Cycloalkyl and cycloalkenyl prostaglandin congeners

Abstract

This disclosure describes novel 15-hydroxy prostanoic acids and derivatives thereof useful as bronchodilators and hypotensive agents.

Description

BRIEF SUMMARY OF THE INVENTION

This invention relates to novel 15-hydroxy prostanoic acids and derivatives thereof as well as to intermediates and methods for their preparation. The novel prostanoic acids and derivatives of this invention embrace all the optical antipodes, diastereomers, enantiomers, racemates, racemic mixtures, and diastereomeric mixtures represented by the following general formulae: ##STR1## wherein Y is a divalent radical selected from the group consisting of those of the formulae: ##STR2## and Z is a divalent radical selected from the group consisting of those of the formulae: ##STR3## WHEREIN M IS AN INTEGER FROM 3 TO 8, INCLUSIVE, P IS AN INTEGER FROM 1 TO 5, INCLUSIVE, R.sub.4 is an alkyl group having up to 3 carbon atoms, R.sub.5 is an alkyl group having up to 3 carbon atoms, a fluorine atom, or a phenyl group, and R.sub.6 is hydrogen or an alkyl group having up to 4 carbon atoms; the moiety --C.sub.13 --C.sub.14 -- is ethylene or trans-vinylene; R.sub.1 is an alkyl group having up to 3 carbon atoms; X is a divalent radical selected from the group consisting of ##STR4## wherein R.sub.2 is selected from the group consisting of hydrogen, triphenylmethyl, and mono- or di-methoxy substituted triphenylmethyl and R.sub.7 is hydrogen or an alkyl group having up to 3 carbon atoms with the proviso that when R.sub.7 is alkyl then R.sub.2 is hydrogen; R.sub.3 is hydroxy, alkoxy having from one to twelve carbon atoms, tetrahydropyranyloxy or tri-(lower alkyl)silyloxy; R.sub.8 is selected from the group consisting of hydrogen, tetrahydropyranyl, and tri(lower alkyl)silyl; s is zero or an integer having the value one to five, inclusive; t is zero or one; and R is selected from the group consisting of cycloalkyl groups having from three to nine carbon atoms, cycloalkenyl groups having from five to nine carbon atoms, mono- or di-(lower alkyl) substituted cycloalkyl groups having from three to eight carbon atoms in the ring, and mono- or di-(lower alkyl) substituted cycloalkenyl groups having from five to eight carbon atoms in the ring; with the second proviso that only one double bond or cyclopropyl group can be immediately adjacent to C.sub.15 and with the third proviso that when Z is ##STR5## and R is a saturated cycloalkyl group then the sum of s and t is at least one; and the moieties ##STR6##

DETAILED DESCRIPTION OF THE INVENTION

A preferred embodiment of this invention is represented by general formulae (A) and (B) hereinabove, wherein X, Y, Z, R, R.sub.1, R.sub.3, R.sub.8, --C.sub.13 --C.sub.14 --, s, t, ##STR7## are as hereinabove defined with all the provisos assigned thereto and with the additional proviso that at least one of R.sub.1, R.sub.4, R.sub.5, and R.sub.6 is present as an alkyl group when R.sub.5 is not phenyl or fluorine.

A most preferred embodiment of this invention is represented by general formulae (C) and (D), which follow. ##STR8## wherein X, Y, X, R.sub.1, R.sub.3, R.sub.8, C.sub.13 --C.sub.14, s, t, ##STR9## are as hereinabove defined with all the provisos assigned thereto; E is selected from the group consisting of cycloalkenyl groups having from five to nine carbon atoms and the cyclopropyl, cyclobutyl, and cyclononyl groups; and R.sub.11 is hydrogen or a lower alkyl group; with the proviso that when E is a saturated cycloalkyl group and Z is --(CH.sub.2).sub.m -- or ##STR10## then the sum of s and t is at least one.

Suitable lower alkyl groups contemplated by the present invention are those having up to four carbon atoms such as methyl, ethyl, isopropyl, sec-butyl, and the like.

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, tri(.beta.-hydroxyethyl)amine, procaine, and the like. The compounds of this invention include all possible optical isomers and mixtures thereof.

The novel compounds of the present invention have 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 hydroxy are, in general, white to yellow crystalline solids having characteristic melting points and absorption spectra. They are relatively insoluble in water, methanol, and ethanol but are relatively insoluble in benzene, diethyl ether and petroleum ether.

In the above general formulae, the two side chains attached to the C.sub.8 and C.sub.12 positions of the cyclopentane or cyclopentene ring are trans to each other. When the side-chain is attached to C.sub.8 or C.sub.12 by a - - - - bond, then it is considered to be behind the plane of the paper. When it is attached by a -- bond, then it is considered to be in front of the plane of paper. Thus, all such isomers of trans configuration are included within the purview of the present invention. For the sake of convenience, in subsequent formulae only one isomer may be represented.

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, Experientia 21, 113 (1965) and references cited therein. All of the so called natural prostaglandins are derivatives of prostanoic acid: ##STR11## 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 invention include all possible optical isomers.

The C.sub.15 position is a particularly important one and when it is substituted by a hydroxy or a blocked hydroxy group and a hydrogen atom or lower alkyl group (R.sub.7) it is assymetric with the possibility of two configurations, deemed S or R. In partial formulae (E) below is shown the "normal" configuration of C.sub.8, C.sub.12, and C.sub.15 as it is found in all known mammallian prostaglandins. The configuration at C.sub.8 and C.sub.12 is referred to as l and at C.sub.15 as S; thus formulae (E) is the l 15(S) form. The enantiomer of (E) is represented by partial formula (F), and d 15(R) form, and a substance deemed a dl-racemate without designation with regard to the situation at C.sub.15 consists of (E) and (F). Partial formula (G) represents a structure wherein the configuration at C.sub.8 and C.sub.12 is as in (E), the l form, but the configuration at C.sub.15 is inverted to the R form. A structure embracing the configuration at C.sub.8, C.sub.12, and C.sub.15 as shown in (G) is referred to as an l 15-epi derivative, the enantiomeric structure is represented by partial formula (H), the d 15-epi derivative, and (G) and (H) is a dl-15-epi racemate. ##STR12##

The compounds of this invention include both possible configurations for C.sub.15.

The novel compounds of the present invention may be readily prepared from certain 4-oxycyclopentenone intermediates, some of which may be represented by the following general formula: ##STR13## wherein Z is as defined above, and R'.sub.3 has all the possibilities given above for R.sub.3 except that it is not hydroxy, and R'.sub.8 has all the possibilities given above for R.sub.8 except that it is not hydrogen.

Those 4-oxycyclopentenones wherein Z does not embrace a carbon-carbon double bond are prepared from the corresponding 4-unsubstituted cyclopentenone acids or esters. The preparation of certain of these cyclopentenones is described in Belgium Pat. No. 786,215 (granted and opened to inspection Jan. 15, 1973). Others of the requisite cyclopentenones are prepared by extension of the methods described therein. Introduction of the requisite 4-oxy function is illustrated in Flowsheet A, below, wherein Z' has all the possibilities given above for Z except that it does not include ##STR14## R'.sub.3 and R'.sub.8 are as described hereinabove and R".sub.3 is hydroxy or alkoxy having from one to twelve carbon atoms. ##STR15##

Introduction of the 4-oxy function into the 4-unsubstituted cyclopentenones (I) is accomplished by first halogenating the 4-position with an allylic halogenating reagent, preferably N-bromosuccinimide. The resulting 4-bromocyclopentenone (II) 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 (III). When solvolysis is carried out with a silver lower alkanoate in the corresponding lower alkanoic acid, such as the silver acetate-acetic acid system, the 4-lower alkanoyloxy (4-acetoxy) derivative (IV) is obtained. Careful alkaline hydrolysis of this product with potassium carbonate in aqueous methanol provides the free 4-hydroxy derivative (III); when R".sub.3 is lower alkyl further hydrolysis with barium hydroxide gives the free carboxylic acid (III, R".sub.3 =hydroxy).

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 (III) can be obtained by hydrolysis to the acid and esterification in the usual way, for example with the appropriate diazoalkane or 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. Particularly useful blocking groups for both functions are the tetrahydropyranyl group or tri(lower alkyl)silyl groups since these groups can easily be cleaved with weak acid under conditions which do not disrupt the subsequently-prepared, relatively-unstable 11-oxy-9-keto system (.beta.-hydroxyketone). 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. However, enzymatic or microbiological hydrolysis is possible and of course these stability considerations do not apply in the "F" (9-hydroxy) series. Appropriately blocked 4-oxycyclopentenone derivatives are represented by formula (V).

The preparation of the 4-oxycyclopentenone intermediates wherein Z is ##STR16## is illustrated in Flowsheet B, which follows, and in which R.sub.6, p, R'.sub.3 and R'.sub.8 are as hereinabove defined. ##STR17##

In accordance with the above reaction scheme the 3,4-epoxylactol (VI) [E. J. Corey and R. Noyori, Tetrahedron Letters, 311 (1970)] is treated with the ylide (VII) to give the 3,4-epoxycyclopentanol (VIII). Oxidation (for example with H.sub.2 CrO.sub.4.H.sub.2 SO.sub.4 -ether or Jones reagent) of (VIII) provides the epoxy ketone (IX), mild base treatment of which results in the initial formation of the 4-hydroxycyclopent-2-en-1-one (XII) and the isomeric 3-hydroxycyclopent-4-en-1-one (XI) as a mixture. Further treatment of this mixture with dilute base under mild conditions results in the isomerization of the 3-hydroxy isomer (XI) to the desired (XII). The transformation of the epoxy ketone (IX) to the hydroxycyclopentenones (XI) and (XII) and the isomerization of (XI) to (XII) may take place through the intermediacy of the 3,4-diol (X). It is also conceivable that isomerization of (XI) to (XII) proceeds via the epoxy derivative (IX) or the corresponding .alpha.-epoxide (XIV); it is further conceivable that (IX) proceeds to (XI) and (XII) directly without the intermediacy of (X). Another possible intermediate for the isomerization of (XI) to (XII) is the corresponding diene (XIII). The preparation of (XII) is also possible via the .alpha.-epoxide series from (XV) via the .alpha.-epoxides corresponding to (VIII) and (IX) such as (XIV) or most conveniently via a mixture of the .alpha.- and .beta.-epoxides. The hydroxy and acid function in the 4-hydroxycyclopentenones (XII) are then blocked to give (XVI). Suitable blocking groups for the hydroxy and acid functions are tetrahydropyranyl, trimethylsilyl, dimethyl-isopropylsilyl, dimethyl-t-butylsilyl and the like; the carboxylic acid group also can be converted to the corresponding alkyl ester.

The 9-keto-13-trans-prostenoic acids and esters of this invention may be prepared by the novel conjugate addition process outlined in the Flowsheet C which follows. In Flowsheet C, R, R.sub.1, Z, R'.sub.3, R".sub.3, s and t are as defined hereinabove; R.sub.9 is a lower alkyl group (each of the three R.sub.9 radicals bonded to an aluminum atom does not necessarily have to be the same), R'.sub.2 has all the possibilities given hereinabove for R.sub.2 except hydrogen, and R' has all the possibilities given hereinabove for R except that it does not include cycloalkenyl, or cyclopropyl groups. ##STR18##

In accordance with reaction scheme of Flowsheet C, acetylene (XVII) is treated with a cycloalkyl, or a cycloalkyl substituted alkyl acid chloride (XVIII) in the presence of aluminum trichloride to provide the 1-chloro-3-keto-trans-1-alkene (XIX). Interchange with sodium iodide, preferably in a ketone solvent such as acetone, provides the corresponding trans-vinyl iodide (XX). Reduction of the keto function in (XX) with sodium borohydride furnishes the alcohol (XXII), which is then blocked with the triphenylmethyl group or a triphenylmethyl group substituted with one or two methoxy groups. Introduction of the methoxy group(s) increases the rate of etherification and more importantly increases the facility by which acid hydrolysis later cleaves the trityloxy group. Blocking the hydroxy function can also be accomplished with a trialkylsilyl group, a tetrahydropyranyl group, an .alpha.-alkoxyethyl group or any other hydroxy blocking group compatible with the conjugate addition process described below and which can later be removed by conditions to which the final products (XXIX) are stable.

Alternatively, trans-1-alkenyliodide (XXII) can be obtained from the aldehyde (XXIII) by reaction of (XXIII) with lithio acetylide and treatment of the resulting 3-hydroxy terminal acetylene (XXIV) with disiamylborane followed with trimethylamine oxide and then with iodine and sodium hydroxide solution.

Submission of the blocked vinyl iodide (XXI) 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 (XXV), the trans-configuration of the double bond being retained. After one to four hours, addition of a trialkyl aluminum, e.g. trimethyl aluminum, triethylaluminum, tripropylaluminum, tri-isobutyl aluminum and the like, to the solution of the lithio derivative (XXV) furnishes the key alanate intermediate (XXVI), also with retention of the trans-configuration of the double bond. The cycloalkenone (XXVII) dissolved in ether or other non-prototropic solvent, is then added to the alanate solution. The resulting solution is allowed to warm to room temperature and is kept for about six to eighteen hours at ambient temperatures. The carboxylic acid group in cycloalkenone (XXVII) is blocked as an ester. Interaction of alanate (XXVI) with cycloalkenone (XXVII) results in the transfer of the trans-1-alkenyl ligand in (XXVI) with retention of the trans-configuration to the cycloalkenone (XXVII) furnishing, after quenching the reaction solution, the 1,4-conjugate addition product (XXVIII). In (XXVIII) we are not certain of the relative configuration of the side-chains to each other. The situation is indicated in structure (XXVIII) by the bond between the ring and the ##STR19## chain and is indicated in the nomenclature of the compounds involved by the designation 8. In any event, deblocking to (XXIX) with acid, e.g., treatment with acetic acid:tetrahydrofuran:water in the ratio of 3:1:1 at 25.degree.-45.degree. C. for some three to forty-eight hours, results in the trans-relationship between the chains. This procedure also results in de-O-tritylatior as well as hydrolysis of tetrahydropyranyl and trialkylsilyl groups. Alkyl esters are not cleaved by this procedure. Saponification can not be accomplished by the usual alkaline procedures; but can be effected by enzymatic or microbiological techniques.

In order to ensure a trans-relationship in (XXVIII) these products can be submitted to conditions known in the literature to equilibrate 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.

The 13-dihydro derivative (C.sub.13 -C.sub.14 is ethylene) of this invention can be prepared by reduction of the .DELTA..sup.13 function in the corresponding 13-prostenoic acids or esters. This reduction can be accomplished by catalytic reduction, preferably at low pressure with a noble metal catalyst in an inert solvent at ambient temperatures.

The 13-dihydro derivatives can also be prepared by treating cycloalkenones of formula (XXVII) with Grignard reagent (XXX) in the usual manner in the presence of a catalyst such as the tributylphosphine cuprous iodide complex. The 15-O-t-butyl blocking group in the conjugate addition product can be efficiently removed by treatment with neat trifluoroacetic acid in the cold for about twenty minutes followed by brief treatment with aqueous ammonia because of potential 15-O-trifluoroacetylation. ##STR20##

The 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, (XXXII) and (XXXIII), respectively as set forth in the reaction scheme of Flowsheet D which follows and in which Z, R".sub.3, s, t, R, R.sub.7 and C.sub.13 -C.sub.14 are as hereinabove defined. The 9.alpha. and 9.beta. derivatives are separable from each other by chromatographic procedures well known in the art.

When the reduction of the 9-keto function is carried out with lithium perhydro-9b-boraphenylalyl hydride [H. C. Brown and W. C. Dickason, Journ. Amer. Chem. Soc., 92, 709 (1970)] or with lithium (tri-sec-butyl)borahydride the product is at least predominantly the 9.alpha.-hydroxy derivative (XXXII), wherein the 9-hydroxy group is cis to the side-chain attached to C.sub.8 and to the 11-substituent. 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 where both are indicated. ##STR21##

A useful procedure for the introduction of the 15-lower alkyl group (R'.sub.7) is illustrated by the sequences of Flowsheet E, which follows. ##STR22##

In Flowsheet E above R, R.sub.1, R'.sub.3, s, t and Z are as hereinabove defined, and R'.sub.7 is a lower alkyl group. In the sequence depicted in Flowsheet E the 9.alpha., 11.alpha., 15-triol (XXXIV) is treated with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (XXXV), which preferentially oxidizes the allylic alcohol function at C.sub.15 to give the 15-ketone (XXXVI). Blocking of the remaining hydroxy functions as trimethylsilyl ethers gives (XXXVII), which is reacted with the alkyl Grignard, R'.sub.7 MgI, to give the 15-alkyl-15-hydroxy derivative (XXXVIII). Hydrolysis of the silyl ether blocking group then furnishes the triol ester (XXXIX), saponification of which gives (XL).

Preferential blocking of the 11.alpha.-hydroxy function in triol (XXXIX) to give the 11.alpha.-trimethylsilyloxy derivative (XLI) is accomplished by treating (XXXIX) with N,N-diethyl-1,1,1-trimethylsilylamine. Oxidation of the secondary 9.alpha.-hydroxy group in (XLI) followed by the de-O-silylation provides the 9-oxo-11.alpha.-hydroxy-15-alkyl derivative (XLII). This procedure leads to two epimeric C.sub.15 alcohols and these are separable by chromatographic procedures.

When the 9-oxo-11-oxy derivative (XLIII), preferably the 11-hydroxy derivative, are treated with dilute acid it is possible to effect elimination and the formation of the corresponding .DELTA..sup.10 derivative (XLIV) (prostaglandins of the A type). A preferred procedure involves treatment in tetrahydrofuran:water (2:1) solvent 0.5 N in hydrochloric acid for about twenty hours at ambient temperatures. Under these conditions tetrahydropyranyl or trialkylsilyl esters undergo hydrolysis. More prolonged treatment with acid or preferably treatment with dilute base effects the conversion of (XLIII) or (XLIV) to the .DELTA..sup.8(12) derivative (XLV, prostaglandins of the B type). The novel compounds of formula (XLV) are also embraced within the scope of this invention. See Flowsheet F, which follows and in which Z, R, R.sub.1, R.sub.3, R".sub.3, R.sub.8, s, t, and C.sub.13 -C.sub.14 are as hereinabove defined. ##STR23##

The prostanoic and prostenoic carboxylic acids of this invention are convertible to the corresponding alkyl esters by treatment with the appropriate diazoalkane in the usual manner.

The 9-oxo derivatives of this invention are convertible to the corresponding compounds A and B (see above, the third proviso noted above not applying) wherein Y is ##STR24## and in which R.sub.10 is selected from the group consisting of hydroxy, lower alkoxy, ureido, thioureido, anilino and anilino mono- or di-substituted with halogen, lower alkyl, lower alkoxy or carboxylic acid groups or a combination of such groups. The novel compounds A and B (the third proviso listed above not applying) wherein Y is ##STR25## are also embraced within the purview of this invention.

All of the compounds of this invention can be isolated and purified by conventional methods. Isolation can be accomplished, for example, by dilution of the reaction mixture with water, extraction with a water-immiscible solvent such as methylene chloride, ethyl acetate, benzene, cyclohexane, ether, toluene and the like; chromatography; adsorption on ion-exchange resins, distillation, or a combination of these. Purification of the compounds of this invention can be accomplished by means known in the art for the purification of prostaglandins and lipids, fatty acids, and fatty esters. For example, liquid-liquid partition chromatography, reverse phase partition chromatography, countercurrent distribution, adsorption chromtography on Florisil.RTM.(synthetic magnesium silicate) or silica gel, dry column chromatography, high speed liquid chromatography, preparative paper chromatography, preparative thin layer chromatography, chromatography over silver loaded cation exchange resins, and combinations thereof can be used effectively to purify the compounds produced by the processes of this invention.

The individual optical isomers of this invention can be obtained by resolution of the corresponding racemates. This can be accomplished by various methods of resolution well-known in the art. Thus, the prostenoic acids can be treated with an optically active base such as cinchonine, quinine, brucine, d- or l-.alpha.-phenylethylamine and the like to produce diastereoisomeric salts which can be separated by crystallization. Resolution of the racemic prostaglandin-like compounds of this invention can also be accomplished by reverse phase and absorption chromatography on an optically active support and absorption chromatography on an optically active support and adsorbent or by selective transformation of one isomer with a biologically-active prostaglandin transforming system. Such transformations can be carried out by incubation or perfusion using methods well established in the art, followed by isolation and recovery of the isomer resistant to the metabolic transformation applied.

Additional procedures for effecting the resolution of the racemic products of this invention involve conversion of a 9.alpha.-hydroxy racemic (the component enantiomers are illustrated by LXVI and LXVII below) wherein the C.sub.11 and C.sub.15 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.15 hydroxy functions and conversion of the diacid (e.g., XLVIII) to a bis salt (e.g., IL)with an optically active amine (e.g., l-(-)-.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). The resulting diastereoisomers 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 enantiomers (XLVI) and (XLVII), oxidation of which, after preferential blocking of the C.sub.11 and C.sub.15 hydroxy functions with tetrahydropyranyl or trialkylsilyl groups, provides the corresponding individual 9-oxo enantiomers (L) and (LI). ##STR26##

Another procedure involves conversion of the 9.alpha.-hydroxy racemate (as the prostenoic acid ester and with the C.sub.11 and C.sub.15 alcohol functions preferentially blocked as tetrahydropyranyl or trialkylsilyl ethers) to the diastereoisomeric carbamates with an optically active isocyanate, e.g., (+)-1-phenylethylisocyanate or (-)-1-phenylethylisocyanate, followed by deblocking. Separation of the diastereoisomers, for example (LII) and (LIII), 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. [See G. Fallick, American Laboratory, 19-27 (August, 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 Associates Inc., Maple St., Milford, Mass.]. Base-treatment of the individual diasteromeric carbamates affords the individual enantiomeric alcohols, for example (XLVI) and (XLVII). ##STR27##

It is also possible to effect resolution of the 9.alpha.-hydroxy racemate, preferably as the prostenoate ester, by esterification of the 9.alpha.-hydroxy function (prior preferential blocking of C.sub.11 and C.sub.15 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.15 alcohol groups. Suitable optically active acids include .omega.-camphoric acid, menthoxyacetic 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 diastereoisomeric esters, for example (LIV) and (LV), are then separated by fractional crystallization or by chromatographic techniques including, if necessary, the use of high speed liquid chromatography. Saponification of the individual diastereoisomers then provides the individual 9.alpha.-hydroxyprostenoic acid enantiomers (XLVI) and (XLVII). ##STR28##

Another resolution procedure, less useful than the methods described above based on the 9.alpha.-hydroxy, derivative, involves derivatization of the keto function of the racemic 9-oxoprostenoic acid or ester (the component enantiomers of which are illustrated by L and LI) with the usual type of ketone derivatizing agents bearing an optically active center. The resulting mixture of diastereoisomeric derivatives can then be separated by fractional crystallization or by chromatography or, if necessary, by high speed liquid chromatography. The individual diastereoisomeric keto derivatives, for example, (LVI) and (LVII), are then convertable to the individual 9-oxo enantiomers (L) and (LI) by any of the usual cleavage techniques, provided that they are sufficiently mild so as not to distrub the sensitive 11-hydroxy-9-keto system. Ketone reduction of the 9-oxo-enantiomer as described hereinabove then provides the corresponding 9.alpha.-hydroxy or 9.beta.-hydroxy enantiomer (XLVI) or (XLVII). Among the optically active reagents useful for ketone derivatization are l-.alpha.-aminoxy-.gamma.-methylpentanoic acid hydrochloride [E. Testa et al., Helv. Chimica Acta, 47 (3), 766 (1973)], methylhydrazine, and 4-.alpha.-methylbenzylsemicarbazide. A useful procedure for the cleavage of oximes such as (LVI) and (LVII) 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. ##STR29##

When the compounds of this invention are prepared from non-resolved starting compounds usually two racemates are obtained. In the .DELTA..sup.13 -trans series 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. Formulae (L) and (LI) above illustrate the enantiomeric components of one racemate, usually referred to as the "15-normal" racemate. Formulae (LVIII) and (LIX) below represent the enantiomeric components of the second racemate, usually referred to as the "15-epi" racemate. Separation of the enantiomeric components of the "15-epi" racemate proceeds as described above for the "15-normal" racemate, preferably via the 9.alpha.-hydroxy intermediates. ##STR30##

It is also possible to prepare the individual enantiomers via the conjugate addition procedure discussed above by starting with a resolved 4-hydroxycyclopentenone (see XXVII) and a resolved .beta.-chain precursor (see XXII).

The 4-hydroxycyclopentenone racemates may be resolved into their component enantiomers (LX) and (LXI) by derivatizing the ketone function with a reagent having an optically active center. The resulting diastereomeric mixture can then be separated by fractional crystallization, or by chromatography, or by high speed liquid chromatography involving, if necessary, recycling techniques. Among the useful optically active ketone derivatizing reagents are l-.alpha.-aminoxy-.gamma.-methylpentanoic acid hydrochloride (to give LXII), (R)-2-aminoxy-3,3-dimethylbutyric acid hydrochloride, methyl hydrazine and 4-.alpha.-methylbenzyl semicarbazide. After separation of the diastereomeric derivatives, reconstitution of the keto function provides the individual 4-hydroxycyclopentenone enantiomers (LX) and (LXI). A useful procedure for the resolution of a 4-hydroxycyclopentenone racemate via an oxime such as (LXII) is described in the art [R. Pappo, P. Collins and C. Jing, Tetrahedron Letters, 943 (1973)]. ##STR31##

An alternative procedure for the preparation of the 4(R)-hydroxycyclopentenone enantiomers such as (LX) involves as a key step the selective microbiological or chemical reduction of trione (LXIII) to the 4(R)-hydroxycyclopentanedione (LXIV). 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 (LXIV) to an enol ether or enol ester, wich as (LXV, 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 (LXV) 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 (LXVI), which can then be saponified to (LX). The ester (LXVI), 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., Jour. 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 description of the baker's yeast procedure see C. J. Sih et al., Jour. Amer. Chem. Soc., 94, 3643 (1972). ##STR32##

Procedures for the preparation of the requisite cyclopentanetriones (LXIII) are well-established in the art and generally involve the treatment of an .omega.-1 oxo long chain ester (LXVII) 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 dealkoxalkylation 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. ##STR33##

The intermediate keto esters (LXVII) 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 (LXIX) in the usual manner with the appropriate side-chain precursor (LXX, X=Cl, Br, I, preferably Br or I) followed by decarbethoxylation and reesterification, all in the usual manner. ##STR34##

The side-chain precursors (LXX) are commercially available where Z is --(CH.sub.2).sub.m --, and can be prepared as described in Belgian Patent 786,215 (granted and opened to inspection Jan. 15, 1973) where Z is ##STR35## Where Z is ##STR36## precursor (LXX) can be prepared as indicated below by mono-tetrahydropyranylation of the diol (LXXIII) to (LXXIV), followed by mesylation, treatment of the resulting mesylate (LXXVI) with the appropriate substituted sodio malonate to give (LXXV), decarbethoxylation and reesterification to (LXXVII), mesylation of the second hydroxy function to (LXXIX) and displacement with lithium bromide (or iodide) to (LXXXI). Alternatively, the .omega.-bromo alcohol (LXXX) after blocking as the tetrahydropyranyl derivative (LXXVIII), on treatment with the substituted sodio malonate provides (LXXV). ##STR37##

Those precursors wherein Z is --(CH.sub.2).sub.m --O--CH.sub.2 -- can be prepared by the transformations shown directly below starting with the mono-tetrahydropyranyl derivative (LXXIV). Thus, (LXXIV) is converted to the lithium alcoholate by treatment with butyl lithium, the alcoholate is then O-alkylated with ethyl bromoacetate to provide (LXXXII), which an de-tetrahydropyranylation, mesylation and reaction with lithium bromide gives the required (LXXXV). (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 patent 786,215.) ##STR38##

Procedures for the preparation of precursors (LXX) wherein Z is ##STR39## also can be found in the art [see J. B. Heather et al., Tetrahedron Letters, 2313 (1973)].

