Prostaglandin F{HD 3{B {331 {0 analogs
United States Patent Axen Apr. 22, 1975 PROSTAGLANDIN F ANALOGS {56] References Cited [75] Inventor: Udo F. Axen, Comstock. Mich. FOREIGN NTS OR APPLICATIONS [73] Assignee: The Upjohn Company, Kalamazoo. 1118x786 11/197] Germany Mlch&#39; Primary Examiner-Robert Gesstl [22] Filed: Nov. 5, 1973 21 Appl. No: 412,957 [571 ABSTRACT This disclosure relates to prostaglandins of the PG; se- Related U.S. Application Data r1es 1nclud1ng PGD PGFM, PGF and PGB to Continuation-impart 0f l F various analogs of those in racemic form, and to novel 3, i w g&#39;p&#39;f processes for making those. This disclosure also relates to certain fluorine and alkyl substituted analogs and certain acetylenic analogs of PGDg, PGF a, 52 us. (:1. 260/468 D- 260/ 11 R 260/247 2 R 136F319 .PGAM and P033 in both racemic 760/268 2607243 760/356 cally act1ve form, and to processes for making those. 260/410: 760/410 16 9 6 1 5: These various analogs are useful for the same pharma- 7&#39;60/479 9560/1139 260/448 f cological purposes as the known optically active forms 6 1 15560601 f of PGE PGFga, P F and PGB including anti- 260/561 4 ulcer, inhibition of platelet aggregation, increase of [51] Int Cl C07c 6162&#39;. CO7C 64/74 nasal patency, labor inducement. fertility control. and 581 Field of Search 260/468 D, 514 D 23 Claims. No Drawings PROSTAGLANDIN F36 ANALOGS CROSS REFERENCE TO RELATED APPLICATION This application is a continuation-in-part of copending application Ser. No. ll2.032, filed Feb. 2. 1971. now US. Pat. No. 3,775.462 which is a continuationin-part of copcnding application Ser. No. 30.312. filed Apr. 20, I970, and now abandoned.  
 BRIEF DESCRIPTION OF THE INVENTION This invention relates to compositions of matter. and to methods and intermediates for producing them. In particular, the several aspects of this.invention relate to racemic prostaglandin E (PGEn). racemic prostaglandin F (PGF and PGF racemic prostaglandin A (PGA prostaglandin B (P683). to the corresponding acetylenic prostaglandins. 5.6.17.18- dehydro PGE 5,6,17,18-dehydr-PGF 5,6,17,18- dehydro-PGF 5,6,17,18-dehydro-PGA .and 5.6.l 7.18-dehydro-PGBhd 3; to analogs of those prostaglandins and 5.6.17.18-dehydro-prostaglandins; to processes for producing racemic PGE PGF PGF PGA PGB the corresponding 5,6,17,18- dehydro-prostaglandins, and the analogs thereof; to processes for resolving the racemates into the dand lforms; and to chemical intermediates useful in those methods.  
  Optically active PGE3 (the natural or dconfiguration) is a known substance. Bergstrom. Science l57. 382 (1967); Samuelson. J. Amer. Chem. Soc.. 85, I878 (I963). Optically active PGF (a and [3). obtained by the borohydride reduction of optically active PGE is also a known substance; Samuelson. Biochemica Biophysica Acta. 84, 707 (l964); so also is optically active PGA British Specification No. 1.097.533. Optically active PGE optically active PGF and optically active PGF are also disclosed in British specification No. l.()40.544.  
  The prior art methods for producing prostaglandins are costly and difficult. the necessary biological materials are limited. and the methods are not adaptable to production of a wide variety of prostaglandin intermediates and analogs.  
  It is the purpose of this invention to provide pro cesses for the production of compounds with prostaglandin-like activity in substantial amounts and at reasonable cost. The useful compounds produced according to the processes of this invention comprise racemic POP racemic PGF racemic POI- racemic PGA racemic PGB the corresponding 5,6,l7,l8 dehydro-prostaglandins. and other hitherto unavailable racemic and optically active analogs thereofsuch as the enantiomorphs (dand lforms) of PGB and the 5.6.17.18-dehydro compounds.  
 PGE has the following structure:  
 PGF 00 has the following structure:  
 The above formulas represent natural configuration. RaCOInIC PGFg PGFgfl. PGA3, and are each represented by the combination of one of the above formulas and the mirror image (enantiomorph) of that formula. See Nature. 212, 38 (1966) for discussion of the stereochemistry of the prostaglandins.  
