.sup.-1 (triphenylmethoxy group).

A 0.05 M solution of crude tetrahydropyran-2-yl-9-oxy-11-tetrahydropyranyloxy-20-triphenylmethoxy-8.x i.-13-trans-prostenoate (Example 280) in glacial acetic acid-tetrahydrofuran-water (4:2:1) is heated at 45.degree. for 7 hours. The solution is diluted with aqueous sodium chloride solution and extracted with ether. The extract is washed with water and concentrated using toluene for azeotropic removal of aqueous acetic acid. The residue is purified by column chromatography on silica gel to give an oil .nu. max, 1735 (ketone carbonyl group), 1710 (acid carbonyl group), and 967 cm.sup.-1 (transvinyl group). 20-triphenylmethoxy-9-oxo-18,19-dinor-8-13-trans-prostenoate

A stirred solution of 16.35 g. (48.0 mmoles) of 1-triphenylmethoxy-5-hexyne (Example 277) in 24 ml. of benzene is treated with 40 ml. of 1.2 M diisobutylaluminum hydride in hexane, and the resulting solution is heated at 50.degree. for 2 hours. The solution is cooled, diluted with 35 ml. of ether, and treated at 3.degree.-10.degree. with 27.5 ml. of 1.6 M n-butyl lithium in hexane. After 20 minutes at ambient temperature the alanate solution is cooled to 0.degree. and treated with a solution of 9.53 g. (40 mmoles) of 2-(6-carbethoxyhexyl)-cyclopent-2-en-1-one (Example 13), in 10 ml. of ether. The reaction mixture is stirred at ambient temperature for 18 hours, diluted with ether, and poured into a stirred mixture of ice and 4N hydrochloric acid. The mixture is stirred for 1 hour at ambient temperature, and the ether phase is separated, washed successively with water and saturated sodium chloride solution, and dried over magnesium sulfate. The residue obtained after evaporation of the solvent is purified by chromatography on silica gel to give an oil, .nu. max. 1735 (carbonyl groups), 968 (trans vinyl group), and 705 cm.sup.-1 (triphenylmethoxy group).

A 0.05 M solution of ethyl 20-triphenyl-methoxy-9-oxo-18,19-dinor-13-trans-prostenoate (Example 281) in glacial acetic acid-tetrahydrofuran-water (4:2:1) is heated at 45.degree. for 9 hours. The residue obtained after evaporation of the solvent is purified by chromatography on silica gel to give an oil, .nu. max. 3450 (hydroxyl group), 1735 (carbonyl groups), and 967 cm.sup.-1 (trans vinyl group).

A solution of 2.54 g. (7.5 mmoles) of ethyl 20-hydroxy-9-oxo- 18,19-dinor-13-trans-prostenoate (Example 282), 1.49 g. (22.5 mmoles) of 85% potassium hydroxide, 45 ml. of water is allowed to stand at room temperature for 20 hours. The solution is concentrated, diluted with water, extracted with ether, acidified with 4N hydrochloric acid, and extracted with ether. The final extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated to give an oil, .nu. max. 1735 (ketone carbonyl group), 1710 (acid carbonyl group), and 967 cm.sup.-1 (trans vinyl group).

Treatment of the alanate solution, prepared by the addition of 24 ml. (0.05 moles) of 2.1 M methyl lithium in ether to a solution of 18.4 g. (0.05 moles) of 4-triphenylmethoxy-1-octyne (Example 278) in 25 ml. of dry benzene treated with 34.6 ml. (0.05 moles) of 1.45 M diisobutyl aluminum hydride in benzene, with 9.5 g. (0.04 moles) of 2-(6-carbethoxyhexyl)-cyclopent-2-en-1one (Example 13) according to the procedure, except for chromatography, described in Example 281 gave 27.65 g. of oily material; .lambda. max. 5.78 (carbonyl groups), 10.25 (trans vinyl group), and 14.20 (triphenyl-methoxy group).

A solution of 26.65 g. of ethyl 16-triphenylmethoxy-9-oxo-8.xi.-13-trans-prostenoate (Example 284) in glacial acetic acid-tetrahydrofuran-water (4:2:1) is heated at 45.degree. C for 3.5 hours. The residue obtained after evaporation of the solvent is partially purified by chromatography on silica gel. Total purification by partition chromatography affords an oil; .nu. max. 2.88 (hydroxyl group), 5.77 (carbonyl group), and 10.25 (trans vinyl group).

Treatment of 3.2 g. of ethyl 16-hydroxy-9-oxo-13-trans-prostenoate (Example 285) in 50 ml. of methanol water (1:1) containing 1.37 g. of potassium hydroxide according to the procedure described in Example 283 gives 2.76 g. of oil; 5.80 (carbonyl groups) and 10.25 M (trans vinyl group).

The triphenylmethoxy substituted 1-alkynes listed in the table below are prepared by the method of Example 278 from triphenylmethyl bromide and the corresponding hydroxy substituted 1-alkynes, appropriate literature references to which are provided in the table. ______________________________________ Reference to starting hydroxy substituted Product triphenylmethoxy Example 1-alkyne       substituted 1-alkyne ______________________________________ 287    Reference 1    4-triphenylmethoxy-1- pentyne 288    Reference 1    4-triphenylmethoxy-1- heptyne 289    Reference 1    4-triphenylmethoxy-5- methyl-1-hexyne 290    Reference 2    4-triphenylmethoxy-1- nonyne 291    Reference 3    4-triphenylmethoxy-1-decyne 292    Reference 4    5-triphenylmethoxy-1-pentyne 293    Reference 5    7-triphenylmethoxy-1-heptyne 294    Reference 6    9-triphenylmethoxy-1-nonyne 295    Reference 7    10-triphenylmethoxy-1- decyne 296    Reference 8    11-triphenylmethoxy-1- undecyne 297    Reference 9    5-triphenylmethoxy-1-hexyne 298    Reference 10   4-triphenylmethoxy-7-methyl- 1-octyne 299    Reference 10   4-triphenylmethoxy-5-ethyl- 1-heptyne 300    Reference 11   5-triphenylmethoxy-4-methyl- 1-pentyne 301    Reference 11   5-triphenylmethoxy-4-ethyl- 1-pentyne 302    Reference 11   5-triphenylmethoxy-4-methyl- 1-hexyne 303    Reference 11   5-triphenylmethoxy-4-ethyl- 1-hexyne ______________________________________

References: 50, 13737 (1956). (1965). Abstr., 57, 14930a (1962). Abstr., 70, 3219j (1969).

To a stirred suspension of 68.1 g. (0.18 moles) of 1-chloro-6-triphenymethoxyhexane, prepared from 1-chloro-6-hydroxyhexane and triphenylmethyl chloride in the manner of Example 277, in 60 ml. of dimethylsulfoxide is added a solution of 19.9 g. (0.216 moles) of lithium acetylideethylenediamine complex in 120 ml. of dimethylsulfoxide during 20 minutes. The temperature is maintained at 25.degree. C. with an ice bath during the addition, after which the mixture is stirred at ambient temperature for 3.5 hours and then at 30.degree. C. for 15 minutes. The mixture is diluted with 100 ml. of ether and treated dropwise with 150 ml. of water with ice bath cooling. The mixture is diluted with 400 ml. of water and 250 ml. of 2:1 ether-pet ether and acidified with 120 ml. of 4N hydrochloric acid in the ice bath. The phases are separated, and the aqueous phase is extracted with 3:1 ether-pet ether. The combined extracts are washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the residue on Florisil affords the subject compound as white crystals, m.p. 43.degree.-45.degree. C. after recrystallization from pet-ether, .nu. max 3300 (acetylenic hydrogen), 2360 (triple bond), 1600, 1068, and 706 cm.sup.-1 (triphenylmethoxy group).

Conjugate addition of the alanates obtained by treatment of the triphenylmethoxy (trityloxy)-1-alkyne (indicated in the following table) with diisobutylaluminum hydride followed by methyl lithium, to the cyclopentenones of the table according to the method described in Example 280 followed by de-O-tritylation of the intermediate triphenylmethoxyprostenoates according to the method of Example 280a is productive of the prostenoic acids and esters of the table.