It is also possible to resolve the 4-hydroxycyclopentenone racemate (LXXXVI) by microbiological means. Thus, treatment of the 4-O-alkanoyl derivatives (LXXXVIII, R.sub.12 =alkyl) of racemate (LXXXVI) (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 (LXXXVIII), which is then separated from the unreacted 4(S)-O-acyl enantiomer (LXXXIX) by chromatographic procedures. After separation, mild hydrolysis of the 4(S) derivative (LXXXIX) provides the 4(S)-hydroxycyclopentenone (XC). [See N. J. Marsheck and M. Miyano, Biochimica et Biophysica Acta, 316, 363 (1973) for related examples.] ##STR40##

It is also possible to prepare the 4-hydroxycyclopentenones (LXXXVIII) and (XC) directly by selective microbial hydroxylations of the corresponding 4-unsubstituted cyclopentenone (XCI), for example, with Aspergillus niger ATCC 9142; other organisms can also accomplish this hydroxylation; for a literature example, see S. Kurozumi, T. Tora and S. Ishimoto, Tetrahedron Letters, 4959 (1973). ##STR41##

The .beta.-chain precursors racemates can be resolved at either the acetylenic alcohol stage (XXIV, Fl. C) or the trans-vinyl iodide stage (XXII, Fl. C) by a variety of methods well-known in the art. These methods will be illustrated below with the acetylenic alcohol (XXIV), but they apply equally well to the trans-vinyl iodide (XXII). Furthermore, the resolved acetylenicalcohol (XXIV) can be converted to the trans-vinyl iodide (XXII) 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)]. The more detailed discussion above concerning the use of each individual derivative type applies to these racemates as well. ##STR42##

Racemates (XXIV) or (XXII) 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 diastereomer then provides the individual enantiomeric alcohols, e.g., (XVII) and (XCIII) from racemate (XXIV). ##STR43##

Useful derivatives for resolution purposes include the salts of the phthalates half acid ester (XCIV) with an optically active amine (e.g., l-(-)-.alpha.-methylbenzylamine, d-(+)-.alpha.-methylbenzylamine, brucine, dehydroabietylamine, strychinine, quinine, cinchonine, cinchonidine, quinidine, ephedrine, deoxyephedrine, amphetamine, (+)-2-amino-1-butanol, (-)-2-amino-1-butanol and the like). ##STR44##

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 (XCV) obtained by treatment of racemate (XXIV) with an optically active isocyanate (e.g., (+)-1-phenylethylisocyanate and (-)-1-phenylethylisocyanate). ##STR45##

Various esters of racemate (XXIV) 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, menthoxyacetic acid, 3.alpha.-acetoxy-.DELTA..sup.5 -etianic acid, 3.alpha.-acetoxy-5,16-etiadienoic acid, (-)-.alpha.-methoxy-.alpha.-trifluoromethylphenylacetic acid (see XCVI), (+)-.alpha.-methoxy-.alpha.-trifluoromethylphenylacetic acid, and the like. ##STR46##

The resolution of the related 1-octyne-3-ol with 3.beta.-acetoxy-.DELTA..sup.5 -etianic acid and 3.beta.-acetoxy-5,16-etiadienic 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 3-hydroxy-trans-vinyl iodides can also be accomplished by microbial techniques, involving a selective de-esterification of 3-O-alkanoyl or aroyl derivatives (XCVII) followed by chromatographic separation to the individual enantiomers and hydrolysis of the non de-esterified ester. ##STR47##

Alternatively, it is possible to effect selective microbial reduction of the corresponding 3-keto derivatives (XCVIII) and (IC) to a single enantiomer. Microbial reduction is preferably carried out in the trans-vinyl iodide series (IC); useful microorganisms for this purpose are Penicillium decumbens and Aspergillus ustus. The preparation of ketone (XCVIII) is described hereinabove [see XX, Flowsheet C]. Ketones (XCVIII) and (IC) are also ##STR48## 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 (XCVIII) or (IC) 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.-D-glucofuranose complex, and lithium hydrodipinan-3.alpha.-ylborate. For pertinant 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, ether the .beta.-chain or the 4-hydroxycyclopentenone, in the conjugate addition process will lead to the formation of two diastereomers, which, in the .DELTA..sup.13 series at least, can then be separated by chromatographic and other procedures (as described above for the corresponding racemate) into the individual component enantiomers.

It is also possible to introduce the 15-normal (in distinction to 15-epi) hydroxy function by stereoselective reduction of 15-keto intermediates such as (XXXVI) or (XXXVII) of Flowsheet E with reagents such as lithium hexyltetrahydrolimonyl borohydride. For maximum selectivity it is best to block the 11.alpha.-hydroxy function in (XXXVI) with bulky groups such as p-phenylbenzoyl or p-phenylcarbamoyl. These groups can later be saponified prior to oxidation of the 9-hydroxy function. Alternative borohydride reagents include lithium hexyl-di-sec-butylborohydride and lithium tri-sec-butylborohydride. For examples and further discussion of this procedure see Corey et al., J.A.C.S., 94, 8616 (1972); Corey et al., ibid., 93, 1491 (1971); and Miyano et al., Chem. Communications, 180 (1973).

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, bronchodilators, 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, serum-cholesterol lowering agents, anti-inflammatory agents and as agents for the inhibition of platelet aggregation. Certain of the novel compounds of this invention possess utility as intermediates for the preparation of other of the novel compounds of this invention. The compounds of this invention provide protection against the ulcerogenic properties of indomethacin. A measure of this utility which also measures potential anti-ulcer properties is the assay which follows.

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 three 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 ulcers was as previously reported. [Abdel-Galil et al., Brit. J. Pharmac. Chemotherapy 33:1-14 (1968)].

______________________________________Score______________________________________NormalPetechial hemorrhage or pin point ulcer21 or 2 small ulcers3Many ulcers, a few large4Many ulcers, mainly large______________________________________

Control animals treated with indomethacin but not tested compound consistently give scores of about 3.0. 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 A below. Compounds producing a lowering of the control score by 0.5 or more are considered to be active.

TABLE A______________________________________ Total Oral dose; mg./kg of body ScoreCompound weight Treated Control______________________________________d,l 9-oxo-11.alpha.,15-dihydroxy-17,20-methano-13-trans-prostenoic acid 6.25 1.5 3.0d,l 9-oxo-11.alpha.,15-epi-dihydroxy-17,20-methano-13-trans-prostenoicacid 6.25 2.3 3.0______________________________________

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 three spasmogenic agents is expressed as an ED.sub.50 determined from the results obtained with three logarithemic cumulative intravenous doses.

TABLE B______________________________________Brochodilator Activity (Konzett Assays)ED.sub.50, mg./kg. Spasmogenic Agent 5-hydroxy- acetylCompound tryptamine histamine choline______________________________________d,1-9-oxo-11.alpha.-15-dihydroxy- 1.8 .444 1.317,20-methano- x x x13-trans-pro- 10.sup.-3 10.sup.-3 10.sup.-3stenoic acidd,1-9-oxo-11.alpha.-15-epi-dihydro- .228 42.0xy-17,20-methano- x13-trans-pro- 10.sup.-3 73.2stenoic acidd,1-9-oxo-15-hy-droxy-17,20-meth- 54.6 41.0 292ano-10,13-trans- x x xprostadienoic 10.sup.-3 10.sup.-3 10.sup.-3acid______________________________________

The novel compounds of the present invention are useful as hypotensive agents and their prostaglandin-like hypotensive activity may be demonstrated in the following test procedure. This procedure is a modification of the technique described by Pike et al., Prostaglandins, Nobel Symposium 2, Stockholm, June, 1966; p. 165.

Male Wistar strain rats (Royal Hart Farms) averaging approximately 250 grams in weight are fastened to rat boards in a supine position by means of canvas vests and limb ties. The femoral area is infiltrated subcutaneously with lidocaine and the iliac artery and vein are exposed and cannulated. Arterial blood pressure (systol astolic) is recorded using a Statham P.sub.23 Db pressure gauge. The animals are anethetized before use with pentobarbital, 30 mg./kg. of body weight intravenously, and also are given hexamethonium bitartrate, 2 mg./kg. of body weight intravenously. The test compounds are prepared by ultrasonic dispersion in a Saline-Tween 80.RTM. vehicle. A constant intravenous dose volume of 0.5 ml. is administered and test doses can range from 0.02 to 10.0 mg./kg. of body weight. In Table C below are set forth doses which will produce a decrease of about 10 mm. or more in diastolic blood pressure for typical compounds of the present invention.

TABLE C__________________________________________________________________________HYPOTENSIVE ACTIVITY Hypotensive dose (mg./kg. ofCompound body weight)__________________________________________________________________________9-oxo-11.alpha.,15-dihydroxy-16-methyl-18,20-ethano-13-trans- 0.5prostenoic acid9-oxo-11.alpha.,15-dihydroxy-17,20-ethano-13-trans-prostenoicacid <1.09-oxo-11.alpha.,15-dihydroxy-6,20-methano-13-trans-17-pro-stadienoic acid 0.059-oxo-11.alpha.,15-dihydroxy-17,18-methano-13-trans-prostenoicacid 0.059-oxo-11.alpha.,15-dihydroxy-2-ethyl-16,20-methano-13-trans,17-prostadienoic acid <1.09-oxo-11.alpha.,15-dihydroxy-2-methyl-17,18-methano-13-trans-prostenoic acid 0.259-oxo-11.alpha.,15-epi-dihydroxy-2-methyl-17,18-methano-13-trans-prostenoic acid 2.09-oxo-11.alpha.,15-dihydroxy-3-oxa-16,20-methano-13-trans-prostadienoic acid <1.09-oxo-11.alpha.,15-epi-dihydroxy-3-oxa-16,20-methano-13-trans,18-prostadienoic acid 4.09-oxo-11.alpha.,15-dihydroxy-20-cyclopentyl-5-cis-13-trans-prostadienoic acid 0.59-oxo-11.alpha.,15-epi-dihydroxy-20-cyclopentyl-5-cis-13-trans-prostadienoic acid <2.01-methyl 9-oxo-11.alpha.,15-dihydroxy-16-methyl-18,20(1,3-pro-pano)-5-cis,13-trans-prostadienoate 0.051-methyl 9-oxo-11.alpha.,15-epi-dihydroxy-16-methyl-18,20-(1,3-propano)-5-cis,13-trans-prostadienoate 1.01-methyl 9-oxo-11.alpha.,15-dihydroxy-17,18-methano-5-cis,13-trans-prostadienoate 0.051-methyl 9-oxo-11.alpha.,15-epi-dihydroxy-17,18-methano-5-cis,13-trans-prostadienoate 1.01-methyl 9-oxo-11.alpha.,15-dihydroxy-16,20-methano-5-cis,13-trans,18-prostadienoate 0.51-methyl 9-oxo-11.alpha.,15-epi-dihydroxy-16,20-methano-5-cis,13-trans,18-prostatrienoate 2.09-oxo-11.alpha.,15-dihydroxy-4-propyl-16,20-methano-5-cis,13-trans,17-prostatrienoic acid 0.59-oxo-11.alpha.,15-epi-dihydroxy-4-propyl,16,20-methano-5-cis,13-trans,17-prostatrienoic acid 2.09-oxo-11.alpha.,15-dihydroxy-4-propyl-16-methyl-18,20-(1,3-propano)-5-cis,13-trans-prostadienoic acid 0.59-oxo-11.alpha.,15-epi-dihydroxy-4-propyl-16-methyl-18,20-(1,3-propano)-5-cis,13-trans-prostadienoic acid 2.09-oxo-11.alpha.,15-dihydroxy-15-methyl-17,18-methano-13-trans-prostenoic acid 0.059-oxo-11.alpha.,15-epi-dihydroxy-15-methyl-17,18-methano-13-trans-prostenoic acid 1.09-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-ethano-13-trans,18-prostadienoic acid 0.59-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-ethano-13-trans-18-prostadienoic acid <2.09-oxo-11.alpha.,15-dihydroxy-15-methyl-20-cyclopentyl-5-cis,13-trans-prostadienoic acid 0.59-oxo-11.alpha.,15-epi-dihydroxy-15-methyl-20-cyclopentyl-5-cis,13-trans-prostadienoic acid <2.01 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,18-methano-5-cis,13-trans-prostadienoic acid 0.051 9-oxo-11.alpha.,15-epi-dihydroxy-15-methyl-17,18-methano-5-cis,13-trans-prostadienoic acid 1.09-oxo-15-hydroxy-16-methyl-18,20-ethano,10,13-trans-prostadienoic acid <1.09-oxo-15-hydroxy-17,18-methano-10,13-trans-prostadienoic 0.5d9-oxo-15-hydroxy-3-oxa-16,20-methano-10,13-trans,18-prostatrienoic acid 0.51 methyl 9-oxo-15-hydroxy-17,18-methano-5-cis,10,13-trans-prostadienoic acid <0.59-oxo-11.alpha.,15-dihydroxy-17,18-methano-prostanoic acid 0.259-oxo-11.alpha.,15-epi-dihydroxy-17,20-methano-13-trans-prostenoic acid 2.09-oxo-11.alpha.,15-dihydroxy-17,20-methano-13-trans-prostenoic 0.059-oxo-15-hydroxy-17,20-methano-10,13-trans-prostadienoic 0.2d9-oxo-15-epi-hydroxy-17,20-methano-10.13-trans-prostadienoic 8.0acid__________________________________________________________________________

EXAMPLE 1

Preparation of 2-(6-carboxy-6-fluorohexyl)cyclopent-2-en-1-one

This cyclopentenone is prepared by the procedure described in Belgium Pat. No. 786,215 (Jan. 15, 1973) for the preparation of 2-(6-carboxyoctyl)cyclopent-2-en-1-one by substituting diethyl fluoromalonate for diethyl ethylmalonate.

EXAMPLE 2

Preparation of 2-(6-carboxy-6-phenylhexyl)cyclopent-2-en-1-one

This cyclopentenone is prepared by the procedure described in Belgium Pat. No. 786,215 (Jan. 15, 1973) for the preparation of 2-(6-carboxyoctyl)cyclopent-2-en-1-one by substituting diethyl phenylmalonate for diethyl ethylmalonate.

EXAMPLE 3

Preparation of 2-(6-carboxyheptyl)cyclopent-2-en-1-one

This cyclopentenone is prepared by the procedure described in Belgium Pat. No. 786,215 (Jan. 15, 1973) for the preparation of 2-(6-carboxyheptyl)cyclopent-2-en-1-one by substituting diethyl methyl malonate for diethyl ethylmalonate.

EXAMPLE 4

Preparation of 2-(6-carbo-n-butoxyhexyl)cyclopent-2-en-1-one

A solution of 50 g. of 2-(6-carboxyhexyl)cyclopent-2-en-1-one [Bagli et al., Tetrahedron Letters, No. 5, 485 (1966)] in 1400 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.

EXAMPLES 5-7

Treatment of 2-(6-carboxyhexyl)cyclopent-2-en-1-one by the procedure of Example 4 with the appropriate alcohol affords the esters of the following table.

TABLE 4______________________________________Example Alcohol Product Ester______________________________________5 isopropanol 2-(6-carboisopropoxy- hexyl)cyclopent-2-en- 1-one6 methanol 2-(6-carbomethoxyhexyl)- cyclopent-2-en-1-one7 1-hydroxy- 2-(6-carbo-n-decyloxy- n-decane hexyl)cyclopent-2-en- 1-one______________________________________

EXAMPLE 8

Preparation of 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one

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..sub.max..sup.MeOH =225 m.mu. (8850); .nu.max.=1705 (carbonyl groups and 1625 cm.sup.-1 (olefin group).

EXAMPLES 9-24

In the manner of the preceding Example 8, the carious cyclopentenones of Table I, which follows, are converted to the corresponding 4-bromo derivatives.

Table 1______________________________________Ex- Starting cyclo- Product 4-Bromocyclo-ample pent-2-en-1-one pentenones______________________________________ 9 2-(6-carbethoxy- 4-bromo-2-(6-carbeth- hexyl)-cyclo- oxyhexyl)-cyclopent- pent-2-en-1-one 2-en-1-one10 2-(6-carbomethy- 4-bromo-2-(6-carbo- oxyhexyl)cyclo- methoxyhexyl)cyclopent- pent-2-en-1-one 2-en-1-one11 2-(4-carboxy 4-bromo-2-(4-carboxy- butyl)cyclopent- butyl)cyclopent-2-en- 2-en-1-one 1-one12 2-(3-carboxy- 4-bromo-2-(3-carboxy- propyl)cyclo- propyl)cyclopent-2-en- pent-2-en-1-one 1-one13 2-(8-carboxy- 4-bromo-2-(8-carboxy- octyl)cyclo- octyl)cyclopent-2-en- pent-2-en-1-one 1-one14 2-(6-carboxy- 4-bromo-2-(6-carboxy- octyl)cyclopent- octyl)cyclopent-2-en- 2-en-1-one 1-one15 2-(6-carboxy- 4-bromo-2-(6-carboxy- 5,5-dimethyl- 5,5-dimethylhexyl)- hexyl)cyclopent- cyclopent-2-en-1-one 2-en-1-one16 2-(carboxy-5- 4-bromo-2-(6-carboxy- oxahexyl)cyclo- 5-oxahexyl)cyclo- pent-2-en-1-one pent-2-en-1-one17 2-(6-carboxy-6- 4-bromo-2-(6-carboxy- fluorohexyl)- 6-fluorohexyl)cyclo- cyclopent-2-en- pent-2-en-1-one 1-one (Example 1)18 2-(5-carboxy- 4-bromo-2-(5-carboxy- pentyl)cyclo- pentyl)cyclopent-2-en- pent-2-en-1-one 1-one19 2-(7-carboxy- 4-bromo-2-(7-carboxy- heptyl)cyclo- heptyl)cyclpent-2-en- pent-2-en-1-one 1-one20 2-(6-carboxy-6- 4-bromo-2-(6-carboxy- pentylhexyl)- 6-phenylhexyl)cyclo- cyclopent-2-en- pent-2-en-1-one 1-one (Ex. 2)21 2-(6-carbo-n- 4-bromo-2-)6-carbo-n- butoxyphenyl)- butoxyhexyl)cyclopent- cyclopent-2-en- 2-en-1-one 1-one (Ex. 4)22 2-(6-carbo-iso- 4-bromo-2-(6-carbo- propoxyhexyl)- isopropoxyhexyl)- cyclopent-2-en- cyclopent-2-en-1-one (Example 5)23 2-(6-carbo-n- 4-bromo-2-(6-carbon-n- decyloxyhexyl)- decyloxyhexyl)cyclo- cyclopent-2-en- pent-2-en-1-one 1-one (Ex. 7)24 2-(6-carboxy- 4-bromo-2-(6-carboxy- heptyl)cyclo- heptyl)-cyclopent-2- pent-2-en-1-one 1-one (Example 3)______________________________________ *Belgium Patent Number 786,215 (January 15, 1973).

EXAMPLE 25

Preparation of 4-hydroxy-2-(8-carboxyoctyl)cyclopent-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 13) 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..sub.max..sup.MeOH =223 m.mu. (7800); .nu.max (KBr)=3340 (hydroxyl groups), 1705 (carbonyl groups), and 1625.sup.-1 (olefin group).

EXAMPLE 26

Preparation of 4-acetoxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one

A mixture of 51.6 g. (0.137 moles) of crude 4-bromo-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one (Example 9), 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..sub.max..sup.MeOH 223 m.mu. (10700); .nu.max.=1745 (ester carbonyl groups), 1725 (ketone carbonyl groups), and 1235 cm.sup.-1 (acetoxy group).

EXAMPLE 27

Preparation of 4-hydroxy-2-(6-carboxyhexyl)cyclopent-2-en-1-one

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 26) 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 4 N 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..sub.max..sup.MeOH =223 m.mu. (7360); .nu.max.=3380 (hydroxyl groups), 1710 (carbonyl groups), and 1632 cm.sup.-1 (olefin group).

EXAMPLE 28

Preparation of 2-(6-carboxyhexyl)-4-hydroxy-cyclopent-2-en-1-one

To a stirred solution of 10.6 g. (ca. 34 mmoles) of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 8) in 100 ml. of acetone and 65 ml. of water is added 8.0 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 half saturated sodium bicarbonate solution. The basic extract 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 27.

EXAMPLES 29-43

By the procedure of the preceding Example 28 the various 4-bromocyclopentenones of the following Table 2 are solvolyzed in acetone-water in the presence of silver fluoroborate to provide the 4-hydroxycyclopentenones of the Table. In the instance of the carboxylic acid esters the sodium bicarbonate extraction step is omitted.

TABLE 2______________________________________ Starting Product cyclopentenones 4-hydroxycyclopente-Example of Example 2-en-ones______________________________________29 9 4-hydroxy-2-(6-car- bethoxyhexyl)cyclo- pent-2-en-1-one30 10 4-hydroxy-2-(6-carbo- methoxyhexyl)cyclo- pent-2-en-1-one31 11 4-hydroxy-2-(4-car- boxybutyl)cyclopent- 2-en-1-one32 12 4-hydroxy-2-(3-carboxy- propyl)cyclopent-2- en-1-one33 14 4-hydroxy-2-(6-car- boxyoctyl)-cyclopent- 2-en-1-one34 15 4-hydroxy-2-(6-car- boxy-5,5-dimethylhexyl)- cyclopent-2-en-1-one35 16 4-hydroxy-2-(6-carboxy- 5-oxahexyl)cyclopent- 2-en-1-one36 17 4-hydroxy-2-(6-car- boxy-6-fluorohexyl)- cyclopent-2-en-1-one37 18 4-hydroxy-2-(5-car- boxypentyl)cyclopent- 2-en-1-one38 19 4-hdyroxy-2-(7-carboxy- heptyl)cyclopent-2- en-1-one39 20 4-hydroxy-2-(6-carboxy- 6-phenylhexyl)cyclo- pent-2-en-1-one40 21 4-hydroxy-2-(6-carbo- n-butoxyhexyl)cyclo- pent-2-en-1-one41 22 4-hydroxy-2-(6-carbo- isopropoxyhexyl)cyclo- pent-2-en-1-one42 23 4-hydroxy-2-(6-carbo-n- decyoxyhexyl)cyclo- pent-2-en-1-one43 24 4-hydroxy-2-(6-carboxy- heptyl)cyclopent-2-en- 1-one______________________________________

EXAMPLE 44

Preparation of 4-tetrahydropyranyloxy-2-(6-tetrahydropyranylcarboxyhexyl)cyclopent-2-en-1-one

To a stirred solution of 5.59 g. (24.6 mmoles) of 4-hydroxy-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 28) 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 separated 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..sub.max..sup.MeOH =223 m.mu. (9500); .nu.max. 1730 (ester carbonyl group), 1705 (ketone carbonyl group), and 1030.sup.-1 (tetrahydropyranyloxy groups).

EXAMPLES 45-55

By the procedure of Example 44, the various 4-hydroxycyclopentenones of Table 3, which follows, are converted to the tetrahydropyranyl 4-tetrahydropyranyloxycyclopentenone esters of the table.

TABLE 3__________________________________________________________________________ Starting 4-hydroxycyclo- Product Tetrahydropyran-2'-yl 4-tetrahydropyran-2'-yl-Example pentenone of Example oxycyclopent-2-en-1-one__________________________________________________________________________45 31 4-tetrahydropyran-2'-yloxy-2-(4-carbotetrahydropyran- 2'-yloxybutyl)cyclopent-2:en-1-one46 32 4-tetrahydropyran-2'-yloxy-2-(3-carbotetrahydropyran- 2'-yloxypropyl)cyclopent-2-en-1-one47 25 4-tetrahydropyran-2'-yloxy-2-(8-carbotetrahydropyran- 2'-yloxyoctyl)cyclopent-2-en-1-one48 33 4-tetrahydropyran-2'-yloxy-2-(6-carbotetrahydropyran- 2'-yloxyoctyl)cyclopent-2-en-1-one49 34 4-tetrahydropyran-2'yloxy-2-(6-carbotetrahydropyran- 2'-yloxy-5,5-dimethylhexyl)cyclopent-2-en-1-one50 35 4-tetrahydropyran-2'-yloxy-2-(6-carbotetrahydropyran- 2'-yloxy-5-oxahexyl)cyclopent-2-en-1-one51 36 4-tetrahydropyran-2'-yloxy-2-(6-carbotetrahydropyran- 2'-yloxy-6-fluorhexyl)cyclopent-2-en-1-one52 37 4-tetrahydropyran-2'-yloxy-2-(5-carbotetrahydropyran- 2'-yloxypentyl)cyclopent-2-en-1-one53 38 4-tetrahydropyran-2'-yloxy-2-(7-carbotetrahydropyran- 2'-yloxyheptyl)cyclopent-2-en-1-one54 39 4-tetrahydropyran-2'-yloxy-2-(6-carbotetrahydropyran- 2'-yloxy-6-phenylhexyl)-cyclopent-2-en-1-one55 43 4-tetrahydropyran-2'-yloxy-2-(6-carbotetrahydropyran- 2'-yloxyheptyl)-cyclopent-2-en-1-one__________________________________________________________________________

EXAMPLE 56

Preparation of 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 29) 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..sub.max..sup.MeOH =224 m.mu. (7950); .nu.max.=1735 (ester carbonyl group), 1710 (ketone carbonyl group), and 1030 cm.sup.-1 (tetrahydropyranyloxy group).

EXAMPLES 57-60

In the manner of Example 56 the alkyl 4-hydroxycyclopentenone esters of Table 4, which follows, are converted to the corresponding 4-tetrahydropyranyloxy alkyl esters of the table.

TABLE 4__________________________________________________________________________ Starting 4-hydroxycyclo-Example pentenone Esters of Product 4-tetrahydropyran-2'-yloxycyclopent-2- Exampleen-1-one esters__________________________________________________________________________57 30 4-tetrahydropyran-2'-yloxy-2-(6-carbomethoxyhexyl)-cyclopent-2-en-1-one57a 2-(6-carbomethoxyhexyl)- 4(R)-tetrahydropyran-2'-yloxy-2-(6-carbomethoxyhexyl)-4-(R)-hydroxycyclopent-cyclopent-2-en-1-one 2-en-1-one (Ref. 1 & 2)57b 2-(6-carbomethoxyhexyl)- 4(S)-tetrahydropyran-2'-yloxy-2-(6-carbomethoxyhexyl)- 4(S)-hydroxycyclopent- cyclopent-2-en-1-one 2-en-1-one (Ref. 1)58 40 4-tetrahydropyran-2'-yloxy-2-(6-carbo-n-butoxyhexyl)- cyclopent-2-en-1-one59 41 4-tetrahydropyran-2'-yloxy-2-(6-carbo-isopropoxyhexyl)- 3 cyclopent-2-en-1-one60 42 4-tetrahydropyran-2'-yloxy-2-(6-carbo-n-decyloxyhexyl)- 2 cyclopent-2-en-1-one__________________________________________________________________________ Ref. 1. R. Pappo, P. Collins and C. Jung, Tetrahedron Letters, 943 (1973) 2. C.J. Sih, et al., Jour. Amer. Chem. Soc., 95, 1676 (1973).