  In formulas I. II. III. IV, and V. as well as in the formulas given hereinafter. broken line attachments to the cyclopentane ring indicate substituents in alpha configuration, i.e. below the plane of the cyclopentane ring. Heavy solid line attachments to the cyclopentane ring indicate substituents in beta configuration, i.e.. above the plane of the cyclopentane ring.  
  PGE PGF PGF PGA and PGB3 are derivatives of prostanoic acid which has the following structure and atom numbering:  
 @ NM W0 A systematic name for iso-prostanoic acid is 7-[(2B- octyl)-cyclopent-lB-yl)]heptanoic acid.  
  Prostaglandin E and its analogs and isomers produced according to the processes of this invention are represented by the formula:  
  H H 0 /c=C/\ CH A-COOR,  
  R C-C OH H H HO H C C=C R3 nHzn Rz Vllle H wherein R, is hydrogen. alkyl ofone to 8 carbon atoms. inclusive. cycloalkyl of 3 to 10 carbon atoms. inclusive. aralkyl of 7 to 12 carbon atoms. inclusive. phenyl. phenyl substituted with one to 3 chloro or alkyl of one to 4 carbon atoms. inclusive. or ethyl substituted in the B-position with 3 chloro, 2 or 3 bromo. or 1. 2. or 3 iodo; wherein R is alkyl of one to 4 carbon atoms. inclusive substituted with zero to 3 fluoro; wherein R and R, are hydrogen or alkyl of one to 4 carbon atoms. inclusive; wherein n is an integer of one to 4. inclusive;  
 wherein A is alkylene of one to [0 carbon atoms. inclusive. substituted with zero to 2 fluoro. and with one to 5 carbon atoms. inclusive. between COOR, and  
 and pharmacologically acceptable salts thereof wherein R, is hydrogen.  
  Prostaglandin F and its analogs and isomers produced according to the processes of this invention are represented by the formula:  
  A-cook H lXe wherein R,. R R R and A are as defined above for 0 an: A-COOR,  
 wherein R,. R R,,. R,. and A are as defined above for formula Vllle. and the pharmacologically acceptable salts thereof wherein R, is hydrogen.  
 Prostaglandin B &#39;and its analogs and isomers (including its enantiomorphs) produced according to the processes of this invention are represented by the formula:  
 wherein R,. R R R,. and A are defined above for formula Vllle. and pharmacologically acceptable salts thereof wherein R, is hydrogen.  
  The wavy line. as used above. and elsewhere herein. includes both configurations. i.e.. alpha and beta. or endo or exo. The word racemic&#34; indicates an equal mixture of a compound of the formula shown. which is the natural configuration. and its enantiomorph.  
  Compounds of formula Vllle. lxe. Xe. and Xle have their counterpart where the cis-ethylenes are dehydro. i.e.. ethynylene. These dehydro analogs here designated as Vllld. lXd. Xd. and Xld. are intermediates. as will be shown. for making the compounds of formulas Vllle. lXe. Xe. and Xle. Racemic dehydro compounds give racemic final products. An enantiomorph of the dehydro compound (the configuration as shown or the mirror image thereof) gives the corresponding enantiomorph of the final compound.  
  Also included in formulas Vlll. IX. X. and X] are separate isomers wherein the side chain hydroxy is in R or S configuration. All of the compounds encompassed by formulas Vlll. lX. and X have the trans CH=C- R,CR,,OH-side chain attached in beta configuration.  
  Formulas Vllle. lXe. Xe. and Xle represent PGE PGF,,. PGA,,. and P68 respectively. when in these formulas R,, R and R, are each hydrogen. :1 is 1. R is ethyl. A is&#39;trimethylene. the attachment of CH- CH=CHACOOR, to the cyclopentane ring is in alpha configuration. and the configuration of the side chain hydroxy is 5.  