Those compounds isolated and identified in the table as prostenoic acids are prepared via the corresponding tetrahydropyran-2-yl esters and these compounds bearing a free hydroxy function at the 11.alpha.-position or as part of an 11.alpha.-(.omega.-hydroxyalkoxy) moiety are prepared via the corresponding tetrahydropyran-2-yl ethers. The hydroxy function in the .beta.-side chain (that portion of the molecule deriving from the triphenylmethoxy-1-alkyne) of all compounds in the table are initially present in the molecule as the corresponding triphenylmethyl ethers. During the acetic acid treatment (de-O-tritylation step) the triphenylmethyl ether as well as the tetrahydropyran-2-yl ethers and esters functions are hydrolyzed to provide the corresponding free hydroxy and carboxylic acid groups of the compounds listed in the table. __________________________________________________________________________ Starting cyclo- Starting trityloxy- pentenone of 1-alkyne of Product Example Example  Example    Hydroxy Prostenoic Acid or Ester __________________________________________________________________________ 305   13      304        Ethyl 9-oxo-20-hydroxy-13-trans-prostenoate 306   13      288        Ethyl 9-oxo-16-hydroxy-20-nor-13-trans- prostenoate 307   13      290        Ethyl 9-oxo-16-hydroxy-20-methyl-13-trans- prostenoate 308   13      297        Ethyl 9-oxo-17-hydroxy-19,20-dinor-13-trans- prostenoate 309   13      294        Ethyl 9-oxo-20-hydroxymethyl-13-trans- prostenoate 310   81      298        Butyl 9-oxo-16-hydroxy-19-methyl-13-trans- prostenoate 311   82      303        Isopropyl 9-oxo-17-hydroxy-16-ethyl-13-trans- prostenoate 312   83      296        Methyl 9-oxo-20-(3-hydroxypropyl)-13-trans- prostenoate 313   84      278        Decyl 9-oxo-16-hydroxy-13-trans-prostenoate 314   14      295        Ethyl 5,6,7-trinor-9-oxo-20-(2-hydroxy- ethyl)-13-trans-prostenoate 315   23      278        Ethyl 7a,7b-bishomo-9-oxo-16-hydroxy-13- trans-prostenoate 316   23      279        Ethyl 7a,7b-bishomo-9-oxo-19,20-dinor-16- hydroxy-13-trans-prostenoate 317   41      291        Ethyl 3,3-dimethyl-9-oxo-16-hydroxy-20- ethyl-13-trans-prostenoate 318   46      278        Ethyl 3-oxo-9-oxo-16-hydroxy-13-trans- prostenoate 319   46      293        Ethyl 3-oxa-9-oxo-19-hydroxy-20-nor-13 trans-prostenoate 320   53      278        Ethyl 7-nor-9-oxo-16-hydroxy-13-trans- prostenoate 321   53      300        Ethyl 7-nor-9-oxo-16-methyl-17-hydroxy-18,19, 20-trinor-13-trans-prostenoate 322   70      278        Ethyl 2-fluoro-9-oxo-16-hydroxy-13-trans- prostenoate 323   74      277        Ethyl 7-a-homo-9-oxo-18-hydroxy-19,20-dinor- 13-trans-prostenoate 324   74      278        Ethyl 7a-homo-9-oxo-16-hydroxy-13-trans- prostenoate 325   79      278        Ethyl 2-phenyl-9-oxo-16-hydroxy-13-trans- prostenoate 326   79      299        Ethyl 2-phenyl-9-oxo-16-hydroxy-17-ethyl-20- nor-13-trans-prostenoate 327   31      304        Ethyl 2-ethyl-9-oxo-20-hydroxy-13-trans- prostenoate 328  273      278        Ethyl 2-methyl-9-oxo-16-hydroxy-13-trans- prostenoate 329  276      278        Ethyl 3-thia-9-oxo-16-hydroxy-13-trans- prostenoate 330  276      304        Ethyl 3-thia-9-oxo-20-hyroxy-13-trans- prostenoate 331  276      302        Ethyl 3 thia-9-oxo-17-hydroxy-16-methyl-19,20- dinor-13-trans-prostenoate 332  174      278        Ethyl 9-oxo-11.alpha.-ethoxy-16-hydroxy-13-trans- prostenoate 333  175      278        Methyl 9-oxo-11.alpha.-methoxy-16-hydroxy-13-tran s- prostenoate 334  175      304        Methyl 9-oxo-11.alpha.-methoxy-20-hydroxy-13-tran s- prostenoate 335  175      292        Ethyl 9-oxo-11.alpha.-propoxy-6,7,18,19,20-pentan or- 17-hydroxy-13-trans-prostenoate 336  177      289        Ethyl 9-oxo-11.alpha.-isopropoxy-5,6,7,19,20-pent a- nor-16-hydroxy-17-methyl-13-trans-prostenoate 337  181      287        Ethyl-9-oxo-7a,7b-bishomo-11.alpha.-isopropoxy-16 - hydroxy-18,19,20-trinor-13-trans-prostenoate 338  183      301        Ethyl 2-ethyl-9-oxo-11.alpha.-butoxy-16-ethyl-17- hydroxy-18,19,20-trinor-13-trans-prostenoate 339  185      304        Ethyl 3,3-dimethyl-9-oxo-11.alpha.-methoxy-20- hydroxy-13-trans:prostenoate 340  187      278        Ethyl 3-oxa-9-oxo-11.alpha.-ethoxy-16-hydroxy-13- trans-prostenoate 341  189      293        Ethyl 2-fluoro-9-oxo-11.alpha.-propoxy-19-hydroxy -20- nor-13-trans-prostenoate 342  191      298        Ethyl 7-nor-9-oxo-11.alpha.-sec-butoxy-16-hydroxy - 19-methyl-13-trans-prostenoate 343  193      297        Ethyl 7a-homo-9-oxo-11.alpha.-methoxy-17-hydroxy- 19, 20-dinor-13-trans-prostenoate 344  195      290        Ethyl 2-phenyl-9-oxo-11.alpha.-ethoxy-16-hydroxy- 20-methyl-13-trans-prostenoate 345  196      278        Butyl 9-oxo-11.alpha.-methoxy-16-hydroxy-13-trans - prostenoate 346  197      278        Isopropyl 9-oxo-11.alpha.-methoxy-16-hydroxy-13- trans-prostenoate 347  198      278        Decyl 9-oxo-11.alpha.-methoxy-16-hydroxy-13-trans - prostenoate 348   242a    278        9-oxo-11.alpha.-methoxy-16-hydroxy-13-trans-pro- stenoic acid 349   242a    340        9-oxo-11.alpha.-methoxy-20-hydroxy-13-trans-pro- stenoic acid 350  229      291        6,7-dinor-9-oxo-11.alpha.-methoxy-16-hydroxy-20- ethyl-13-trans-prostenoic acid 351  230      294        5,6,7-trinor-9-oxo-11.alpha.-ethoxy-20-hydroxymet hyl- 13-trans-prostenoic acid 352  231      302        7a,7b-bishomo-9-oxo-11.alpha.-methoxy-16-methyl-1 7- hydroxy-19,20-dinor-13-trans-prostenoic acid 353  232      288        2-ethyl-9-oxo-11.alpha.-methoxy-16-hydroxy-20-nor - 13-trans-prostenoic acid 354  233      293        3,3-dimethyl-9-oxo-11.alpha.-methoxy-19-hydroxy-2 0- nor-13-trans-prostenoic acid 355  234      278        3-oxa-9-oxo-11.alpha.-methoxy-16-hydroxy-13-trans - prostenoic acid 356  235      295        2-fluoro-9-oxo-11.alpha.-methoxy-20-(2-hydroxyeth yl)- 13-trans-prostenoic acid 357  236      296        7-nor-9-oxo-11.alpha.-methoxy-20-(3-hydroxypropyl )- 13-trans-prostenoic acid 358  237      298        7a-homo-9-oxo-11.alpha.-methoxy-16-hydroxy-19-met hyl- 13-trans-prostenoic acid 359  238      303        2-phenyl-9-oxo-11.alpha.-methoxy-16-ethyl-17-hydr oxy- 19,20-dinor-13-trans-prostenoic acid 360  239      278        9-oxo-11.alpha.-ethoxy-16-hydroxy-13-trans- prostenoic acid 361  240      278        9-oxo-11.alpha.-propoxy-16-hydroxy-13-trans-pro- stenoic acid 362  241      304        9-oxo-11.alpha.-isopropoxy-20-hydroxy-13-trans- prostenoic acid 363  242      279        9-oxo-11.alpha.-n-butoxy-16-hydroxy-19,20-dinor-1 3- trans-prostenoic acid 364  147      278        9-oxo-11.alpha.-hydroxy-16-hydroxy-13-trans-pro- stenoic acid 365  147      288        9-oxo-11.alpha.-hydroxy-16-hydroxy-20-nor-13-tran s- prostenoic acid 366  147      289        9-oxo-11.alpha.-hydroxy-16-hydroxy-17-methyl-19,2 0- dinor-13-trans-prostenoic acid 367  147      297        9-oxo-11.alpha.-hydroxy-17-hydroxy-19,20-dinor-13 - trans-prostenoic acid 368  147      298        9-oxo-11.alpha.-hydroxy-16-hydroxy-19-methyl-13- trans-prostenoic acid 369  147      299        9-oxo-11.alpha.-hydroxy-16-hydroxy-17-ethyl-20-no r- 13-trans-prostenoic acid 370  147      277        9-oxo-11.alpha.-hydroxy-18-hydroxy-19,20-dinor-13 - trans-prostenoic acid 371  147      293        9-oxo-11.alpha.-hydroxy-19-hydroxy-20-nor-13-tran s- prostenoic acid 372  147      294        9-oxo-11.alpha.-hydroxy-20-hydroxymethyl-13-trans - prostenoic acid 373  147      296        9-oxo-11.alpha.-hydroxy-20-(3-hydroxypropyl)-13- trans-prostenoic acid 374  147      302        9-oxo-11.alpha.-hydroxy-16-methyl-17-hydroxy-19,2 0- dinor-13-trans-prostenoic acid 375  148      291        9-oxo-11.alpha.-hydroxy-6,7-dinor-16-hydroxy-20- ethyl-13-trans-prostenoic acid 376  149      304        9-oxo-11.alpha.-hydroxy-5,6,7-trinor-20-hydroxy-1 3- trans-prostenoic acid 377  150      278        9-oxo-11.alpha.-hydroxy-7a,7b-bishomo-16-hydroxy- 13- trans-prostenoic acid 378  150      304        9-oxo-11.alpha.-hydroxy-7a,7b-bishomo-20-hydroxy- 13- trans-prostenoic acid 379  150      294        9-oxo-11.alpha.-hydroxy-7a,7b-bishomo-20-hydroxym ethyl- 13-trans-prostenoic acid 380  151      287        9-oxo-11.alpha.-hydroxy-2-ethyl-16-hydroxy-18,19, 20- trinor-13-trans-prostenoic acid 381  152      278        9-oxo-11.alpha.-hydroxy-3,3-dimethyl-16-hydroyx-1 3- trans-prostenoic acid 382  152      304        9-oxo-11.alpha.-hydroxy-3,3-dimethyl-20-hydroxy-1 3- trans-prostenoic acid 383  153      278        9-oxo-11.alpha.-hydroxy-3-oxa-16-hydroxy-13-trans - prostenoic acid 384  154      300        9-oxo-11.alpha.-hydroxy-2-fluoro-16-methyl-17-hyd roxy- 18,19,20-trinor-13-trans-prostenoic acid 385  155      278        9-oxo-11.alpha.-hydroxy-7-nor-16-hydroxy-13-trans - prostenoic acid 386  156      278        9-oxo-11.alpha.-hydroxy-7a-homo-16-hydroxy-13-tra ns- prostenoic acid 387  157      291        9-oxo-11.alpha.-hydroxy-2-phenyl-16-hydroxy-20- ethyl-13-trans-prostenoic acid 388   157a    278        9-oxo-11.alpha.-hydroxy-2-methyl-16-hydroxy-13- trans-prostenoic acid 389   157a    304        9-oxo-11.alpha.-hydroxy-2-methyl-20-hydroxy-13- trans-prostenoic acid 390  158      278        Ethyl 9-oxo-11.alpha.-hydroxy-16-hydroxy-13-trans - prostenoate 391  158      304        Ethyl 9-oxo-11.alpha.-hydroxy-20-hydroxy-13-trans - prostenoate 392  159      278        Methyl 9-oxo-11.alpha.-hydroxy-16-hydroxy-13-tran s- prostenoate 393  160      294        Ethyl 9-oxo-11.alpha.-hydroxy-6,7-dinor-20-hydrox y- methyl-13-trans-prostenoate 394  161      298        Ethyl 9-oxo-11.alpha.hydroxy-5,6,7-trinor 16- hydroxy-19-methyl-13-trans-prostenoate 395  162      293        Ethyl 9-oxo-11.alpha.-hydroxy-7a,7b-bishomo-19- hydroxy-20-nor-13-trans-prostenoate 396  163      299        Ethyl 9-oxo-11.alpha.-hydroxy-2-ethyl-16-hydroxy- 17-ethyl-20-nor-13-trans-prostenoate 397  164      297        Ethyl 9-oxo-11.alpha.-hydroxy-3,3-dimethyl-17- hydroxy-19,20-dinor-13-trans-prostenoate 398  165      294        Ethyl 9-oxo-11.alpha.-hydroxy-3-oxa-20-hydroxy- methyl-13-trans-prostenoate 399  166      304        Ethyl 9-oxo-11.alpha.-hydroxy-2-fluoro-20-hydroxy - 13-trans-prostenoate 400  167      290        Ethyl 9-oxo-11.alpha.-hydroxy-7-nor-16-hydroxy-20 - methyl-13-trans-prostenoate 401  168      289        Ethyl 9-oxo-11.alpha.-hydroxy-7a-homo-16-hydroxy- 17-methyl-19,20-dinor-13-trans-prostenoate 402  169      297        Ethyl 9-oxo-11.alpha.-hydroxy-2-phenyl-17-hydroxy - 19,20-dinor-13-trans-prostenoate 403  170      278        Butyl 9-oxo-11.alpha.-hydroxy-16-hydroxy-13-trans - prostenoate 404  170      304        Butyl-9-oxo-11.alpha.-hydroxy-20-hydroxy-13-trans - prostenoate 405  171      278        Isopropyl 9-oxo-11.alpha.-hydroxy-16-hydroxy-13- trans-prostenoate 406  171      304        Isopropyl 9-oxo-11.alpha.-hydroxy-20-hydroxy-13- trans-prostenoate 407  172      278        Decyl 9-oxo-11.alpha.-hydroxy-16-hydroxy-13-trans - prostenoate 408  172      304        Decyl 9-oxo-11.alpha.-hydroxy-20-hydroxy-13-trans - prostenoate 409  203      278        Ethyl 9-oxo-11.alpha.-t-butyloxy-16-hydroxy-13-tr ans- prostenoate 410  243      278        Ethyl 9-oxo-11.alpha.(.beta.-hydroxyethyoxy)-16-h ydroxy- 13-trans-prostenoate 411  244      304        Methyl 9-oxo-11.alpha.(.beta.-hydroxyethoxy)-20-h ydroxy- 13-trans-prostenoate 412  245      294        Ethyl 9-oxo-11.alpha.(.gamma.-hydroxypropoxy)-6,7 -dinor- 20-hydroxymethyl-13-trans-prostenoate 413  246      298        Ethyl 9-oxo-11.alpha.(.beta.-hydroxyethoxy)-5,6,7 -trinor- 16-hydroxy-19-methyl-13-trans-prostenoate 414  247      278        9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-16-hydroxy -13- trans-prostenoate 415  247      304        9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-20-hydroxy -13- trans-prostenoic acid 416  247      292        9-oxo-11.alpha.(.beta.-hydroxyethoxy)-17-hydroxy- 18,19, 20-trinor-13-trans-prostenoic acid 417  247      293        9-oxo-11.alpha.(.beta.hydroxyethoxy)-19-hydroxy-2 0- nor-13-trans-prostenoic acid 418  247      294        9-oxo-11.alpha.-(.beta.-hydroethoxy)-20-hydroxyme thyl- 13-trans-prostenoic acid 419  247      298        9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-16-hydroxy -19, methyl-13-trans-prostenoic acid 420  248      296        9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-6,7-dinor- 20- (3-hydroxypropyl)-13-trans-prostenoic acid 421  249      299        9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-5,6,7,20-t etranor- 16-hydroxy-17-ethyl-13-trans-prostenoic acid 422  251      278        9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-7a,7b-bish omo-16- hydroxy-13-trans-prostenoic acid 423  251      277        9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-7a,7b-bish omo-18- hydroxy-19,20-dinor-13-trans-prostenoic acid 424  250      297        Ethyl 9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-7a,7 b-bis- homo-17-hydroxy-19,20-dinor-13-trans- prostenoate 425  253      287        Ethyl 9-oxo-11.alpha.(.gamma.-hydroxypropoxy)-2-e thyl- 16-hydroxy-18,19,20-trinor-13-trans- prostenoate 426  252      278        9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-2-ethyl-16 -hydroxy- 13-trans-prostenoic acid 427  252      304        9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-2-ethyl-20 -hydroxy- 13-trans-prostenoic acid 428  254      278        9-oxo-11.alpha.-(.beta.hydroxyethoxy)-3,3-dimethy l-16- hydroxy-13-trans-prostenoic acid 429  254      297        9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-3,5-dimeth yl-17- hydroxy-19,20-dinor-13-trans-prostenoic acid 430  255      293        Ethyl 9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-3,3- dimethyl- 19-hydroxy-20-nor-13-trans-prostenoate 431  257      302        Ethyl 9-oxo-11.alpha.-(.gamma.-hydroxypropoxy)-3- oxa-16- methyl-17-hydroxy-19,20-dinor-13-trans- prostenoate 432  256      278        9-oxo-11.alpha.-(.beta.-hyddroxyethoxy)-3-oxa-16- hydroxy- 13-trans-prostenoic acid    j -433 258 278 9-oxo- 11.alpha.-(.beta.-hyd roxyethoxy)-2-fluoro- 16-hydroxy- 13-trans-prostenoic acid 434  258      304        9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-2-fluoro-2 0- hydroxy-13-trans-prostenoic acid 435  258      291        9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-2-fluoro-1 6- hydroxy-20-ethyl-13-trans-prostenoic acid 436  259      295        Ethyl 9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-2-fl uoro- 20-(2-hydroxyethyl)-13-trans-prostenoate 437  260      290        9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-7-nor-16-h ydroxy- 20-methyl-13-trans-prostenoic acid 438  261      278        9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-7a-homo-16 -hydroxy- 13-trans-prostenoic acid 439  262      293        9-oxo-11.alpha.-8.beta.-hydroxyethoxy)-2-phenyl-1 9- hydroxy-20-nor-13-trans-prostenoic acid 440  263      278        Ethyl 9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-2-ph enyl-16- hydroxy-13-trans-prostenoate 441  264      278        Butyl 9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-16-h ydroxy- 13-trans-prostenoate 442  264      304        Butyl 9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-20-h ydroxy- 13-trans-prostenoate 443  265      278        Isopropyl 9-oxo-11.alpha.-(.beta.hydroxtyethoxy)- 16-hydroxy- 13-trans-prostenoate 444  265      304        Isopropyl 9-oxo-11.alpha.-(.beta.-hydroxyethoxy)- 20- hydroxy-13-trans-prostenoate 445  266      278        Decyl 9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-16- hydroxy-13-trans-prostenoate 446  266      304        Decyl 9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-20-h ydroxy- 13-trans-prostenoate 447  267      278        9-oxo-11.alpha.-(.beta.-hydroxypropoxy)-16-hydrox y-13- trans-prostenoic acid 448  267      304        9-oxo-11.alpha.-(.beta.-hydroxypropoxy)-20-hydrox y-13- trans-prostenoic acid 449  267      303        9-oxo-11.alpha.-(.beta.-hydroxypropoxy)-16-ethyl- 17- hydroxy-19,20-dinor-13-trans-prostenoic acid 450  269      278        9-oxo-11.alpha.-(4-hydroxybutoxy)-16-hydroxy-3- trans-prostenoic acid 451  269      304        9-oxo-11.alpha.-(4-hydroxybutoxy)-20-hydroxy-13-t rans- prostenoic acid __________________________________________________________________________

Saponification of the alkyl esters listed in Table 15 below by the method described in Example 283 is productive of the prostenoic acids of the table. ______________________________________ Starting alkyl prostenoate of Product Example Example     Hydroxy Prostenoic Acid ______________________________________ 151a  305         9-oxo-20-hydroxy-13-trans- j -  prostenoic acid 452    306         9-oxo-16-hydroxy-20-nor-13- trans-prostenoic acid 453    307         9-oxo-16-hydroxy-20-methyl- 13-trans-prostenoic acid 454    308         9-oxo-17-hydroxy-19,20-dinor- 13-trans-prostenoic acid 455    309         9-oxo-20-hydroxymethyl-13- trans-prostenoic acid 456    312         9-oxo-20-(3-hydroxypropyl)- 13-trans-prostenoic acid 457    314         5,6,7-trinor-9-oxo-20-(2- hydroxyethyl)-13-trans-pro- stenoic acid 458    315         7a,7b-bishomo-9-oxo-16-hydroxy- 13-trans-prostenoic acid 459    316         7a,7b-bishomo-9-oxo-19,20- dinor-16-hydroxy-13-trans- prostenoic acid 460    317         3,3-dimethyl-9-oxo-16-hydroxy- 20-ethyl-13-trans-prostenoic acid 461    318         3-oxa-9-oxo-16-hydroxy-13- trans-prostenoc acid 462    319         3-oxa-9-oxo-19-hydroxy-20-nor- 13-trans-prostenoic acid 463    320         7-nor-9-oxo-16-hydroxy-13- trans-prostenoic acid 464    321         7-nor-9-oxo-16-methyl-17- hydroxy-18,19,20-trinor-13- trans-prostenoic acid 465    322         2-fluoro-9-oxo-16-hydroxy-13- trans-prostenoic acid 466    323         7a-homo-9-oxo-18-hydroxy-19, 20-dinor-13-trans-prostenoic acid 467    324         7a-homo-9-oxo-16-hydroxy-13- trans-prostenoic acid 468    325         2-phenyl-9-oxo-16-hydroxy-13- trans-prostenoic acid 469    326         2-phenyl-9-oxo-16-hydroxy-17- ethyl-20-nor-13-trans- prostenoic acid 470    327         2-ethyl-9-oxo-20-hydroxy-13- trans-prostenoic acid 471    328         2-methyl-9-oxo-16-hydroxy-13- trans-prostenoic acid 472    329         3 thia-9-oxo-16-hydroxy-13- trans-prostenoic acid 473    330         3-thia-9-oxo-20-hydroxy-13- trans-prostenoic acid 474    331         3-thia-9-oxo-17-hydroxy-16- methyl-19,20-dinor-13-trans- prostenoic acid ______________________________________

A solution containing 1.4 g. (4.3 mmoles) of 16-hydroxy-9-oxo-13-trans-prostenoic acid (Example 286) in 45 ml. of absolute ethanol is hydrogenated using 650 mg. of 10% palladium or carbon. Filtration followed by evaporation of the solvent gives 1.31 g. of subject compound as an oil; .nu. max 5.78 (ketone carbonyl group) and 5.82 m.mu. (acid carbonyl group).