EXAMPLE 61

Preparation of all-cis-2(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanol

A solution of 1.42 g. (10.0 moles) of all-cis-5-hydroxy-2,3-oxidocyclopentylacetaldehyde-.gamma.-lactol (E. J. Corey and R. Noyori, Tetrahedron Letters, 1970, 211) in 5 ml. of DMSO is added to a stirred solution of the Wittig reagent [E. J. Corey et al., JACS, 91, 5675 (1969)] prepared from 13.3 g. (30 moles) of 4-carboxybutyltriphenylphosphonium bromide (Example 68) 2.52 g. (0.60 moles) of 57% sodium hydride dispersion, and 70 ml. of DMSO at 16.degree. C. during 1 minute.

The solution is stirred at ambient temperature for 20 hours and poured into a stirred mixture of methylene chloride, ice, and hydrochloric acid. The organic phase is separated, and the aqueous phase is extracted with methylene chloride, saturated with sodium chloride, and extracted with ether. The combined organic extracts are partitioned with sodium bicarbonate. The aqueous basic extract is acidified with dilute HCl, saturated with sodium chloride, and extracted with ethyl acetate. The extract is washed with brine, dried over manesium sulfate, and concentrated to give the crude title compound as an orange oil.

EXAMPLE 62

Preparation of all-cis-2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanone

To a stirred solution of ca 1.6 moles of crude all-cis-2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanol (Example 61) in 1.6 ml. of ether is added 1.6 mol. of 4.0 N chromic acid in 4 N sulfuric acid at 0.degree. C. during 9 minutes. After stirring for 5 minutes at 0.degree. C. the solution is diluted with brine, ether, and ethyl acetate. The organic phase is treated with isopropanol, washed with brine and dried over magnesium sulfate. Evaporation of the solvent gives the subject compound as an oil.

EXAMPLE 63

Preparation of 2-(6-carboxy-2-cis-hexenyl)-4-hydroxycyclopent-2-en-1-one

A solution of 1.0 mmole of all-cis-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanone (Example 62) and 3.0 mmoles of sodium carbonate in 15 ml. of water is allowed to stand at room temperature for 3 hours. The solution is acidified with HCL, saturated with sodium chloride, and extracted with ether. The extract is washed with brine, dried over magnesium sulfate and concentrated to give a mixture of the title compound and the isomeric compound, 2-(6-carboxy-2-cis-hexenyl)-3-hydroxycyclopent-4-en-1-one. Further treatment of this mixture with 0.1 N sodium hydroxide at room temperature for 30 minutes causes the rearrangement of the latter isomer to the title compound, which is isolated from the basic solution as above.

EXAMPLE 64

Preparation of 2-(6-carboxy-2-cis-hexenyl)-4-hydroxycyclopent-2-en-1-one

Treatment of cis-anti-cis-5-hydroxy-2,3-oxidocyclopentylacetaldehyde-.gamma.-lactol (E. J. Corey and R. Noyori Tetrahedron Letters, 1970, 311), prepared from the corresponding lactone and diisobutylaluminum hydride as disclosed for the preparation of the corresponding cis-syn-cis lactol, with 4-carboxybutyltriphenylphosphonium bromide as described in Example 61 is productive of 2.beta.-(6-carboxy-2-cis-hexenyl)-3.alpha.,4.alpha.-oxidocyclopentan-1.beta.-ol, which on oxidation by the method of Example 62 provides 2.beta.-(6-carboxy-2-cis-hexenyl)-3.alpha.,4.alpha.-oxidocyclopentanone, which in turn on treatment with aqueous base by the procedure of Example 63 furnishes the subject compound.

EXAMPLE 65

Preparation of 2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanol

A solution of 5.0 g. (35 mmoles) of 5-hydroxy-2,3-oxidocyclopentylacetaldehyde-.gamma.-lactol (isomeric mixture; E. J. Corey and R. Noyroi, Tetrahedron Letters, 1970, 311) in 25 ml. of DMSO is added during 0.5 minute at 20.degree. C. to a stirred solution of the Wittig reagent [E. J. Corey et al. JACS, 91, 5675 (1969); also Example 61] and dimsyl sodium prepared from 23.5 g. (53 mmoles) of 4-carboxybutyltriphenylphosphonium bromide, 6.1 g. (140 mmoles) of 57% sodium hydride dispersion, and 230 ml. of DMSO (dimethylsulfoxide).

The solution is stirred at ambient temperatures for 2 hours and poured into a stirred mixture of methylene chloride, ice, and hydrochloric acid. The reaction mixture is worked up as described in Example 61, and the crude product is purified by dry column chromatography on silica gel to provide the title compound (mixture of two stereoisomers) as an oil, I (film) 3450, 1710, and 832 cm.sup.-1.

EXAMPLE 66

Preparation of b 2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanone

A stirred solution of 2.98 g. (13.2 mmoles) of 2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanol (Example 65) in 66 ml. of acetone is treated dropwise with 3.30 ml. of 8 N chromic acid in 8 N M.sub.2 SO.sub.4 during 20 minutes at -10.degree. to 5.degree. C. The solution is stirred at -5.degree. C. for 10 minutes and treated successively with a few drops of isopropanol and 12 ml. of water. The mixture is filtered, and the filtrate is concentrated, saturated with sodium chloride, and extracted with ethyl acetate. The extract is washed with brine, dried over MgSO.sub.4, and evaporated to give an oil, IR (film) 1740, 1710, and 840 cm.sup.-1.

EXAMPLE 67

Preparation of 2-(6-carboxy-2-cis-hexenyl)-4-hydroxycyclopent-2-en-1-one

A solution (pH: 10.2-10.5) of 2.42 g. (10.8 mmoles) of 2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanone (Example 66), 4.58 g. (43.2 mmoles) of sodium carbonate, and 216 ml. of water is allowed to stand at room temperature under nitrogen for 24 hours. The solution is acidified at 15.degree. C. with hydrochloric acid and extracted with ethyl acetate. The extract is washed with brine, dried over MgSO.sub.4, and evaporated to give an oil; IR (film) 1700 (carbonyl groups) and 1630 cm.sup.-1 (conjugated olefin); NMR 7.11 (1), 5.54 (2), and 495 (1).

EXAMPLE 68

Preparation of 4-carboxybutyltriphenylphosphonium bromide

A mixture of 103 g. of 5-bromovaleric acid and 152 g. of triphenylphosphine in 400 ml. of acetonitrile is refluxed for 48 hours, cooled, diluted with 100 ml. of benzene and allowed to crystallize. The crystals are filtered, washed with benzene and ether, to yield colorless material, m.p. 207.degree.-209.degree. C.

EXAMPLE 69-75

Treatment of the indicated .omega.-bromoalkanoic acids of Table 5 below with triphenylphosphine by the method described in Example 68 produces the phosphonium bromides of the table.

TABLE 5______________________________________Ex- Starting .omega.-bromo- Productample alkanone acid Phosphonium bromide______________________________________69 4-bromo-n-butyric 3-carboxypropyltri- acid phenylphosphonium bromide70 6-bromo-n-hexa- 5-carboxypentyltri- noic acid phenylphosphonium bromide71 7-bromo-n-hepta- 6-carboxyhexyltri- noic acid phenylphosphonium bromide72 5-bromo-4-methyl- (2-methyl-4-carboxy- n-pentanoic acid butyl)triphenylphos- phonium bromide73 5-bromo-4(R)- (2[R]-methyl-4-car- methyl-n-penta- boxybutyl)triphenyl- noic acid.sup.1 phosphonium bromide74 5-bromo-4-ethyl- (2-ethyl-4-carboxy- n-pentanoic butyl)triphenylphos- acid phonium bromide75 5-bromo-4-propyl- (2-propyl-4-carboxy- n-pentanoic acid butyl)triphenylphos- phonium bromide______________________________________ .sup.1 J.S. Dalby, G.W. Kenner and R.C. Sheppard, J. Chem. Soc., 4387 (1962).

EXAMPLES 76-82

Treatment of 5-hydroxy-2,3-oxidocyclopentylacetaldehyde-.gamma.-lactol (isomeric mixture) with the Wittig reagent prepared from the indicated phosphonium bromides of Table 6 below, all by the procedures of Examples 61 and 65 is productive of the product compounds of the table.

TABLE 6______________________________________ Reagent phos- ProductEx- phonium bromide 3,4-oxidocyclopentanolample of Example (isomeric mixture)______________________________________76 69 2-(5-carboxy-2-cis- pentenyl)-3,4-oxido- cyclopentan-1-ol77 70 2-(7-carboxy-2-cis- heptenyl)-3,4-oxido- cyclopentan-1-ol78 71 2-(8-carboxy-2-cis- octenyl)-3,4-oxido- cyclopentan-1-ol79 72 2-(6-carboxy-4-methyl- 2-cis-hexenyl)-3,4- oxidocyclopentan-1-ol80 73 2-(6-carboxy-4(R)- methyl-2-cis-hexenyl)- 3,4-oxidocyclopentan- 1-ol81 74 2-(6-carboxy-4-ethyl- 2-cis-hexenyl)-3,4- oxidocyclopentan-1-ol82 75 2-(6-carboxy-4-propyl- 2-cis-hexenyl)-3,4- oxidocyclopentan-1-ol______________________________________

EXAMPLES 83-89

Oxidation of the cyclopentanols indicated in Table 7 below by the method described in Example 66 furnishes the corresponding product 3,4-oxidocyclopentanones of the table.

TABLE 7______________________________________Ex- Starting cyclo- Productample pentan-1-ol of 3,4-oxidocyclopent-Example an-1-one______________________________________83 76 2-(5-carboxy-2-cis- pentenyl)-3,4-oxido- cyclopentan-1-ol84 77 2-(7-carboxy-2-cis- heptenyl)-3,4-oxido- cyclopentan-1-one85 78 2-(8-carboxy-2-cis- octenyl)-3,4-oxido- cyclopentan-1-one86 79 2-(6-carboxy-4-methyl- 2-cis-hexenyl)-3,4- oxidocyclopentan-1-one87 80 2-(6-carboxy-4(R)- methyl-2-cis-hexenyl)- 3,4-oxidocyclopentan- 1-one88 81 2-(6-carboxy-4-ethyl-2- cis-hexenyl)-3,4-oxido- cyclopentan-1-one89 82 2-(6-carboxy-4-propyl- 2-cis-hexenyl)-3,4- oxidocyclopentan-1-one______________________________________

EXAMPLES 90-96

Alkaline treatment of the 3,4-oxidocyclopentanones of Table 8 below by the process described in Example 67 is productive of the 4-hydroxycyclopentenones of the table.

TABLE 8______________________________________ Starting 3,4- Product oxidocyclo- 4-hydroxycyclopent-ample pentanone of 2-en-1-one______________________________________90 83 2-(5-carboxy-2-cis- pentenyl)-4-hydroxy- cyclopent-2-en-1-one91 84 2-(7-carboxy-2-cis- heptenyl)-4-hydroxy- cyclopent-2-en-1-one92 85 2-(8-carboxy-2-cis- octenyl)-4-hydroxy- cyclopent-2-en-1-one93 86 2-(6-carboxy-4-methyl- 2-cis-hexenyl)-4-hy- droxycyclopent-2-en-1- one94 87 2-(6-carboxy-4(R)-methyl- 2-cis-hexenyl)-4-hydroxy- cyclopent-2-en-1-one95 88 2-(6-carboxy-4-ethyl-2- cis-hexenyl)-4-hydroxy- cyclopent-2-en-1-one96 89 2-(6-carboxy-4-propyl-2- cis-hexenyl)-4-hydroxy- cyclopent-2-en-1-one______________________________________

EXAMPLE 97

Preparation of 4-tetrahydropyranyloxy-2-(6-carbotetrahydropyranyloxy-2-cis-hexenyl)cyclopent-2-en-1-one

A vigorously stirred, ice-cold solution of 9.45 g. (42.5 mmoles) of 2-(6-carboxy-cis-2-hexenyl)-4-hydroxycyclopent-2-en-1-one (Example 67) and 14.3 g (170 mmoles of dihydropyran in 212 ml. of methylene chloride is treated with 81 mg. (0.425 mmoles) of p-toluenesulfonic acid monohydrate. After stirring for 5 minutes at 0.degree. C. and 60 minutes at 25.degree. C. the solution is poured into a stirred mixture of 40 ml. of saturated brine, 40 ml. of saturated sodium bicarbonate and 80 ml. of water. The organic phase is washed with brine, dried over magnesium sulfate, and concentrated to give an oil, .nu.max (film) 1730 (ester carbonyl), 1710 (ketone carbonyl), and 1030 cm.sup.-1 (tetrahydropyranyloxy groups).

EXAMPLE 97a

Preparation of 4(R)-tetrahydropyranyloxy-2-(6-carbomethoxy-2-cis-hexenyl)cyclopent-2-en-1-one

This compound is prepared as described in the literature; J. B. Heather et al., Tetrahedron Letters, 2313 (1973).

EXAMPLES 98-104

Treatment of the 4-hydroxycyclopent-2-en-1-ones listed in Table 9 below with dihydropyran in the manner of Example 97 is productive of the corresponding bis-tetrahydropyranyl ether-esters of the table.

TABLE 9______________________________________ Starting 4-hy- droxycyclopent- ProductEx- 2-en-1-one of bis-tetrahydropyranylample Example ether-ester______________________________________98 90 4-tetrahydropyranyloxy- 2-(5-carbotetrahydro- pyranyloxy-2-cis-pent- enyl)cyclopent-2-en-1- one99 91 4-tetrahydropyranyloxy- 2-(7-carbotetrahydro- pyranyloxy-2-cis-hep- tenyl)-cyclopent-2-en- 1-one100 92 4-tetrahydropyranyloxy- 2-(8-carbotetrahydro- pyranyloxy-2-cis-oct- enyl)-cyclopent-2-en-1- one101 93 4-tetrahydropyranyloxy- 2-(6-carbotetrahydro- pyranyloxy-4-methyl-2- cis-hexenyl)-cyclopent- 2-en-1-one102 94 4-tetrahydropyranyloxy- 2-(6-carbotetrahydro- pyranyloxy-4(R)- methyl)-2-cis-hexenyl- cyclopent-2-en-1-one103 95 4-tetrahydropyranyloxy- 2-(6-carbotetrahydro- pyranyloxy-4-ethyl- 2-cis-hexenyl)- cyclopent-2-en-1-one104 96 4-tetrahydropyranyloxy- 2-(6-carbotetrahydro- pyranyloxy-4-propyl-2- cis-hexenyl)cyclopent- 2-en-1-one______________________________________

EXAMPLE 105

Preparation of 4-(trimethylsiloxy)-2-(6-carbotrimethylsiloxy-2-cis-hexenyl)cyclopent-2-en-1-one

To a solution of 5 g. of 2-(6-carboxy-2-cis-hexenyl)-4-hydroxy-cyclopent-2-en-1-one (Example 67) in 10 ml. of dry N,N-dimethylformamide is added 5.4 g. of trimethylsilyl chloride in a nitrogen atmosphere. To the resulting solution cooled in a tap water bath is added 5.05 g. of triethylamine in 10 ml. of N,N-dimethylformamide, dropwise. The resulting mixture is stirred at 60.degree. C. in an oil-bath for 2 hours, then at ambient temperatures for 18 hours. Triethylamine hydrochloride is removed by filtration and the filtrate is taken to dryness. The residual oil is further purified by distillation at high vacuum.

EXAMPLES 106-113

Treatment of the 4-hydroxycyclopent-2-en-1-ones listed in Table 10 below with the indicated trialkylsilyl chloride by the method described in Example 105 is productive of the bis-trialkylsilyl ether-esters of the table.

TABLE 10__________________________________________________________________________ Starting 4-hydroxy-Ex- cyclopentenone of Trialkylsilyl- Productample Example chloride bis-trialkylsilyl ether-ester__________________________________________________________________________106 90 (CH.sub.3).sub.3 SiCl 4-trimethylsiloxy-2-(5-carbotrimethylsiloxy- 2-cis-pentyl)cyclopent-2-en-1-one107 91 (CH.sub.3).sub.3 SiCl 4-trimethylsiloxy-2-(7-carbotrimethylsiloxy- 2-cis-heptenyl)cyclopent-2-en-1-one108 92 (CH.sub.3).sub.3 SiCl 4-trimethylsiloxy-2-(8-carbotrimethylsiloxy- 2-cis-octenyl)cyclopent-2-en-1-one109 67 dimethyliso- 4-dimethylisopropylsiloxy-2-(6-carbodimethyl- propyl silyl isopropylsiloxy-2-cis-hexenyl)cyclopent-2-en-1- chloride one110 93 (CH.sub.3).sub.3 SiCl 4-trimethylsilyloxy-2-(6-carbotrimethylsilyloxy- 4-methyl-2-cis-hexenyl)cyclopent-2-en-1-one111 94 (CH.sub.3).sub.3 SiCl 4-trimethylsilyloxy-2-(6-carbotrimethylsilyloxy- 4(R)-methyl-2-cis-hexenyl)cyclopent-2-en-1-one112 95 (CH.sub.3 SiCl 4-trimethylsilyloxy-2-(6-carbotrimethylsilyloxy- 4-ethyl-2-cis-hexenyl)cyclopent-2-en-1-one113 96 (CH.sub.3).sub.3 SiCl 4-trimethylsilyloxy-2-(6-carbotrimethylsilyloxy- 4-propyl-2-cis-hexenyl)cyclopent-2-en-1-one__________________________________________________________________________ .sup.a E.J. Corey, R.K. Varma, J. Amer. Chem. Soc., 93, 7320 (1970).

EXAMPLE 113A

Preparation of 4-(t-butyldimethylsiloxy)-2-(6-carbo-t-butyldimethylsiloxyhexyl)cyclopent-2-en-1-one

To a stirred solution of 2-(6-carboxyhexyl)-4-hydroxycyclopent-2-en-1-one and 7.9 g. of imidazole in 12.5 ml. of dry dimethylformamide is added 10.2 g. of t-butyldimethylsilyl chloride in 12.5 ml. of dimethylformamaide at 0.degree. C. The solution is then stirred for 4 hours at 37.degree. C. The solution is poured into 350 ml. of ice cold water and extracted twice with hexane. The combined extracts are washed with 5% sodium carbonate solution; saturated sodium chloride solution, dried with anhydrous magnesium sulfate and evaporated under reduced pressure. The residue is twice evaporated with toluene to give 9.52 g. (95%) of product as an oil.

EXAMPLE 114

Preparation of cyclopentylacetyl chloride

To a solution of 50 g. of cyclopentaneacetic acid containing 2.9 ml of N,N-dimethylformamide is added dropwise with stirring, 51 g. of thionyl chloride over a period of 15 minutes. After stirring for an additional 60 minutes excess thionyl chloride is removed in vacuo and the residual oil is distilled to give 55.4 g. (97%) of product, b.p. 57.degree.-58.degree. C. (10 mm.).

EXAMPLE 115

Preparation of 1-chloro-4-cyclopentyl-1-trans-buten-3-one

A three-necked flask fitted with a stirrer, a gas inlet tube and a gas outlet tube protected with a calcium chloride tube is surrounded by an ice-water bath. The system is flushed with acetylene for 3 minutes. Carbon tetrachloride (150 ml.) is added to the flask and acetylene is bubbled through at a fast rate for 3 minutes. Aluminum chloride (59 g.) is added and acetylene is bubbled through the mixture for 5 minutes. The gas inlet tube is replaced by a dropping funnel protected by a calcium chloride drying tube. Cyclopentylacetyl chloride (55.4 g., Example 114) is added to the reaction mixture stirring over a period of about 20 minutes. The dropping funnel is replaced by the gas inlet tube and with stirring, acetylene gas is bubbled through at a rate in excess of the saturation rate. After about 15 minutes the rate of absorption of acetylene suddenly becomes very rapid, and the acetylene is passed through as rapidly as it is absorbed. The introduction of acetylene is continued for 45 minutes after the rapid absorption (which lasts about 1 hour) has subsided.

The reaction mixture is poured with stirring onto 430 g. of ice and 180 ml. of saturated sodium chloride solution. The aqueous phase is extracted three times with ether. The combined extracts are dried with anhydrous magnesium sulfate and evaporated to dryness in vacuo. After addition of 1.5 g. of hydroquinone the residual oil is distilled to give 57.degree. g. (80%) of oil, b.p. 67.degree.-69.degree. C. (0.14 mm. )

EXAMPLE 116

Preparation of 4-cyclopentyl-1-iodo-1-trans-buten-3-one

A solution of 57 g. of 1-chloro-4-cyclopentyl-trans-buten-3-one (Example 115) in 360 ml. of acetone containing 55 g. of sodium iodide is stirred at the reflux temperature for 18 hours. The resulting mixture is cooled, filtered and and the water liquor is taken to dryness. The residual oil is dissolved in ether washed successively with water, dilute sodium thiosulfate solution, and saturated sodium chloride solution, dried with anhydrous magesium sulfate and taken to dryness to give 87 g. (99%) of orange oil. Vapor phase chromatography shows one peak.

EXAMPLE 117

Preparation of 4-cyclopentyl-1-iodo-1-trans-buten-3-ol

To a solution of 7.1 g. of sodium borohydride in 60 ml of absolute alcohol, stirred in an ice bath under nitrogen atmosphere, is added dropwise, over a period of about 2 hours, a solution containing 7 g. of 4-cyclopentyl-1-iodo-1-trans-buten-3-one (Example 116) in 160 ml. of absolute alcohol. The temperature is maintained at 5.degree.-10.degree. C. The solution is poured into 850 ml. of iced water and the resulting mixture is extracted three times with ether. The combined extracts are washed with dilute sodium bisulfite solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 81 g. of yellow oil. Column chromatography on a column of 1 kg. of silica gel using benzene gives 75 g. (88%) of oily product.

EXAMPLES 118-141

Treatment of the listed carboxylic acids in Table 11 below with thionyl chloride by the procedure disclosed in Example 114 followed by treatment of the resulting acid chloride with acetylene by the procedure described in Example 115, and thence by treatment of the resulting 1-chloro-1-trans-alkene-3-one with sodium iodide by the procedure described in Example 116, and then by treatment of the resulting 1-iodo-1-trans-alkene-3-one with sodium borohydride by the procedure described in Example 117 is productive of the product 3-hydroxy-1-iodo-1-trans-alkenes of the table.

Table 11______________________________________ Product 3-hydroxy-Ex- Starting 1-iodo-1-ample Carboxylic acid trans-alkene______________________________________118 Cyclobutylacetic 4-Cyclobutyl-3-hydroxy- acid.sup.1 1-iodo-1-trans-butene119 3-Cyclopentyl- 5-Cyclopentyl-3-hydroxy- propionic acid 1-iodo-1-trans-pentene120 4-Cyclopentyl- 6-Cyclopentyl-3-hydroxy- butyric acid.sup.2 1-iodo-1-trans-hexene121 5-Cyclopentyl- 7-Cyclopentyl-3-hydroxy- pentanoic acid.sup.2 1-iodo-1-trans-heptene122 6-Cyclopentyl- 8-Cyclopentyl-3-hydroxy- hexanoic acid.sup.2 1-iodo-1-trans-octene123 2-Methyl-3-cyclo- 5-Cyclopentyl-4-methyl- pentylpropanoic 3-hydroxy-1-iodo-1- acid.sup.3 trans-pentene124 2-Ethyl-4-cyclo- 6-cyclopentyl-4-ethyl- pentylbutyric 3-hydroxy-1-iodo-1- acid.sup.4 trans-hexene125 (2-trans-methyl- 4-(2-trans-methyl- cyclopentyl)- cyclopentyl)-3-hydroxy- acetic acid.sup.5 1-iodo-1-trans-butene126 4-(2-trans- 6-(2-trans-methylcyclo- methylcyclo- pentyl)-3-hydroxy-1- pentyl)butyric iodo-1-trans-hexene acid.sup.5127 Cyclohexylacetic 4-Cyclohexyl-3-hydroxy- acid 1-iodo-1-trans-1-trans- butene128 3-Cyclohexyl- 5-cyclohexyl-3-hydroxy- propionic acid 1-iodo-1-trans-pentene129 4-Cyclohexyl- 6-cyclohexyl-3-hydroxy- butyric acid.sup.6 1-iodo-1-trans-hexene130 Cycloheptyl- 4-Cycloheptyl-3-hydroxy- acetic acid.sup.7 1-iodo-1-trans-butene131 (4-methylcyclo- 4-(4-methylcycloheptyl)- heptyl)acetic 3-hydroxy-1-iodo-1- acid.sup.8 trans-butene132 Cyclooctylacetic 4-Cyclooctyl-3-hydroxy- acid.sup.8,9 1-iodo-1-trans-butene133 (4-methylcyclo- 4-(4-methylcyclohexyl)- hexyl)acetic 3-hydroxy-1-iodo-1- acid.sup.10 trans-butene134 (3-methylcyclo- 4-(3-methylcyclohexyl)- hexyl)acetic 3-hydroxy-1-iodo-1- acid.sup.11 trans-butene135 3-Cycloheptane 3-Cycloheptyl-3-hydroxy- carboxylic acid 1-iodo-1-trans-propene136 Cyclopentane- 3-Cyclopentyl-3-hydroxy- carboxylic acid 1-iodo-1-trans- propene137 Trans-2-methyl- 3-(Trans-2-methylcyclo- cyclopentane pentyl-3-hydroxy-1- carboxylic acid.sup.12 iodo-1-trans-propene138 all-trans-2,3- 3-(all-trans-2,3-di- dimethylcyclo- methylcyclopentyl)-1- pentane car- iodo-1-trans-propene boxylic acid.sup.13139 Cyclohexane car- 3-Cyclohexyl-3-hydroxy- boxylic acid 1-iodo-1-trans-propene140 Trans-4-methyl- 3-(trans-4-methylcyclo- cyclohexane hexyl)-3-hydroxy-1-iodo- carboxylic acid 1-trans-propene141 Cyclooctane, car- 3-Cyclooctyl-3-hydroxy- boxylic acid.sup.14 1-iodo-1-trans-propene______________________________________ 1 C. G. Overberger et al., J. Polymer Sci., Pt. A, 2, 755(196 2 m. i. goryaev et al., Chem. Abs., 69, 1742, No. 186462 (1968). 3 C. D. Nenitzescu and G. G. Vantu, Bull. Soc. Chim. 4 France [5]. 2, 2209 (1935). 4 G. R. Yohe and R. Adams, J. Amer. Chem. Soc., 50, 1503 (1928). 5 W. Herz, J. Org. Chem., 20, 1062 (1955). 6 G. S. Hiers and R. Adams, J. Amer. Chem. Soc., 48, 2385 (1926). 7 E. E. Royals and A. N. Neal, J. Org. Chem., 21, 1449 (1956). 8 F. F. Blicke and W. K. Johnson, J. Am. Pharm. Assoc. Sci. Ed., 45, 443 (1956). 9 L. Ruzicka and H. A. Bookenoogen, Helv. Chim. Acta, 14, 1319 (1931). 10 A. W. Burgstahler and I. C. Nordin, J. Amer. Chem. Soc., 83, 198 (1961). 11 J. von Braun and W. Teuffert, Ber., 58B, 2210 (1925). 12 m. julia and F. LeGoffie, Bull. Soc. Chim. Fr., 1550 (1965). 13 V. N. Ipatieff et al., J. Amer. Chem. Soc., 75, 6222 (1953). 14 A. T. Blomquist and F. W. Sehlaefe, J. Amer. Chem. Soc., 83 4547 (1961).