  With regard to formulas Vlll to Xl, inclusive. examples of alkyl of one to 4 carbon atoms, inclusive, are methyl. ethyl. propyl. butyl. and isomeric forms thereof. Examples of alkyl of one to 8 carbon atoms. inclusive. are those given above. and pentyl. hexyl. heptyl. octyl. and isomeric forms thereof. Examples of alkyl of one to 10 carbon atoms. inclusive. are those given above. and nonyl. decyl. and isomeric forms thereof. Examples of cycloalkyl of 3 &#39;to 10 carbon atoms. inclusive. which includes alkyl-substituted cycloalkyl. are cyclopropyl. 2-methylcyclopropyl. 2.Z-dimethylcyclopropyl. 2.3-diethylcyclopropyl. 2-butylcyclopropyl. cyclobutyl. Z-methylcyclobutyl. 3-propylcyclobutyl, 2.3.4-triethylcyclobutyl, cyclopentyl. 2,2-dimethylcyclopentyl. 3-tert-butylcyclopentyl. cyclohexyl. 4-tertbutylcyclohexyl. 3-isopropylcyclohexyl. 2.2-dimethyl- 3pentylcyclopentyl.  
 cyclohexyl. cycloheptyl. cyclooctyl. cyclononyl. and cyclodecyl. Examples of aralkyl of 7 to 12 carbon atoms. inclusive. are benzyl. phenethyl. l-phenethyl. l-phenylethyl. 2-phenylpropyl. 4-phenylbutyl. 3- phenylbutyl. 2-( l-naphthylethyl and l-( 2- naphthylmethyl). Examples of phenyl substituted by one to 3 chloro or alkyl of one to 4 carbon atoms. inclusive. are p-chlorophenyl. m-chlorophenyl. ochlorophenyl. 2.4-dichlorophenyl. 2.4.6- trichlorophenyl. p-tolyl. m-tolyl. o-tolyl. p-ethylphenyl. p-tert-butyl-phenyl. 2.5-dimethylphenyl. 4-chloro-2- methylphenyl. and 2.4-dichloro- 3-methylphenyl.  
  Examples of alkylene of one to carbon atoms. inclusive. are methylene. ethylene. trimethylene. tetramethylene. pcntamethylene. and isomeric branched chain forms thereof. 1-. 2-. and 3- methylpentamethylene. l-. 2-. 3-ethylpentamethylene. l-. 2-. and 3-propylpentamethylene. l-. 2-. and 3- butylpentamethylene. and l-. 2-. and 3-pentylpentamethylene.  
  Examples of alkyl of one to 4 carbon atoms. inclusive. substituted with one to 3 fluoro. are Z-fluoroethyl. 2-fluorobutyl. 3 fluorobutyl. 4-fluorobutyl. 3.4- difluorobutyl. 2.2.2&#39;trifluoroethyl. and 4.4.4- trifluorobutyl.  
  Examples of alkylene of one to l0 carbon atoms. inclusive. substituted with one or 2 fluoro. have the formulas (1963); Bergstrom et al.. acta physiol. science. 59, 493 (1963): Heinberg et al.. 1. Clinic. Investigation. 43. 1533 (1964); Bergstrom et al.. acta physiol. science, 60. 170 1964); and Sandberg et al.. Acta Obstetrica et Gynecolojica Science. 43. 95 (1964). Optically active PGE, and PGA;; which are obtained from optically active PGE also cause the same biological responses as PGF and PGA.  
  Because of these biological responses. these known prostaglandins are useful to study, prevent. control. or alleviate a wide variety of diseases and undesirable physiological conditions in birds and mammals. including humans. useful domestic animals, pets. and zoological specimens. and in laboratory animals. for example. mice. rats. rabbits. and monkeys.  
  For example. these compounds. and especially PGE are useful in mammals. including man. as nasal decongestantsfFor this purpose. the compounds are used in a dose range of about 10 pg. to about 10 mg. per ml. of a pharmacologically suitable liquid vehicle or as an aerosol spray. both for topical application. PGE is similarly useful when administered in equivalent doses.  