Hydrogenation of the 13-prostenoic acids and esters listed in the table below by the procedure described in Example 475 is productive of the prostanoic acids and esters of the table. ______________________________________ Starting 13-pro- stenoic acid or Product Example ester of example Prostanoic acid or ester ______________________________________ 476    318          Ethyl 3-oxa-9-oxo-16-hydroxy- prostanoate 477    319          Ethyl 3-oxa-9-oxo-19-hydroxy- 20-nor-prostanoate 478    320          Ethyl 7-nor-9-oxo-16-hydroxy- prostanoate 479    321          Ethyl 7-nor-9-oxo-16-methyl- 17-hydroxy-18,19,20-trinor- prostanoate 480    322          Ethyl 2-fluoro-9-oxo-16- hydroxy-prostanoate 481    324          Ethyl 7a-homo-9-oxo-16- hydroxy-prostanoate 482    325          Ethyl 2-phenyl-9-oxo-16- hydroxy-prostanoate 483    327          Ethyl 2-ethyl-9-oxo-20- hydroxy-prostanoate 484    328          Ethyl 2-methyl-9-oxo-16- hydroxy-prostanoate 485    305          Ethyl 9-oxo-20-hydroxy- prostanoate 486    306          Ethyl 9-oxo-16-hydroxy-20- nor-prostanoate 487    307          Ethyl 9-oxo-16-hydroxy-20- methyl-prostanoate 488    308          Ethyl 9-oxo-17-hydroxy-19,20- dinor-13-prostanoate 489    309          Ethyl 9-oxo-20-hydroxymethyl- prostanoate 490    310          Butyl 9-oxo-16-hydroxy-19- methyl-prostanoate 491    311          Isopropyl 9-oxo-17-hydroxy-16- ethyl-prostanoate 492    312          Methyl 9-oxo-20-(3-hydroxy- propyl)-prostanoate 493    313          Decyl 9-oxo-16-hydroxy- prostanoate 494    314          Ethyl 5,6,7-trinor-9-oxo- 20-(2-hydroxyethyl)- prostanoate 495    315          Ethyl 7a,7b-bishomo-9-oxo- 16-hydroxy-prostanoate 496    316          Ethyl 7a,7b-bishomo-9-oxo- 19,20-dinor-16-hydroxy- prostanoate 497    317          Ethyl 3,3-dimethyl-9-oxo-16- hydroxy-20-ethyl-prostanoate 498    332          Ethyl 9-oxo-11.alpha.-ethoxy-16- hydroxy-prostanoate 499    333          Methyl 9-oxo-11.alpha.-methoxy-16- hydroxy-prostanoate 500    337          Ethyl 9-oxo-7a,7b-bishomo-11.alpha.- isopropoxy-16-hydroxy-18,19, 20-trinor-prostanoate 501    338          Ethyl 2-ethyl-9-oxo-11.alpha.- butoxy-16-ethyl-17-hydroxy- 18,19,20-rinor-prostanoate 502    339          Ethyl 3,3-dimethyl-9-oxo-11.alpha.- methoxy-20-hydroxy-prostanoate 503    340          Ethyl 3-oxa-9-oxo-11.alpha.-ethoxy- 16-hydroxy-prostanoate 504    341          Ethyl 2-fluoro-9-oxo-11.alpha.- propoxy-19-hydroxy-20-nor- prostanoate 505    342          Ethyl 7-nor-9-oxo-11.alpha.-sec- butoxy-16-hydroxy-19-methyl- prostanoate 506    347          Decyl 9-oxo-11.alpha.-methoxy-16- hydroxy-prostanoate 507    348          9-oxo-11.alpha.-methoxy-16-hydroxy- prostanoic acid 508    349          9-oxo-11.alpha.-methoxy-20-hydroxy- prostanoic acid 509    352          7a,7b-bishomo-9-oxo-11.alpha.- methoxy-16-methyl-17-hydroxy- 19,20-dinor-prostanoic acid 510    353          2-ethyl-9-oxo-11.alpha.-methoxy-16- hydroxy-20-nor-prostanoic acid 511    354          3,3-dimethyl9-oxo-11.alpha.-methoxy- 19-hydroxy-20-nor-prostanoic acid 512    355          3-oxa-9-oxo-11.alpha.-methoxy-16- hydroxy-prostanoic acid 513    356          2-fluoro-9-oxo-11.alpha.-methoxy- 20-(2-hydroxyethyl) prostanoic acid 514    357          7-nor-9-oxo-11.alpha.-methoxy-20- (3-hydroxypropyl)-prostanoic acid 515    358          7a-homo-9-oxo-11.alpha.-methoxy-16- hydroxy-19-methyl-prostanoic acid 516    359          2-phenyl-9-oxo-11.alpha.-methoxy- 16-ethyl-17-hydroxy-19,20- dinor-prostanoic acid 517    360          9-oxo-11.alpha.-ethoxy-16-hydroxy- prostanoic acid 518    361          9-oxo-11.alpha.-propoxy-17-hydroxy- prostanoic acid 519    362          9-oxo-11.alpha.-isopropoxy-20- hydroxy-prostanoic acid 520    363          9-oxo-11.alpha.-n-butoxy-16-hydroxy- 19,20-dinor-prostanoic acid 521    364          9-oxo-11.alpha.-hydroxy-16-hydroxy- prostanoic acid 522    365          9-oxo-11.alpha.-hydroxy-16-hydroxy- 20-nor-prostanoic acid 523    367          9-oxo-11.alpha.-hydroxy-17-hydroxy- 19,20-dinor-prostanoic acid 4524   368          9-oxo-11.alpha.-hydroxy-16-hydroxy- 19-methyl-prostanoic acid 525    370          9-oxo-11.alpha.-hydroxy-18-hydroxy- 19,20-dinor-prostanoic acid 526    371          9-oxo-11.alpha.-hydroxy-19-hydroxy- 20-nor-prostanoic acid 527    372          9-oxo-11.alpha.-hydroxy-20-hydroxy- methyl-prostanoic acid 528    373          9-oxo-11.alpha.-hydroxy-20-(3- hydroxypropyl)-prostanoic acid 529    374          9-oxo-11.alpha.-hydroxy-16-methyl- 17-hydroxy-19,20-dinor-pro- stanoic acid 530    375          9-oxo-11.alpha.-hydroxy-6,7-dinor- 16-hydroxy-20-ethyl-prostanoic acid 531    377          9-oxo-11.alpha.-hydroxy-7a,7b- bishomo-16-hydroxy-prostanoic acid 532    378          9-oxo-11.alpha.-hydroxy-7a,7b- bishomo-20-hydroxy-prostanoic 533    381          9-oxo-11.alpha.-hydroxy-3,3-dimethyl- 16-hydroxy-prostanoic acid 534    382          9-oxo-11.alpha.-hydroxy-3,3-dimethyl- 20-hydroxy-prostanoic acid 535    383          9-oxo-11.alpha.-hydroxy-3-oxa-16- hydroxy-prostanoic acid 536    384          9-oxo-11.alpha.-hydroxy-2-fluoro- 16-methyl-17-hydroxy-18,19, 20-trinor-prostanoic acid 537    385          9-oxo-11.alpha.-hydroxy-7-nor-16- hydroxy-prostanoic acid 538    386          9-oxo-11.alpha.-hydroxy-7a-homo- 16-hydroxy-prostanoic acid 539    387          9-oxo-11.alpha.-hydroxy-2phenyl- 16-hydroxy-20-ethyl-prostanoic acid 540    388          9-oxo-11.alpha.-hydroxy-2-methyl-16- hydroxy-prostanoic acid 541    389          9-oxo-11.alpha.-hydroxy-2-methyl-20- hydroxy-prostanoic acid 542    390          Ethyl 9-oxo-11.alpha.-hydroxy-16- hydroxy-prostanoate 543    391          Ethyl 9-oxo-11.alpha.-hydroxy-20- hydroxy-prostanoate 544    400          Ethyl 9-oxo-11.alpha.-hydroxy-7-nor- 16-hydroxy-20-methyl- prostanoate 546    403          Butyl 9-oxo-11.alpha.-hydroxy-16- hydroxy-prostanoate 547    407          Decyl 9-oxo-11.alpha.-hydroxy-16- hydroxy-prostanoate 548    408          Decyl 9-oxo-11.alpha.-hydroxy-20- hydroxy-prostanoate 549    409          Ethyl 9-oxo-11.alpha.-t-butoxy-16- hydroxy-prostanoate 550    410          Ethyl 9-oxo-11.alpha.-(.beta.-hydroxy- ethoxy)-16-hydroxy-prostanoate 551    411          Methyl 9-oxo-11.alpha.-(.beta.-hydroxy- ethoxy-20-hydroxy-prostanoate 552    414          9-oxo-11.alpha.-(.beta.-hydroxyethoxy)- 16-hydroxy-prostanoic acid 553    415          9-oxo-11.alpha.-(.beta.-hydroxyethoxy)- 20-hydroxy-prostanoic acid 554    417          9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-19- hydroxy-20-nor-prostenoic acid 555    419          9-oxo-11.alpha.-(.beta.-hydroxyethoxy- 16-hydroxy-19-methyl- prostanoic acid 556    422          9-oxo-11.alpha.-(.beta.-hydroxyethoxy)- 7a,7b-bishomo-16-hydroxy- prostanoic acid 557    423          9-oxo-11.alpha.-(.beta.-hydroxyethoxy- 7a,7b-bishomo-18-hydroxy- 29,20-dinor-prostanoic acid 558    424          Ethyl 9-oxo-11.alpha.-(.beta.-hydroxy- ethoxy)-7a,7b-bishomo-17- hydroxy-19,20-dinor-prostanoate 559    426          9-oxo-11.alpha.-(.beta.-hydroxyethoxy)- 2-ethyl-16-hydroxy-prostanoic acid 560    427          9-oxo-11.alpha.-(.beta.-hydroxyethoxy)- 2-ethyl-20-hydroxy-pro- stanoic acid 561    428          9-oxo-11.alpha.-(.beta.-hydroxyethoxy)- 3,3-dimethyl-16-hydroxy- prostanoic acid 562    429          9-oxo-11.alpha.-(.beta.-hydroxyethoxy)- 3,3-dimethyl-17-hydroxy-19,20- dinor-prostanoic acid 563    432          9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-3- oxa-16-hydroxy-prostanoic acid 564    433          9-oxo-11.alpha.-(.beta. -hydroxyethoxy)-2- fluoro-16-hydroxy-prostanoic acid 565    434          9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-2- fluoro-20-hydroxy-prostanoic acid 566    437          9-oxo-11.alpha.-(.beta.-hydroxyethoxy)-7- nor-16-hydroxy-20-methyl- prostanoic acid 567    438          9-oxo-11.alpha.-(.beta.-hydroxyethoxy)- 7a-homo-16-hydroxy- prostanoic acid 568    439          9-oxo-11.alpha.-(.beta.-hydroxyethoxy)- 2-phenyl-19-hydroxy-20-nor- prostanoic acid 569    445          Decyl 9-oxo-11.alpha.-(.beta.-hydroxy- ethoxy)-16-hydroxy- prostanoate 570    446          Decyl 9-oxo-11.alpha.-(.beta.-hydroxy- ethoxy)-20-hydroxy- prostanoate 571    447          9-oxo-11.alpha.-(.beta.-hydroxypropoxy)- 16-hydroxy-prostanoic acid 572    448          9-oxo-11.alpha.-(.beta.-hydroxypropoxy)- 20-hydroxy-prostanoic acid 573    450          9-oxo-11.alpha.-(4-hydroxybutoxy)- 16-hydroxy-prostanoic acid 574    451          9-oxo-11.alpha.-(4-hydroxybutoxy)- 20-hydroxy-prostanoic acid ______________________________________

To a stirred solution of 459 mg. (1.29 mmoles) of 11.alpha. ,20-dihydroxy-9-oxo-13-trans-prostenoic acid (Example 280a) in 4.0 ml. of tetrahydrofuran is added 5.2 ml. of a 0.65M solution of lithium perhydro 9b-boraphenalyl hydride in tetrahydrofuran at -78.degree. C. under nitrogen. The solution is stirred at -78.degree. C. for 45 minutes and at ambient temperatures for 15 minutes. The solution is diluted with 10 ml. of water and extracted with ether. The extract is back-extracted with N/4 sodium bicarbonate solution. The combined aqueous phases are acidified with 4N hydrochloric acid, saturated with sodium chloride, and extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue is purified by thin layer chromatography on silica gel to give a colorless oil, .nu. max. = 3310 (hydroxyl groups), 1705 (acid carbonyl group), and 970 cm.sup.-1 (trans-vinyl group).

Reduction of the 9-oxo derivative listed in the table below with lithium perhydro-9.beta.-boraphenyalyl hydride by the method described in Example 575 is productive of the 9.alpha.-hydroxy derivative of the table.

When the starting 9-oxo-derivative is an ester, the original ether extract is washed with brine, dried over magnesium sulfate, and concentrated. Chromatography of the residue on silica gel to separate the boron-containing compounds affords the product esters of the table. ______________________________________ Starting 9-oxo derivative of Product Example Example     9.alpha.-hydroxy Derivative ______________________________________ 576    305         Ethyl 9.alpha.,20-dihydroxy-13- trans-prostenoate 577    306         Ethyl 9.alpha.,16-dihydrox-20-nor- 13-trans-prostenoate 578    307         Ethyl 9.alpha.,16-dihydroxy-20- methyl-13-trans-prostenoate 579    308         Ethyl 9.alpha.,17-dihydroxy-19,20- dinor-13-trans-prostenoate 580    309         Ethyl 9.alpha.hydroxy-20-hydroxy- methyl-13-trans-prostenoate 581    310         Butyl 9.alpha.,16-dihydroxy-19- meythyl-13-trans-prostenoate 582    311         Isopropyl 9.alpha.,17-dihydroxy-16- ethyl-13-trans-prostenoate 583    313         Decyl 9.alpha.,16-dihydroxy-13- trans-prostenoate 584    315         Ethyl 7a,7b-bishomo-9.alpha.,16- dihydroxy-13-trans-prostenoate 585    317         Ethyl 3,3-dimethyl-9.alpha.,16-di- hydroxy-20-ethyl-13-trans- prostenoate 586    318         Ethyl 3-oxa-9.alpha.,16-dihydroxy- 13-trans-prostenoate 587    320         Ethyl 7-nor-9.alpha.,16-dihydroxy- 13-trans-prostenoate 588    323         Ethyl 7a-homo-9.alpha.,18-dihydroxy- 19,20-dinor-13-trans- prostenoate 589    324         Ethyl 7a-homo-9.alpha.,16-dihydroxy- 13-trans-prostenoate 590    326         Ethyl 2-phenyl-9.alpha.,16-dihydroxy- 17-ethyl-20-nor-13-trans- prostenoate 591    328         Ethy l2-methyl-9.alpha.,16-dihydroxy- 13-trans-prostenoate 592    329         Ethyl 3-thia-9.alpha.,16-dihydroxy- 13-trans-prostenoate 593    330         Ethyl 3-thia-9.alpha.,20-dihydroxy- 13-trans-prostenoate 594    332         Ethyl 11.alpha.-ethoxy-9.alpha.,16-di- hydroxy-13-trans-prostenoate 595    333         methyl 11.alpha.-methoxy-9.alpha.,16- dihydroxy-13-trans- prostenoate 596    334         Methyl 11.alpha.-methoxy-9.alpha.,20-di- hydroxy-13-trans-prostenoate 597    337         Ethyl 7a,7b-bishomo-11.alpha.-iso- propoxy-9.alpha.,16-dihydroxy-18,19, 20-trinor-13-transprostenoate 598    338         Ethyl 2-ethyl-11.alpha.-butoxy-16- ethyl-9.alpha.,17-dihdroxy-18,19, 20-trinor-13-trans-prostenoate 599    339         Ethyl 3,3-dimethyl-11.alpha.-methoxy- 9.alpha.,20-dihydroxy-13-trans- prostenoate 600    341         Ethyl 2-fluoro-9-oxo-11.alpha.-pro- poxy-9.alpha.,19-dihydroxy-20- nor-13-trans-prostenoate 601    342         Ethyl 7-nor-11.alpha.-sec-butoxy-9.alpha., 16-dihydroxy-19-methyl-13- trans-prostenoate 602    343         Ethyl 7a-homo-11.alpha.-methoxy-9.alpha., 17-dihydroxy-19,20-dinor-13- trans-prostenoate 603    347         Decyl 11.alpha.-metoxy-9.alpha.,16-di- hydroxy-13-trans-prostenoate 604    348         11.alpha.-methyl-9.alpha.,16-dihydroxy- 13-trans prostenoic acid 605    349         11.alpha.-methoxy-9.alpha.,20-dihydroxy- 13-trans-prostenoic acid 606    351         5,6,7-trinor-9.alpha.-hydroxy-11.alpha.- ethoxy-20-hydroxymethyl-13- trans-prostenoic acid 607    352         7a,7b-bishomo-11.alpha.-methoxy-16- methyl-9.alpha.,17-dihydroxy-19,20- dinor-13-trans-prostenoic acid 608    353         2-ethyl-11.alpha.-methoxy-9.alpha.,16-di- hydroxy-20-nor-13-trans- prostenoic acid 609    355         3-oxa-11.alpha.-methoxy-9.alpha.,16-di- hydroxy-13-trans-prostenoic acid 610    356         2-fluoro-9.alpha.-hydroxy-11.alpha.- methoxy-20-(2-hydroxyethyl)- 13-trans-prostenoic acid 611    357         7-nor-9.alpha.-hydroxy-11.alpha.-methoxy- 20-(3-hydroxypropyl)-13- trans-prostenoic acid 612    358         7a-homo-9-oxo-11.alpha.-methoxy-9.alpha., 16-dihydroxy-19-methyl-13- trans-prostenoic acid 613    360         11.alpha.-ethoxy-9.alpha.,16-dihydroxy- 13-trans-prostenoic acid 614    361         11.alpha.-propoxy-9.alpha.,16-dihydroxy- 13-trans-prostenoic acid 615    362         11.alpha.-isopropoxy-9.alpha.,20-dihydroxy- 13-trans-prostenoic acid 616    363         11.alpha.-n-butoxy-9.alpha.,16-dihydroxy- 19,20-dinor-13-trans- prostenoic acid 617    364         9.alpha.,11.alpha.,16-trihydroxy-13-trans- prostenoic acid 618    365         9.alpha.,11.alpha.,16-trihydroxy-20-nor- 13-trans-prostenoic acid 619    366         9.alpha.,11.alpha.,16-trihydroxy-17- methyl-19,120-dinor-13-trans- prostenoic acid 620    367         9.alpha.,11.alpha.,17-trihydroxy-19,20- dinor-13-trans-prostenoic acid 621    368         9.alpha.,11.alpha.,16-trihydroxy-19-methyl- 13-trans-prostenoic acid 622    369         9.alpha.,11.alpha.,16-trihydroxy-17- ethyl-20-nor-13-trans- prostenoic acid 623    370         9.alpha.,11.alpha.,18-trihydroxy-19,20- dinor-13-trans-prostenoic acid 624    371         9.alpha.,11.alpha.,19-trihydroxy-20-nor- 13-trans-prostenoic acid 625    372         9.alpha.,11.alpha.-dihydroxy-20-hydroxy- methyl-13-trans-prostenoic acid 626    373         9.alpha.,11.alpha.-dihydroxy-20-(3-hydroxy- propyl)-13-trans-prostenoic acid 627    374         9.alpha.,11.alpha.,1l7-trihydroxy-16- methyl-19,20-dinor-13-trans- prostenoic acid 628    375         9.alpha.,11.alpha.,16-trihydroxy-6,7- dinor-20-ethyl-13-trans- prostenoic acid 629    376         9.alpha.,11.alpha.,20-trihydroxy-5,6,7- trinor-13-trans-prostenoic acid 630    377         9.alpha.,11.alpha.,16-trihydroxy-7a,7b- bishomo-13-trans-prostenoic acid 631    378         9.alpha.,11.alpha.,20-trihydroxy-7a,7b- bishomo-13-trans-prostenoic acid 632    380         9.alpha.,11,16-trihydroxy-2-ethyl- 18,19,20-trinor-13-trans- prostenoic acid 633    381         9.alpha.,11.alpha.,16-trihydroxy-3,3-di- methyl-13-trans-prostenoic acid 634    382         9.alpha.,11.alpha.,20-trihydroxy-3,3-di- methyl-13-trans-prostenoic acid 635    383         9.alpha.,11.alpha.,16-trihydroxy-3-oxa- 13-trans-prostenoic acid 636    384         9.alpha.,11.alpha.,17-trihydroxy-2-fluoro- 16-methyl-18,19,20-trinor- 13-trans-prostenoic acid 637    385         9.alpha.,11.alpha.,16-trihydroxy-7-nor-13- trans-prostenoic acid 638    386         9.alpha.,11.alpha.,16-trihydroxy-7a-homo- 13-trans-prostenoic acid 639    387         9.alpha.,11.alpha.,16-trihydroxy-2-phenyl- 20-ethyl-13-trans-prostenoic- acid 640    388         9.alpha.,11.alpha.,16-trihydroxy-2-methyl- 13-trans-prostenoic acid 641    389         9.alpha.,11.alpha.,20-trihydroxy-2-methyl- 13-trans-prostenoic acid 642    390         Ethyl 9.alpha.,11.alpha.,16-trihydroxy- 13-trans-prostenoate 643    391         Ethyl 9.alpha.,11.alpha.,20-trihydroxy- 13-trans-prostenoate 644    403         Butyl 9.alpha.,11.alpha.,16-trihydroxy- 13-trans-prostenoate 645    407         Decyl 9.alpha.,11.alpha.,16-trihydroxy- 13-trans-prostenoate 646    408         Decyl9.alpha..11.alpha..20-trihydroxo- 13-trans-prostenoate 647    409         Ethyl 11.alpha.-t-butoxy-9.alpha..15- dihydroxy-13-trans- prostenoic acid 648    410         Ethyl 11.alpha.-(.beta.-hydroxyethoxy)- 9.alpha.16-dihydroxy-13-trans- prostenoate 649    411         Methyl 11.alpha.-(.beta.-hydroxyethoxy)- 9.alpha..20-dihydroxy-13-trans- prostenoate 650    414         9.alpha..16-dihydroxy-11.alpha.-(.beta.- hydroxyethoxy)-13-trans- prostenoic acid 651    415         9.alpha..20-dihydroxy-11-60 -(.beta.-hydroxy- ethoxy)-13-trans-prostenoic acid 652    416         9.alpha.,17-dihydroxy-(.beta.-hydroxy- ethoxy)-18,19,20-trinor-13- trans-prostenoic acid 653    417         9.alpha..19-dihydroxy-(.beta.-hydroxy- ethoxy)-20-nor-13-trans- prostenoic acid 654    418         9.alpha.-hydroxy-(.beta.-hydroxyethoxy)- 20-hydroxymethyl-13-trans- prostenoic acid 655    419         9.alpha.,16-dihydroxy-(.beta.-hydroxy- ethoxy)-19-methyl-13-trans- prostenoic acid 656    422         9.alpha..16-dihydroxy-(.beta.-hydroxy- ethoxy)-7a, 7b-bishomo-13- trans-prostenoic acid 657    426         9.alpha.,16-dihydroxy-11.alpha.-(.beta.-hydroxy- ethoxy)-2-ethyl-13-trans- prostenoic acid 658    427         9.alpha.,20-dihydroxy-11.alpha.-(.beta.-hydroxy- etoxy)-2-ethyl-13-trans- prostenoic acid 659    428         9.alpha.,16-dihydroxy-11.alpha.-(.beta.-hydroxy- ethoxy)-3,3-dimethyl-13- trans-prostenoic acid 660    432         9.alpha.,16-dihydroxy-11.alpha.-(.beta.-hydroxy- ethoxy)-3-oxa-13-trans- prostenoic acid 661    433         9.alpha.,16-dihydroxy-11.alpha.-(.beta.-hydroxy- ethoxy)-2-fluoro-13-trans- prostenoic acid 662    437         9.alpha.,16-dihydroxy-11.alpha.-(.beta.-hydroxy- ethoxy)-7-nor-20-methyl-13- trans-prostenoic acid 663    438         9.alpha..16-dihydroxy-11.alpha.-(.beta.-hydroxy- ethoxy)-7a-homo-13-trans- prostenoic acid 664    440         Ethyl9.alpha.,16-dihydroxy-11-.alpha.-(.beta.- hydroxyethoxy)-2-phenyl-13- trans-prostenoic acid 665    443         Isoproyl 9.alpha.,16-dihydroxy-11.alpha.- .beta.-hydroxyethoxy)-13-trans- prostenoic acid 666    445         Decyl 9.alpha..16-dihydroxy-11-60 - (.beta.-hydroxyethoxy)-13-trans- prostenoic acid 667    446         Decyl 9.alpha.-20-dihydroxy-11.alpha.- (.beta.-Hydroxyethoxy)-13-trans- prostenoic acid 668    447         9.alpha..16-dihydroxy-11.alpha.-(.beta.-hydroxy- propoxy)-13-trns-prostenoic acid 669    450         9.alpha..16-dihydroxy-11-60 -(4-hydroxy- butoxy)-13-trans-prostenoic acid 670    507         9.alpha..16-dihydroxy-11.alpha.-methoxy- prostanoic acid 671    511         9.alpha..19-dihyroxy-3,3-dimethyl- 11.alpha.-methoxy-20-nor- prostanoate 672    531         9.alpha.,11.alpha.,16-trihydroxy-7a, 7b- bishomo-prostanoic acid 673    527         9.alpha.,11.alpha.-dihydroxy-20-hydroxy- methyl-prostanoic acid 674    534         9.alpha.,11.alpha.,20-trihydroxy-3,3-di- methyl-prostanoic acid 675    538         9.alpha.,11.alpha.,6-trihydroxy-7a-homo- prostanoic acid 676    547         Decyl 9.alpha.,11.alpha.,16-trihydroxy- prostanoate 677    558 hydroxyethoxy) prostanoic acid 678    560         9.alpha.,20-dihydroxy-2-ethyl-11.alpha.- (.beta.-hydroxyethoxy)-prostaoic acid 678a  745         9.alpha.,20-dihydroxy-13-trans- prostenoic acid ______________________________________