EXAMPLE 142

Preparation of 4-cyclopentyl-1-iodo-3-triphenylmethoxy-1-trans-butene

A mixture of 21.4 g. of 4-cyclopentyl-1-iodo-trans-buten-3-ol (Example 117) in 170 ml. of dry pyridine containing 31 g. of triphenylmethyl bromide is heated on the steam bath for 2 hours. The dark mixture is poured into 850 ml. of iced water and the resulting solution is extracted three times with ether. The combined extracts are washed with ice cold 2% hydrochloric acid until the washings are acidic, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Trituration of the residue followed by filtration removes triphenylcarbinol. The mother liquor is taken to dryness and the residual syrup is chromatographed on 400 g. of florisil using hexane gives 32 g. (78%) of syrup which solidifies on standing. Recrystallization from hexane affords white crystals, m.p. 87.degree.-88.degree. C.

EXAMPLE 143

Preparation of 4-cyclopentyl-1-iodo-3-(p-methoxyphenyldiphenyl)methoxy-1-trans-butene

A solution of 20 g. of 4-cyclopentyl-1-iodo-1-trans-buten-3-ol (Example 117) and 25 g. of p-anisylchlorodiphenylmethane in 170 ml. of dry pyridine is kept at 60.degree. C. for 18 hours, then at 70.degree. C. for 3 hours. The cooled solution is poured into 850 ml. of iced water. The resulting solution is partitioned between ether and water. The ether layer is washed with water, dried with anhydrous magnesium sulfate and taken to dryness. Further evaporation with toluene removes residual pyridine. The resulting oil is chromatographed on 300 g. of florisil with hexanes to give 22.3 g. of product. The material is homogeneous according to thin layer chromatography.

EXAMPLES 144-167

Treatment of the listed 3-hydroxy-1-iodo-trans-1-alkenes of Table 12 below with triphenylmethylbromide by the procedure described in Example 142 above is productive of the product 3-triphenylmethoxy-1-iodo-trans-1-alkenes of the table.

Table 12______________________________________ Starting 3-hydroxy- 1-iodo-1- ProductEx- trans-alkene 3-triphenylmethoxy-ample of Example 1-iodo-trans-1-alkene______________________________________144 118 4-Cyclobutyl-3-tri- phenylmethoxy-1-iodo- 1-trans-butene145 119 5-Cyclopentyl-3-tri- phenylmethoxy-1-iodo- 1-trans-pentene146 120 6-Cyclopentyl-3-tri- phenylmethoxy-1-iodo- 1-trans-hexene147 121 7-Cyclopentyl-3-tri- phenylmethoxy-1-iodo- 1-trans-heptene148 122 8-Cyclopentyl-3-tri- phenylmethoxy-1-iodo- 1-trans-octene149 123 5-Cyclopentyl-4-meth- yl-3-triphenylmethoxy- 1-iodo-1-trans-pentene150 124 6-Cyclopentyl-4-ethyl- 3-triphenylmethoxy-1- iodo-1-trans-hexene151 125 4-(2-trans-methylcyclo- pentyl)-3-triphenyl- methoxy-1-iodo-1-trans- butene152 126 6-(2-trans-methylcyclo- pentyl)-3-triphenyl- methoxy-1-iodo-1-trans- hexene153 127 4-Cyclohexyl-3-tri- phenylmethoxy-1-iodo- 1-trans-butene154 128 5-Cyclohexyl-3-tri- phenylmethoxy-1-iodo- 1-trans-pentene155 129 6-Cyclohexyl-3-tri- phenylmethoxy-1-iodo- 1-trans-hexene156 130 4-Cycloheptyl-3-tri- phenylmethoxy-1-iodo- 1-trans-butene157 131 4-(4-methylcycloheptyl)- 3-triphenylmethoxy-1- iodo-1-trans-butene158 132 4-Cyclooctyl-3-triphen- ylmethoxy-1-iodo-1- trans-butene159 133 4-(4-methylcyclohexyl)- 3-triphenylmethoxy-1- iodo-1-trans-butene160 134 4-(3-methylcyclohexyl)- 3-triphenylmethoxy- 1-iodo-1-trans-butene161 135 3-Cycloheptyl-3-tri- phenylmethoxy-1-iodo- 1-trans-propene162 136 3-Cyclopentyl-3-tri- phenylmethoxy-1-iodo- 1-trans-propene163 137 3-(trans-2-methylcyclo- pentyl)-3-triphenyl- methoxy-1-iodo-1-trans- propene164 138 3-(all-trans-2,3-di- methylcyclopentyl)-3- triphenylmethoxy-1- iodo-1-trans-propene165 139 3-Cyclohexyl-3-triphen- ylmethoxy-1-iodo-1- trans-propene166 140 3-(trans-4-methylcyclo- hexyl)-3-triphenyl- methoxy-1-iodo-1-trans- propene167 141 3-Cyclooctyl-3-tri- phenylmethoxy-1-iodo-1- trans-propene______________________________________

EXAMPLE 168

Preparation of 1,1-dimethyl-cis-3,4-methylenehexane(cis-1-ethyl-2(2,2-dimethoxyethyl)cyclopropane

To an ethereal suspension of zinc-silver couple, prepared according to the procedure of J. M. Denis, G. Girard, and J. M. Conia (Synthesis, 1972, 549) from 0.400 g. of silver acetate, 400 ml. of acetic acid, 68 g. of granular zinc, silver wool, and 600 ml. of ether is added dropwise 136 g. of diiodomethane at a rate to maintain a gentle reflux. The mixture is then stirred at room temperature for 1 hour and to it is then added 57.7 g. of 1,1-dimethoxy-cis-3-hexene. [(M. Winter, Helvetica Chimica Acta, 46, 1792 (1963)] over a period of 20 minutes and the mixture is refluxed for 5 hours. The mixture is cooled to 0.degree. C., 600 ml. of ether is added followed by 50.5 g. of pyridine dropwise over a period of 1 hour. The resulting precipiate is filtered and washed with ether. The filtrate and washings are combined and evaporated and the residue is fractionally distilled at 12 torr to yield the title compound as a colorless oil.

EXAMPLE 169

Preparation of cis-3,4-methylene-1-hexanol

To a vigorously stirred solution of 31.6 g. of 1,1-dimethoxy-cis-3,4-methylene-hexane (Example 168), 75 mg. of hydroquinone, 6 g. of oxalic acid in 150 ml. of acetone heated at 45.degree. C. under an inert atmosphere is added 700 ml. of water over a period of 0.5 hours. The mixture is cooled and extracted well with ether. The organic phase is separated, washed with saturated sodium bicarbonate solution and saturated brine, dried (Na.sub.2 SO.sub.4) and evaporated. The residue is distilled at 30 torr. to yield the title compound.

EXAMPLE 170

Preparation of cis-5,6-methylene-1-octyn-3-ol

To a solution of 15.2 g. (0.165 mole) of lithium acetylide-ethylenediamine complex in 100 ml. of dry dimethylsulfoxide is added 16.8 g. (0.150 mole) of cis-3,4-methylene-1-hexanol (Example 169) in 25 ml. of dimethylsulfoxide at a rate to maintain a temperature of 25.degree. C. (cooling). The mixture is then maintained at 25.degree. C. for 2 hours and is poured onto ice and excess hydrochloric acid. The mixture is extracte with ether and the organic phase is washed with water and saturated brine, dried (Na.sub.2 SO.sub.4), and evaporated to an oil. Distillation in vacuo yields the title compound as a colorless oil.

EXAMPLE 171

Preparation of 3-triphenylmethoxy-cis-5,6-methylene-1-octyne

A mixture of 13.8 g. of cis-5,6-methylene-1-octyn-3-ol (Example 170) and 33.0 g. of triphenylmethyl bromide in 100 ml. of pyridine is heated to 100.degree. C. for 1.5 hours under an inert atmosphere. The mixture is cooled and filtered. The filtrate is partitioned between ice water and ether. The organic phase is washed with cold dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine, dried (NaSO.sub.4), and evaporated to an oil. The latter is dissolved in hexane and passed through 400 g. of Florisil.RTM. to yield after evaporation the title compound as a colorless oil.

EXAMPLE 172

Preparation of 1-iodo-3-triphenylmethoxy-cis-5,6-methylene-trans-1-octene

To 160 ml. of a 0.50 M solution of disiamylborane in diglyme cooled to 0.degree. C. under an inert atmosphere is added 28.6 g. (0.075 mole) 3-triphenylmethoxy-cis-5,6-methylene-1-octyne (Example 171). The mixture is allowed to come to room temperature and is stirred at ambient temperature for 3 hours. The solution is cooled to 0.degree. C. and 16.9 g. (0.225 mole) of triethylamine oxide is added portionwise such that the temperature is maintained at 0.degree.-5.degree. C. The mixture is stirred at 0.degree. C. for 1 hour and is then poured into 300 ml. of 1 N sodium hydroxide followed immediately by a solution of 57 g. (0.225 mole) of iodine in 150 ml. of tetrahydrofuran. The mixture is stirred at ambient temperatures for 0.5 hour and poured into 1000 ml. of water. The mixture is decolorized by addition of sodium thiosulfate solution and is extracted into ether. The organic phase is washed with water and the solvent is removed in vacuo. The residue is purified by dry-column chromatography upon 1.5 kg. of alumina using hexane as eluent. The title compound is obtained as an oil.

EXAMPLES 173-179

Treatment of the carboxaldehydes listed in Table 13 below with lithium acetylide by the procedure described in Example 170 followed by treatment of the resulting 3-hydroxy-1-alkyne with triphenylmethyl bromide by the procedure of Example 171 furnishes the product 3-triphenylmethoxy-1-alkynes of the table.

Table 13______________________________________Ex- Starting carbox- Product 3-triphenyl-ample aldehyde methoxy-1-alkynes______________________________________173 (2-cyclopenten- 4-(2-cyclopentenyl)-3- yl)acetaldehyde.sup.1 triphenylmethoxy-1- butyne174 (2-cyclohexenyl) 4-(2-cyclohexenyl-3- acetaldehyde.sup.1 triphenylmethoxy-1- butyne175 (3-cyclohexenyl)- 4-(3-cyclohexenyl)-3- acetaldehyde.sup.1 triphenylmethoxy-1- butyne176 1-methyl-1-form- 1-methyl-1-(3-tri- ylmethylcyclo- phenylmethoxy-1-butyn- hexane yl-4)cyclohexane177 2-cyclohexene 3-(2-cyclohexenyl)-3- carboxaldehyde triphenylmethoxy-1- propyne178 3-cyclohexene 3-(3-cyclohexenyl)-3- carboxaldehyde triphenylmethoxy-1- propyne179 3-cyclohexyl-2- 5-cyclohexyl-4-methyl- methylpropion- 3-triphenylmethoxy-1- aldehyde pentyne______________________________________

References (Table 13)

1 C. W. Whitehead et al., J. Org. Chem., 26, 2814 (1961). 2 A. I. Meyers et al., ibid., 38, 2136 (1973).

EXAMPLES 180-186

Treatment of the 3-triphenylmethoxy-1-alkynes listed in Table 14 below with disiamylborane, trimethylamine oxide; iodine and aqueous sodium hydroxide by the procedure described in Example 172 furnishes the product 3-triphenylmethoxy-1-iodo-1-trans-alkenes of the table.

Table 14______________________________________ Starting 3-tri- phenylmethoxy- Product 3-triphenyl-Ex- 1-alkynes of methoxy-1-iodo-1-trans-ample Example alkene______________________________________180 173 4-(2-cyclopentenyl)-3- triphenylmethoxy-1- iodo-1-trans-butene181 174 4-(2-cyclohexenyl)-3- triphenylmethoxy-1-iodo- 1-trans-butene182 175 4-(3-cyclohexenyl)-3- triphenylmethoxy-1- iodo-1-trans-butene183 176 1-methyl-1-(3-triphen- ylmethoxy-1-iodo-trans- 1-butenyl-4)cyclo- hexene184 177 3-(2-cyclohexenyl)-3- triphenylmethoxy-1- iodo-1-trans-propene185 178 3-(3-cyclohexenyl)-3- triphenylmethoxy-1- iodo-1-trans-propene186 179 5-cyclohexyl-4-methyl- 3-triphenylmethoxy- 1-iodo-1-trans-pentene______________________________________

EXAMPLE 187

Preparation of 9-oxo-11.alpha.,15-dihydroxy-17,20-methano-13-trans-prostenoic acid and 9-oxo-11.alpha.,15-epi-dihydroxy-17,20-methano-13-trans-prostenoic acid

To a solution of 13.7 g. of 4-cyclopentyl-1-iodo-3-triphenylmethoxy-trans-1-butene (Example 142) in 35 ml. of dry toluene, cooled to -75.degree. C., under nitrogen atmosphere is added dropwise in 5 minutes, 11.3 ml. of 2.34 molar solution of n-butyllithium in hexane. The solution is allowed to warm to -40.degree. C. and maintained at that temperature for one hour. This solution containing (3-triphenylmethoxy-4-cyclopentyl-trans-1-butenyl)lithium is cooled to -75.degree. C. and to it is added 18.1 ml. of a 1.45 molar solution of trimethylaluminum in hexane. The solution is then allowed to warm to -20.degree. C. during 45 minutes. This solution containing lithio 3-triphenylmethoxy-4-cyclopentyl-1-trans-butenyl)trimethyl alanate is treated dropwise with 9.5 g. Of 2-(6-carbotetrahydropyranyloxyhexyl)-4-tetrahydropyranyloxy-2-cyclopentenone in 10 ml. of ether, rinsing with 5 ml. of ether. The resulting yellow brown solution is allowed to warm to ambient temperature and then kept at that temperature for 18 hours. The solution is poured cautiously onto a mixture of 14 ml. of concentrated hydrochloric acid with 400 g. of crushed ice and the resulting mixture is stirred for 15 minutes. Extraction with ether followed by evaporation given 22 g. of an oily material. A solution of the oil in 350 ml. of acetic acid-tetrahydrofuran-water (3:1:1) is stirred at ambient temperature for 48 hours under nitrogen atmosphere and then taken to dryness. Evaporation to dryness with xylene affords 20 g. of oily material, which is chromatographed on 350 g. of Silic Ar (cc 4). Elution is effected with increasing percentages of benzene in ethyl acetate; the fraction eluted with 80% ethyl acetate in benzene (1.2. l.) affords 1.4 g. of 9-oxo-11.alpha., 15-epi-dihydroxy-17,20-methano-13-trans-prostenoic acid, crystallization of which from ethyl acetate give white crystals, m.p. 98.degree.-99.degree. C.

EXAMPLE 188

To a solution of 13.7 g. (26.3 mmoles) of 4-cyclopentyl-1-iodo-3-mono-p-methoxytriphenylmethoxy-trans-1-butene (Example 143) in 35 ml. of dry toluene, cooled to -75.degree. C., under nitrogen atmosphere is added dropwise in 5 minutes, 11.3 ml. (26.3 mmoles) of 2.34 molar solution of 2.34 molar solution of n-butyllithium in hexane. The solution is allowed to warm to -40.degree. C. and maintained at that temperature for one hour. This solution containing (3-mono-p-methoxytriphenylmethoxy-4-cyclopentyl-trans-1-butenyl)lithium is cooled to -75.degree. C. and to it is added 18.1 ml. (26.3 mmoles) of a 1.45 molar solution of trimethylaluminum in hexane. The solution is then allowed to warm to -20.degree. C. during 45 minutes. This solution containing lithio(3-mono-p-methoxytriphenylmethoxy-4-cyclopentyl-1-trans-butenyl)trimethyl alanate is treated dropwise with 9.5 g. (20.8 mmoles) of 2-(6-carbo-t-butyldimethylsiloxyhexyl)-4-t-butyldimethylsiloxy-2-cyclopentenone (Example 113A) in 10 ml. of ether, rinsing with 5 ml. of ether. The resulting yellow brown solution is allowed to warm to ambient temperature and then kept at that temperature for 18 hours. The solution is poured cautiously onto a mixture of 14.5 ml. of concentrated hydrochloric acid with 400 g. of crushed ice and the resulting mixture is stirred for 15 minutes. Extraction with ether followed by evaporation gives 22 g. of an oily material. A solution of the oil in 350 ml. of acetic acid-tetrahydrofuran-water (3:1:1) is stirred at ambient temperature for 48 hours under nitrogen atmosphere and then taken to dryness. Evaporation to dryness with xylene affords 20 g. of oily material, which is chromatographed on 350 g. of Silic Ar (cc 4). Elution is effected with increasing percentages of benzene in ethyl acetate and finally with ethyl acetate. The following 600 ml. fractions are obtained: fractions 1-5 (11 g.) monomethoxytriphenylcarbinol and t-butyldimethylsilylated products; fraction 6 (0.931 g.), 9-oxo-11.alpha.-t-butyldimethylsiloxy-15-hydroxy-17,20-methano-13-trans-prostenoic acid; fraction 7-8 (1.9 g.), 15-35% 9-oxo-11.alpha.-t-butyldimethylsiloxy-15-hydroxy-17,20-methano-13-trans-prostenoic acid and 65.8% 9-oxo-15-hydroxy-17,20-methano-10,13-trans-prostadienoic acid; fractions 10 and 11 (1.43 g.), a mixture of 9-oxo-11.alpha.,15-epi-dihydroxy-17,20-methano-13-trans-prostenoic acid and 9-oxo-15-epi-17,20-methano-10,13-trans-prostadienoic acid; fraction 12 (1.2 g.) 9-oxo-11.alpha.,15-dihydroxy-17,20-methano-13-trans-prostenoic acid, crystallization of which twice from ethyl acetate furnishes white crystals, m.p. 98.degree.-99.degree. C.

EXAMPLE 188A

9-Oxo-15-epi-17,20-methano-10,13-trans-prostadienoic acid

A solution of 50 mg. of 9-oxo-15-epi-17,20-methano-10,13-trans-prostenoic acid (Example 187) is stirred in 1 ml. of 1.5 N hydrochloric acid and 2 ml. of tetrahydrofuran and described in Example 486 to give 43.4 mg. of product. Recrystallization from ether affords white crystals, m.p. 86.degree.-88.degree. C., .lambda..sub.max..sup.EtOH 218 m.mu. (.epsilon.10,000); tlc Rf 0.75 on silica gel plate, ethyl acetate-acetone-acetic acid (90:20:1) development.

EXAMPLE 188B

9.alpha.,11.alpha.,15-trihydroxy-17,20-methano-13-trans-prostenoic acid

To a stirred solution of 931 mg. of 9-oxo-11.alpha.-t-butyldimethylsilyloxy-15-hydroxy-17,20-methano-13-trans-prostenoic acid in 5 ml. of tetrahydrofuran at 0.degree. C. is added 6.7 ml. (2.2 mole equivalents) of 0.65 M lithium perhydro-9b-boraphenalyl hydride. After 40 minutes the solution is quenched with 4 ml. of 3 N sodium hydroxide followed by 4 ml. of 30% hydrogen peroxide. Ether is added and the solution is acidified with 5% hydrochloric acid solution. The ether portion is separated and washed with saturated sodium chloride solution; dried with anhydrous magnesium sulfate and taken to dryness to give 11.alpha.-t-butyldimethylsiloxy-9.alpha.,15-dihydroxy-17,20-methano-13-trans-prostenoic acid. This material is then treated with 20 ml. of acetic acid-tetrahydrofuran-water (3:1:1) under nitrogen atmosphere at 30.degree.-35.degree. C. for 70 hours. The solution is taken to dryness under reduced pressure then evaporated twice from toluene under reduced pressure to give 748 mg. of product as an oil.

EXAMPLES 189-325

Treatment by the procedure of Example 187 of the 4-oxycyclopentenone esters listed in Table 15 below with the lithio trimethyl (3-triphenylmethoxy-trans-1-alkenyl)alanate corresponding to the listed 1-iodo-3-triphenylmethoxy-trans-1-alkene and prepared from it by the procedure of Example 187 by treatment first with butyl lithium and thence with trimethyl aluminum, followed by deblocking of the intermediate tetrahydropyranyl (or alkyl) 9-oxo-11.alpha.-tetrahydropyranyl-15-triphenylmethoxy-13-prostenoates with acetic acid: water:tetrahydrofuran, also as described in Example 187, provides the product 9-oxo-11.alpha.,15-dihydroxy-13-trans-prostenoic acids of the table. In the instance of the alkyl esters the deblocking procedure does not result in ester hydrolysis and the product is obtained as an alkyl prostenoate ester. When both the 4-oxycyclopentenone and 1-iodo-3-triphenylmethoxy-trans-1-alkene components of these preparations are utilized in their optically resolved forms then the product will be one optical antipode inasmuch as the various conditions of this synthesis do not induce racemization. When neither of the components are in the resolved form then two racemates, the 15-" normal" and the 15-"epi", are formed. These are separable by chromatographic procedures, in the more difficult instance with high speed liquid chromatography and if necessary using the recycling technique. If either of the components are resolved then two diastereomers, rather than racemates, are formed and these are similarly separable by chromatography.

TABLE 15__________________________________________________________________________ Starting 1-iodo-3- Stating 4-oxy- triphenylmethoxy- Product cyclopentenonetrans-1-alkene of 9-oxo-11.alpha.,15-dihydroxy-13-trans-prostenoicExample of Example Example acid or ester and 15-epi isomer thereof__________________________________________________________________________189 44 145 9-oxo-11.alpha.,15-dihydroxy-18,20-ethano-13-trans- 2 prostenoic acid190 44 146 9-oxo-11.alpha.,15-dihydroxy-19,20-(1,3-propano)- 13-trans-prostenoic acid191 44 149 9-oxo-11.alpha.,15-dihydroxy-16-methyl-18,20-ethano - 13-trans-prostenoic acid192 44 153 9-oxo-11.alpha.,15-dihydroxy-17,20-ethano-13-trans- 7 prostenoic acid193 44 181 9-oxo-11.alpha.,15-dihydroxy-17,20-ethano-13-trans- 4 18-prostadienoic acid194 45 147 9-oxo-11.alpha.,15-dihydroxy-6,7-dinor-20,20-(1,4- N butano)-13-trans-prostenoic acid195 45 184 9-oxo-11.alpha.,15-dihydroxy-6,7-dinor-16,20-methan o- 13-trans,17-prostadienoic acid196 44 172 9-oxo-11.alpha.,15-dihydroxy-17,18-methano-13- trans-prostenoic acid197 46 155 9-oxo-11.alpha.,15-dihydroxy-5,6,7-trinor-19,20- (1,4-butano)-13-trans-prostenoic acid198 46 172 9-oxo-11.alpha.,15-dihydroxy-5,6,7-trinor-17,18- methano-13-trans-prostenoic acid199 46 182 9-oxo-11.alpha.,15-dihydroxy-17,20-ethano-13-trans- 19-prostadienoic acid200 47 172 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-17,18- methano-13-trans-prostenoic acid201 47 147 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-20,20- (1,4-butano)-13-trans-prostenoic acid202 47 181 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-17,20- ethano-13-trans,18-prostadienoic acid203 47 185 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-16,20- methano-13-trans,18-prostadienoic acid204 48 180 9-oxo-11.alpha.,15-dihydroxy-2-ethyl-17,20-methano- 13-trans,18-prostadienoic acid205 48 184 9-oxo-11.alpha.,15-dihydroxy-2-ethyl-16,20-methano- 13-trans,17-prostadienoic acid206 48 172 9-oxo-11.alpha.,15-dihydroxy-2-ethyl-17,18-methano- 13-trans-prostenoic acid207 48 166 9-oxo-11.alpha.,15-dihydroxy-2-ethyl-16,19-ethano- 13-trans-prostenoic acid208 48 150 9-oxo-11.alpha.,15-dihydroxy-2,16-diethyl-19,20- (1,3-propano)-13-trans-prostenoic acid209 55 172 9-oxo-11.alpha.,15-dihydroxy-2-methyl-17,18-methano - 13-trans-prostenoic acid210 55 167 9-oxo-11.alpha.,15-dihydroxy-2-methyl-16,20-(1,3- propano)-13-trans-prostenoic acid211 55 148 9-oxo-11.alpha.,15-dihydroxy-2-methyl-20-cyclo- pentyl-13-trans-prostenoic acid212 55 181 9-oxo-11.alpha.,15-dihydroxy-2-methyl-17,20-ethano- O 13-trans,18-prostadienoic acid213 49 182 9-oxo-11.alpha.,15-dihydroxy-3,3-dimethyl-17,20- ethano-13-trans,18-prostadienoic acid214 49 184 9-oxo-11.alpha.,15-dihydroxy-3,3-dimethyl-16,20- methano-13-trans,17-prostadienoic acid215 49 172 9-oxo-11.alpha.,15-dihydroxy-3,3-dimethyl-17,18- methanol-13-trans-prostenoic acid216 49 165 9-oxo-11.alpha.,15-dihydroxy-3,3-dimethyl-16,20- methano-13-trans-prostenoic acid217 49 186 9-oxo-11.alpha.,15-dihydroxy-3,3,16-trimethyl-18,20 - (1,3-propano)-13-trans-prostenoic acid218 49 146 9-oxo-11.alpha.,15-dihydroxy-3,3-dimethyl-19,20- (1,3-propano)-13-trans-prostenoic acid219 50 149 9-oxo-11.alpha.,15-dihydroxy-3-oxa-16-methyl-18,20- ethano-13-trans-prostenoic acid220 50 146 9-oxo-11.alpha.,15-dihydroxy-3-oxa-19,20-(1,3-pro- pano)-13-trans-prostenoic acid221 50 163 9-oxo-11.alpha.,15-dihydroxy-3-oxa-17-methyl-20-nor - 16,19-methano-13-trans-prostenoic acid222 50 172 9-oxo-11.alpha.,15-dihydroxy-3-oxa-17,18-methano- 13-trans-prostenoic acid223 50 180 9-oxo-11.alpha.,15-dihydroxy-3-oxa-17,20-methano- 13-trans-prostenoic acid224 50 185 9-oxo-11.alpha.,15-dihydroxy-3-oxa-16,20-methano- 13-trans,18-prostadienoic acid225 51 181 9-oxo-11.alpha.,15-dihydroxy-2-fluoro-17,20-ethano- 13-trans,18-prostadienoic acid226 51 172 9-oxo-11.alpha.,15-dihydroxy-2-fluoro-17,18-methano - 13-trans-prostenoic acid227 51 162 9-oxo-11.alpha.,15-dihydroxy-2-fluoro-16,19-methano - 20-nor-13-trans-prostenoic acid228 51 151 9-oxo-11.alpha.,15-dihydroxy-2-fluoro-17,20-methano - 18-methyl-13-trans-prostenoic acid229 52 144 9-oxo-11.alpha.,15-dihydroxy-6,20-dinor-17,19- methano-13-trans-prostenoic acid230 52 149 9-oxo-11.alpha.,15-dihydroxy-6-nor-16-methyl-18,20- ethano-13-trans-prostenoic acid231 52 172 9-oxo-11.alpha.,15-dihydroxy-6-nor-17,18-methano-13 - trans-prostenoic acid232 52 180 9-oxo-11.alpha.,15-dihydroxy-6-nor-17,20-methano-13 - trans,18-prostadienoic acid233 52 185 9-oxo-11.alpha.,15-dihydroxy-6-nor-16,20-methano- 13-trans,18-prostadienoic acid234 53 184 9-oxo-11.alpha.,15-dihydroxy-7-homo-16,20-methano- 13-trans-17-prostadienoic acid235 53 182 9-oxo-11.alpha.,15-dihydroxy-7-homo-17,20-ethano- 13-trans,19-prostadienoic acid236 53 172 9-oxo-11.alpha.,15-dihydroxy-7-homo-17,18-methano-13-trans-prostenoic acid237 53 186 9-oxo-11.alpha.,15-dihydroxy-7-homo-16-methyl-18,20 - (1,3-propano)-13-trans-prostenoic acid238 54 172 9-oxo-11.alpha.,15-dihydroxy-2-phenyl-17,18-methano - 13-trans-prostenoic acid239 54 164 9-oxo-11.alpha.,15-dihydroxy-2-phenyl-17-methyl-20- O nor-16,18-ethano-13-trans-prostenoic acid240 54 167 9-oxo-11.alpha.,15-dihydroxy-2-phenyl-16,20-(1,3- propano)-13-trans-prostenoic acid241 54 149 9-oxo-11.alpha.,15-dihydroxy-2-phenyl-16-methyl- 18,20-ethano-13-trans-prostenoic acid242 54 155 9-oxo-11.alpha.,15-dihydroxy-2-phenyl-19,20-(1,4- butano)-13-trans-prostenoic acid243 54 180 9-oxo-11.alpha.,15-dihydroxy-2-phenyl-17,20-methano - 13-trans,18-prostadienoic acid244 54 184 9-oxo-11.alpha.,15-dihydroxy-2-phenyl-16,20- methano-13-trans,18-prostadienoic acid245 56 183 ethyl 9-oxo-11.alpha.,15-dihydroxy-17-methyl-17,20- ethano-13-trans-prostenoate246 57 182 methyl 9-oxo-11.alpha.,15-dihydroxy-17,20-ethano- 13-trans,19-prostadienoate247 57a 184 1 methyl 9-oxo-11.alpha.,15-dihydroxy-16,20-methano - 13-trans,17-prostadienoate248 57a 172 1 methyl 9-oxo-11.alpha.,15-dihydroxy-17,18-methano - 13-trans-prostenoate249 57a 186 1 methyl 9-oxo-11.alpha.,15-dihydroxy-16-methyl- 18,20-(1,3-propano)-13-trans-prostenoate250 57a 159 1 methyl 9-oxo-11.alpha.,15-dihydroxy-17,20-ethano- 20-methyl-13-trans-prostenoate251 57b 158 d methyl 9-oxo-1.alpha.,15-dihydroxy-17,20-(1,4- butano)-13-trans-prostenoate252 57b 150 d methyl-11.alpha.,15-dihydroxy-16-ethyl-19,20- (1,3-propano)-13-trans-prostenoate253 57b 172 d methyl-11.alpha.,15-dihydroxy-17,18-methano- 13-trans-prostenoate254 57b 185 d methyl 11.alpha.,15-hydroxy-16,20-methano- 13-trans,18-prostadienoate255 57b 180 d methyl-11.alpha.,15-dihydroxy-17,20-methano-13- trans,18-prostadienoate256 58 172 butyl 9-oxo-11.alpha.,15-dihydroxy-17,18-methano- 13-trans-prostenoate257 58 184 butyl 9-oxo-11.alpha.,15-dihydroxy-16,20-methano- 13-trans,17-prostadienoate258 59 186 isopropyl 9-oxo-11.alpha.,15-dihydroxy-16-methyl- 18,20-(1,3-propano)-13-trans-prostenoate259 59 155 isopropyl 9-oxo-11.alpha.,15-dihydroxy-19,20- (1,4-butano)-13-trans-prostenoate -260 60 151 decyl 9-oxo-11.alpha.,15-dihydroxy-17,2 0-methano- 18-methyl-13-trans-prostenoate261 60 172 decyl 9-oxo-11.alpha.,15-dihydroxy-17,18-methano- 13-trans-prostenoate262 60 181 decyl 9-oxo-11.alpha.,15-dihydroxy-17,20-ethano- 13-trans,18-prostadienoate263 97 143 9-oxo-11.alpha.,15-dihydroxy-17,20-methano-5-cis,- O 13-trans,18-prostadienoate264 97 145 9-oxo-11.alpha.,15-dihydroxy-18,20-ethano-5-cis, 13-trans-prostadienoic acid265 97 148 9-oxo-11.alpha.,15-dihydroxy-20-cyclopentyl-5- cis,13-trans-prostadienoic acid266 97 150 9-oxo-11.alpha.,15-dihydroxy-16-ethyl-19,20-(1,3- propano)-15-cis,13-trans-prostadienoic acid267 97 154 9-oxo-11.alpha.,15-dihydroxy-18,20-(1,3-propano)- 5-cis,13-trans-prostadienoic acid268 97 156 9-oxo-11.alpha.,15-dihydroxy-17,20-(1,3-propano)- 5-cis,13-trans-prostadienoic acid269 109 160 9-oxo-11.alpha.,15-dihydroxy-17,19-(1,3-propano)- 5-cis,13-trans-prostadienoic acid270 97 172 9-oxo-11.alpha.,15-dihydroxy-17,18-methano-5-cis,13 - trans-prostadienoic acid271 105 180 9-oxo-11.alpha.,15-dihydroxy-17,20-methano-5-cis, 13-trans,-18-prostatrienoic acid272 97 184 9-oxo-11.alpha.,15-dihydroxy-16,20-methano-5-cis,13 - trans,17-prostatrienoic acid273 97a 146 1 methyl 9-oxo-11.alpha.,15-dihydroxy-19,20-(1,3- propano)-5-cis,13-trans-prostadienoate274 97A 149 1 methyl 9-oxo-11.alpha.,15-dihydroxy-16-methyl- 18,20-ethano-5-cis,13-trans-prostadienoate275 97A 152 1 methyl 9-oxo-11.alpha.,15-dihydroxy-20-methyl-19, O 20-(1,3-propano)-5-cis,13-trans-prostadienoate276 97A 153 1 methyl 9-oxo-11.alpha.,15-dihydroxy-16,20-methano - 5-cis,13-trans-prostadienoate277 97A 172 1 methyl 9-oxo-11.alpha.,15-dihydroxy-17,18-methano - 5-cis,13-trans-prostadienoate278 97A 186 1 methyl 9-oxo-11.alpha.,15-dihydroxy-16-methyl-18, 20-(1,3-propano)-5-cis,13-trans-prostadienoate279 97A 157 1 methyl 9-oxo-11.alpha.,15-dihydroxy-20-methyl-17, 20-(1,3-propano)-5-cis,13-trans-prostadienoate280 97A 158 1 methyl 9-oxo-11.alpha.,15-dihydroxy-17,20-(1,4- butano)-5-cis,13-trans-prostadienoate281 97A 159 1 methyl 9-oxo-11.alpha.,15-dihydroxy-17,20- ethano-20-methyl-5-cis,13-trans-prostadienoate282 97A 181 1 methyl 9-oxo-11.alpha.,15-dihydroxy-17,20-ethano- 5-cis,13-trans,18-prostatrienoate283 97A 185 1 methyl 9-oxo-11.alpha.,15-dihydroxy-16,20-methano - 5-cis,13-trans,18-prostatrienoate284 98 144 9-oxo-11.alpha.,15-dihydroxy-7,20-bisnor-17,19- methano-5-cis,13-trans-prostadienoic acid285 98 145 9-oxo-11.alpha.,15-dihydroxy-7-nor-18,20-ethano- 5-cis,13-trans-prostadienoic acid286 98 149 9-oxo-11.alpha.,15-dihydroxy-7-nor-16-methyl-18, 20-ethano-5-cis,13-trans-prostadienoic acid287 106 157 9-oxo-11.alpha.,15-dihydroxy-7-nor-20-methyl-17,20- (1,3-propano)-5-cis,13-trans-prostadienoic acid288 98 172 9-oxo-11.alpha.,15-dihydroxy-7-nor-17,18-methano-5- A cis,13-trans-prostadienoic acid289 98 159 9-oxo-11.alpha.,15-dihydroxy-7-nor-17,20-ethano- 20-methyl-5-cis,13-trans-prostadienoic acid290 98 180 9-oxo-11.alpha.,15-dihydroxy-7-nor-17,20-methano-5- B cis,13-trans,18-prostatrienoic acid291 98 184 9-oxo-11.alpha.,15-dihydroxy-7-nor-16,20-methano-5- S cis,13-trans,17-prostatrienoic acid292 99 185 9-oxo-11.alpha.,15-dihydroxy-7a-homo-16,20-methano- T 5-cis,13-trans,18-prostatrienoic acid293 99 180 9-oxo-11.alpha.,15-dihydroxy-7a-homo-17,20-methano- 5-cis,13-trans,18-prostatrienoic acid294 100 181 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bis-homo-17,20- ethano-5-cis,13-trans,18-prostatrienoic acid295 100 184 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bis-homo-16,20- methano-5-cis,13-trans,17-prostatrienoic acid296 99 172 9-oxo-11.alpha.,15-dihydroxy-7a-homo-17,18-methano- 5-cis,13-trans-prostadienoic acid297 99 186 9-oxo-11.alpha.,15-dihydroxy-7a-homo-16-methyl-18,2 0- (1,3-propano)-5-cis,13-trans-prostadienoic acid298 99 146 9-oxo-11.alpha.,15-dihydroxy-7a-homo-19,20-(1,3-pro - pano)-5-cis,13-trans-prostadienoic acid299 99 160 9-oxo-11.alpha.,15-dihydroxy-7a-homo-17,19-(1,3- propano)-5-cis,13-trans-prostadienoic acid300 100 172 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-17,18-me th- ano-5-cis,13-trans-prostadienoic acid301 100 183 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-17-methy l- 17,20-ethano-5-cis,13-trans-prostadienoic acid302 100 149 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-16-methy l- 18,20-ethano-5-cis,13-trans-prostadienoic acid303 100 148 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-20-cyclo - pentyl-5-cis-13-trans-prostadienoic acid304 100 159 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-17,20- ethano-20-methyl-5-cis,13-trans-prostadienoic acid305 101 145 9-oxo-11.alpha.,15-dihydroxy-5-methyl-18,20-ethano- 5- cis,13-trans-prostadienoic acid306 101 149 9-oxo-11.alpha.,15-dihydroxy-4,16-dimethyl-18,20- ethano-5-cis,13-trans-prostadienoic acid307 101 154 9-oxo-11.alpha.,15-dihydroxy-4-methyl-18,20-(1,3- propano)-5-cis,13-trans-prostadienoic acid308 101 166 9-oxo-11.alpha.,15-dihydroxy-4-methyl-16,19-ethano- N 5-cis,13-trans-prostadienoic acid309 101 172 9-oxo-11.alpha.,15-dihydroxy-4-methyl-17,18-methano - 5-cis,13-trans-prostadienoic acid310 101 180 9-oxo-11.alpha.,15-dihydroxy-4-methyl-17,20-methano - 5-cis,13-trans,18-prostatrienoic acid311 101 185 9-oxo-11.alpha.,15-dihydroxy-4-methyl-16,20- methano-5-cis-13-trans,18-prostatrienoic acid312 102 184 9-oxo-11.alpha.,15-dihydroxy-4(R)-methyl-16,20- methano-5-cis,13-trans,17-prostatrienoic acid313 102 182 9-oxo-11.alpha.,15-dihydroxy-4(R)-methyl-17,20- ethano-5-cis,13-trans,19-prostatrienoic acid314 102 172 9-oxo-11.alpha.,15-dihydroxy-4(R)-methyl-17,18- methano-5-cis,13-trans-prostadienoic acid315 102 186 9-oxo-11.alpha.,15-dihydroxy-4(R),16-dimethyl-18,20 - (1,3-propano)-5-cis,13-trans-prostadienoic acid316 102 161 9-oxo-11.alpha.,15-dihydroxy-4(R)-methyl-16,20- ethano-5-cis,13-trans-prostadienoic acid317 102 146 9-oxo-11.alpha.,15-dihydroxy-4(R)-methyl-19,20-(1,3 - propano)-5-cis,13-trans-prostadienoic acid318 102 164 9-oxo-11.alpha. ,15-dihydroxy-4(R),17-dimethyl-20- 3 nor-16,18-ethano-5-cis,13-trans-prostadienoic acid319 103 147 9-oxo-11.alpha.,15-dihydroxy-4-ethyl-20,20-(1,4- butano)-5-cis,13-trans-prostadienoic acid320 103 151 9-oxo-11.alpha.,15-dihydroxy-4-ethyl-17,20-methano- 18-methyl-5-cis,13-trans-prostadienoic acid321 103 153 9-oxo-11.alpha.,15-dihydroxy-4-ethyl-17,20-ethano- 5-cis,13-trans-prostadienoic acid322 103 167 9-oxo-11.alpha.,15-dihydroxy-4-ethyl-16,20-(1,3- propano)-5-cis,13-trans-prostadienoic acid323 103 172 9-oxo-11.alpha.,15-dihydroxy-4-ethyl-17,18-methano- 5-cis,13-trans-prostadienoic acid324 103 181 9-oxo-11.alpha.,15-dihydroxy-4-ethyl-17,20-ethano- 5-cis,13-trans,18-prostatrienoic acid325 103 185 9-oxo-11.alpha.,15-dihydroxy-4-ethyl-16,20-methano- 5-cis,13-trans,18-prostatrienoic acid326 104 184 9-oxo-11.alpha.,15-dihydroxy-4-propyl-16,20-methano 5-cis,13-trans-prostatrienoic acid327 104 180 9-oxo-11.alpha.,15-dihydroxy-4-propyl-17,20- methano-5-cis,13-trans-prostatrienoic acid328 104 172 9-oxo-11.alpha.,15-dihydroxy-4-propyl-17,18- methano-5-cis,13-trans-prostadienoic acid329 104 145 9-oxo-11.alpha.,15-dihydroxy-4-propyl-18,20-ethano- 5-cis,13-trans-prostadienoic acid330 104 186 9-oxo-11.alpha.,15-dihydroxy-4-propyl-16-methyl-l8, 20-(1,3-propano)-5-cis,13-trans-prostadienoic acid331 104 148 9-oxo-11.alpha.,15-dihydroxy-4-propyl-20-cyclopenty l- 5-cis,13-trans-prostadienoic acid332 104 152 9-oxo-11.alpha.,15-dihydroxy-4-propyl-20-methyl-19, N 20-(1,3-propano)-5-cis,13-trans-prostadienoic acid333 104 164 9-oxo-11.alpha.,15-dihydroxy-4-propyl-17-methyl-20- O nor-16,18-ethano-5-cis,13-trans-prostadienoic acid334 104 165 9-oxo-11.alpha.,15-dihydroxy-4-propyl-16,20-methano - 5-cis,13-trans-prostadienoic acid335 104 156 9-oxo-11.alpha.,15-dihydroxy-4-propyl-17,20-(1,3- propano)-5-cis,13-trans-prostadienoic acid336 104 161 9-oxo-11.alpha.,15-dihydroxy-4-propyl-16,20-ethano- 5-cis,13-trans-prostadienoic acid__________________________________________________________________________

EXAMPLE 337

Preparation of 9.alpha.,11.alpha.,15-trihydroxy-17,20-methano-13-trans-prostenoic acid

To a solution of 433 mg. of 9-oxo-11.alpha.,15.alpha.-dihydroxy-17,20-methano-13-trans-prostenoic acid (Example 187) in 4.5 ml. of tetrahydrofuran, stirred in an ice bath under nitrogen atmosphere, is added dropwise 3.7 ml. of 0.76 M lithium perhydro-9b-boraphenalyl hydride. After 40 minutes at 0.degree. C. there is added 1.62 ml. of 3 N sodium hydroxide followed by 1.62 ml. of 30% hydrogen peroxide. Ether is added and the resulting solution is acidified with 2 N hydrochloric acid. The ether layer is washed several times with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and then to dryness to give the subject product as an oil.

EXAMPLES 338-485

Treatment of the 9-oxo derivatives designated in Table 16 below with lithium perhydro-9b-boraphenalyl hydride by the procedure described in Example 337 provides the 9.alpha.,11.alpha.,15-trihydroxy derivatives of the table.