To a stirred, ice-cold solution of 355 mg. (1.00 mmoles) of 11.alpha. ,20-dihydroxy-9-oxo-13-trans-prostenoic acid (Example 280a) in 50 ml. of ethanol is added 409 mg. (10.8 mmoles) of sodium borohydride in small portions during 1 minute. The mixture is stirred at 0.degree. C. for 5 minutes and at ambient temperature for 1.5 hour. The bulk of the ethanol is evaporated at room temperature, and the residue is treated with ether followed by dilute hydrochloric acid while cooling in an ice bath. The organic phase is separated and washed with water and saturated sodium chloride solution. The solution is dried over magnesium sulfate and concentrated. The residue is purified by thin layer chromatography on silica gel to give an oil, .nu. max. 3310 (hydroxyl groups), 1705 (acid carbonyl group), and 970 cm.sup.-1 (trans vinyl group).

Treatment of the 9-oxo-derivatives listed in the table below with sodium borohydride in accordance with the procedure described in Example 674 is productive of the 9-hydroxy derivatives of the table. Each of these derivatives represents a mixture of 9.alpha.- and 9.beta.-hydroxy compounds. ______________________________________ Startng 9-oxo- derivative of Product Example Example      9.alpha./9.beta.-hydroxy derivative ______________________________________ 680    305          Ethyl9.alpha./9.beta.,20-dihydroxy-13- trans-prostenoate 681    329          Ethyl9.alpha./9.beta.,16-dihydroxy-3- thia-13-trans-prostenoate 682    355          3-oxa 9.alpha./9.beta.16-dihyroxy-11.alpha.- methoxy-13-trans-prostanoic acid 683    364          9.alpha./9.beta.,11.alpha.,16-trihydroxy-13- trans-prostenoic acid 684    378          9.alpha./9.beta.,11.alpha.20-trihydroxy-7a,7b- bisheo-13-trans-prostenoic acid 685    414          9.alpha./9.beta.16-dihydroxy-11-60 -(.beta.- hydroxyethoxy)-13-trans- prostenoic acid ______________________________________

A solution of 355 mg. (1.00 mmoles) of 11.alpha. ,20-dihydroxy-9-oxo-13-trans-prostenoic acid (Example 280a) in 6.67 ml. of 1.5N hydrochloric acid and 13.3 ml. of tetrahydrofuran is allowed to stand at room temperature for 70 hours. The solution is treated with saturated sodium chloride solution and extracted with ether. The extract is washed successively with water and saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after evaporation of the solvent is purified by chromatography on silica gel to give an oil, .nu. max.sup. MeOH =  217 m.mu. (9500); .nu. max = 1700 (acid carbonyl group), 1690 (ketone carbonyl group), 1585 (conjugated olefin group), and 965 cm.sup.-1 (trans vinyl group).

Acid treatment by the procedure described in Example 686 of the 11.alpha.-hydroxy-9-oxo derivatives listed in the table below is productive of the .DELTA..sup.10 derivatives of the table. ______________________________________ Starting 11.alpha.- hydroxy-9-oxo-     Product derivative of    9-0x0-10-prostenoic acids and Example Example          esters ______________________________________ 687    387         9-oxo-2-phenyl-16-hydroxy-20- ethyl-10,13-trans-prostadienoic acid 688    388         9-oxo-methyl-15-hydroxy-10,13- trans-prostadienoic acid 689    389         9-oxo-2-methyl-20-hydroxy-10,13- trans-prostadienoic acid 690    390         Ethyl 9-oxo-16-hydroxy-10,13- trans-prostadienoate 691    391         Ethyl 9-oxo-20 hydroxy-10,13- trans-prostadienoate 692    392         Methyl 9-oxo-16-hydroxy-10,13- trans-prostadienoate 693    393         Ethyl9-oxo-6,7-dinor-20-hydroxy- methyl-10,13-trans-prostadienoate 694    394         Ethyl-9-oxo-5,6,7-trnor-16- hydroxy-19-methyl-10,13-trans- prostadienoate 695    395         Ethyl 9-oxo-7a,7b-bishomo-19- hydroxy-20-nor-10,13-trans- prostadienoate 696    396         Ethyl 9-oxo-2-ethyl-16-hydroxy- 17-ethyl-20-nor-10,13-trans- prostadienoate 697    397         Ethyl 9-oxo-3,3-dimethyl-17- hydroxy-19,20-dinor-10,13-trans- prostadienoate 698    398         Ethyl 9-oxo-3-oxa-20-hydroxy- methyl-10,13-trans-prostadienoate 699    399         Ethyl 9-oxo-2-fluoro-20-hydroxy- 10,13-trans-prostadienoate 700    400         Ethyl 9-oxo-7-nor-16-hydroxy- 20-methyl-10,13-trans- prostadienoate 701    401         EThyl9-oxo-7a,homo-16-hydroxy- 17-methyl-19,20-dinor-10,13- trans-prostadienoate 702    402         Ethyl 9-oxo-2-phenyl-17-hydroxy- 19,20-dinor-10,13-trans- prostadienoate 703    403         Butyl 9-oxo-16-hydroxy-10,13- trans-prostadienoate 704    404         Butyl 9-oxo-20-hyroxy-10,13- trans-prostadienoate 705    405         Isopropyl 9-oxo-16-hydroxy- 10,13-trans-prostadienoate 706    406         Isopropyl 9-oxo-20-hydroxy-10, 13-trans-prostadienoate 707    407         Decyl 9-oxo-16-hydroxy-10,13- trans-prostadienoate 708    408         Decyl 9-oxo-20-hydroxy-10,13- trans-prostadienoate 709    364         9-oxo-16-hyroxy-10,13-trans- prostadienoic acid 710    365         9-oxo-16-hydroxy-20-nor-10,13- trans-prostadienoic acid 711    366         9-oxo-16-hydroxy-17-methyl-19- 20-dinor-10,13-trans-prosta- dienoic acid 712    367         9-oxo-17-hydroxy-19,20-dinor- 10,13-trans-prostadienoic acid 713    368         9-oxo16-hydroxy-19-methyl-10- 13-trans-prostadienoic acid 714    369         9-oxo-16-hyroxy-17-ethyl-20- nor-10,13-trans-prostadienoic acid 715    370         9-oxo-18-hydroxy-10,20-dinor- 10,13-trans-prostadienoic acid 716    371         9-oxo-19-hydroxy-nor-10,13- trans-prostadienoic acid 717    372         9-oxo-20-hyroxymethyl-10,13- trans-prostadienoic acid 718    373         9-oxo-20-(3-hydroxypropyl)-10- 13-trans-prostadienoic acid 719    374         9-oxo-16-methyl-17-hydroxy-19- 20-dinor-10,13-trans-prosta- dienoic acid 720    375         9-oxo-6,7-dinor-16-hydroxy-20- ethyl-10,13-trans-prostadienoic acid 721    376         9-oxo-5,6,7-trinor-20-hyroxy- 10,13-trans-prostadienoic acid 722    377         9-oxo-7a,7b-bishomo-16-hydroxy- 10,13-trans-prostadienoic acid 723    378         9-oxo-7a,7b-bishomo-20-hydroxy- 10,13-trans-prostadienoic acid 724    380         9-oxo-2-ethyl-16-hydroxy-18,19. 20-trinor-10,13-trans-prost- dienoic acid 725    381         9-oxo-3,3-dimethyl-16-hyroxy- 10,13-trans-prostadienoic acid 726    382         9-oxo-3,3-dimethyl-20-hydroxy- 10,13-trans-prostadienoic acid 727    383         9-oxo-3-oxa-16-hydroxy-10,13- trans-protadienoic acid 728    384         9-oxo-2-fluoro-16-methyl-17- hydroxy-18,19,20-trinor-10,13- trans-prostadienoic acid 729    385         9-oxo-7-nor-16-hyroxy-10,13- trans-oprostadienoic acid 730    386         9-oxo-7a-homo-16-hydroxy-10,13- trans-prostadienoic acid 731    521         9-oxo-16-hydroxy-10-prostenoic acid 732    523         9-oxo-17-hydroxy-10,20-dinor- 10-prostenoic acid 733    526         9-oxo-19-hydroxy-20-nor-10- prostenoic acid 734    529         9-oxo-17-hydroxy-16-methyl-10- 20-dinor-10-prostenoic acid 735    531         9-oxo-16-hydroxy 7a,7b-bishomo- 10-prostenoic acid 736    534         9-oxo-20-hydroxy-3,3-dimethy- 10-prostenoic acid 737    535         9-oxo-16-hydroxy-3-oxa-10- prostenoic acid ______________________________________

A solution of 1.102 g. of 1-octyne in 2 ml. of benzene is treated with 11.5 ml. of 15% diisobutylaluminum hydride in toluene and the solution is heated to 50.degree. C. for 2 hours. The solution is cooled, its solvent is removed in vacuo, and the resulting oil is treated with 5.45 ml. of 5.10% methyl lithium in diethyl ether with ice cooling. To the resulting solution is added 1.830 g. of 2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 13) and the solution is stirred at ambient temperatures for 18 hours. The solution is poured onto ice and dilute hydrochloric acid, and the mixture is extracted with diethyl ether. The organic phase is washed with dilute sodium bicarbonate, water, and saturated brine, dried, and evaporated. The residue is purified by chromatography on Florisil and distilltion to yield 1.878 g. of an oil, IR 1736 cm.sup.-1 (ester and ketone carbonyls) 969 cm.sup.-1 (trans vinyl group); NMR (CDCl.sub.3) .delta.  5.14-5.87 (multiplet, 2H, vinyl protons, J trans=15 Hz); Mass Spectrum, parent peak at 350 m.mu..

In the manner described in Example 738, 2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 13) is added to the reagent prepared from 8-chloro-1-octyne [W. J. Gensler and G. R. Thomas, J. Amer. Chem. Soc., 73, 4601 (1951)], diisobutylaluminum hydride, and methyl lithium. The crude product obtained by acid hydrolysis is purified by silica gel chromatography to give an oil, IR 1740 cm.sup.-1 (ester and ketone carbonyls), 967 cm.sup.-1 (trans vinyl group).

A stirred mixture of 30 g. of ethyl 20-chloro-9-oxo-13-trans-prostenoate (Example 739), 25 g. of sodium iodide and 225 ml. of acetone is refluxed for 12 hours. The reaction mixture is concentrated, diluted with water, and extracted with ether. The extract is washed with saturated sodium chloride, dried, and evaporated to give an oil.