Table 16__________________________________________________________________________ Starting 9-oxo-derivative Product 9.alpha.-hydroxy derivative andExample of Example 15-epi isomer thereof__________________________________________________________________________338 189 9.alpha.,11.alpha.,15-trihydroxy-18,20-ethano-13-trans -prost- enoic acid339 190 9.alpha.,11.alpha.,15-trihydroxy-19,20-(1,3-propano)-1 3-trans- prostenoic acid340 191 9.alpha.,11.alpha.,15-trihydroxy-16-methyl-18,20-ethan o-13- trans-prostenoic acid341 192 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano-13-trans -prost- enoic acid342 193 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano-13-trans ,18- prostadienoic acid343 194 9.alpha.,11.alpha.,15-trihydroxy-6,7-dinor-20,20-(1,4- N butano)-13-trans-prostenoic acid344 195 9.alpha.,11.alpha.,15-trihydroxy-6,7-dinor-16,20-metha no-13- trans,17-prostadienoic acid345 196 9.alpha.,11.alpha.,15-trihydroxy-17,18-methano-13-tran s-pro- stadienoic acid346 197 9.alpha.,11.alpha.,15-trihydroxy-5,6,7-trinor-19,20-(1 ,4- butano)-13-trans-prostenoic acid347 198 9.alpha.,11.alpha.,15-trihydroxy-5,6,7-trinor-17,18-me thano- 13-trans-prostenoic acid348 199 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano-13-trans ,19- prostadienoic acid349 200 9.alpha.,11.alpha.,15-trihydroxy-7a,7b-bishomo-17,18- methano-13-trans-prostenoic acid350 201 9.alpha.,11.alpha.,15-trihydroxy-7a,7b-bishomo-20,20-( 1,4- butano)-13-trans-prostenoic acid351 202 9.alpha.,11.alpha.,15-trihydroxy-7a,7b-bishomo-17,20-e thano- 13-trans,18-prostadienoic acid352 203 9.alpha.,11.alpha.,15-trihydroxy-7a,7b-bishomo-16,20-m ethano- 13-trans,18-prostadienoic acid353 204 9.alpha.,11.alpha.,15-trihydroxy-2-ethyl-17,20-methano -13- trans,18-prostadienoic acid354 205 9.alpha.,11.alpha.,15-trihydroxy-2-ethyl-16,20-methano -13- trans,17-prostadienoic acid355 206 9.alpha.,11.alpha.,15-trihydroxy-2-ethyl-17,18-methano -13- trans-prostenoic acid356 207 9.alpha.,11.alpha.,15-trihydroxy-2-ethyl-16,19-ethano- 13- trans-prostenoic acid357 208 9.alpha.,11.alpha.,15-trihydroxy-2,16-diethyl-19,20-(1 ,3- propano)-13-trans-prostenoic acid358 209 9.alpha.,11.alpha.,15-trihydroxy-2-methyl-17,18-methan o-13- trans-prostenoic acid359 210 9.alpha.,11.alpha.,15-trihydroxy-2-methyl-16,20-methan o-(1,3-propano)- 13-trans-prostenoic acid360 211 9.alpha.,11.alpha.,15-trihydroxy-2-methyl-20-cyclopent yl-13- trans-prostenoic acid361 212 9.alpha.,11.alpha.,15-trihydroxy-2-methyl-17,20-ethano -13- trans,18-prostadienoic acid362 213 9.alpha.,11.alpha.,15-trihydroxy-3,3-dimethyl-17,20-et hano- 13-trans,18-prostadienoic acid363 214 9.alpha.,11.alpha.,15-trihydroxy-3,3-dimethyl-16,20-me thano- 13-trans,17-prostadienoic acid364 215 9.alpha.,11.alpha.,15-trihydroxy-3,3-dimethyl-17,18-me thano- 13-trans-prostenoic acid365 216 9.alpha.,11.alpha.,15-trihydroxy-3,3-dimethyl-16,20-me thano- 13-trans-prostenoic acid366 217 9.alpha.,11.alpha.,15-trihydroxy-3,3,16-trimethyl-18,2 0-(1, 3-propano)-13-trans-prostenoic acid367 218 9.alpha.,11.alpha.,15-trihydroxy-3,3-dimethyl-19,20-(1 ,3- propano)-13-trans-prostenoic acid368 219 9.alpha.,11.alpha.,15-trihydroxy-3-oxa-16-methyl-18,20 -ethano- 13-trans-prostenoic acid369 220 9.alpha.,11.alpha.,15-trihydroxy-3-oxa-19,20-(1,3-prop ano)- 13-trans-prostenoic acid370 221 9.alpha.,11.alpha.,15-trihydroxy-3-oxa-17-methyl-20-no r- 16,19-methano-13-trans-prostenoic acid371 222 9.alpha.,11.alpha.,15-trihydroxy-3-oxa-17,18-methano-1 3 trans-prostenoic acid372 223 9.alpha.,11.alpha.,15-trihydroxy-3-oxa-17,20-methano-1 3-trans- prostenoic acid373 224 9.alpha.,11.alpha.,15-trihydroxy-3-oxa-16,20-methano-1 3- trans,18-prostadienoic acid374 225 9.alpha.,11.alpha.,15-trihydroxy-2-fluoro-17,20-ethano -13- trans,18-prostadienoic acid375 226 9.alpha.,11.alpha.,15-trihydroxy-2-fluoro-17,18-methan o- 13-trans-prostenoic acid376 227 9.alpha.,11.alpha.,15-trihydroxy-2-fluoro-16,19-methan o-20- nor-13-trans-prostenoic acid377 228 9.alpha.,11.alpha.,15-trihydroxy-2-fluoro-17,20-methan o-18- methyl-13-trans-prostenoic acid378 229 9.alpha.,11.alpha.,15-trihydroxy-6,20-dinor-17,19-meth ano- 13-trans-prostenoic acid379 230 9.alpha.,11.alpha.,15-trihydroxy-6-nor-16-methyl-18,20 - ethano-13-trans-prostenoic acid380 231 9.alpha.,11.alpha.,15-trihydroxy-6-nor-17,18-methano-1 3- trans-prostenoic acid381 232 9.alpha.,11.alpha.,15-trihydroxy-6-nor-17,20-methano-1 3- trans,18-prostadienoic acid382 233 9.alpha.,11.alpha.,15-trihydroxy-6-nor-16,20-methano-1 3- trans,18-prostadienoic acid383 234 9.alpha.,11.alpha.,15-trihydroxy-7-homo-16,20-methano- 13- trans,17-prostadienoic acid384 235 9.alpha.,11.alpha.,15-trihydroxy-7-homo-17,20-ethano-1 3- trans,19-prostadienoic acid385 236 9.alpha.,11.alpha.,15-trihydroxy-7-homo-17,18-methano- 13- trans-prostenoic acid386 237 9.alpha.,11.alpha.,15-trihydroxy-7-homo-16-methyl-18,2 0- (1,3-propano)-13-trans-prostenoic acid387 238 9.alpha.,11.alpha.,15-trihydroxy-2-phenyl-17,18-methan o- 13-trans-prostenoic acid388 239 9.alpha.,11.alpha.,15-trihydroxy-2-phenyl-17-methyl-20 - nor-16,18-ethano-13-trans-prostenoic acid389 240 9.alpha.,11.alpha.,15-trihydroxy-2-phenyl-16,20-(1,3-p ro- pano-13-trans-prostenoic acid390 241 9.alpha.,11.alpha.,15-trihydroxy-2-phenyl-16-methyl-18 ,20- ethano-13-trans-prostenoic acid391 242 9.alpha.,11.alpha.,15-trihydroxy-2-phenyl-19,20-(1,4- 0 butano)-13-trans-prostenoic acid392 243 9.alpha.,11.alpha.,15-trihydroxy-2-phenyl-17,20-methan o- 13-trans,18-prostadienoic acid393 244 9.alpha.,11.alpha.,15-trihydroxy-2-phenyl-16,20-methan o- 13-trans,18-prostadienoic acid394 244 ethyl 9.alpha.,11.alpha.,15-trihydroxy-17-methyl-17,20 - ethano-13-trans-prostenoate395 246 methyl 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano-1 3- trans,19-prostadienoate396 247 1 methyl 9.alpha.,11.alpha.,15-trihydroxy-16,20-methan o- 13-trans,17-prostadienoate397 248 1 methyl 9.alpha.,11.alpha.,15-trihydroxy-17,18-methan o- 13-trans-prostenoate398 249 1 methyl 9.alpha.,11.alpha.,15-trihydroxy-16-methyl-18 ,20- (1,3-propano)-13-trans-prostenoate399 250 1 methyl 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano - 20-methyl-13-trans-prostenoate400 251 d methyl 9.alpha.,11.alpha.,15-trihydroxy-17,20-(1,4-b utano)- 13-trans-prostenoate401 252 d methyl 9.alpha.,11.alpha.,15-trihydroxy-16-ethyl-19, 20- (1,3-propano)-13-trans-prostenoate402 253 d methyl 9.alpha.,11.alpha.,15-trihydroxy-17,18-methan o-13- trans-prostenoate403 254 d methyl 9.alpha.,11.alpha.,15-trihydroxy-16,20-methan o-13- trans,18-prostadienoate404 255 d methyl 9.alpha.,11.alpha.,15-trihydroxy-17,20-methan o-13- trans,18-prostadienoate405 256 butyl 9.alpha.,11.alpha.,15-trihydroxy-17,18-methano-1 3- trans-prostenoate406 257 butyl 9.alpha.,11.alpha.,15-trihydroxy-16,20-methano-1 3- trans,17-prostadienoate407 258 isopropyl 9.alpha.,11.alpha.,15-trihydroxy-16-methyl-1 8,20- (1,3-propano)-13-trans-prostenoate408 259 isopropyl 9.alpha.,11.alpha.,15-trihydroxy-19,20-(1,4- S butano)-13-trans-prostenoate409 260 decyl 9.alpha.,11.alpha.,15-trihydroxy-17,20-methano-1 8- methyl-13-trans-prostenoate410 261 decyl 9.alpha.,11.alpha.,15-trihydroxy-17,18-methano-1 3- trans-prostenoate411 262 decyl 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano-13 - trans,18-prostadienoate412 263 9.alpha.,11.alpha.,15-trihydroxy-17,20-methano-5-cis,1 3- trans-prostadienoic acid413 264 9.alpha.,11.alpha.,15-trihydroxy-18,20-ethano-5-cis,13 - trans-prostadienoic acid414 265 9.alpha.,11.alpha.,15-trihydroxy-20-cyclopentyl-5-cis, 13- trans-prostadienoic acid415 266 9.alpha.,11.alpha.,15-trihydroxy-16-ethyl-19,20-(1,3-p ro- pano)-5-cis,13-trans-prostadienoic acid416 267 9.alpha.,11.alpha.,15-trihydroxy-18,20-(1,3-propano)-5 ,cis, 13-trans-prostadienoic acid417 268 9.alpha.,11.alpha.,15-trihydroxy-17,20-(1,3-propano)-5 -cis, 13-trans-prostadienoic acid418 269 9.alpha.,11.alpha.,15-trihydroxy-17,19-(1,3-propano)-5 -cis, trans-prostadienoic acid419 270 9.alpha.,11.alpha.,15-trihydroxy-17,18-methano-5-cis,1 3- trans-prostadienoic acid420 271 9.alpha.,11.alpha.,15-trihydroxy-17,20-methano-5-cis,1 3- trans,18-prostatrienoic acid421 272 9.alpha.,11.alpha.,15-trihydroxy-16,20-methano-5-cis,1 3- trans,17-prostatrienoic acid422 273 1 methyl 9.alpha.,11.alpha.,15-trihydroxy-19,20-(1,3- v propano)-5-cis,13-trans-prostadienoate423 274 1 methyl 9.alpha.,11.alpha.,15-trihydroxy-16-methyl-18 ,20- ethano-5-cis,13-trans-prostadienoate -424 275 1 methyl 9.alpha.,11.alpha.,15-trihydroxy-20-methyl-19,2 0- (1,3-propano)-5-cis,13-trans-prostadienoate425 276 1 methyl 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano - 5-cis,13-trans-prostadienoate426 277 1 methyl 9.alpha.,11.alpha.,15-trihydroxy-17,18-methan o- 5-cis,13-trans-prostadienoate427 278 1 methyl 9.alpha.,11.alpha.,15-trihydroxy-16-methyl-18 ,20- (1,3-propano)-5-cis,13-trans-prostadienoate428 279 1 methyl 9.alpha.,11.alpha.,15-trihydroxy-20-methyl-17 ,20- (1,3-propano)-5-cis,13-trans-prostadienoate429 280 1 methyl 9.alpha.,11.alpha.,15-trihydroxy-17,20-(1,4-b utano)- 5-cis,13-trans-prostadienoate430 281 1 methyl 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano -20- methyl-5-cis,13-trans-prostadienoate431 282 1 methyl 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano -5- cis,13-trans,18-prostatrienoate432 283 1 methyl 9.alpha.,11.alpha.,15-trihydroxy-16,20-methan o-5- cis,13-trans,18-prostatrienoate433 284 9.alpha.,11.alpha.,15-trihydroxy-7,20-bisnor-17,19-met hano- 5-cis,13-trans-prostadienoic acid434 285 9.alpha.,11.alpha.,15-trihydroxy-7-nor-18,20-ethano-5- cis, 13-trans-prostadienoic acid435 286 9.alpha.,11.alpha.,15-trihydroxy-7-nor-16-methyl-18,20 - ethano-5-cis,13-trans-prostadienoic acid436 287 9.alpha.,11.alpha.,15-trihydroxy-7-nor-20-methyl-17,20 -(1,3- propano)-5-cis,13-trans-prostadienoic acid437 288 9.alpha.,11.alpha.,15-trihydroxy-7-nor-17,18-methano-5 -cis, 13-trans-prostadienoic acid438 289 9.alpha.,11.alpha.,15-trihydroxy-7-nor-17,20-ethano-20 -methyl- 5-cis,13-trans-prostadienoic acid439 290 9.alpha.,11.alpha.,15-trihydroxy-7-nor-17,20-methano-5 -cis, 13-trans,18-prostatrienoic acid440 291 9.alpha.,11.alpha.,15-trihydroxy-7-nor-16,20-methano-5 -cis, 13-trans,17-prostatrienoic acid441 292 9.alpha.,11.alpha.,15-trihydroxy-7a-homo-16,20-methano -5- cis,13-trans,18-prostatrienoic acid442 293 9.alpha.,11.alpha.,15-trihydroxy-7a-homo-17,20-methano -5- cis,13-trans,18-prostatrienoic acid443 294 9.alpha.,11.alpha.,15-trihydroxy-7a,7b-bis-homo-17,20- 3 ethano-5-cis,13-trans,18-prostatrienoic acid444 295 9.alpha.,11.alpha.,15-trihydroxy-7a,7b-bis-homo-16,20- methano- 5-cis,13-trans,17-prostatrienoic acid445 296 9.alpha.,11.alpha.,15-trihydroxy-7a-homo-17,18-methano -5- cis,13-trans-prostadienoic acid446 297 9.alpha.,11.alpha.,15-trihydroxy-7a-homo-16-methyl-18, 20- (1,3-propano)-5-cis,13-trans-prostadienoic acid447 298 9.alpha.,11.alpha.,15-trihydroxy-7a-homo-19,20-(1,3-pr opano)- 5-cis,13-trans-prostadienoic acid448 299 9.alpha.,11.alpha.,15-trihydroxy-7a-homo-17,19-(1,3-pr opano)- 5-cis,13-trans-prostadienoic acid449 300 9.alpha.,11.alpha.,15-trihydroxy-7a,7b-bishomo-17,18-m ethano- 5-cis,13-trans-prostadienoic acid450 301 9.alpha.,11.alpha.,15-trihydroxy-7a,7b-bishomo-17-meth yl- 17,20-ethano-5-cis,13-trans-prostadienoic acid451 302 9.alpha.,11.alpha.,15-trihydroxy-7a,7b-bishomo-16-meth yl- 18,20-ethano-5-cis,13-trans-prostadienoic acid452 303 9.alpha.,11.alpha.,15-trihydroxy-7a,7b-bishomo-20-cycl opentyl- 5-cis,13-trans-prostadienoic acid453 304 9.alpha.,11.alpha.,15-trihydroxy-7a,7b-bishomo-17,20-e thano- 20-methyl-5-cis,13-trans-prostadienoic acid454 305 9.alpha.,11.alpha.,15-trihydroxy-4-methyl-18,20-ethano -5- cis,13-trans-prostadienoic acid455 306 9.alpha.,11.alpha.,15-trihydroxy-4,16-dimethyl-18,20-e thano- 5-cis,13-trans-prostadienoic acid456 307 9.alpha.,11.alpha.,15-trihydroxy-4-methyl-18,20-(1,3-p ropano)- 5-cis,13-trans-prostadienoic acid457 308 9.alpha.,11.alpha.,15-trihydroxy-4-methyl-16,19-ethano -5- cis,13-trans-prostadienoic acid458 309 9.alpha.,11.alpha.,15-trihydroxy-4-methyl-17,18-methan o-5- cis,13-trans-prostadienoic acid459 310 9.alpha.,11.alpha.,15-trihydroxy-4-methyl-17,20-methan o-5- cis,13-trans,18-prostatrienoic acid460 311 9.alpha.,11.alpha.,15-trihydroxy-4-methyl-16,20-methan o-5- cis,13-trans,18-prostatrienoic acid461 312 9.alpha.,11.alpha.,15-trihydroxy-4(R)-methyl-16,20-met hano- 5-cis,13-trans,17-prostatrienoic acid462 313 9.alpha.,11.alpha.,15-trihydroxy-4(R)-methyl-17,20-eth ano- 5-cis,13-trans,19-prostatrienoic acid463 314 9.alpha.,11.alpha.,15-trihydroxy-4(R)-methyl-17,18-met hano- 5-cis,14-trans-prostadienoic acid464 315 9.alpha.,11.alpha.,15-trihydroxy-4(R),16-dimethyl-18,2 0- (1,3-propano)-5-cis,13-trans-prostadienoic acid465 316 9.alpha.,11.alpha.,15-trihydroxy-4(R)-methyl-16,20-eth ano- 5-cis,13-trans-prostadienoic acid466 317 9.alpha.,11.alpha.,15-trihydroxy-4(R)-methyl-19,20-(1, 3- propano)-5-cis,13-trans-prostadienoic acid467 318 9.alpha.,11.alpha.,15-trihydroxy-4(R),17-dimethyl-20-n or- 16,18-ethano-5-cis,13-trans-prostadienoic acid468 319 9.alpha.,11.alpha.,15-trihydroxy-4-ethyl-20,20-(1,4-bu tano)- 5-cis,13-trans-prostadienoic acid469 320 9.alpha.,11.alpha.,15-trihydroxy-4-ethyl-17,20-methano -18- methyl-5-cis,13-trans-prostadienoic acid470 321 9.alpha.,11.alpha.,15-trihydroxy-4-ethyl-17,20-ethano- 5- cis,13-trans-prostadienoic acid471 322 9.alpha.,11.alpha.,15-trihydroxy-4-ethyl-16,20-(1,3-pr opano)- 5-cis,13-trans-prostadienoic acid472 323 9.alpha.,11.alpha.,15-trihydroxy-4-ethyl-17,18-methano -5- cis,13-trans-prostadienoic acid473 324 9.alpha.,11.alpha.,15-trihydroxy-4-ethyl-17,20-ethano- 5- cis,13-trans,18-prostatrienoic acid474 325 9.alpha.,11.alpha.,15-trihydroxy-4-ethyl-16,20-ethano- 5- cis,13-trans,18-prostatrienoic acid475 326 9.alpha.,11.alpha.,15-trihydroxy-4-propyl-16,20-methan o- 5-cis,13-trans,17-prostatrienoic acid476 327 9.alpha.,11.alpha.,15-trihydroxy-4-propyl-17,20-methan o- 5-cis,13-trans,18-prostatrienoic acid477 328 9.alpha.,11.alpha.,15-trihydroxy-4-propyl-17,18-methan o-5- cis,13-trans-prostadienoic acid478 329 9.alpha.,11.alpha.,15-trihydroxy-4-propyl-18,20 - cis,13-trans-prostadienoic acid479 330 9.alpha.,11.alpha.,15-trihydroxy-4-propyl-16-methyl-18 ,20- (1,3-propano)-5-cis,13-trans-prostadienoic acid480 331 9.alpha.,11.alpha.,15-trihydroxy-4-propyl-20-cyclopent yl- 5-cis,13-trans-prostadienoic acid481 332 9.alpha.,11.alpha.,15-trihydroxy-4-propyl-20-methyl-19 ,20- (1,3-propano)-5-cis,13-trans-prostadienoic acid482 333 9.alpha.,11.alpha.,15-trihydroxy-4-propyl-17-methyl-20 -nor- 16,18-ethano-5-cis,13-trans-prostadienoic acid483 334 9.alpha.,11.alpha.,15-trihydroxy-4-propyl-16,20-methan o- 5-cis,13-trans-prostadienoic acid484 335 9.alpha.,11.alpha.,15-trihydroxy-4-propyl-17,20-(1,3-p ro- pano)-5-cis,13-trans-prostadienoic acid485 336 9.alpha.,11.alpha.,15-trihydroxy-4-propyl-16,20-ethano -5- cis,13-trans-prostadienoic acid__________________________________________________________________________

EXAMPLE 486

9-Oxo-15-hydroxy-17,20-methano-10,13-trans-prostadienoic acid

A solution of 50 mg. of 9-oxo-11.alpha.,15-dihydroxy-17,20-methano-13-trans-prostenoic acid (Example 187) in 1 ml. of 1.5 N hydrochloric acid and 2 ml. of tetrahydrofuran is stirred at ambient temperature for 70 hours. The solution is diluted with 6 ml. of saturated sodium chloride solution and extracted several times with ether. The combined ether extracts are washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and taken to dryness under reduced pressure to give 50 mg. of the subject compound as an oil; tlc R.sub.f 0.62 on silica gel plate, ethyl acetate-acetone-acetic acid (90:20:1) development.

EXAMPLES 487-634

Treatment of the starting 9-oxo-11.alpha.-hydroxy derivative listed in Table 17 below with dilute hydrochloric acid at ambient temperatures by the procedure described in Example 486 gives the product 9-oxo-.DELTA..sup.10(11) derivative of the table.

TABLE 17__________________________________________________________________________ Starting 11.alpha.-hydroxy-9-oxo 9-oxo-.DELTA..sup.10(11) -derivative andExample derivative of Example 15-epi isomers thereof__________________________________________________________________________487 189 9-oxo-15-hydroxy-18,20-ethano-10,13-trans- prostadienoic acid488 190 9-oxo-15-hydroxy-19,20-(1,3-propano)-10,13- trans-prostadienoic acid489 191 9-oxo-15-hydroxy-16-methyl-18,20-ethano-10,13- trans-prostadienoic acid490 192 9-oxo-15-hydroxy-17,20-ethano-10,13-trans- prostadienoic acid491 193 9-oxo-15-hydroxy-17,20-ethano-10,13-trans,18- prostatrienoic acid492 194 9-oxo-15-hydroxy-6,7-dinor-20,20-(1,4-butano)- 10,13-trans-prostadienoic acid493 195 9-oxo-15-hydroxy-6,7-dinor-16,20-methanol-10,13- trans,17-prostatrienoic acid494 196 9-oxo-15-hydroxy-17,18-methano-10,13-trans- prostadienoic acid503 205 9-oxo-15-hydroxy-2-ethyl-16,20-methano-10,13- trans,17-prostatrienoic acid504 206 9-oxo-15-hydroxy-2-ethyl-17,18-methano-10,13- trans-prostadienoic acid505 207 9-oxo-15-hydroxy-2-ethyl-16,19-ethano-10,13- trans-prostadienoic acid506 208 9-oxo-15-hydroxy-2,16-diethyl-19,20-(1,3-pro- pano)-10,13-trans-prostadienoic acid507 209 9-oxo-15-hydroxy-2-methyl-17,18-methano-10,13- trans-prostadienoic acid508 210 9-oxo-15-hydroxy-2-methyl-16,20-(1,3-propano)- 10,13-trans-prostadienoic acid509 211 9-oxo-15-hydroxy-2-methyl-20-cyclopentyl-10,13- trans-prostadienoic acid510 212 9-oxo-15-hydroxy-2-methyl-17,20-ethano-10,13- trans,18-prostatrienoic acid495 197 9-oxo-15-hydroxy-5,6,7-trinor-19,20-(1,4- butano)-10,13-trans-prostadienoic acid496 198 9-oxo-15-hydroxy-5,6,7-trinor-17,18-methano- 10,13-trans-prostadienoic acid497 199 9-oxo-15-hydroxy-5,6,7-trinor-17,20-ethano- 10,13-trans,19-prostatrienoic acid498 200 9-oxo-15-hydroxy-7a,7b-bishomo-17,18-methano- 10,13-trans-prostadienoic acid499 201 9-oxo-15-hydroxy-7a,7b-bishomo-20,20-(1,4- butano)-10,13-trans-prostadienoic acid500 202 9-oxo-15-hydroxy-7a,7b-bishomo-17,20-ethano- 10,13-trans,18-prostatrienoic acid501 203 9-oxo-15-hydroxy-7a,7b-bishomo-16,20-methano- 10,13-trans,18-prostatrienoic acid502 204 9-oxo-15-hydroxy-2-ethyl-17,20-methanol-10,13- trans,18-prostatrienoic acid511 213 9-oxo-15-hydroxy-3,3-dimethyl-17,20-ethano-10,13- trans,18-prostatrienoic acid512 214 9-oxo-15-hydroxy-3,3-dimethyl-16,20-methano-10,13- trans,17-prostatrienoic acid513 215 9-oxo-15-hydroxy-3,3-dimethyl-17,18-methano-10,13- trans-prostadienoic acid514 216 9-oxo-15-hydroxy-3,3-dimethyl-16,20-methanol-10,13- trans-prostadienoic acid515 217 9-oxo-15-hydroxy-3,3,16-trimethyl-18,20-(1,3- propano)-10,13-trans-prostadienoic acid516 218 9-oxo-15-hydroxy-3,3-dimethyl-19,20-(1,3-propano)- 10,13-trans-prostadienoic acid517 219 9-oxo-15-hydroxy-3-oxa-16-methyl-18,20-ethano- 10,13-trans-prostadienoic acid518 220 9-oxo-15-hydroxy-3-oxa-19,20-(1,3-propanol)-10,13- trans-prostadienoic acid519 221 9-oxo-15-hydroxy-3-oxa-17-methyl-20-nor-16,19- methano-10,13-trans-prostadienoic acid520 222 9-oxo-15-hydroxy-3-oxa-17,18-methano-10,13-trans- prostadienoic acid521 223 9-oxo-15-hydroxy-3-oxa-17,20-methano-10,13-trans- 18-prostatrienoic acid522 224 9-oxo-15-hydroxy-3-oxa-16,20-methano-10,13-trans, 18-prostatrienoic acid523 225 9-oxo-15-hydroxy-2-fluoro-17,20-ethano-10,13- trans,18-prostatrienoic acid524 226 9-oxo-15-hydroxy-2-fluoro-7,18-methano-10,13- trans-prostadienoic acid525 227 9-oxo-15-hydroxy-2-fluoro-16,19-methanol-20-nor- 13-trans-prostadienoc acid526 228 9-oxo-15-hydroxy-2-fluoro-17,20-methanol-18-methyl- 10,13-trans-prostadienoic acid527 229 9-oxo-15-hydroxy-6,20-dinor-17,19-methano-10,13- trans-prostadienoic acid528 230 9-oxo-15-hydroxy-6-nor-16-methyl-18,20-ethano-10, 13-trans-prostadienoic acid529 231 9-oxo-15-hydroxy-6-nor-17,18-methano-10,13- trans-prostadienoic acid530 232 9-oxo-15-hydroxy-6-nor-17,20-methano-10,13-trans, 18-prostatrienoic acid531 233 9-oxo-15-hydroxy-6-nor-16,20-methano-10,13-trans, 18-prostatrienoic acid532 234 9-oxo-15-hydroxy-7-homo-16,20-methano-10,13-trans, 17-prostatrienoic acid533 235 9-oxo-15-hydroxy-7-homo-17,20-methanol-10,13-trans, 19-prostatrienoic acid534 236 9-oxo-15-hydroxy-7-homo-17,18-methanol-10,13-trans, prostadienoic acid535 237 9-oxo-15-hydroxy-7-homo-16-methyl-18,20-(1,3-pro- pano)-10,13-trans-prostadienoic acid536 238 9-oxo-15-hydroxy-2-phenyl-17,18-methano-10,13- trans-prostadienoic acid537 239 9-oxo-15-hydroxy-2-phenyl-17-methyl-20-nor-16,18- ethano-10,13-trans-prostadienoic acid538 240 9-oxo-15-hydroxy-2-phenyl-16,20-(1,3-propano)- 10,13-trans-prostadienoic acid539 241 9-oxo-15-hydroxy-2-phenyl-16-methyl-18,20-ethano- 10,13-trans-prostadienoic acid540 242 9-oxo-15-hydroxy-2-phenyl-19,20-(1,4-butano)-10,13- trans-prostadienoic acid541 243 9-oxo-15-hydroxy-2-phenyl-17,20-methano-10,13- trans,18-prostatrienoic acid542 244 9-oxo-15-hydroxy-2-phenyl-16,20-methano-10,13- trans,18-prostatrienoic acid543 245 ethyl 9-oxo-15-hydroxy-17-methyl-17,20-ethano- 10,13-trans-prostadienoate544 246 methyl 9-oxo-15-hydroxy-17,20-ethano-10,13- trans,19-prostatrienoate545 247 1 methyl 9-oxo-15-hydroxy-16,20-methanol-10,13- trans,17-prostatrienoate546 248 1 methyl 9-oxo-15-hydroxy-17,18-methanol-10,13- trans-prostadienoate547 249 1 methyl 9-oxo-15-hydroxy-16-methyl-18,20-(1,3- propano)-10,13-trans-prostadienoate548 250 1 methyl 9-oxo-15-hydroxy-17,20-ethano-20-methyl- 10,13-trans-prostadienoate549 251 d methyl 9-oxo-15-hydroxy-17,20-(1,4-butano)- 10,13-trans-prostadienoate550 252 d methyl 9-oxo-15-hydroxy-16-ethyl-19,20-(1,3- propano)-10,13-trans-prostadienoate551 253 d methyl 9-oxo-15-hydroxy-17,18-methano-10,13- trans-prostadienoate552 254 d methyl 9-oxo-15-hydroxy-16,20-methano-10,13- trans,18-prostatrienoate553 255 d methyl 9-oxo-15-hydroxy-17,20-methano-10,13- trans,18-prostatrienoate554 256 butyl 9-oxo-15-hydroxy-17,18-methano-10,13- trans-prostadienoate555 257 butyl 9-oxo-15-hydroxy-16,20-methano-10,13- trans,17-prostatrienoate556 258 isopropyl 9-oxo-15-hydroxy-16-methyl-18,20-(1,3- propanol)-10,13-trans-prostadienoate557 259 isopropyl 9-oxo-15-hydroxy-19,20-(1,4-butano)- 10,13-trans-prostadienoate558 260 decyl 9-oxo-15-hydroxy-17,20-methanol-18-methyl- 10,13-trans-prostadienoate559 261 decyl 9-oxo-15-hydroxy-17,18-methano-10,13-trans- prostadienoate560 262 decyl 9-oxo-15-hydroxy-17,20-ethanol-10,13-trans- 18-prostatrienoate561 263 9-oxo-15-hydroxy-17,20-methano-10,5-cis,13-trans- prostatrienoic acid562 264 9-oxo-15-hydroxy-18,20-ethano-10,5-cis,13-trans- prostatrienoic acid563 265 9-oxo-15-hydroxy-20-cyclopentyl-10,5-cis,13-trans- prostatrienoic acid564 266 9-oxo-15-hydroxy-16-ethyl-19,20-(1,3-propano)-10, 5-cis,13-trans-prostatrienoic acid565 267 9-oxo-15-hydroxy-18,20-(1,3-propano)-10,5-cis,13- trans-prostatrienoic acid566 268 9-oxo-15-hydroxy-17,20-(1,3-propano)-10,5-cis,13- trans-prostatrienoic acid567 269 9-oxo-15-hydroxy-17,19-(1,3-propano)-10,5-cis, 13-trans-prostatrienoic acid568 270 9-oxo-15-hydroxy-17,18-methano-5-cis,10,13-trans- prostatrienoic acid569 271 9-oxo-15-hydroxy-17,20-methano-5-cis,10,13-trans, 18-prostatetraenoic acid570 272 9-oxo-15-hydroxy-16,20-methano-5-cis,10,13-trans, 17-prostatetraenoic acid571 273 1 methyl 9-oxo-15-hydroxy-19,20-(1,3-propano)-5- cis,10,13-trans-prostatrienoate572 274 1 methyl 9-oxo-15-hydroxy-16-methyl-18,20-ethano- 5-cis,10,13-trans-prostatrienoate573 275 1 methyl 9-oxo-15-hydroxy-20-methyl-19,20-(1,3- propano)-5-cis,10,13-trans-prostatrienoate574 276 1 methyl 9-oxo-15-hydroxy-17,20-ethano-5-cis,10,13- trans-prostatrienoate575 277 1 methyl 9-oxo-15-hydroxy-17,18-methano-5- cis,10,13-trans-prostatrienoate576 278 1 methyl 9-oxo-15-hydroxy-16-methyl-18,20-(1,3- propano)-5-cis,10,13-trans-prostatrienoate577 279 1 methyl 9-oxo-15-hydroxy-20-methyl-17,20-(1,3- propano)-5-cis,10,13-trans-prostatrienoate578 280 1 methyl 9-oxo-15-hydroxy-17,20-(1,4-butano)-5- cis,10,13-trans-prostatrienoate579 281 1 methyl 9-oxo-15-hydroxy-17,20-ethanol-20-methyl- 5-cis,10,13-trans-prostatrienoate580 282 1 methyl 9-oxo-15-hydroxy-17,20-ethanol-5-cis,10,13- trans,18-prostatetraenoate581 283 1 methyl 9-oxo-15-hydroxy-16,20-methano-5-cis,10,13- trans,18-prostatetraenoate582 284 9-oxo-15-hydroxy-7,20-bisnor-17,19-methano-5-cis, 10,13-trans-prostatrienoic acid583 285 9-oxo-15-hydroxy-7-nor-18,20-ethano-5-cis,10,13- trans-prostatrienoic acid584 286 9-oxo-15-hydroxy-7-nor-16-methyl-18,20-ethano-5- cis,10,13-trans-prostatrienoic acid585 287 9-oxo-15-hydroxy-7-nor-20-methyl-17,20-(1,3- propano)-5-cis,13-trans-prostatrienoic acid586 288 9-oxo-15-hydroxy-7-nor-17,18-methano-5-cis,13- trans-prostatrienoic acid587 289 9-oxo-15-hydroxy-7-nor-17,20-ethano-20-methyl-5- cis,10,13-trans-prostatrienoic acid588 290 9-oxo-15-hydroxy-7-nor-17,20-methano-5-cis,10,13- trans,18-prostatetraenoic acid589 291 9-oxo-15-hydroxy-7-nor-16,20-methano-5-cis,10,13- trans,17-prostatetraenoic acid590 292 9-oxo-15-hydroxy-7a-homo-16,20-methano-5-cis,10,13- trans,18-prostatetraenoic acid591 293 9-oxo-15-hydroxy-7a-homo-17,20-methano-5-cis,10,13- trans,18-prostatetraenoic acid592 294 9-oxo-15-hydroxy-7a,7b-bishomo-17,20-ethano-5-cis, 10,13-trans,18-prostatetraenoic acid593 295 9-oxo-15-hydroxy-7a,7b-bishomo-16,20-methano-5- cis,10,13-trans,17-prostatetraenoic acid594 296 9-oxo-hydroxy-7a-homo-17,18-methano-5-cis,10,13- trans-prostatrienoic acid595 297 9-oxo-15-hydroxy-7a-homo-16-methyl-18,20-(1,3- propano)-5-cis,10,13-trans-prostatrienoic acid596 298 9-oxo-15-hydroxy-7a-homo-19,20-(1,3-propano)-5- cis,10,13-trans-prostatrienoic acid597 299 9-oxo-15-hydroxy-7a-homo-17,19-(1,3-propano)-5-cis, 10,13-trans-prostatrienoic acid598 300 9-oxo-15-hydroxy-7a,7b-bishomo-17,18-methanol-5- cis,10,13-trans-prostatrienoic acid599 301 9-oxo-15-hydroxy-7a,7b-bishomo-17-methyl-17,20- ethano-5-cis,10,13-trans-prostatrienoic acid600 302 9-oxo-15-hydroxy-7a,7b-bishomo-16-methyl-18,20- ethano-5-cis,10,13-trans-prostatrienoic acid601 303 9-oxo-15-hydroxy-7a,7b-bishomo-20-cyclopentyl- 5-cis10,13-trans-prostatrienoic acid602 304 9-oxo-15-hydroxy-7a,7b-bishomo-17,20-ethano-20- methyl-5-cis,10,13-trans-prostatrienoic acid603 305 9-oxo-15-hydroxy-4-methyl-18,20-ethano-5-cis,10,13- trans-prostatrienoic acid604 306 9-oxo-15-hydroxy-4,16-dimethyl-18,20-ethano-5-cis, 10,13-trans-prostatrienoic acid605 307 9-oxo-15-hydroxy-4-methyl-18,20-(1,3-propano)-5- cis,10,13-trans-prostatrienoic acid606 308 9-oxo-15-hydroxy-4-methyl-16,19-ethano-5-cis,10,13- trans-prostatrienoic acid607 309 9-oxo-15-hydroxy-4-methyl-17,18-methano-5-cis, 10,13-trans-prostatrienoic acid608 310 9-oxo-15-hydroxy-4-methyl-17,20-methano-5-cis,10,13- trans,18-prostatetraenoic acid609 311 9-oxo-15-hydroxy-4-methyl-16,20-methano-5-cis,10,13- trans,18-prostatetraenoic acid610 312 9-oxo-15-hydroxy-4(R)-methyl-16,20-methano-5-cis, 10,13-trans,17-prostatetraenoic acid611 313 9-oxo-15-hydroxy-4(R)-17,20-ethano-5-cis,10,13- trans,19-prostatetraenoic acid612 314 9-oxo-15-hydroxy-4(R)-17,18-methano-5-cis,10,13- trans-prostatrienoic acid613 315 9-oxo-15-hydroxy-4(R),16-dimethyl-18,20(1,3-propano) 5-cis,10,13-trans-prostatrienoic acid614 316 9-oxo-15-hydroxy-4(R)-methyl-16,20-ethano-5-cis, 10,13-trans-prostatrienoic acid615 317 9-oxo-15-hydroxy-4(R)-methyl-19,20-(1,3-propano)- 5-cis,10,13-trans-prostatrienoic acid616 318 9-oxo-15-hydroxy-4(R),17-dimethyl-20-nor-16,18- ethano-5-cis,10,13-trans-prosttrienoic acid617 319 9-oxo-15-hydroxy-4-ethyl-20,20-(1,4-butano)-5- cis-10,13-trans-prostatrienoic acid618 320 9-oxo-15-hydroxy-4-ethyl-17,20-methanol-18-methyl- 5-cis-10,13-trans-prostatrienoic acid619 321 9-oxo-15-hydroxy-4-ethyl-17,20-ethano- - trans-prostatrienoic acid620 322 9-oxo-15-hydroxy-4-ethyl-16,20-(1,3-propano)-5- cis,10,13-trans-prostatrienoic acid621 323 9-oxo-15-hydroxy-4-ethyl-17,18-methano-5-cis,10,13- trans-prostatrienoic acid622 324 9-oxo-15-hydroxy-4-ethyl-4-17,20-ethano-5-cis,10,13- trans,18-prostatetraenoic acid623 325 9-oxo-15-hydroxy-4-ethyl-16,20-methano-5-cis,10,13- trans,18-prostatetraenoic acid624 326 9-oxo-15-hydroxy-4-propyl-16,20-methano-5-cis,10,13- trans,17-prostatetraenoic acid625 327 9-oxo-15-hydroxy-4-propyl-17,20-methano-5-cis,10,13- trans,18-prostatetraenoic acid626 328 9-oxo-15-hydroxy-4-propyl-17,18-methano-5-cis,10, 13-trans-prostatrienoic acid627 329 9-oxo-15-hydroxy-4-propyl-18,20-ethano-5-cis,10,13- trans-prostatrienoic acid628 330 9-oxo-15-hydroxy-4-propyl-16-methyl-18,20-(1,3- propano)-5-cis,10,13-trans-prostatrienoic acid629 331 9-oxo-15-hydroxy-4-propyl-20-cyclopentyl-5-cis,10, 13-trans-prostatrienoic acid630 332 9-oxo-15-hydroxy-4-propyl-20-methyl-19,20-(1,3- propano)-5-cis,10,13-trans-prostatrienoic acid631 333 9-oxo-15-hydroxy-4-propyl-17-methyl-20-nor-16,18- ethano-5-cis,10,13-trans-prostatrienoic acid632 334 9-oxo-15-hydroxy-4-propyl-16,20-methano-5-cis,10, 13-trans-prostatrienoic acid633 335 9-oxo-15-hydroxy-4-propyl-17,20-(1,3-propano)-5 cis,10,13-trans-prostatrienoic acid634 336 9-oxo-15-hydroxy-4-propyl-16,20-ethano-5-cis,10,13-trans-prostatrienoic acid__________________________________________________________________________

EXAMPLE 635

Preparation of 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano-13-trans,19-prostadienoic acid

A suspension of 500 mg. of methyl 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano-13-trans,19-prostadienoate (Example 395) in 10 ml. of methanol-water (1:1) containing 200 mg. of potassium hydroxide is stirred under nitrogen atmosphere at 50.degree. C. for 1 hour. The resulting solution is then stirred at ambient temperature for 18 hours. The solution is cooled in an ice-bath, acidified with 1 N hydrochloric acid and extracted several times with ether. The combined extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 410 mg. of product as an oil.

EXAMPLES 636-656

Saponification of the 9.alpha.-hydroxy esters listed in Table 18 below by the procedure described in Example 635 furnishes the corresponding product carboxylic acids.

Table 18__________________________________________________________________________ Starting 9.alpha.-hydroxy ester Product 9.alpha.-hydroxy-prostenoic acidExample of Example and 15-epi isomer thereof__________________________________________________________________________636 396 l 9.alpha.,11.alpha.,15-trihydroxy-16,20-methano-13-tran s, 17-prostadienoic acid637 397 l 9.alpha.,11.alpha.,15-trihydroxy-17,18-methano-13-tran s- prostenoic acid638 398 l 9.alpha.,11.alpha.,15-trihydroxy-16-methyl-18,20-(1,3- pro- pano)-13-trans prostenoic acid639 399 l 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano-20-methy l-13- trans-prostenoic acid640 400 d 9.alpha.,11.alpha.,15-trihydroxy-17,20-(1,4-butano)-13 -trans- prostenoic acid641 401 d 9.alpha.,11.alpha.,15-trihydroxy-16-ethyl-19,20-(1,3-p ropano)- 13-trans-prostenoic acid642 402 d 9.alpha.,11.alpha.,15-trihydroxy-17,18-methano-13-tran s- prostenoic acid643 403 d 9.alpha.,11.alpha.,15-trihydroxy-16,20-methano-13-tran s,18- prostadienoic acid644 404 d 9.alpha.,11.alpha.,15-trihydroxy-17,20-methano-13-tran s,18- prostadienoic acid645 422 l 9.alpha.,11.alpha.,15-trihydroxy-19,20-(1,3-propano)-5 -cis, 13-trans-prostadienoic acid646 423 l 9.alpha.,11.alpha.,15-trihydroxy-16-methyl-18,20-ethan o-5- cis,13-trans-prostadienoic acid647 424 l 9.alpha.,11.alpha.,15-trihydroxy-20-methyl-19,20-(1,3- pro- prano)-5-cis,13-trans-prostadienoic acid648 425 l 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano-5-cis,13 - trans-prostadienoic acid649 426 l 9.alpha.,11.alpha.,15-trihydroxy-17,18-methano-5-cis,1 3- trans-prostadienoic acid650 427 l 9.alpha.,11.alpha.,15-trihydroxy-16-methyl-18,20-(1,3- pro- pano)-5-cis,13-trans-prostadienoic acid651 428 l 9.alpha.,11.alpha.,15-trihydroxy-20-methyl-17,20-(1,3- 9 propano)-5-cis,13-trans-prostadienoic acid652 429 l 9.alpha.,11.alpha.,15-trihydroxy-17,20-(1,4-butano)-5- cis, 13-trans-prostadienoic acid653 430 l 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano-20-methy l- 5-cis,13-trans-prostadienoic acid654 431 l 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano-5-cis,13 - trans,18-prostatrienoic acid655 432 l 9.alpha.,11.alpha.,16-trihydroxy-16,20-methano-5-cis,1 3- trans,18-prostatrienoic acid__________________________________________________________________________

EXAMPLE 657

A solution of 9-oxo-11.alpha.,15-dihydroxy-17,20-methano-13-trans-prostenoic acid (Example 187) in tetrahydrofuran is added to 2.2 equivalents of lithium perhydro-9b-boraphenyalyl hydride in tetrahydrofuran at -78.degree. C. After 30 minutes the solution is diluted with water and extracted with ether. The aqueous phase is acidified, saturated with sodium chloride and extracted with ether. The combined ether extracts are dried (magnesium sulfate) and concentrated in vacuo to give 9.alpha.,11.alpha.,15-trihydroxy-17,20-methano-13-trans-prostenoic acid, contaminated with 9.beta.,11.alpha.,15-trihydroxy-17,20-methano-13-trans-prostenoic acid. The crude mixture of acids is dissolved in methylene chloride and added to a refluxing solution of 1.2 equivalents of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in methylene chloride. After 5 hours, the solution is cooled and filtered. The filtrate is concentrated in vacuo and the residue is purified by column chromatography to give 9.alpha.,11.alpha.-dihydroxy-15-oxo-17,20-methano-13-trans-prostenoic acid. This material is dissolved in benzene and 3.3 equivalents each of triethylamine and trimethylsilyl chloride is added. The triethylamine hydrochloride is removed by filtration and the solution is concentrated in vacuo to give trimethylsilyl 9.alpha.,11.alpha.-bis(trimethylsiloxy)-15-oxo-17,20-methano-13-trans-prostenoate.

The siloxy derivative is dissolved in ether at 0.degree. C. and 1.3 equivalents of methyl magnesium bromide in ether is added. After 12 hours the solution is poured into saturated aqueous ammonium chloride and extracted with ether. The ether is dried and concentrated in vacuo to give an oil. Hydrolysis of the siloxy function in methanol:water:acetic acid (approximately 10:1:1), gives 9.alpha.,11.alpha.,15.alpha.-trihydroxy-15.beta.-methyl-17,20-methano-13-trans-prostenoic acid and 9.alpha.,11.alpha.,15.beta.(epi)-trihydroxy-15.alpha.-methyl-17,20-methano-13-trans-prostenoic acid, which are separated by chromatographic procedures.

Treatment of a solution of 9.alpha.,11.alpha.,15.alpha.-trihydroxy-15.beta.-methyl-17,20-methano-13-trans-prostenoic acid with an excess of N-trimethylsilyldiethylamine in acetone at -45.degree. C. gives trimethylsiloxy 9.alpha.,15.alpha.-dihydroxy-11.alpha.-trimethylsiloxy-15.beta.-methyl-17,20-methano-13-trans-prostenoate. The resulting bis trimethylsilyl derivative is oxidized with chromic acid-pyridine in methylene chloride (Collins Reagent) to give trimethylsiloxy 9-oxo-11.alpha.-trimethylsiloxy-15.alpha.-hydroxy-15.beta.-methyl-17,20-methano-13-trans-prostenoate, which without purification is treated with aqueous methanol containing a trace of acetic acid to furnish 9-oxo-11.alpha.,15.alpha.-dihydroxy-15.beta.-methyl-17,20-methano-13-trans-prostenoic acid.

Similar treatment of the corresponding 15.beta.-hydroxy acid gives 9-oxo-11.alpha.,15.beta.-dihydroxy-15.alpha.-methyl-17,20-methano-13-trans-prostenoic acid.

EXAMPLES 658-738

Treatment of the 9-oxo-15-hydroxyprostenoic acids of Table 19 below by the sequence of reactions described in Example 657 is productive of the 9-oxo-15-hydroxy-15-methyl products of the table. Also prepared in the course of these reaction sequences are the 9.alpha.-hydroxy derivatives corresponding to the 9-oxo products of the table, and 15-keto derivatives of the 9.alpha.- and 9.beta.-hydroxy compounds corresponding to the 9-oxo starting compounds, and the 9.alpha.- or 9.beta.-trimethylsilyloxy trimethyl silyl esters of the 15-keto and 15-hydroxy-15-methyl compounds. In all cases both the 15.alpha.-hydroxy-15.beta.-methyl and the 15.beta.-hydroxy-15.alpha.-methyl products and intermediates are obtained. The epimers are separable by chromatographic procedures, usually by column or dry column chromatography, or preparative thin layer chromatography and in more difficult cases by high speed liquid chromatograph applying if necessary, the recycling technique, described hereinabove.

TABLE 19__________________________________________________________________________ Starting 9-oxo-15-hydroxy- Product 9-oxo-15-hydroxy-15-methylExample derivative of Example derivative and 15-epi isomer thereof__________________________________________________________________________658 189 9-oxo-11.alpha.,15-dihydroxy-15-methyl-18,20-ethano- 13-trans-prostenoic acid659 190 9-oxo-11.alpha.,15-dihydroxy-15-methyl-19,20-(1,3-pro- pano)-13-trans-prostenoic acid660 192 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-ethano-13- N trans-prostenoic acid661 193 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-ethano-13- O trans,18-prostadienoic acid662 194 9-oxo-11.alpha.,15-dihydroxy-6,7-dinor-15-methyl-20,20- Z (1,4-butano)-13-trans-prostenoic acid663 196 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,18-methano- 13-trans-prostenoic acid664 197 9-oxo-11.alpha.,15-dihydroxy-15-methyl-5,6,7-trinor- 19,20-(1,4-butano)-13-trans-prostenoic acid665 198 9-oxo-11.alpha.,15-dihydroxy-5,6,7-trinor-15-methyl- 17,18-methano-13-trans-prostenoic acid666 199 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-ethano- 13-trans,19-prostadienoic acid667 200 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-15-methyl- 17,18-methano-13-trans-prostenoic acid668 201 9-oxo-11.alpha.,15-dihydroxy-15-methyl-7a,7b-bishomo- 20,20-(1,4-butano)-13-trans-prostenoic acid669 202 9-oxo-11.alpha.,15-dihydroxy-15-methyl-7a,7b-bishomo- 17,20-ethano-13-trans,18-prostadienoic acid670 204 9-oxo-11.alpha.,15-dihydroxy-15-methyl-2-ethyl-17,20- methano-13-trans,18-prostadienoic acid671 206 9-oxo-11.alpha.,15-dihydroxy-15-methyl-2-ethyl-17,18- methano-13-trans-prostenoic acid672 209 9-oxo-11.alpha.,15-dihydroxy-2,15-dimethyl-17,18- methano-13-trans-prostenoic acid673 211 9-oxo-11.alpha.,15-dihydroxy-2,15-dimethyl-20-cyclo- pentyl-13-trans-prostenoic acid674 212 9-oxo-11.alpha.,15-dihydroxy-2,15-dimethyl-17,20- ethano-13-trans,18-prostadienoic acid675 213 9-oxo-11.alpha.,15-dihydroxy-3,3,15-trimethyl-17,20- ethano-13-trans,18-prostadienoic acid676 215 9-oxo-11.alpha.,15-dihydroxy-3,3,15-trimethyl-17,18- methano-13-trans-prostenoic acid677 218 9-oxo-11.alpha.,15-dihydroxy-3,3,15-trimethyl-19,20- (1,3-propano)-13-trans-prostenoic acid678 220 9-oxo-11.alpha.,15-dihydroxy-3-oxa-15-methyl-19,20- (1,3-propano)-13-trans-prostenoic acid679 222 9-oxo-11.alpha.,15-dihydroxy-15-methyl-3-oxa-17,18- methano-13-trans-prostenoic acid680 223 9-oxo-11.alpha.,15-dihydroxy-15-methyl-3-oxa-17,18- methano-13-trans-prostenoic acid681 225 9-oxo-11.alpha.,15-dihydroxy-2-fluoro-15-methyl-17,20- ethano-13-trans,18-prostadienoic acid682 226 9-oxo-11.alpha.,15-dihydroxy-15-methyl-2-fluoro-17,18- methano-13-trans-prostenoic acid683 229 9-oxo-11.alpha.,15-dihydroxy-6,20-dinor-15-methyl-17, 19-methano-13-trans-prostenoic acid684 230 9-oxo-11.alpha.,15-dihydroxy-6-nor-15-methyl-17, 18-methano-13-trans-prostenoic acid685 232 9-oxo-11.alpha.,15-dihydroxy-6-nor-15-methyl-17,20- methano-13-trans,18-prostadienoic acid686 234 9-oxo-11.alpha.,15-dihydroxy-7-homo-15-methyl-16,20- ethano-13-trans,1 -prostadienoic acid687 236 9-oxo-11.alpha.,15-dihydroxy-15-methyl-7-homo-17,18- methano-13-trans-prostenoic acid688 238 9-oxo-11.alpha.,15-dihydroxy-2-phenyl-15-methyl-17, 18-methano-13-trans-prostenoic acid689 242 9-oxo-11.alpha.,15-dihydroxy-2-phenyl-15-methyl-19,20- (1,4-butano)-13-trans-prostenoic acid690 243 9-oxo-11.alpha.,15-dihydroxy-2-phenyl-15-methyl-17,20- methano-13-trans,18-prostadienoic acid691 263 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-methano- 5-cis,13-trans-prostadienoic acid692 264 9-oxo-11.alpha.,15-dihydroxy-15-methyl-18,20-ethano- 5-cis,13-trans-prostadienoic acid693 265 9-oxo-11.alpha.,15-dihydroxy-15-methyl-20-cyclopentyl- 5-cis,13-trans-prostadienoic acid694 268 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-(1,3- propano)-5-cis,13-trans-prostadienoic acid695 270 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,18-methano- 5-cis,13-trans-prostadienoic acid696 271 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-methano- 5-cis,13-trans,18-prostatrienoic acid697 285 9-oxo-11.alpha.,15-dihydroxy-7-nor-15-methyl-18,20- ethano-5-cis,13-trans-prostadienoic acid698 287 9-oxo-11.alpha.,15-dihydroxy-7-nor-15,20-dimethyl- 17,20-(1,3-propano)-5-cis,13-trans-prostadienoic acid699 288 9-oxo-11.alpha.,15-dihydroxy-7-nor-15-methyl-17,18- methano-5-cis,13-trans-prostadienoic acid700 290 9-oxo-11.alpha.,15-dihydroxy-7-nor-15-methyl-17,20- methano-5-cis,13-trans,18-prostatrienoic acid701 293 9-oxo-11.alpha.,15-dihydroxy-7a-homo-15-methyl-17,20- methano-5-cis,13-trans,18-prostatrienoic acid702 294 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-15-methyl- 17,20-ethano-5-cis,13-trans,18-prostatrienoic acid703 296 9-oxo-11.alpha.,15-dihydroxy-7a-homo-15-methyl-17,18- methano-5-cis,13-trans-prostadienoic acid704 298 9-oxo-11.alpha.,15-dihydroxy-7a-homo-15-methyl-19,20- (1,3-propano)-5-cis,13-trans-prostadienoic acid705 300 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-15-methyl- 17,18-methano-5-cis,13-trans-prostadienoic acid706 303 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-15-methyl- 20-cyclopentyl-5-cis,13-trans-prostadienoic acid707 304 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-15-methyl- 17,20-ethano-20-methyl-5-cis,13-trans-prosta- dienoic acid708 305 9-oxo-11.alpha.,15-dihydroxy-4,15-dimethyl-18,20- ethano-5-cis,13-trans-prostadienoic acid709 307 9-oxo-11.alpha.,15-dihydroxy-4,15-dimethyl-18,20-(1,3- propano)-5-cis,13-trans-prostadienoic acid710 309 9-oxo-11.alpha.,15-dihydroxy-4,15-dimethyl-17,18- methano-5-cis,13-trans-prostadienoic acid711 310 9-oxo-11.alpha.,15-dihydroxy-4,15-dimethyl-17,20- methano-5-cis,13-trans,18-prostatrienoic acid712 312 9-oxo-11.alpha.,15-dihydroxy-4(R),15-dimethyl-16,20- methano-5-cis,13-trans,17-prostatrienoic acid713 313 9-oxo-11.alpha.,15-dihydroxy-4(R),15-dimethyl-17,20- ethano-5-cis,13-trans,18-prostatrienoic acid714 314 9-oxo-11.alpha.,15-dihydroxy-4(R),15-dimethyl-17,18- methano-5-cis,13-trans-prostadienoic acid715 317 9-oxo-11.alpha.,15-dihydroxy-4(R),15-dimethyl-19,20-(1, N 3-propano)-5-cis,13-trans-prostadienoic acid716 319 9-oxo-11.alpha.,15-dihydroxy-4-ethyl-15-methyl-20,20- (1,4-butano)-5-cis,13-trans-prostadienoic acid717 321 9-oxo-11.alpha.,15-dihydroxy-4-ethyl-15-methyl-17,20- ethano-5-cis,13-trans-prostadienoic acid718 323 9-oxo-11.alpha.,15-dihydroxy-4-ethyl-15-methyl-17,18- methano-5-cis,13-trans-prostadienoic acid719 324 9-oxo-11.alpha.,15-dihydroxy-4-ethyl-15-methyl-17,20- ethano-5-cis,13-trans,18-prostatrienoic acid720 326 9-oxo-11.alpha., 15-dihydroxy-4-propyl-15-methyl-16,20- O methano-5-cis,13-trans,17-prostatrienoic acid721 328 9-oxo-11.alpha.,15-dihydroxy-4-propyl-15-methyl-17,18- methano-5-cis,13-trans-prostadienoic acid722 329 9-oxo-11.alpha.,15-dihydroxy-4-propyl-15-methyl-18,20- ethano-5-cis,13-trans-prostadienoic acid723 331 9-oxo-11.alpha.,15-dihydroxy-4-propyl-20-cyclopentyl- 5-cis,13-trans-prostadienoic acid724 332 9-oxo-11.alpha.,15-dihydroxy-4-propyl-15,20-dimethyl- 19,20-(1,3-propano)-5-cis,13-trans-prosta- dienoic acid725 636 l 9-oxo-11.alpha.,15-dihydroxy-15-methyl-16,20-methano- 1 13-trans,17-prostadienoic acid726 637 l 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,18-methano- 1 13-trans-prostenoic acid727 638 l 9-oxo-11.alpha.,15-dihydroxy-15,16-dimethyl-18,20- (1,3-propano)-13-trans-prostenoic acid728 640 d 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-(1,4- butano)-13-trans-prostenoic acid729 642 d 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,18-methano- Z 13-trans-prostenoic acid730 644 d 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-methano- 1 13-trans,18-prostadienoic acid731 645 l 9-oxo-11.alpha.,15-dihydroxy-15-methyl-19,20-(1,3- propano)-5-cis,13-trans-prostadienoic acid732 646 l 9-oxo-11.alpha.,15-dihydroxy-15-methyl-16,20-methano- 2 5-cis,13-trans,18-prostatrienoic acid733 648 l 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-ethano- 5-cis,13-trans-prostadienoic acid734 649 l 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,18-methano- Z 5-cis,13-trans-prostadienoic acid735 651 l 9-oxo-11.alpha.,15-dihydroxy-15,20-dimethyl-17,20- (1,3-propano)-5-cis,13-trans-prostadienoic acid736 652 l 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-(1,4- butano)-5-cis,13-trans-prostadienoic acid737 653 l 9-oxo-11.alpha.,15-dihydroxy-15,20-dimethyl-5-cis, 13-trans-prostadienoic acid738 654 1 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-ethano- 5-cis,13-trans,18-prostatrienoic acid__________________________________________________________________________

EXAMPLE 739

Preparation of 9-oxo-11.alpha.,15-dihydroxy-17,20-methanoprostanoic acid

A 2 g. sample of 9-oxo-11.alpha.,15-dihydroxy-17,20-methano-13-trans-prostenoic acid (Example 187) dissolved in 50 ml. ethanol is hydrogenated at about 30 p.s.i. in a Parr shaker using 700 mg. of 10% palladium on carbon. The catalyst is removed by filtration and the momother liquor is taken to dryness to give 2 g. of subject compound as an oil.

EXAMPLES 740-863

Catalytic hydrogenation with 10% palladium-on-carbon catalyst by the procedure described in Example 739 of the various prostenoic acids or esters listed below in Table 20 provides the corresponding product prostanoic acids or esters of the table.