A mixture of 0.140 g. of ethyl 9-oxo-13-trans-prostenoate (Example 738) and 0.072 g. of potassium hydroxide in 6 ml. of 1:1 aqueous methanol is stirred at ambient temperature for 17 hours. The resulting solution is acidified with hydrochloric acid, extracted with diethyl ether, and the organic phase is washed with water and saturated brine, dried, and the solvent removed to yield 0.128 g. of an oil, IR 1739 cm.sup.-1 (ketone carbonyl) 1706 cm.sup.-1 (acid carbonyl), 969 cm.sup.-1 (trans vinyl group); NMR (CDCl.sub.3) 5.34-5.67 (multiplet, 2H, vinyl protons, J trans=15 Hz), 10.47 (broad singlet, 1H, carboxyl proton, exchangeable); Mass spectrum, parent peak at 322 m.mu..

A solution of 25.2 g. of ethyl 20-iodo-9-oxo-13-trans-prostenoate (Example 740), 5.6 ml. of ethylene glycol and 110 mg. of p-toluenesulfonic acid monohydrate in 170 ml. of benzene is refluxed for 4 hours with azeotropic removal of water. The solution is concentrated to a volume of 50 ml. Column chromatography of the solution on Florisil with benzene gives a liquid, IR 1740 (ester carbonyl), 967 (trans vinyl group), and 952 cm.sup.-1 (ethylene ketal).

A stirred mixture pf 7.80 g. (15 mmoles) of ethyl 9,9-ethylenedioxy-20-iodo-13-trans-prostenoate, (Example 742), 8.65 g. (60 mmoles) of sodium benzoate, and 100 ml. of dry methylformamide is maintained at 115.degree. C. for 2 hours. The mixture is cooled, diluted with water and extracted with ether. The extract is washed successively with water, saturated sodium becarbonate solution, and saturated sodium chloride solution. The extract is dried over magnesium sulfate. The crude product obtained by evaporation of the solvent is purified by chromatography on silica gel to give an oil, .nu. max. 1745 (alkanoate ester group), 1730 (benzoate ester group), 967 (trans vinyl group), and 948 cm.sup.-1 (ethylenedioxy group).

A solution of 5.35 g. (10.4 mmoles) of ethyl 20-benoyloxy-9,9-ethylenedioxy-13-trans-prostenoate (Example 743), 99 mg. (0.52 mmoles) of p-toluenesulonic acid monohydrate, and 40 ml. of acetone is allowed to stand at room temperature for 41 hours. The acetone is evaporated, and the residue is dissolved in ether. The solution is washed successively with sodium chloride solution, dilute sodium bicarbonate solution, and saturated sodium chloride solution. The solution is dried over magnesium sulfate and concentrated to give an oil, .nu. max. 1740 (ketone and alkanoate ester groups), 1730 benzoate ester group), and 967 cm.sup.-1 (trans vinyl group).

A solution of 4.75 g. (10.1 mmoles) of ethyl 20-benzoyloxy-9-oxo-13-trans-prostenoate (Example 744), 3.31 g. (50 mmoles) of 85% potassium hydroxide, 90 ml. of methanol, and 9 ml. of water is allowed to stand at room temperature for 24 hours. The solution is concentrated, diluted with water, and extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Column chromatography of the crude product on silica gel gives an oil, .nu. max. 1735 (ketone carbonyl group), 1710 (acid carbonyl group), and 967 cm.sup.-1 (trans vinyl group).

Inoculum Preparation:

A typical medium used to grow the inoculum was prepared according to the following formula: Sodium Nitrate     3          grams Dipotassium Hydrogen Phosphate 1          gram Magnesium Sulfate Heptahydrate 5          grams Potassium Chloride 5          grams Ferrous Sulfate Heptahydrate 0.01       grams Sucrose            30         grams Water to           1000       milliliters ______________________________________

The washed or scraped spores from an agar slant of Lederle Culture V89 (a strain of Diplodia malorum received from Centraalbureau voor Schirnmel cultures Baarn, Netherlands) is used to inoculate a flask containing 50 milliliters of the above medium in a 250 milliliter flask. The flask is placed on a rotary shaker and agitated vigorously for 5 days at 22.degree. C.

Ten milliliters of the above first stage inoculum is introduced into two additional 250 milliliter flasks each containing 50 milliliters of medium, using 5 milliliters per flask. The flasks are incubated from 72 hours under the same conditions described for the first stage inoculum.

The 100 milliliters of second stage inoculum is used to inoculate a 4 liter glass fermentor containing 2 liters of sterile medium. The fermentor is aerated with sterile air while growth is continued for 72 hours at 25.degree. C. This 2 liters of inoculum is used to inoculate a 40 liter tank fermentor containing 20 liters of liquid medium.

Fermentation:

A fermentation medium is prepared according to the same formula used for the inoculum medium. The fermentation medium is sterilized at 120.degree. C. with steam at 20 pounds pressure for 45-60 minutes. The pH of the medium after sterilization is 6.6. Twenty liters of sterile medium in a 40 liter tank fermentor is inoculated with 2 liters of inoculum and the fermentation is carried out at 22.degree. C. using lard oil, as necessary, as a defoaming agent. Aeration is supplied at the rate of 1.0 liters of sterile air per liter of mash per minute. The mash is agitated by air impeller driven at 400 revolutions per minute. At the end of 42 hours of fermentation time, a 5.15 gram sample of CL82, 680 dissolved in 150 milliliters of acetone is added to the fermentation. The fermentation is continued for an additional 5 hours whereupon the mash is harvested.

Isolation:

Twenty liters of fermentation mash (pH 7.5) is clarified by filtration through Hyflo, and the filtrate is extracted with three one-fifth volumes of chloroform after prior adjustment to pH 2.8 with hydrochloric acid. The combined chloroform extract is concentrated to a residue (4.85 g.) in vacuo, which after trituration with two 100 milliliter portions of cold hexane gives 4.28 g. residue.

This residue is further purified by adsorption chromatography on 100 grams of Davison Grade No. 62 silica gel slurry-packed in chloroform. The residue is dissolved in a small volume of chloroform, applied to the column and the column developed with a linear gradient between 1 liter each of chloroform and 10% ethanol-in-chloroform. Fractions of about 15 milliliters each are collected automatically. The progress of development is followed by monitoring the column effluent at 240 nanometers and also by thin layer chromatography of appropriate fractions. The fractions (47-80) containing the subject product are combined and concentrated to a residue (3.55 g.) in vacuo.

This residue is further purified by means of partition chromatography on 300 grams Celite. The column support is prepared by mixing 0.5 milliliters of the lower phase from the solvent system hexane-ethyl acetate-methanol-water (9:3:2:1) with each 1 gram of Celite. The residue from above, dissolved in 5 milliliters of lower phase is treated similarly and packed on top of the column which is then eluted with this upper phase. Fractions of about 60 milliliters each are collected automatically. The progress of development is followed by monitoring the column effluent at 270 nanometers and also by thin layer chromatography of appropriate fractions. The fractions (16-36) containing the desired compound are combined and concentrated to a residue (2.93 g.) in vacuo. This is dissolved in some chloroform, poured over 50 grams of Davison Grade No. 62 silica gel slurry-packed in chloroform, and, following washing the column with chloroform, it is eluted with 10% ethanol-in-chloroform to give, following evaporation, 2.9 grams product, which by nmr analysis contains a mixture of the 18-hydroxy and 19-hydroxy derivative in a ratio of about 3:1 to 1:1.

A 1.5 gram sample of the product from Example 746 is dissolved in 20 milliliters of acetone and Jones Reagent (6.68 grams CrO.sub.3 in 5.75 milliliters concentrated H.sub.2 SO.sub.4 diluted to 25 milliliters with water) is added slowly with stirring until the color persist. The reaction mixture is stirred an additional 15 minutes whereupon the excess reagent is destroyed by the addition of methanol. The mixture is diluted to about 200 milliliters with water and extracted with three 50 milliliter portions of chloroform, which is then dried with anhydrous sodium sulfate and evaporated to give 1.5 grams of a pale yellow oil. This dissolved in some chloroform, poured over 30 grams of Davison Grade No. 62 silica gel slurry-packed in chloroform and, following washing the column with chloroform it is eluted with 5% ethanol-in-chloroform to give, following evaporation, 1.46 grams of subject product ketones.

Treatment of the 3-hydroxymethyl-1-alkynes, listed in Table 20 below, with triphenylmethyl bromide by the procedure described in Example 278 is productive of the 3-triphenylmethoxymethyl-1-alkynes of the Table. ______________________________________ Starting 3-hydroxy- Product 3-triphenylmethoxy- Example methyl-1-alkyne methyl-1-alkyne ______________________________________ 748    3-hydroxymethyl-1- 3-triphenylmethoxymethyl- hexyne*       1-hexyne 749    3-hydroxymethyl-1- 3-triphenylmethoxymethyl- heptyne*      1-heptyne 750    3-hydroxymethyl-1- 3-triphenylmethoxymethyl- octyne*       1-octyne ______________________________________ *A. Schaap, L. Brandsma and J.F. Arens, Rec. trav. chim., 86. 393 (1967).

A stirred solution of 27.3 g. (0.20 moles) of 1-chloro-3-hexanol, 77.6 g. (0.24 moles) of triphenylmethyl bromide, 30.0 g. (0.28 moles of 2,6-lutidine, and 200 ml. of chlorobenzene is heated at 95.degree. C. for 1 hour. The cooled mixture is treated with water, and the organic phase is washed successively with water and saturated sodium chloride solution. The solution is dried over magnesium sulfate and concentrated. Column chromatography of the residue on Florisil affords the subject compound as an oil, .nu. max. 1600, 1030, and 705 cm.sup.-1 (triphenylmethoxy group).

To a stirred solution of 32.2 g. (85 mmoles) of 1-chloro-3-triphenylmethoxyhexane (Example 750a) in 25 ml. of dimethylsulfoxide (DMSO) is added a solution of 9.4 g. (102 mmoles) of lithium acetylide-ethylene diamine complex in 60 ml. of DMSO during 10 minutes while maintaining a temperature of 25.degree.-30.degree. C. After 3.5 hours the mixture is diluted with ether and treated successively with water and 4N hydrochloric acid while cooling in an ice bath. The phases are separated, and the aqueous phase is extracted with ether-petroleum ether. The combined extracts are washed successively with water and saturated sodium chloride solution dried over magnesium sulfate, and concentrated. The product is then purified by column chromtography of the residue of Florisil.

Conjugate addition of the alanates obtained by treatment of the triphenylmethoxy (trityloxy)-1-alkynes (indicated in the following table) with diisobutylaluminum hydride followed by methyl lithium, to the cyclopentenones of the table according to the method described in Example 280 followed by de-O-tritylation of the intermediate triphenylmethoxyprostenoates according to the method of Example 280a is productive of the prostenoic acids and esters of the table.

Those compounds isolated and identified in the table as prostenoic acids are prepared via the corresponding tetrahydropyran-2-yl esters and these compounds bearing a free hydoxy function at the 11 .alpha.-position or as part of an 11.alpha.-(.omega.-hydroxyalkoxy) moiety are prepared via the corresponding tetrahydropyran-2-yl ethers. The hydroxy function in the .beta.-side chain (that portion of the molecule deriving from the triphenylmethoxy-1-alkyne) of all compounds in the table are initially present in the molecule as the corresponding triphenylmethyl ethers. During the acetic acid treatment (de-O-tritylation step) the triphenylmethyl ether as well as the tetrahydropyran-2-yl ethers and esters functions are hydrolyzed to provide the corresponding free hydroxy and carboxylic acid groups of the compounds listed in the table. __________________________________________________________________________ Starting cyclo- Starting trityloxy pentenones of 1-alkyne of Product Example Example   Example   Hydroxy Prostenoic Acid or Ester __________________________________________________________________________ 752   13      748        Ethyl 9-oxo-15-hydroxymethyl-19,20-dinor-13- trans-prostenoate 753   13      749        Ethyl 9-oxo-15-hydroxymethyl-20-nor-13-trans- prostenoate 754   13      750        Ethyl 9-oxo-15-hydroxymethyl-13-trans- prostenoate 755   13      751        Ethyl 9-oxo-17-hydroxy-13-trans-prostenoate 756   23      751        Ethyl 9-oxo-17-hydroxy-7a,7b-bishomo-13- trans-prostenoate 757   41      750        Ethyl 9-oxo-15-hydroxymethyl-3,3-dimethyl- 13-trans-prostenoate 758  276      750        Ethyl 9-oxo-15-hydroxymethyl-3-thia-13-trans- prostenoate 759  276      751        Ethyl 9-oxo-17-hydroxy-3-thia-13-trans- prostenoate 760  147      751        9-oxo-11.alpha.,17-dihydroxy-13-trans-prostenoic acid 761  147      748        9-oxo-11.alpha.-hydroxy-15-hydroxymethyl-19,20- dinor-13-trans-prostenoic acid 762  147      749        9-oxo-11.alpha.-hydroxy-15-hydroxymethyl-20-nor- O 13-trans-prostenoic acid 763  147      750        9-oxo-11.alpha.-hydroxy-15-hydroxymethyl-13-trans - prostenoic acid 764  151      750        9-oxo-11.alpha.-hydroxy-15-hydroxymethyl-2-ethyl- 13-trans-prostenoic acid 765  152      751        9-oxo-11.alpha.,17-dihydroxy-3,3-dimethyl-13-tran s- prostenoic acid 766  153      751        9-oxo-11.alpha.,17-dihydroxy-3-oxa-13-trans- prostenoic acid 767  153      750        9-oxo-11.alpha.-hydroxy-15-hydroxymethyl-3-oxa-13 - trans-prostenoic acid 768  154      750        9-oxo-11.alpha.-hydroxy-15-hydroxymethyl-2-fluoro - 13-trans-prostenoic acid 769  155      749        9-oxo-11.alpha.-hydroxymethyl-7,20-dinor- 13-trans-prostenoic acid 770  157      750        9-ox-11.alpha.-hydroxy-15-hydroxymethyl-2-phenyl- N 13-trans-prostenoic acid 771   157a    750        9-oxo-11.alpha.-hyddroxy-15-hydroxynethyl-7a-homo -13- trans-prostenoic acid 772   242a    750        9-oxo-11.alpha.-methoxy-15-hydroxymethyl-13-trans prostenoic acid 773   242a    751        9-oxo-11.alpha.-methoxy-17-hydroxy-13-trans- prostenoic acid 774  247      750        9-oxo-11.alpha.-(2-hydroxyethoxy)-15-hydroxymethy l- 13-trans-prostenoic acid 775  247      751        9-oxo-11.alpha.-(2-hydroxyethoxy)-17-hydroxy-13- trans-prostenoic acid __________________________________________________________________________

Saponification of the designated esters in Table 22 below by the method described in Example 283 is productive of the prostenoic acids of the table. ______________________________________ Starting alkyl prostenoate of Example Example     Product Prostenoic Acid ______________________________________ 776    752         9-oxo-15-hydroxymethyl-19,20- dinor-13-trans-prostenoic acid 777    753         9-oxo-15-hydroxymethyl-20-mor- 13-trans-prostenoic acid 778    754         9-oxo-15-hydroxymethyl-13,trans- prostenoic acid 779    755         9-oxo-17-hydroxy-13-trans- prostenoic acid 780    756         9-oxo-17-hydroxy-7a,7b-bishomo- 13-trans-prostenoic acid 781    757         9-oxo-15-hydroxymethyl-3,3- dimethyl-13-trans-prostenoic acid 782    758         9-oxo-15-hydroxymethyl-3-thia- 13-trans-prostenoic acid 783    759         9-oxo-17-hydroxy-3-thia-13- trans-prostenoic acid ______________________________________

Hydrogenation of the 13-prostenoic acids and esters listed in Table 23 below furnishes the prostanoic acids and esters of the table. ______________________________________ Starting 13-prostanoic Ex-   acid or ester ample of Example  Product Prostanoic Acid or Ester ______________________________________ 784   752         ethyl 9-oxo-15-hydroxymethyl- 19,20-dinor prostanoate 785   753         ethyl 9-oxo-15-hydroxymethyl- 20-nor-prostanoate 786   754         ethyl 9-oxo-15-hydroxymethyl- prostanoate 787   755         ethyl 9-oxo-17-hydroxy- prostanoate 788   757         ethyl 9-oxo-17-hydroxymethyl- 7a,7b-bishomo-prostanoate 789   757         ethyl 9-oxo-15-hydroxymethyl- 3,3-dimethyl-prostanoate 790   758         ethyl 9-oxo-15-hydroxymethyl- 3-thia-prostanoate 791   759         ethyl 9-oxo-17-hydroxy-3-thia- prostanoate 792   760         9-oxo-11.alpha.,17-dihydroxy-prostanoic acid 793   761         9-oxo-11.alpha.-hydroxy-16-hydroxy- methyl-19,20-dinor-prostanoic acid 794   762         9-oxo-11.alpha.-hydroxy-15-hydroxy- methyl-20-nor-prostanoic acid 795   763         9-oxo-11.alpha.-hydroxy-15-hydroxy- methyl-prostanoic acid 796   764         9-oxo-11.alpha.-hydroxy-15-hydroxy- methyl-2-ethyl-prostanoic acid 797   765         9-oxo-11.alpha.,17-dihydroxy-3,5- dimethyl-prostanoic acid 798   766         9-oxo-11.alpha.,17-dihydroxy-3-oxa- prostanoic acid 799   767         9-oxo-11.alpha.-hydroxy-15-hydroxy- methyl-3-oxa-prostanoic acid 800   768         9-oxo-11.alpha.-hydroxy-15-hydroxymethyl- 2-fluoro-prostanoic acid 801   769         9-oxo-11.alpha.-hydroxy-15-hydroxy- methyl-7,20-dinor prostanoic acid 802   770         9-oxo-11.alpha.-hydroxy-15-hydroxymethyl- 2-phenyl-prostanoic acid 803   771         9-oxo-11.alpha.-hydroxy-15-hydroxymethyl- 7a-homo-prostanoic acid 804   772         9-oxo-11.alpha.-methoxy-15-hydroxymethyl- prostanoic acid 805   773         9-oxo-11.alpha.-methoxy-17-hydroxy- prostanoic acid 806   774         9-oxo-11.alpha.-(2-hydroxyethoxy)- 15-hydroxymethyl-prostanoic acid 807   775         9-oxo-11.alpha.-(2-hydroxyethoxy)- 17-hydroxy-prostanoic acid 808   776         9-oxo-15-hydroxymethyl-19,20- dinor-prostanoic acid 809   777         9-oxo-15-hydroxymethyl-20-nor 810   778         9-oxo-15-hydroxymethyl-prostanoic acid 811   779         9-oxo-17-hydroxy-prostanoic acid 812   780         9-oxo-17-hydroxy-7a,7b-bishomo- prostanoic acid 813   781         9-oxo-15-hydroxymethyl-3,3- dimethyl-prostanoic acid 814   782         9-oxo-15-hydroxymethyl-3-thia- prostanoic acid 815   783         9-oxo-17-hydroxy-3-thia-prostanoic acid ______________________________________

Reduction of the 9-oxo-derivatives listed in Table 24 below with lithium perhydro-9.beta.-boraphenalyl hydride by the procedure described in Example 575 is productive of the 9.alpha.-hydroxy derivative of the Table. ______________________________________ Starting 9-oxo Ex-   derivative of ample Example      Product 9.alpha.-hydroxy derivative ______________________________________ 816   752          Ethyl 9.alpha.-hydroxy-15-hydroxy- methyl-19,20-dinor-13-trans- prostenoate 817   753          Ethyl 9.alpha.-hydroxy-15-hydroxy- methyl-20-nor-13-trans- prostenoate 818   754          Ethyl 9.alpha.-hydroxy-16-hydroxy- methyl-13-trans-prostenoate 819   755          Ethyl 9.alpha.,17-dihydroxy-13- trans-prostenoate 820   756          Ethyl 9.alpha.,17-dihydroxy 7a,7b- bishomo-113-trans-prostenoate 821   757          Ethyl 9.alpha.-hydroxy-15-hydroxy- methyl-3,3-dimethyl-13-trans- prostenoate 822   758          Ethyl 9.alpha.-hydroxy-15-hydroxy- methyl-3-thia-13-trans- prostenoate 823   759          Ethyl 9.alpha.,17-dihydroxy-3-thia- 13-trans-prostenoate 824   760          9.alpha.,11.alpha.,17-trihydroxy-13-trans- prostenoic acid 825   761          9.alpha.,11.alpha.-dihydroxy-15-hydroxy- methyl-19,20-dinor-13-trans- prostenoic acid 826   762          9.alpha.,11.alpha.-dihydroxy-15-hydroxy- methyl-20-nor-13-trans- prostenoic acid 827   763          9.alpha.,11.alpha.-dihydroxy-15-hydroxy- methyl-13-trans-prostenoic acid 828   764          9.alpha.,11.alpha.-dihydroxy-15-hydroxy- methyl-2-ethyl-13-trans- prostenoic acid 829   765          9.alpha.,11.alpha.,17-trihydroxy-3,3-di- methyl-13-trans-prostenoic acid 830   766          9.alpha.,11.alpha.,17-trihydroxy-3-oxa-13- trans-prostenoic acid 831   767          9.alpha.,11.alpha.-dihydroxy-15-hydroxy- methyl-3-oxa-13-trans- prostenoic acid 832   768          9.alpha.,11.alpha.-dihydroxy-15-hydroxy- methyl-2-fluoro-13-trans- prostenoic acid 833   769          9.alpha.,11.alpha.-dihydroxy-15-hydroxy- methyl-7,20-dinor-13-trans- prostenoic acid 834   770          9.alpha.,11.alpha.-dihydroxy-15-hydroxy- methyl-2-phenyl-13-trans- prostenoic acid 835   771          9.alpha.,11.alpha.-dihydroxy-15-hydroxy- methyl-7a-homo-13-trans- prostenoic acid 836   772          9.alpha.-hydroxy-11.alpha.-methoxy-15- hydroxymethyl-13-trans- prostenoic acid 837   773          9.alpha.-hydroxy-11.alpha.-methoxy-9.alpha.,1l7- dihydroxy-13-trans-prostenoic acid 838   774          9.alpha.-hydroxy-11.alpha.-(2-hydroxy- ethoxy)-15-hydroxymethyl-13- trans-prostenoic acid 839   775          9.alpha.-hydrox-11.alpha.-(2-hydroxy- ethoxy)-17-hydroxy-13-trans- prostenoic acid 840   776          9.alpha.-hydroxy-15-hydroxymethyl- 19,20-dinor-13-trans- prostenoic acid 841   777          9.alpha.-hydroxy-15-hydroxymethyl- 20-nor-13-trans-prostenoic 842   778          9.alpha.-hydroxy-15-hydroxymethyl-13- trans-prostenoic acid 843   779          9.alpha.,17-dihydroxy-13-trans- prostenoic acid 844   780          9.alpha.,17-dihydroxy-7a,7b-bishomo- 13-trans-prostenoic acid 845   781          9.alpha.-hydroxy-15-hydroxymethyl- 3,3-dimethyl-13-trans- prostenoic acid 846   782          9.alpha.-hydroxy-15-hydroxymethyl- 3-thia-13-trans-prostenoic acid 847   809          9.alpha.-hydroxy-15-hydroxymethyl- 19,20-dinor-prostanoic acid 848   809          9.alpha.-hydroxy-15-hydroxymethyl- 20-nor-prostanoic acid 849   810          9.alpha.-hydroxy-15-hydroxymethyl- prostanoic acid 850   811          9.alpha.,17-dihydroxy-prostanoic acid 851   812          9.alpha.,17-dihydroxy-7a,7b-bishomo- prostanoic acid 852   813          9.alpha.-hydroxy-15-hydroxymethyl- 3,3-dimethyl-prostanoic acid 853   792          9.alpha.,11.alpha.,17-trihydroxy-prostanoic acid 854   793          9.alpha.,11-dihydroxy-15-hydroxy- methyl-19,20-dinor-prostanoic acid 855   794          9.alpha.,11-dihydroxy-15-hydroxy- methyl-20-nor-prostanoic acid 856   795          9.alpha.,11-dihydroxy-15-hydroxy- methyl-prostanoic acid 857   796          9.alpha.,11-dihydroxy-15-hydroxy- methyl-2-ethyl-prostnoc acid 858   798          9.alpha.,11.alpha.,17-trihydroxy-3-oxa- methyl-prostanoic acid 859   798          9.alpha.,11.alpha.,17-trihydroxy-3-oxa- prostanoic acid 860   799          9.alpha.,11.alpha.-dihydroxy-15-hydroxy- methyl-3-oxa-prostanoic acid 861   800          9.alpha.,11.alpha.-dihydroxy-15-hydroxy- methyl-2-fluoro-prostanoic acid 862   801          9.alpha.,11.alpha.-dihydroxy-15-hydroxy- methyl-7,20-dinor-prostanoic acid 863   802          9.alpha.,11.alpha.-dihydroxy-15-hydroxy- methyl-2-phenyl-prostanoic acid 864   803          9.alpha.,11.alpha.-dihydroxy-15-hydroxy- methyl-7a-homo-prostanoic acid 865   804          9.alpha.-hydroxy-11.alpha.-methoxy-15- hydroxymethyl-prostanoic acid 866   805          9.alpha.-hydroxy-11.alpha.-methyl-17- hydroxy-prostanoic acid 867   806          9.alpha.,11.alpha.-(2-hydroxyethoxy)-15- hydroxymethyl-prostanoic acid 868   807          9.alpha.,11.alpha.-(2-hydroxyethoxy)-17- hydroxy-prostanoic acid ______________________________________

Acid treatment of the method described in Example 686 of the 11.alpha.-hydroxy-9-oxo derivatives listed in the table below furnishes the .DELTA..sup.10 -derivatives of the table. ______________________________________ Starting 11.alpha.- hydroxy-9-oxo- derivative of Product 9-oxo-10-prostenoic noic Example Example     acids and esters ______________________________________ 869    760         9-oxo-17-hydroxy-10,13-trans- prostadienoic acid 870    761         9-oxo-15-hydroxymethyl-19,20- dinor-10,13-trans-prostadienoic acid 871    762         9-oxo-15-hydroxymethyl-20-nor-10, 13-trans-prostadienoic acid 872    763         9-oxo-15-hydroxymethyl-10,13- trans-prostadienoic acid 873    764         9-oxo-15-hydroxymethyl-2-ethyl- 10,13-trans-prostadienoic acid 874    765         9-oxo-17hydroxy-3,3-dimethyl- 10,13trans-prostadienoic acid 875    766         9-oxo-17-hydroxy-3-oxa-10,13- trans-prostadienoic acid 876    767         9-oxo-15-hydroxymethyl3-oxa-10, 13-trans-prostadienoic acid 877    768         9-oxo-15-hydroxymethyl-2-fluoro- 10,13-trans-prostadienoic acid 878    770         9-oxo-15-hydroxymethyl-2-phenyl- 10,13-trans-prostandienoic acid 879    770         9-oxo-15-hydroxymethyl-2-phenyl- 10,13-trans prostandienoic acid 880    771         9-oxo-15-hydroxymethyl-7a-homo- 10,13-trans- prostadienoic acid 881    792         9-oxo-17-hydroxy-10-prostenoic acid 882    793         9-oxo-15-hydroxymethyl-19,20- dinor-prostenoic acid 883    794         9-oxo-15-hydroxymethyl-20-nor- prostenoic acid 884    795         9-oxo-15-hydroxymethyl-prostenoic acid 885    796         9-oxo-15-hydroxymethyl-2-ethyl- prostenoic acid 886    797         9-oxo-17-hydroxy-3,3-dimethyl- prostenoic acid 887    798         9-oxo-17-hydroxy-3-oxa-prostenoic acid 888    799         9-oxo-15-hydroxymethyl-3-oxa- prostenoc acid 889    800         9-oxo-15-hydroxymethyl-2-fluoro- prostenoic acid 890    801         9-oxo-15-hydroxymethyl-7,20- dinor-prostenoic acid 891    802         9-oxo-15-hydroxymethyl-2-phenyl- prostenoic acid 892    803         9-oxo-15-hydroxymethyl-7a-homo- prostenoic acid ______________________________________

A suspension of 24.3 g. (1.0 mole) of magnesium in 90 ml of dry ether is stirred at room temperature under nitrogen with 100 mg. of mercuric chloride. The reaction is initiated by the addition of 2 ml. of propargyl bromide and maintained by the dropwise addition of a solution of 119.5 g. (1.0 mole) of propargyl bromide and 107.7 g. (1.25 mole) of valeraldehyde in 300 ml. of dry ether. While the initial reaction is quite vigorous and is maintained at 30.degree. C. only by cooling in an ice bath it may become necessary to heat the mixture to reflux temperature after about a third of the ether solution is added in order to maintain the reaction. After the addition is complete the reaction mixture is refluxed until most of the magnesium is dissolved (several hours) and the reaction mixture is decanted from excess magnesium into 1500 ml. of stirred ice-cold ammonium chloride solution. The ether layer is separated and the aqueous layer is extracted three times with 300 ml. portions of ether. The combined ether extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered. Evaporation of the ether under vacuum leaves about 115 mg. of yellow oil, which is distilled through a 15 cm. Vigreaux column at 18 mm. The fraction boiling at 81.degree.-82.degree. C. is collected (36 g.) and the higher-boiling and lower-boiling distillates may be redistilled to yield additional product. The infrared absorption spectrum shows at most a trace of allene (5.1 .mu.) and gas-liquid partition chromatography shows a purity of about 98% for the main fraction.

The product 1-alkyn-4-ols of Table 26 below are prepared by treatment of the aldehydes or ketones in Table 26 with propargyl magnesium bromide by the procedure described above in Example 893. ______________________________________ Starting Aldehyde Product 1-Alkyn- Example or Ketone        4-ol ______________________________________ 894     2-trans-hexen-   4-hydroxy-5- aldehyde         trans-ene-1- nonyne 895     3-cis-hexen-     4-hydroxy-6-cis- aldehyde*        ene-1-nonyne 896     2-methylvaler-   4-hydroxy-5- aldehyde         methyl-1-octyne 897     2-hexanone       4-hydroxy-4- methyl-1-octyne ______________________________________ *M. Winter, Melv. Chim. Acta, 46, 1792 (1963).

To a stirred solution of 63 g. (0.50 moles) of 4-hydroxy-1-octyne (Example 893) in 500 ml. of pyridine is added 77 g. (0.55 moles) of benzoyl chloride. After stirring for 1.5 hours the mixture is treated with 10 ml. of water, allowed to stand for 15 minutes, and concentrated. A solution of the residue in ether is washed successively with ice-cold hydrochloric acid, water, sodium bicarbonate solution, and brine. The solution is dried over magnesium sulfate, filtered through Celite, and concentrated to give an oil, .nu. max. 3240 (terminal acetylene) and 1730 cm.sup.-1 (benzoyloxy group). arrhizus

An agar slant of R. arrhizus (MUMF 1638) is used to inoculate 7 shake flasks (250 ml. Erlenmeyer). Each flask contains 50 ml. of a medium consisting of 2% Edamine, 2% glucose, and 0.72% corn steep liquor in water with pH adjusted to 7.0. A total of 14 such flasks are incubated on a rotary shaker at 28.degree. C. After 72 hours incubation, 50 mg. of racemic 4-benzoyloxy-1-octyne (Example 898) in 0.1 ml. of acetone is added to each flask. After 28 hours the flasks are harvested and worked up by extraction of the whole mash with an equal volume of chloroform. The combined extracts are dried over magnesium sulfate and concentrated. The resulting oil is chromatographed on a column of silica gel with hexane progressively enriched in ethyl acetate.

From fractions 3-6 is obtained 150 mg. of colorless oil, identical to 4-benzoyloxy-1-octyne, [.alpha.].sub.D.sbsp.25 = 5 .+-. 1.0.degree.(C=0.91, ethyl acetate). This compound has the (S)-configuration.

From fractions 13-20 is obtained 75 mg. of colorless oil, identical to 4-hydroxy-1-octyne, [.alpha.].sub.D.sbsp.25 = -17 .+-. 1.0.degree.(C=0.77, ethyl acetate). This compound has the (R)-configuration.

The strain of R. arrhizus utilized in this experiment is a higher fungus which grows steadily on a variety of artificial media at 20.degree.-25.degree. C. In this study of the taxonomic aspects of the culture, Petri dishes of potato-dextrose, malt extract, and cornmeal agars were inoculated and incubated at ambient room temperature for 10 days. Observations of cultural and morphological characteristics are recorded in the description below:

Colonies on Petri dishes of Potato-dextrose agar growing rapidly, covering the agar surface in 3-5 days and producing a thick, loose mat of grayish mycelium. Colony surface characterized by abundant black sporangia. Colony reverse grayish white. Colonies on Malt extract agar growing rapidly, covering the agar surface in 3-5 days. Mycelial mat thick, grayish-yellow. Colony surface becoming brownish-black from masses of sporangia. Colony reverse yellowish. Colonies on Cornmeal Agar very thin, whitish; spreading across agar surface. Cultures transparent with relatively few sporangia produced. Visibility of micromorphology is good on this medium. Rhizoids produced sparingly along stoloniferous hyphae. Generally two to three sporangiophores arose from rhizoids. Walls of sporangiophores olive brown, 14.0-20.0 .mu.M in width at base, tapering slightly to apex; 0.5-1.5 mm in length. Sporangiophores terminated by spherical sporangia, 130-225 .mu.M in diameter. Columellae hemispherical, 3-50 .mu.M high by 50-70 .mu.M wide. Spores brownish when mature, 6.0-8.5 .mu.M .times. 4.5-6.0 .mu.M. Spore walls conspicuously marked by longitudinal striations.