TABLE 20__________________________________________________________________________ Starting Prostenoic Acid Product Prostanoic Acid or Ester andExample or Ester of Example 15-epi isomer thereof__________________________________________________________________________740 189 9-oxo-11.alpha.,15-dihydroxy-18,20-ethano-prostanoic acid741 190 9-oxo-11.alpha.,15-dihydroxy-19,20-(1,3-propano)-pro- stanoic acid742 191 9-oxo-11.alpha.,15-dihydroxy-16-methyl-18,20-ethano- prostanoic acid743 192 9-oxo-11.alpha.,15-dihydroxy-17,20-ethano-prostanoic acid744 194 9-oxo-11.alpha.,15-dihydroxy-6,7-dinor-20,20-(1,4- butano)-prostanoic acid745 196 9-oxo-11.alpha.,15-dihydroxy-17,18-methano-prostanoic acid746 197 9-oxo-11.alpha.,15-dihydroxy-5,6,7-trinor-19,20-(1,4- butano)-prostanoic acid747 198 9-oxo-11.alpha.,15-dihydroxy-5,6,7-trinor-17,18-methano- N prostanoic acid748 200 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-17,18-methano - prostanoic acid749 201 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-20,20-(1,4- butano)-prostanoic acid750 206 9-oxo-11.alpha.,15-dihydroxy-2-ethyl-17,18-methano- prostanoic acid751 207 9-oxo-11.alpha.,15-dihydroxy-2-ethyl-16,19-ethano- prostanoic acid752 208 9-oxo-11.alpha.,15-dihydroxy-2,16-diethyl-19,20-(1,3- propano)-prostanoic acid753 209 9-oxo-11.alpha.,15-dihydroxy-2-methyl-17,18-methano- prostanoic acid754 210 9-oxo-11.alpha.,15-dihydroxy-2-methyl-16,20-(1,3-pro- pano)-prostanoic acid755 211 9-oxo-11.alpha.,15-dihydroxy-2-methyl-20-cyclopentyl- prostanoic acid756 215 9-oxo-11.alpha.,15-dihydroxy-3,3-dimethyl-17,18-methano- 1 prostanoic acid757 216 9-oxo-11.alpha.,15-dihydroxy-3,3-dimethyl-16,20-methano- 3 prostanoic acid758 217 9-oxo-11.alpha.,15-dihydroxy-3,3,16-trimethyl-18,20-(1,3 - propano)-prostanoic acid759 219 9-oxo-11.alpha.,15-dihydroxy-3-oxa-16-methyl-18,20- ethano-prostanoic acid760 220 9-oxo-11.alpha.,15-dihydroxy-3-oxa-19,20-(1,3-propano)- - prostanoic acid761 222 9-oxo-11.alpha. ,15-dihydroxy-3-oxa-17,18-methano-pro- Z stanoic acid762 226 9-oxo-11.alpha.,15-dihydroxy-2-fluoro-17,18-methano prostanoic acid763 227 9-oxo-11.alpha.,15-dihydroxy-2-fluoro-16,19-methano-20- 1 nor-prostanoic acid764 229 9-oxo-11.alpha.,15-dihydroxy-6,20-dinor-17,19-methano- prostanoic acid765 230 9-oxo-11.alpha.,15-dihydroxy-6-nor-16-methyl-18,20-ethan o- prostanoic acid766 231 9-oxo-11.alpha.,15-dihydroxy-6-nor-17,18-methano-pro- stanoic acid767 236 9-oxo-11.alpha.,15-dihydroxy-7-homo-17,18-methano- prostanoic acid768 237 9-oxo-11.alpha.,15-dihydroxy-7-homo-16-methyl-18,20- (1,3-propano)-prostanoic acid769 238 9-oxo-11.alpha.,15-dihydroxy-2-phenyl-17,18-methano- prostanoic acid770 240 9-oxo-11.alpha.,15-dihydroxy-2-phenyl-16,20-(1,3-pro- pano)-prostanoic acid771 241 9-oxo-11.alpha.,15-dihydroxy-2-phenyl-16-methyl-18,20- ethano-prostanoic acid772 248 l methyl 9-oxo-11.alpha.,15-dihydroxy-17,18-methano- prostanoate773 249 l methyl 9-oxo-11.alpha.,15-dihydroxy-16-methyl-18,20- (1,3-propano)-prostanoate774 250 l methyl 9-oxo-11.alpha.,15-dihydroxy-17,20-ethano-20- methyl-prostanoate775 251 d methyl 9-oxo-11.alpha.,15-dihydroxy-17,20-(1,4-butano) - prostanoate776 252 d methyl 9-oxo-11.alpha.,15-dihydroxy-16-ethyl-19,20- (1,3-propano)-prostanoate777 253 d methyl 9-oxo-11.alpha.,15-dihydroxy-17,18-methano- prostanoate778 256 butyl 9-oxo-11.alpha.,15-dihydroxy-17,18-methano- prostanoate779 258 isopropyl 9-oxo-11.alpha.,15-dihydroxy-16-methyl-18,20- O (1,3-propano)-prostanoate780 259 isopropyl 9-oxo-11.alpha.,15-dihydroxy-19,20-(1,4-butano )- prostanoate781 260 decyl 9-oxo-11.alpha.,15-dihydroxy-17,20-methano-18- methyl-prostanoate782 261 decyl 9-oxo-11.alpha.,15-dihydroxy-17,18-methano-pro- stanoate783 338 9.alpha.,11.alpha.,15-trihydroxy-18,20-ethano-prostanoic acid784 339 9.alpha.,11.alpha.,15-trihydroxy-19,20-(1,3-propano)-pro stanoic acid785 340 9.alpha.,11.alpha.,15-trihydroxy-16-methyl-18,20-ethano- 5 prostanoic acid786 342 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano-prostanoic acid787 343 9.alpha.,11.alpha.,15-trihydroxy-6,7-dinor-20,20-(1,4-bu tano)- prostanoic acid788 345 9.alpha.,11.alpha.,15-trihydroxy-17,18-methano-prostanoi c acid789 347 9.alpha.,11.alpha.,15-trihydroxy-5,6,7-trinor-17,18-,met hano- prostanoic acid790 349 9.alpha.,11.alpha.,15-trihydroxy-7a,7b-bishomo-17,18-met hano- prostanoic acid791 350 9.alpha.,11.alpha.,15-trihydroxy-7a,7b-bishomo-20,20-(1, 4- butano)-prostanoic acid792 355 9.alpha.,11.alpha.,15-trihydroxy-2-ethyl-17,18-methano- o prostanoic acid793 356 9.alpha.,11.alpha.,15-trihydroxy-2-ethyl-16,19-ethano-pr ostanoic acid794 357 9.alpha.,11.alpha.,15-trihydroxy-2,16-diethyl-19,20-(1,3 - propano)-prostanoic acid795 358 9.alpha.,11.alpha.,15-trihydroxy-2-methyl-17,18-methano- q prostanoic acid796 359 9.alpha.,11.alpha.,15-trihydroxy-2-methyl-16,20-(1,3-pro pano)- prostanoic acid797 360 9.alpha.,11.alpha.,15-trihydroxy-2-methyl-20-cyclopentyl - prostanoic acid798 364 9.alpha.,11.alpha.,15-trihydroxy-3,3-dimethyl-17,18-meth ano- prostanoic acid799 365 9.alpha.,11.alpha.,15-trihydroxy-3,3-dimethyl-16,20-meth ano- prostanoic acid800 366 9.alpha.,11.alpha.,15-trihydroxy-3,3,16-trimethyl-18,20- (1,3- propano-prostanoic acid801 368 9.alpha.,11.alpha.,15-trihydroxy-3-oxa-16-methyl-18,20-e thano- prostanoic acid802 369 9.alpha.,11.alpha.,15-trihydroxy-3-oxa-19,20-(1,3-propan o)- prostanoic acid803 371 9.alpha.,11.alpha.,15-trihydroxy-3-oxa-17,18-methano-pro stanoic acid804 375 9.alpha.,11.alpha.,15-trihydroxy-2-fluoro-17,18-methano- pro- stanoic aci805 376 9.alpha.,11.alpha.,15-trihydroxy-2-fluoro-16,19-methano- 20- nor-prostanoic acid806 378 9.alpha.,11.alpha.,15-trihydroxy-6,20-dinor-17,19-methan o- prostanoic acid807 379 9.alpha.,11.alpha.,15-trihydroxy-6-nor-16-methyl-18,20-e thano- prostanoic acid808 380 9.alpha.,11.alpha.,15-trihydroxy-6-nor-17,18-methano-pro stanoic acid809 385 9.alpha.,11.alpha.,15-trihydroxy-7-homo-17,18-methano- prostanoic acid810 386 9.alpha.,11.alpha.,15-trihydroxy-7-homo-16-methyl-18,20- (1,3- propano)-prostanoic acid811 387 9.alpha.,11.alpha.,15-trihydroxy-2-phenyl-17,18-methano- a prostanoic acid812 389 9.alpha.,11.alpha.,15-trihydroxy-2-phenyl-16,20-(1,3-pro pano)- prostanoic acid813 390 9.alpha.,11.alpha.,15-trihydroxy-16-methyl-18,20-ethano- o prostanoic acid814 391 9.alpha.,11.alpha.,15-trihydroxy-2-phenyl-19,20-(1,4-but ano)- prostanoic acid815 397 l methyl 9.alpha.,11.alpha.,15-trihydroxy-17,18-methano- t prostanoate816 398 l methyl 9.alpha.,11.alpha.,15-trihydroxy-16-methyl-18,2 0- (1,3-propano)-prostanoate817 399 l methyl 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano-2 0- methyl-prostanoate818 400 d methyl 9.alpha.,11.alpha.,15-trihydroxy-17,20-(1,4-but ano)- prostanoate819 401 d methyl 9.alpha.,11.alpha.,15-trihydroxy-16-ethyl-19,20 - (1,3-propano)-prostanoate820 402 d methyl 9.alpha.,11.alpha.,15-trihydroxy-17,18-methano- O prostanoate821 405 butyl 9.alpha.,11.alpha.,15-trihydroxy-17,18-methano- prostanoate822 407 isopropyl 9.alpha.,11.alpha.,15-trihydroxy-16-methyl-18, 20- (1,3-propano)-prostanoate823 408 isopropyl 9.alpha.,11.alpha.,15-trihydroxy-19,20-(1,4-bu tano)- prostanoate824 409 decyl 9.alpha.,11.alpha.,15-trihydroxy-17,20-methano-18- methyl- prostanoate825 410 decyl 9.alpha.,11.alpha.,15-trihydroxy-17,18-methano- prostanoate826 637 l 9.alpha.,11.alpha.,15-trihydroxy-17,18-methano-prostan oic acid827 638 l 9.alpha.,11.alpha.,15-trihydroxy-16-methyl-18,20-(1,3- propano)- prostanoic acid828 639 l 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano-20-methy l- prostanoic acid829 652 l 9.alpha.,11.alpha. ,15-trihydroxy-17,20-(1,4-butano)-p rostanoic acid830 641 d 9.alpha.,11.alpha.,15-trihydroxy-16-ethyl-19,20-(1,3-p ro- pano)-prostanoic acid831 642 d 9.alpha.,11.alpha.,15-trihydroxy-17,18-methano-prostan oic acid832 643 d 9.alpha.,11.alpha.,15-trihydroxy-16,20-methano-prostan oic acid833 644 d 9.alpha.,11.alpha.,15-trihydroxy-17,20-methano-prostan oic acid834 658 9-oxo-11.alpha.,15-dihydroxy-15-methyl-18,20-ethano- prostanoic acid835 659 9-oxo-11.alpha.,15-dihydroxy-15-methyl-19,20-(1,3-pro- pano)-prostanoic acid836 660 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-ethano- prostanoic acid837 663 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,18-methano- prostanoic acid838 667 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-15-methyl- 17,18-methano-prostanoic acid839 668 9-oxo-11.alpha.,15-dihydroxy-7a,7b-bishomo-15-methyl- 20,20-(1,4-butano)-prostanoic acid840 671 9-oxo-11.alpha.,15-dihydroxy-15-methyl-2-ethyl-17,18- methano-prostanoic acid841 672 9-oxo-11.alpha.,15-dihydroxy-2,15-dimethyl-17,18-methano - prostanoic acid842 673 9-oxo-11.alpha.,15-dihydroxy-2,15-dimethyl-20-cyclopenty l- prostanoic acid843 676 9-oxo-11.alpha.,15-dihydroxy-3,3,15-trimethyl-17,18- methano-prostanoic acid844 677 9-oxo-11.alpha.,15-dihydroxy-3,3,15-trimethyl-19,20-(1,3 - propano)-prostanoic acid845 678 9-oxo-11.alpha.,15-dihydroxy-3-oxa-15-methyl-19,20-(1,3- . propano)-prostanoic acid846 679 9-oxo-11.alpha.,15-dihydroxy-15-methyl-3-oxa-17,18- methano-prostanoic acid847 681 9-oxo-11.alpha.,15-dihydroxy-2-fluoro-15-methyl-17,20- ethano-prostanoic acid848 682 9-oxo-11.alpha.,15-dihydroxy-2-fluoro-15-methyl-17,18- methano-prostanoic acid849 683 9-oxo-11.alpha.,15-dihydroxy-6,20-dinor-15-methyl-17,19- d methano-prostanoic acid850 684 9-oxo-11.alpha.,15-dihydroxy-6-nor-15-methyl-17,18- methano-prostanoic acid851 687 9-oxo-11.alpha.,15-dihydroxy-7-homo-15-methyl-17,18- methano-prostanoic acid852 688 9-oxo-11.alpha.,15-dihydroxy-2-phenyl-15-methyl-17,18- methano-prostanoic acid853 689 9-oxo-11.alpha.,15-dihydroxy-2-phenyl-15-methyl-19,20- (1,4-butano)-prostanoic acid854 725 l 9-oxo-11.alpha.,15-dihydroxy-15-methyl-16,20-methano- e prostanoic acid855 726 l 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,18-methano- g prostanoic acid856 727 l 9-oxo-11.alpha.,15-dihydroxy-15,16-dimethyl-18,20- (1,3-propano)-prostanoic acid857 728 d 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-(1,4- butano)-prostanoic acid858 729 d 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,18-methano- r prostanoic acid859 730 d 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-methano- e prostanoic acid860 731 l 9-oxo-11.alpha.,15-dihydroxy-15-methyl-19,20-(1,3- propano)-prostanoic acid861 732 l 9-oxo-11.alpha.,15-dihydroxy-15-methyl-16,20-methano- e prostanoic acid862 733 l 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,20-ethano- prostanoic acid863 735 l 9-oxo-11.alpha.,15-dihydroxy-15,20-dimethyl-17,20-(1, . 3-propano)-prostanoic acid__________________________________________________________________________

EXAMPLE 864

Preparation of 9.alpha.,11.alpha.,15-trihydroxy-17,20-methano-13-transprostenoic acid and 9.beta.,11.alpha.,15-trihydroxy-17,20-methano-13-trans-prostenoic acid

A solution containing 200 mg. of 9-oxo-11.alpha.,15-dihydroxy-17,20-methano-13-trans-prostenoic acid (Example 187) and 20 mg. of sodium borohydride in 1 ml. of absolute ethanol is stirred at ambient temperature for 18 hours. The solution is diluted with 30 ml. of water, acidified with 2 N hydrochloric acid and extracted with ether several times. The combined extracts are washed with saturated sodium chloride, dried with anhydrous magnesium sulfate and taken to dryness to give an oily product, which is a mixture of 9.alpha.- and 9.beta.-hydroxy derivatives, separable by chromatography.

EXAMPLE 865-875

Treatment of the 9-oxo derivative listed in Table 31 below with sodium borohydride in accordance with the procedure described in Example 864 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, which are separable by chromatographic procedures.

Table 21__________________________________________________________________________ Starting 9-oxo-derivative Product 9.alpha./9.beta.-hydroxy derivatives andExample of Example 15-epi isomers thereof__________________________________________________________________________865 190 9.alpha./9.beta.,11.alpha.,15-trihydroxy-19,20-(1,3-prop ano)-13- trans-prostenoic acid866 191 9.alpha./9.beta.,11.alpha.,15-trihydroxy-16-methyl-18,20 -ethano- 13 trans-prostenoic acid867 193 9.alpha./9.beta.,11.alpha.,15-trihydroxy-17,20-ethano-13 -trans, 18-prostadienoic acid868 195 9.alpha./9.beta.,11.alpha.,15-trihydroxy-6,7-dinor-16,20 -methano- 13-trans,17-prostadienoic acid869 196 9.alpha./9.beta.,11.alpha.,15-trihydroxy-17,18-methano-1 3-trans- prostenoic acid870 208 9.alpha./9.beta.,11.alpha.,15-trihydroxy-2,16-diethyl-19 ,20-(1,3- propano)-13-trans-prostenoic acid871 209 9.alpha./9.beta.,11.alpha.,15-trihydroxy-2-methyl-17,18- methano-13- trans-prostenoic acid872 224 9.alpha./9.beta.,11.alpha.,15-trihydroxy-3-oxa-16,20-met hano-13- trans,18-prostadienoic acid873 270 9.alpha./9.beta.,11.alpha.,15-trihydroxy-17,18-methano-5 -cis,13- trans-prostadienoic acid874 272 9.alpha./9.beta.,11.alpha.,15-trihydroxy-16,20-methano-5 -cis,13- trans,17-prostatrienoic acid875 663 9 /9 ,11 ,15-trihydroxy-15-methyl-17,18-methano- 13-trans-prostenoic acid__________________________________________________________________________

EXAMPLES 876-889

Treatment of the prostenoic or prostanoic acids listed in Table 22 below with the inducated diazoalkane in the following manner provides the product esters of the table.

An ethereal solution containing a molar excess of diazoalkane is added to a solution of prostenoic acid in ether (or acetone). After two to four hours the solution is carefully evaporated under reduced pressure and the residual ester is purified in the usual way by chromatography on silica gel.

Table 22__________________________________________________________________________ Starting prostenoic Product alkyl prostenoate andExample acid of Example Diazoalkane 15-epi isomer thereof__________________________________________________________________________876 191 diazopentane pentyl 9-oxo-11.alpha.,15-dihydroxy-16-methyl-18,20- Z ethano-13-trans-prostenoate877 196 diazohexane hexyl 9-oxo-11.alpha.,15-dihydroxy-17,18-methano- 13-trans-prostenoate878 193 diazooctane octyl 9-oxo-11.alpha.,15-dihydroxy-17,20-ethano-13- 2 trans,18-prostadienoate879 205 diazoheptane heptyl 9-oxo-11.alpha.,15-dihydroxy-2-ethyl-16,20- methano-13-trans,17-prostadienoate880 270 diazononane nonyl 9-oxo-11.alpha.,15-dihydroxy-17,18-methano- 5-cis,13-trans-prostadienoate881 271 diazohexane hexyl 9-oxo-11.alpha.,15-dihydroxy-17,20-methano- 5-cis,13-trans,18-prostatrienoate882 272 diazooctane octyl 9-oxo-11.alpha.,15-dihydroxy-16,20-methano- 5-cis,13-trans,17-prostatrienoate883 342 diazononane nonyl 9.alpha.,11.alpha.,15-trihydroxy-17,20-ethano- 13- trans,18-prostadienoate884 345 diazopentane pentyl 9.alpha.,11.alpha.,15-trihydroxy-17,18-methan o-13- trans-prostenoate885 655 diazoethane l ethyl 9.alpha.,11.alpha.,15-trihydroxy-16-,2-metha no-5- cis,13-trans,18-prostadienoate886 477 diazomethane methyl 9.alpha.,11.alpha.,15-trihydroxy-4-propyl-17, 18- methano-5-cis,13-trans-prostadienoate887 494 diazoheptane heptyl 9-oxo-15-hydroxy-17,18-methano-10,13- trans-prostadienoate888 663 diazononane nonyl 9-oxo-11.alpha.,15-dihydroxy-15-methyl-17,18- l methano-13-trans-prostenoate889 745 diazooctane octyl 9-oxo-11.alpha.,15-dihydroxy-17,18-methano- prostanoate__________________________________________________________________________

EXAMPLE 890

9-[(p-carboxyphenyl)hydrazono]-11.alpha.,15-dihydroxy-17,20-methano-13-trans-prostenoic acid

A solution of 660 mg. of 9-oxo-11.alpha.,15-dihydroxy-17,20-methano-13-trans-prostenoic acid (Example 187) in 35 ml. of absolute alcohol containing 600 mg. of p-carboxyphenylhydrazine and one drop of glacial acetic acid is heated to boiling to effect solution then stirred at ambient temperature for 18 hours. The solution is cooled at 0.degree. C. for several hours and the solid which is deposited is collected to give 450 mg. of product, m.p. 125.degree. C. (gas).

EXAMPLE 890B

9-Methoxyimino-11.alpha.,15-dihydroxy-17,20-methano-13-transprostenoic acid

A solution of 1.17 g. of 9-oxo-11.alpha.,15-dihydroxy-17,20-methano-13-trans-prostenoic acid (Example 187) in 15 ml. of absolute alcohol containing 345 mg. of methoxyamine hydrochloride and 0.6 ml. of dry pyridine is stirred at ambient temperature for 18 hours. The resulting solution is poured into 75 ml. of saturated sodium chloride solution and extracted twice with ether. The combined extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to furnish 1.1 g. of product as a viscous oil.

EXAMPLE 890C

9-Hydroxyimino-11.alpha.,15-dihydroxy-17,20-methano-13-trans-prostenoic acid

A solution of 1.02 g. of 9-oxo-11.alpha.,15-dihydroxy-17,20-methano-13-trans-prostenoic acid (Example 187) in 20 ml. of methanol-water (1:1) containing 1 g. of hydroxylamine hydrochloride and 1.25 g. of anhydrous sodium acetate is stirred at ambient temperature for 20 hours. The solution is flooded with water and extracted several times with ether. The combined extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 1 g. of product as an oil.

EXAMPLES 891-907

Treatment of the starting 9-oxo derivatives listed in Table 23 below with hydroxylamine by the procedure of Example 890, or methoxyamine by the procedure described in Example 890B, or with thiosemicarbazide, semicarbazide or the appropriate phenylhydrazine by the procedure described in Example 890 substituting if necessary the required reagent for the p-carboxyphenylhydrazine of the Example furnishes the product 9-substituted derivatives of the table.

Table 23__________________________________________________________________________ Starting 9-oxo derivativeExample of Example Product 9-derivative and 15-epi isomer__________________________________________________________________________ thereof891 191 9-(p-carboxyphenylhydrazono)-11.alpha.,15-dihydroxy-16-m ethyl- 18,20-ethano-13-trans-prostenoic acid892 193 9-phenylhydrazono-11.alpha.,15-dihydroxy-17,20-ethano-13 - trans,18-prostadienoic acid893 196 9-(p-carboxyphenylhydrazono)-11.alpha.,15-dihydroxy-17,1 8- methano-13-trans-prostenoic acid894 196 9(p-methylphenylhydrazono)-11.alpha.,15-dihydroxy-17,18- O methano-13-trans-prostenoic acid895 196 9-(2,5-dichlorophenylhydrazono)-11.alpha.,15-dihydroxy-1 7,18- methano-13-trans-prostenoic acid896 196 9-methoximino-11.alpha.,15-dihydroxy-17,18-methano-13-tr ans- prostenoic acid897 273 l methyl 9-(p-carboxyphenylhydrazono)-11.alpha.,15-dihyd roxy- 19,20-(1,3-propano)-5-cis,13-trans-prostadienoate898 277 l methyl 9-(p-carboxyphenylhydrazono)-11.alpha.,15-dihyd roxy- 17,18-methano-5-cis,13-trans-prostadienoate899 263 9-thiosemicarbazano-11.alpha.,15-dihydroxy-17,20-methano - 5-cis,13-trans-prostadienoic acid900 267 9-oximino-11.alpha.,15-dihydroxy-18,20-(1,3-propano)-5-c is, 13-trans-prostadienoic acid901 663 9-(p-carboxyphenylhydrazono)11.alpha.,15-dihydroxy-15-me thyl- 17,18-methano-13-trans-prostenoic acid902 663 9-(p-fluorophenylhydrazono)-11.alpha.,15-dihydroxy-15-me thyl- 17,18-methano-13-trans-prostenoic acid903 663 9-(p-bromophenylhydrazono)-11.alpha.,15-dihydroxy-15-met hyl- 17,18-methano-13-trans-prostenoic acid904 695 9-(p-carboxyphenylhydrazano)-11.alpha.,15-dihydroxy-15-m ethyl- 17,18-methano-5-cis,13-trans-prostadienoic acid905 695 9-(3,4-bichlorophenylhydrazono)-11.alpha.,15-dihydroxy-1 5- methyl-17,18-methano-5-cis,13-trans-prostadienoic acid906 695 9-(o-methylphenylhydrazono)-11.alpha.,15-dihydroxy-15-me thyl- 17,18-methano-5-cis,13-trans-prostadienoic acid907 695 9- emicarbazano-11.alpha.,15-dihydroxy-15-methyl-17,18- e methano-5-cis,13-trans-prostadienoic acid__________________________________________________________________________

EXAMPLE 908

9-Oxo-15-hydroxy-17,20-methano-8(12),13-trans-prostadienoic acid

A mixture of 110 mg. of 9-oxo-11.alpha.,15-dihydroxy-17,20-methano-13-trans-prostenoic acid (Example 187) in 40 ml. of 95% ethanol and 40 ml. of 1 N sodium hydroxide was stirred under argon at 30.degree.-40.degree. C. for 1 hour. The mixture is concentrated under reduced pressure to remove ethanol, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extracts are washed, dried, evaporated and the residue is chromatographed on acid-washed silica gel to give 55 mg. of product as an oil; .lambda.max. 278 m.mu..

EXAMPLES 909-915

Base treatment of the starting 9-oxo-11.alpha.-hydroxy-derivative listed in Table 24 below by the procedure described in Example 908 furnishes the product 9-oxo.DELTA..sup.8(12) derivatives of the table.

Table 24__________________________________________________________________________ Starting 9-oxo-11.alpha.-hydroxyExample derivative of Example Product 9-Oxo- .DELTA..sup.8(12) derivative__________________________________________________________________________909 191 9-oxo-15-hydroxy-16-methyl-18,20-ethano-8(12),13- trans-prostadienoic acid910 193 9-oxo-15-hydroxy-17,20-ethano-8(12),13-trans,18- prostatrienoic acid911 196 9-oxo-15-hydroxy-17,18-methano-8(12),13-trans- prostadienoic acid912 196 9-oxo-15-epi-hydroxy-17,18-methano-8(12),13-trans- prostadienoic acid913 264 9-oxo-15-hydroxy-18,20-ethano-5-cis,8(12),13-trans- prostatrienoic acid914 270 9-oxo-15-hydroxy-17,18-methano-5-cis,8(12),13- trans-prostatrienoic acid915 270 9-oxo-15-epi-hydroxy-17,18-methano-5-cis,8(12),13- trans-prostatrienoic acid__________________________________________________________________________

Claims

1. An optically active compound of the formula: ##STR49## or a racemic mixture of that formula, and the mirror image thereof, wherein Y is a divalent radical selected from the group consisting of those of the formula: ##STR50## p is an integer from 1 to 5 inclusive; R.sub.1 is an alkyl group having up to 3 carbon atoms; R.sub.3 is hydroxy, alkoxy having from one to twelve carbon atoms, tetrahydropyranyloxy or tri-(lower alkyl)-silyloxy; R.sub.6 is hydrogen or an alkyl group having up to 4 carbon atoms; R.sub.8 is hydrogen, tetrahydropyranyl, or tri-(lower alkyl)-silyl; X is a divalent radical selected from the group consisting of: ##STR51## wherein R.sub.2 is selected from the group consisting of hydrogen, triphenylmethyl, and mono- or di-methoxy substituted triphenylmethyl; R.sub.7 is hydrogen or an alkyl group having up to 3 carbon atoms; with the first proviso that when R.sub.7 is alkyl, R.sub.2 must be hydrogen; s is zero or an integer having the value of one to five inclusive; t is zero or one; R is selected from the group consisting of cyclopropyl, cyclooctyl, cyclononyl, or a cycloalkenyl group having from five to nine carbon atoms, a mono- or di-(lower alkyl) substituted cyclopropyl, or cyclooctyl group, or a mono- or di-(lower alkyl) substituted cycloalkenyl group having from five to eight carbon atoms in the ring; and with the second proviso that when R is a saturated cycloalkyl group, the sum of s and t must be at least one; and the pharmaceutically acceptable cationic salts thereof when R.sub.3 is hydroxy.

2. The compound according to claim 1 wherein R is cis-2-ethylcyclopropyl.

3. The compound according to claim 2 wherein X is selected from the group consisting of: ##STR52##

4. The compound according to claim 3 wherein s is one and t is zero.

5. The compound according to claim 4 wherein R.sub.7 is methyl and R.sub.2 is hydrogen.

6. The racemic compound according to claim 5, 9.alpha.,11.alpha.,15-trihydroxy-15-methyl-17,18-methano-5-cis-13-trans-prostadienoic acid.

7. The racemic compound according to claim 5, 9.alpha.,11.alpha.,15-epi-trihydroxy-15-methyl-17,18-methano-5-cis-13-trans-prostadienoic acid.

8. The enantiomer according to claim 4, l-methyl 9.alpha.,11.alpha.,15-trihydroxy-17,18-methano-5-cis-13-trans-prostadienoate.

9. The enantiomer according to claim 4, l-methyl-9.alpha.,11.alpha.,15-epi-trihydroxy-17,18-methano-5-cis-13-trans-prostadienoate.

10. The compound according to claim 1, wherein R is 2-cyclohexenyl.

11. The compound according to claim 10 wherein Y is: ##STR53## and X is selected from the group consisting of: ##STR54##

12. The compound according to claim 11 wherein s is zero and t is zero.

13. The compound according to claim 12 wherein R.sub.7 is hydrogen and R.sub.2 is hydrogen.

14. The racemic compound according to claim 13, 9.alpha.,11.alpha.,15-trihydroxy-4-propyl-16,20-methano-5-cis-13-trans, 17-prostatrienoic acid.