A solution of 1.15 g. (5.0 mmoles) of (S)-4-benzoyloxy-1-octyne (Example 899) and 1.40 g. (25 mmoles) of potassium hydroxide in 50 ml. of 10:1 methanol-water is allowed to stand at room temperature for 24 hours. The bulk of the methanol is evaporated at room temperature, and the mixture is extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and evaporated to give a colorless oil, identical to 4-hydroxy-1-octyne [.alpha.].sub.D.sbsp.25 = +17 .+-. 1.0.degree.(C=0.77, ethyl acetate). This compound has the (S)-configuration.

To a stirred suspension of 600 g. of triphenylphosphine in 2000 ml. of acetonitrile, under nitrogen atmosphere, is added dropwise 118 ml. of bromide at a temperature not exceeding 35.degree. C. After stirring for an additional hour, the supernatant liquid is decanted and taken to dryness. The solid residue is combined with the previous solid with 1500 ml. of dimethylformamide. The suspension is stirred at -20.degree. C. and a solution of 200 g. of 1-octyne-3-ol in 300 ml. of dimethylformamide is added in three portions. The temperature is allowed to warm up slowly to 20.degree. C. After 3 hours the solution is extracted with three 1600 ml portions of petroleum ether (b.p. 30.degree.-60.degree.). The combined extracts are washed with saturated sodium chloride solution, saturated sodium bicarbonate solution, and finally with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness (bath 30.degree.-35.degree. C.). The residual oil was distilled to give 117 g. (39%) of product, b.p. 66.degree.-68.degree./9mm.

To a suspension of 2.54 g. of magnesium in 15 ml. of ether containing a few crystals of mercuric chloride, under nitrogen atmosphere, is added a small portion of 3-bromo-1-octyne in 20 ml. of ether. When reaction has set in, the flask is cooled in a 15.degree. C. water bath, and the remainder of the halide in ether is added dropwise over a period of about 1 hour. When all of the halide has been added, stirring is continued for 15 minutes. The flask is then fitted with a glass tube which reaches almost to, but not below, the surface of the liquid. This tube connects directly with a round bottom flask containing about 20 mg. of paraformaldehyde which has been previously dried for 2 days in a vacuum desicator over phosphorous pentoxide. This flask contains an inlet tube for nitrogen. The reaction flask is immersed in an ice-bath, and the flask containing the paraformaldehyde is heated in an oil bath at 180.degree.-200.degree. C. The formaldehyde formed by depolymerization is carried over into the Grignard reagent by a slow current of dry nitrogen. At the end of 30-40 minutes formaldehyde addition is terminated and the reaction mixture stirred at room temperature for 18 hours.

The reaction mixture is then cooled in an ice-bath and saturated ammonium chloride is added, followed by water and then ether. The mixture is then acidified with 2M sulfuric acid. The organic phase is separated, washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and the solvent removed in vacuo. The residue is distilled to give 4.4 g. of product; b.p. 91.degree.-93.degree./9mm.

Treatment of the 3-hydroxymethyl-1-alkynes, listed in Table 27 below, with triphenylmethyl bromide by the procedure described in Example 278 is productive of the 3 -triphenylmethoxymethyl-1-alkynes of the Table. ______________________________________ Product hexyne.sup.1 Ex-    Starting 3-hydroxy- phenylmethoxy- ample  methyl-1-alkyne  methyl-1-alkyne ______________________________________ 903    3-hydroxymethyl-1- 3-triphenylmeth- hexyne           oxymethyl-1-hexyne 904    3-hydroxymethyl-1- 3-triphenylmeth- heptyne.sup.1    oxymethyl-1-heptyne 905    3-hydroxymethyl-1- 3-triphenylmeth- octyne.sup.1 (Ex. 902) oxymethyl-1-octyne ______________________________________ .sup.1 A. Schaap. L. Brandsma and J.F. Arens. Rec. trav. chim. 86.393 (1967)

A stirred solution of 27.3 g. (0.20 moles) of 1-chloro-3-hexanol, 77.6 g. (0.24 moles) of triphenylmethyl bromide, 30.0 g. (0.28 moles of 2,6-lutidine, and 200 ml. of chlorobenzene is heated at 95.degree. C. for 1 hour. The cooled mixture is treated with water, and the organic phase is washed successively with water and saturated sodium chloride solution. The solution is dried over magnesium sulfate and concentrated. Column chromatography of the residue on Florisil affords the subject compound as an oil, .lambda. max. 1600, 1030, and 705 cm.sup.-1 (triphenylmethoxy group).

To a stirred solution of 32.2 g. (85 mmoles) of 1-chloro-3-triphenylmethoxyhexane (Example 906) in 25 ml. of dimethylsulfoxide (DMSO) is added a solution of 9.4 g. (102 mmoles) of lithium acetylide-ethylene diamine complex in 60 ml. of DMSO during 10 minutes while maintaining a temperature of 25.degree.-30.degree. C. After 3.5 hours the mixture is diluted with ether and treated successively with water and 4N hydrochloric acid while cooling in an ice bath. The phases are separated, and the aqueous phase is extracted with ether-petroleum ether. The combined extracts are washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The product is then purified by column chromatography of the residue on Florisil.

The triphenylmethoxy substituted 1-alkynes listed in Table 28 below are prepared by the method of Example 278 from triphenylmethoxyl bromide and the corresponding hydroxy substituted 1-alkynes of the table. ______________________________________ Starting hydroxy sub- Product triphenyl- Ex-    stituted alkyne of methoxy substituted ample  Example          alkyne ______________________________________ 908    894              4-triphenylmethoxy- 5-trans-ene-1- nonyne 909    895              4-triphenylmethoxy- 6-cis-ene-1-nonyne 910    896              4-triphenylmethoxy- 5-methyl-1-octyne 911    899              (R)-4-triphenyl- methoxy-1-octyne 912    900              (S)-4-triphenyl- methoxy-1-octyne ______________________________________

To a stirred suspension of 1.78 g. (0.074 mole) of sodium borohydride in 200 ml. of dry glyme at -5.degree. C. under nitrogen is added 15.8 g. (0.22 mole) of 2-methyl-2-butene and 16.2 g. (0.11 mole) of boron trifluoride etherate, and the mixture is stirred for 2 hours at -5.degree. to 0.degree. C. A solution of 37.5 g. (0.10 mole) of 4-trityloxy-1-octyne (Example 278) in 50 ml. of glyme is added to the cold solution during 5-10 minutes, and the solution is allowed to warm to 20.degree. C. during 1.5 hours. The reaction mixture is cooled to 0.degree. C., and 30 g. (0.4 mole) of dry trimethylamine-N-oxide is added during 5 minutes. On removing the cooling bath the temperature rises to 40.degree. C., and the mixture is kept between 30.degree.-40.degree. C. for 1.5 hours. The suspension is poured rapidly into 1 liter of ice cold 15% sodium hydroxide solution during good stirring and a solution of 80 g. of iodine in 200 ml. of tetrahydrofuran is added immediately. Stirring is continued for 30 minutes without further cooling and the organic layer is separated. The aqueous layer is extracted with three 200 ml. portions of ether and the combined organic layers are washed successively with water, 5% sodium thiosulfate solution and saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to yield 50 g. of yellow oil. The bulk of the oil is dissolved in hexane and, after decantantation from a gummy solid the hexane solution is percolated through a 5.1 cm. diameter column at 1500 g. of alumina with additional hexane. Fractions containing the desired product are concentrated to a pale yellow oil (33 g.) which has n.m.r. and infrared spectra characteristics of the desired product.

Treatment of the triphenylmethoxy substituted 1-alkynes listed in Table 29 below with disiamylborane, prepared in situ from 2-methyl-2-butene, boron trifluoride and sodium borohydride, followed by trimethylamine N-oxide, and then sodium hydroxide and iodine  all by the procedure described in Example 913 above furnishes the product triphenylmethoxy substituted 1-iodo-1-trans-alkenes of the table. ______________________________________ Starting triphen- ylmethoxy sub- Product 1-iodo-tri- Ex.    situted 1-alkyne phenylmethoxy substi- ample  of Example     tuted-1-trans-alkene ______________________________________ 914    905            1-iodo-3-triphenylmeth- oxymethyl-1-trans- octene 915    907            1-iodo-5-triphenylmeth- oxy-1-trans-octene 916    290            1-iodo-4-triphenylmeth- oxy-1-trans-nonene 917    908            1-iodo-4-triphenylmeth- oxy-1,5-trans.trans- nonadiene 918    910            1-iodo-4-triphenylmeth- oxy-5-methyl-1-trans- oxlene 919    909            1-iodo-4-triphenylmeth- oxy-1-trans-16-cis- nonadiene 920    911            (R)-1-iodo-4-triphenyl- methoxy-1-trans-octene 921    912            (S)-1-iodo-4-triphenyl- methoxy-1-trans-octene 922    304            1-iodo-8-triphenylmeth- oxy-1-trans-octene ______________________________________

Treatment of the 4-hydroxycyclopentenones, listed in Table 30 below, with dihydropyran by the procedure described in Example 158 is productive of the 4-tetrahydropyranyloxycyclopentenones of the table. ______________________________________ Ex-   Starting 4-hydroxy- Product 4-tetrahydro- amle  cyclopentenone  pyranloxycyclopentenone ______________________________________ 923    (R)-4-hydroxy-2- (R)-4-tetrahydropyranyl- (6-carbomethoxy- oxy-2-(6-carbomethoxy- hexyl)cyclopent- hexyl)cyclopent-2-en-1- 2-en-1-one*    one 924    (S)-4-hydroxy-2- (S)-4-tetrahydropyranyl- (6-carbomethoxy- oxy-2-(6-carbomethoxy- hexyl)cyclopent- hexyl)cyclopent-2-en-1- 2-en-1-one*    one ______________________________________ *R. Pappo et al., Tetrahedron Letters, 1973.943

To a stirred solution of the di-i-butylalkenylalane, prepared from 26.5 g. (72 mmoles) of 5-triphenylmethoxy-1-octyne (Example 907) and 60 ml. of 1.2 M di-i-butylaluminum hydride in hexane in 36 ml. of benzene according to the procedure of Example 281 is added 30 ml. of 2.2M methyllithium in ether.

The resulting alanate is reacted with 4-tetrahydropyranyloxy-2-(6-tetrahydropyranylcarboxyhexyl)-cyclopent-2-en- 1-en-1-one (Example 147) according to the method of Example 280. The crude product thereby obtained is deblocking according to the method of Example 280a. The crude product is purified to provide the title compound as an oil, .nu. max. 1735 (ketone carbonyl group), 1710 (acid carbonyl group), and 967 cm.sup.-1 (trans-vinyl group).

To a stirred solution of 25.2 g. (48 mmoles) of 1-iodo-4-triphenylmethoxy-trans-1-octene (Example 913) in 50 ml. of toluene is added 24.0 ml. of 2.0M n-butyllithium in hexane at -70.degree. C. After 1 hour this solution containing 4-triphenylmethoxy-trans-1-octenyl lithium is treated with 31.7 ml. of 1.45M trimethyl-aluminum in hexane at -40.degree. C. and the resulting solution is stirred at 0.degree. C. for 20 minutes.

To the above solution containing lithio trimethyl-(4-triphenylmethoxy-trans-1-octenyl)alanate is added a solution of 15.4 g. (39 mmoles) of 4-tetrahydropyranyloxy-2-(6-carbotetrahydropyranyloxyhexyl)-cyclopent-2-en -1-one (Example 147) in 50 ml. of ether at 0.degree.-8.degree. C. The mixture is stirred at 0.degree. C. for 1 hour and 25.degree. C. for 20 hours, diluted to 500 ml. with ether, and poured into a stired mixture of ice and 20 ml. of 37% hydrochloric acid. The aqueous phase is separated and extracted with ether. The combined organic phases are washed with water and brine, dried over magnesium sulfate, and concentrated to give an oil.

The crude product is dissolved in 440 ml. of 4:2:1 acetic acid-tetrahydrofuran-water, and the resulting solution is heated at 45.degree. C. for 6 hours. The solvents are removed in vacuo at 20.degree. C. to give a mixture of oil and crystals.

The crude product is purified by partition chromatography on acid-washed silica gel using the conjugate phases from benzene-methanol-water (15:5:2), with further purification by silica gel adsorption chromatography if necessary. The prostenoic acid is thereby obtained as an oil, .nu. max. (film) 3300 (hydroxy), 1735 (cyclopentenone), 1705 (carboxylic acid), and 967 cm.sup.-1 (trans-olefin). ,16-dihydroxy-17-methyl-13-transprostenoate

To a stirred solution of 10.21 g. (20 mmoles) of iodo-5-methyl-4-triphenylmethoxy-trans-1-octene (Example 918) in 10 ml. of toluene is added 10 ml. of 2.0M n-butyllithium in hexane at -70.degree. C. After 2 hours this solution containing 5-methyl-4-triphenylmethoxy-trans-1-octenyl lithium is added during 5 minutes at -75.degree. C. to a stirred solution of 3.93 g. (10.0 mmoles) of cuprous iodide-tri-n-butylphoshine complex in 40 ml. of ether. The resulting solution is stirred at -50.degree. C. for 30 minutes and then treated with a solution of 3.38 g. (10.0 mmoles) of cuprous iodide-tri-n-butylphosphine complex in 40 ml. of ether. The resulting solution is stirred at -50.degree. C. for 30 minutes and then treated with a solution of 3.38 g. (10.0 mmoles) of 4-tetrahydropyranyloxy-2-(6-carbethoxyhexyl)-cyclopent-2-en-1-one (Example 158) in ml. of ether during 10 minutes at -45.degree. C. The solution is allowed to warm to -20.degree. C. during 1 hour and is stirred at 0.degree. C. for 2 hours. The reaction mixture is quenched by pouring into iced ammonium chloride solution, and the product is extracted into ether. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give an oil.

The crude product is dissolved in 100 ml. of 4:2:1 acetic acid-tetrahydrofuran-water, and the resulting solution is heated at 45.degree. C. for 8 hours. The solvents are removed in vacuo at 20.degree. C. to give a mixture of oil and crystals.

The crude product is purified by chromatography on acid-washed silica gel using benzene-ethyl acetate gradient elution to provide the title compound as an oil, .nu. max. 1740 (ketone and ester carbonyl groups) and 967 cm.sup.-1 (trans-vinyl group).

Conjugate addition of the cuprates, obtained by treatment of the triphenylmethoxy (trityloxy)-1-iodo-trans-1-octene (indicated in the following table) with butyldilithium followed by cuprous iodide-tri-n-butylphosphine complex, to the cyclopentenones of the table according to the method described in Example 927 followed by de-O-tritylation of the intermediate triphenylmethoxy prostenoates according to the method of Example 927 is productive of the prostenoic acids or esters of the table.

These compounds isolated and identified in the table as prostenoic acids are prepared via the corresponding tetrahydropyran-2-yl esters and those compounds bearing a free hydroxy function at the 11.alpha.-position or as part of an 11.alpha.(.omega.-hydroxyalkoxy) moiety are prepared via the corresponding tetrahydropyran-2-yl ethers. The hydroxy function in the .beta.-chain (that portion of the molecule deriving from the triphenylmethoxy-1-alkylene) of all compounds in the table are initially present in the molecule as the corresponding triphenylmethyl ethers. During the acetic acid treatment (de-O-tritylation step) the triphenylmethyl ether as well as the tetrahydropyran-2-yl ethers and esters functions are hydrolyzed to provide the corresponding free hydroxy and carboxylic acid groups of the compounds listed in the table. __________________________________________________________________________ Starting cyclo- Starting 1-iodo-triphenyl- pentenone of methoxy substituted 1- Product Hydroxy Prostenoic Example Example trans-alkene of Example Acid or Ester __________________________________________________________________________ 928  243      914            Ethyl 9-oxo-11.alpha.-(.beta.-hydroxyethoxy)- 15- hydroxymethyl-13-trans-prostenoate 929  234      915            3-oxa-9-oxo-11.alpha.-methoxy-17-hydroxy-13- O trans-prostenoic acid 930  147      916            9-oxo-11.alpha.,16-dihydroxy-20-[nor]methyl-1 3- trans-[prostenoate]prostenoic acid 931  147      917            9-oxo-11.alpha.-dihydroxy-20-[nor]methyl- 13,17-trans,trans-prostadienoic acid 932  158      919            Ethyl 9-oxo-11.alpha.,16-dihydroxy-20-[nor] methyl-13-trans-18-cis-prostadienoate 933  147      918            9-oxo-11.alpha.,16-dihydroxy-17-methyl-13- trans-prostenoic acid 934  923      920            Methyl 9-oxo-(11R)11-hydroxy-16(R)-hydroxy- 13-trans-prostenoate 935  923      921            Methyl 9-oxo-(11R)11-hydroxy-16(S)-16- hydroxy-13-trans-prostenoate 936  9224     920            Methyl 9-oxo-(11S)11-hydroxy-(16R)-hydroxy- 13-trans-prostenoate 937  924      921            Methyl 9-oxo-(11S)11-hydroxy-(16S)16- hydroxy-13-trans-prostenoate __________________________________________________________________________

To a stirred solution of 1.366 g. of 9-oxo-11.alpha.,17-dihydroxy-13-trans-prostenoic acid (Example 925) in 19 ml. of tetrahydrofuran is added 10.0 ml. of a 1.0M solution of lithium tris-(sec-butyl)borohydride in 1:1 tetrahydrofuran pentane at -78.degree. C. under nitrogen. The solution is stirred at -78.degree. C. for 45 minutes and then is treated with 5 ml. of water. The mixture is stirred at 30.degree. C. for 30 minutes, diluted with dilute sodium bicarbonate solution and extracted with ether. The aqueous phase is acidified with 4N hydrochloric acid, saturated with sodium chloride, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate and concentrated. The residue is purified by dry column chromatography with silica gel to give a colorless oil, .nu. max. = 3310 (hydroxyl groups), 1705 (carboxyl group), and 970 cm.sup.-1 (trans-olefin group).

A solution of 69 mg. of potassium carbonate (0.50 mmoles) and 81 mg. (0.25 mmoles) of methyl 9-oxo-11.alpha.-methoxy-16-hydroxy-13-trans-prostenoate (Example 333) in 25 ml. of 5:1 methanol-water is allowed to stand at room temperature for 24 hours. The solution is diluted with brine and extracted with ether. The extract is washed with brine, dried over magnesium sulfate and concentrated to give an oil, .nu. max. = 279 .mu..

Treatment by the method described in Example 939 of the esters listed in the table below furnishes the .DELTA..sup.8(12) -derivatives of the table. ______________________________________ Ex-    Starting ester Product 9-oxo-8(12)- ample  of Example  prostenoate ester ______________________________________ 940    430         Ethyl 9-oxo-3,3-di- methyl-19-hydroxy-20- nor-8(12),13-trans- prostadienoate 941    424         Ethyl 9-oxo-7a,7b-bis- homo-17-hydroxy-19, 20-dinor-8(12),13- trans-prostadienoate 942    442         Butyl 9-oxo-20-hydroxy- 8(12(,13-trans-prosta- dienoate 943    344         Ethyl 2-phenyl-9-oxo- 13-hydroxy-20-methyl- 8(12)-13-trans-pro- stadienoate ______________________________________

A solution of 0.56 g. (10 mmoles) of potassium hydroxide and 921 mg. (2.5 mmoles) of 9-oxo-11.alpha.-hydroxy-2-methyl-13-trans-prostenoic acid (Example 388) in 25 ml. of 10:1 methanol-water is allowed to stand at room temperature for 24 hours. The solution is diluted with brine, acidified with hydrochloric acid, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give an oil, .nu. max. = 279 m.mu. .

Treatment by the method described in Example 944 of the esters or acids listed in the Table below furnishes the .DELTA..sup.8(12) prostenoic acids of the table. ______________________________________ Ex-    Starting ester of Product 9-oxo-8(12)- ample  acid of Example prostenoic acid ______________________________________ 945    536            9-oxo-2-fluoro-16- methyl-17-hydroxy- 18,19,20-trinor- 8(12)-prostenoic acid 946    363            9-oxo-16-hydroxy-19, 20-dinor-8(12),13- trans-prostadienoic acid 947    444            9-oxo-20-hydroxy- 8(12),13-trans-pro- stadienoic acid 948    876            9-oxo-15-hyroxymethyl- 3-oxa-8(12),13-trans- prostadienoic acid ______________________________________

Conjugate addition of alanate obtained by treatment of the trityloxy-1-iodo-trans-1-octene (indicated in the following table) with n-butyllithium followed by trimethyl aluminum, to the cyclopentenones of the table according to the method described in Example 926 followed by the blocking group removal process of Example 926, is production of the prostenoate esters of the table. ______________________________________ Starting Starting 1-iodo-tri- cyclo-  phenylmethoxy tenone  substituted- of      1-trans-akene Product Ex.  of Ex. of Example Hydroxy Prostenoate Ester ______________________________________ 949  923     920         Methyl 9-oxo-(11R)-hydroxy- (16R)-hydroxy-13-trans- prostenoate 950  923     921         Methyl 9-oxo-(11R)-hydroxy- (16S)16-hydroxy-13-trans- prostenoate 951  924     920         Methyl 9-oxo-(11S)11-hydroxy- (16R)16-hydroxy-13-trans- prostenoate 952  924     921         Methyl 9-oxo-(11S)11-hydroxy- (16S)16-hydroxy-13-trans- prostenoate ______________________________________

Acid treatment by the procedure described in Example 686 of the 11.alpha.-hydroxy-9-oxo-derivative listed in the table below in productive of the .DELTA..sup.10 derivatives of the table. __________________________________________________________________________ starting 11.alpha.- hydroxy-9-oxo Ex-   derivative of Product 9-oxo-10- ample Example   Prostenoate ester __________________________________________________________________________ 953   949       Methyl 9-oxo-16(R)- hydroxy-10,13-trans- (8R,12R)-prosta- dienoate 954   950       Methyl 9-oxo-16(S)- hydroxy-10,13-trans- (8R,12R)-prosta- dienoate 955   951       Methyl 9-oxo-16(R)- hydroxy-10,13-trans- (8S,12S)-prosta- dienoate 956   952       Methyl 9-oxo-16(S)- hydroxy-10,13-trans- (8S,12S)-prosta- dienoate __________________________________________________________________________

Treatment by the method described in Example 939 of the esters listed in the table below furnishes the .DELTA..sup.8(12) -derivatives of the table. ______________________________________ Starting 11.alpha.-hydroxy- Ex-    9-oxo derivative of Product 9-oxo-10- ample  Example           prostenoate esters ______________________________________ 957    949               (R)-Methyl-9-oxo-16- hydroxy-8(12),13- trans-prostadienoate 958    950               (S)-Methyl-9-oxo-16- hydroxy-8(12),13- trans-prostadienoate ______________________________________

Treatment by the method described in Example 944 of the esters listed in the table below furnishes the .DELTA..sup.8(12) prostenoic acids of the table. ______________________________________ Starting 11.alpha.-hydroxy- Ex-    9-oxo derivative of Product 9-oxo-10- ample  Example           prostenoic acid ______________________________________ 959   951               (R)-9-oxo-16-hy- droxy-8(12),13- trans-prostadien- oic acid 960    952               (S)-9-oxo-16-hy- droxy-8(12),13- trans-prosta- dienoic acid ______________________________________

Reduction of the 9-oxo derivatives listed in the table below with lithium perhydro-9b-borahenalyl hydride by the method described in Example 575 with modification indicated for Example 576 is productive of the 9.alpha.-hydroxy derivative of the table. Starting 9-oxo Ex-    derivative    Product ample  of Example    9.alpha.-hydroxy derivative ______________________________________ 961    949           methyl(9S,11R,16R)- trihydroxy-13-trans- prostenoate 962    950           Methyl (9S,11R,16S)- trihydroxy-13-trans- prostenoate 963    951           Methyl (9R,11S,16R)- trihydroxy-13-trans- prostenoate 964    952           Methyl (9R,11S,16S)- trihydroxy-13-trans) prostenoate ______________________________________

Reduction of the 9-oxo derivatives listed in the table below with sodium borohydride by the method described in Example 679 followed by separation of the 9.alpha.- and 9.beta.-hydroxy derivatives by chromatography on silica gel is productive of the named 9.beta.-hydroxy derivatives of the table. ______________________________________ Starting 9-oxo Ex-    derivative of Product ample  Example       9.beta.-hydroxy derivative ______________________________________ 965    (9R,11R,16R)- Methyl -  trihydroxy-13-trans- prostenoate 966    950           Methyl (9R,11R,16S)- trihydroxy-13-trans- prostenoate 967    951           Methyl (9S,11S,16R)- trihydroxy-13-trans- prostenoate 968    952           Methyl (9S,11S,16S)- trihydroxy-13-trans- prostenoate ______________________________________

## Claims

1. An optically active compound of the formula: ##STR57## or a racemic compound of that formula and the mirror image thereof wherein R.sub.1 is selected from the group consisting of hydroxy, .[.lower alkoxy, tetrahydropyranyloxy, lower alkanoyloxy,.]. .Iadd.methoxy, ethoxy and .Iaddend..omega.-hydroxy substituted .[.lower.]. alkoxy .[.and .omega.-tetrahydropyranyloxy substituted lower alkoxy.]. .Iadd.having from 2 to 4 carbon atoms; .Iaddend.R.sub.2 is a moiety selected from the group consisting of those of the formulae: ##STR58## wherein R' is selected from the group consisting of .[.a straight chain alkyl group having from 2 to 10 carbon atoms and a straight chain alkyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms.]. .Iadd.n-propyl, n-butyl and n-pentyl.Iaddend., and R" is .Iadd.a moiety .Iaddend.selected from the group consisting of .[.a straight chain alkyl group having from 2 to 10 carbon atoms and substituted with an hydroxy group, a straight chain alkyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms and substituted with an hydroxy group, a straight chain alkenyl group having from 2 to 10 carbon atoms and substituted with an hydroxy group and a straight chain alkenyl group having from 2 to 6 carbon atoms and having one branched alkyl group of from 1 to 3 carbon atoms and substituted with an hydroxy group;.]. .Iadd.those of the formulae: .Iadd. ##STR59## .Iaddend. wherein m is an integer from 3 to 5, inclusive, p is an integer from 1 to 3, inclusive, q is zero, 1 or 2, and y is  .Iadd. ##STR60## .Iaddend. R.sub.3 is selected from the group consisting of hydroxy .[.,.]. .Iadd.and .Iaddend.alkoxy having from 1 to .[.12.]. .Iadd.4 .Iaddend.carbon atoms .[.and tetrahydropyranyloxy.].; and Z is a divalent radical selected from the group consisting of those of the formulae: ##STR61## wherein n is an integer from .[.3.].  .Iadd.6 .Iaddend.to 8, inclusive .[., R.sub.4 is an alkyl group having up to 3 carbon atoms, and R.sub.5 is selected from the group consisting of an alkyl group having up to 3 carbon atoms, a fluorine atom and a phenyl group.].; and the pharmacologically acceptable cationic salts thereof when R.sub.3 is hydroxy.

2. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR62## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,20-dihydroxy-13-trans-prostenoic acid.

3. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR63## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,20-dihydroxy-13-trans-prostenoic acid.

4. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR64## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,16(S)-dihydroxy-13-trans-prostenoic acid.

5. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR65## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,16.Iadd.(S).Iaddend.-dihydroxy-13-trans-prostenoic acid.

6. The mixture of the two racemic compounds according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR66## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; 9-oxo-11.alpha.,16-dihydroxy-13-trans-prostenoic acid.

7. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR67## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,16(R)-dihydroxy-13-trans-prostenoic acid.

8. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR68## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,16.[.-epidihydroxy.]..Iadd.(R)-dihydroxy.Iaddend.-13-tr ans-prostenoic acid.

9. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR69## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 ; l-9-oxo-11.alpha.,16(S)-dihydroxy-20-methyl-13-trans-prostenoic acid.

10. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR70## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,16.Iadd.(S).Iaddend.-dihydroxy-20-methyl-13-trans-prost enoic acid.

11. The mixture of the two racemic compounds according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR71## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; 9-oxo-11.alpha.,16-dihydroxy-20-methyl-13-trans-prostenoic acid.

12. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR72## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,16(R)-dihydroxy-20-methyl-13-trans-prostenoic acid.

13. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR73## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,16.Iadd.(R).Iaddend.-.[.epi-.].dihydroxy-20-methyl-13-t rans-prostenoic acid.

14. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR74## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,16(S)-dihydroxy-20-ethyl-13-trans-prostenoic acid.

15. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR75## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,16.Iadd.(S).Iaddend.-dihydroxy-20-ethyl-13-trans-proste noic acid.

16. The mixture of the two racemic compounds according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR76## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; 9-oxo-11.alpha.,16-dihydroxy-20-ethyl-13-trans-prostenoic acid.

17. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR77## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,16(R)-dihydroxy-20-ethyl-13-trans-prostenoic acid.

18. The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR78## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,16.[.-epidihydroxy.]..Iadd.(R)-dihydroxy.Iaddend.-20-et hyl-13-trans-prostenoic acid.

19. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR79## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,16(S)-dihydroxy-20-methyl-13-trans,17-trans-prostadienoi c acid.  .[.

20.  The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR80## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,16(S)-dihydroxy-20-methyl-13-trans,17-trans-prostadieno ic acid..].

21. The mixture of the two racemic compounds according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR81## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; 9-oxo-11.alpha.,16-dihydroxy-20-methyl-13-trans,17-trans-prostadienoic acid.  .[.

22.  The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR82## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,16(R)-dihydroxy-20-methyl-13-trans,17-trans-prostadienoi c acid..]. .[.

23.  The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR83## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,16-epi-dihydroxy-20-methyl-13-trans,17-trans-prostadien oic acid..].

24. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR84## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,17(S)-dihydroxy-13-trans-prostenoic acid.  .[.

25.  The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR85## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,17-dihydroxy-13-trans-prostenoic acid..]. .[.

26.  The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR86## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.,17(R)-dihydroxy-13-trans-prostenoic acid..].  .[.

27.  The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR87## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.,17-epi-dihydroxy-13-trans-prostenoic acid..].

28. The mixture of the two racemic compounds according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR88## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; 9-oxo-11.alpha.,17-dihydroxy-13-trans-prostenoic acid.

29. The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR89## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.-hydroxy-15(S)-hydroxymethyl-13-trans-prostenoic acid. .[.

30.  The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR90## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.-hydroxy-15-hydroxymethyl-13-trans-prostenoic acid..].

31. The mixture of the two racemic compounds according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR91## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; 9-oxo-11.alpha.-hydroxy-15-hydroxymethyl-13-trans-prostenoic acid. .[.

32.  The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR92## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; l-9-oxo-11.alpha.-hydroxy-15(R)-hydroxymethyl-13-trans-prostenoic acid..]. .[.

33.  The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR93## R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.6 --; dl-9-oxo-11.alpha.-hydroxy-15-epi-hydroxymethyl-13-trans-prostenoic acid..]. .Iadd.

34.  The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR94## .Iaddend. R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.4 --O--CH.sub.2 --; l-9-oxo-11.alpha.,16(S)-dihydroxy-3-oxa-13-trans-prostenoic acid. .Iadd.

35.  The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR95## .Iaddend. R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.4 --O--CH.sub.2 --; dl-9-oxo-11.alpha.,16(S)-dihydroxy-3-oxa-13-trans-prostenoic acid. .Iadd.

36.  The mixture of the two racemic compounds according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR96## .Iaddend. R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.4 --O--CH.sub.2 --; 9-oxo-11.alpha.,16-dihydroxy-3-oxa-13-trans-prostenoic acid. .Iadd.

37.  The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR97## .Iaddend. R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.4 --O--CH.sub.2 --; l-9-oxo-11.alpha.,16(R)-dihydroxy-3-oxa-13-trans-prostenoic acid. .Iadd.

38.  The racemic compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is ##STR98## .Iaddend. R.sub.3 is hydroxy, and Z is --(CH.sub.2).sub.4 --O--CH.sub.2 --; dl-9-oxo-11.alpha.,16(R)-dihydroxy-3-oxa-13-trans-prostenoic acid. .Iadd.

39.  The optically active compound according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is .Iadd. ##STR99## .Iaddend. R.sub.3 is ethoxy, and Z is --(CH.sub.2).sub.6 --; l-ethyl 9-oxo-11.alpha.,16(S)-dihydroxy-20-methyl-13-trans,18-cis-prostadienoate. .Iadd.

40.  The mixture of the two racemic compounds according to claim 1 wherein R.sub.1 is hydroxy, R.sub.2 is  .Iadd. ##STR100## .Iaddend. R.sub.3 is ethoxy, and Z is --(CH.sub.2).sub.6 --; ethyl 9-oxo-11.alpha.,16-dihydroxy-20-methyl-13-trans,18-cis-prostadienoate. .Iadd.

41.  The optically active compound ethyl l-9-oxo-11.alpha.,16-dihydroxy-17-methyl-13-transprostenoate. .Iaddend. .Iadd.42. The racemic compound ethyl dl-9-oxo-11.alpha.,16-dihydroxy-17-methyl-13-transprostenoate. .Iaddend. .Iadd.43. The optically active compound l-9-oxo-11.alpha.,16-dihydroxy-17-methyl-13-trans-prostenoic acid. .Iaddend. .Iadd.44. The racemic compound dl-9-oxo-11.alpha.,16-dihydroxy-17-methyl-13-trans-prostenoic acid. .Iaddend. .Iadd.45. The optically active compound l-9-oxo-11.alpha.-hydroxy-16-hydroxy-17-methyl-19,20-dinor-13-trans-proste noic acid. .Iaddend. .Iadd.46. The racemic compound dl-9-oxo-11.alpha.-hydroxy-16-hydroxy-17-methyl-19,20-dinor-13-trans-prost enoic acid. .Iaddend. .Iadd.47. The optically active compound l-9-oxo-11.alpha.-hydroxy-16-hydroxy-17-ethyl-20-nor-13-trans-prostenoic acid. .Iaddend. .Iadd.48.  The racemic compound dl-9-oxo-11.alpha.-hydroxy-16-hydroxy-17-ethyl-20-nor-13-trans-prostenoic acid.