  PGE and PGA- are useful in mammals. including man and certain useful animals. e.g.. dogs and pigs. to reduce and control excessive gastric secretion. thereby reducing or avoiding gastrointestinal ulcer formation. and accelerating the healing of such ulcers already CH CHCH CHF- CH CH CH CHFCHF-,  
 -cH2CHzCHgCF2CH and CHZCHZCFZCHZCHZ&#39; PGE PGF PGF PGAz, and PGB and their esters and pharmacologically acceptable salts. are extremely potent in causing various biological responses. For that reason. these compounds are useful for pharmacological purposes. See. for example. Bergstrom et al.. Pharmacol. Rev. 20. l (1968). and references cited therein. A few of those biological responses are systemic arterial blood pressure lowering in the case of PGE PGF and PGA as measured. for example. in anesthetized (pentobarbital sodium) pentoliniumtreated rats with indwelling aortic and right heart cannulas; pressor activity, similarly measured. for PGFga; stimulation of smooth muscle as shown. for example. by tests on strips of guinea pig ileum. rabbit duodenum. or gerbil colon; potentiation of other smooth muscle stimulants; antilipolytic activity as shown by antagonism of epinephrine-induced mobilization of free fatty acids or inhibition of the spontaneous release of glycerol from isolated rat fat pads; inhibition of gastric secretion in the case of PGE and PGA- as shown in dogs with secretion stimulated by food or histamine infusion; activity on the central nervous system; decrease of blood platelet adhesiveness as shown by platelet-toglass adhesiveness. and inhibition of blood platelet aggregation and thrombus formation induced by various physical stimuli. e.g.. arterial injury. and various biochemical stimuli. e.g.. ADP. ATP, serotonin. thrombin. and collagen; and in the case of PGE2 and PBG stimulation of epidermal proliferation and keratinization as shown when applied in culture to embryonic chick and rat skin segments.  
  Optically active PGE and its esters and pharmacologically acceptable salts. are also extremely potent in causing the same biological responses as PGE- Horton et al.. Brit. J. of Pharm. and Chemotherapy. 21. 182  
 present in the gastrointestinal tract. For this purpose. the compounds are injected or infused intravenously. subcutaneously. or intramuscularly in an infusion dose range about 0.1 pg. to about 500 pg. per kg. of body weight per minute. or in a total daily dose by injection of infusion in the range about 0.1 to about 20 mg. per kg. of body weight per day. the exact dose depending on the age. weight. and condition of the patient or animal. and on the frequency and route of administration. PGE;, and PGA;, are similarly useful when administered in equivalent doses.  
  PGE PGA PCP. and PGF are useful whenever it is desired to inhibit platelet aggregation. to reduce the adhesive character of platelets. and to remove or prevent the formation of thrombi in mammals. including man. rabbits. and rats. For example. these compounds are useful in the treatment and prevention of myocardial infarcts. to treat and prevent post-operative thrombosis. to promote patency of vascular grafts following surgery. and to treat conditions such as atherosclerosis. arteriosclerosis. blood clotting defects due to lipemia. and other clinical conditions in which the underlying etiology is associated with lipid imbalance or hyperlipidemia. For these purposes. these compounds are administered systemically. e.g.. intravenously. subcutaneously. intramuscularly. and in the form of sterile implants for prolonged action. For rapid response. especially in emergency situations. the intravenous route of administration is preferred. Doses in the range about 0.004 to about 20 mg. per kg. of body weight per day are used. the exact dose depending on the age. weight. and condition of the patient or animal. and on the frequency and route of administration. PGE PGA PGF and PGF are similarly useful when administered in equivalent doses.  
  PGFz, PGA- PGF2u, and PGF are especially useful as additives to blood, blood products, blood substitutes, and other fluids which are used in artificial extracorporeal circulation and perfusion of isolated body portions. e.g.. limbs and organs. whether attached to the original body. detached and being preserved or prepared for transplant. or attached to a new body. During these circulations and perfusions. aggregated platelets tend to block the blood vessels and portions of the circulation apparatus. This blocking is avoided by the presence of these compounds. For this purpose. the compound is added gradually or in single or multiple portions to the circulating blood. to the blood of the donor animal. to the perfused body portion. attached or detached. to the recipient. or to two or all of those at a total steady state dose of about 0.001 to 10 mg. per liter of circulating fluid. [t is especially useful to use these compounds in laboratory animals. e.g.. cats. dogs. rabbits. monkeys. and rats. for these purposes in order to develop new methods and techniques for organ and limb transplants. POE PGA PGFM, and PGFa are similarly&#39; useful when administered in equivalent doses.  
  PGE is extremely potent in causing stimulation of smooth muscle. and is also highly active in potentiating other known smooth muscle stimulators. for example. oxytocic agents. e.g.. oxytocin. and the various ergot alkaloids including derivatives and analogs thereof. Therefore PGE is useful in place of or in combination with less than usual amounts of these known smooth muscle stimulators. for example. to relieve the symptoms of paralytic ileus. to control or prevent atonic uterine bleeding after abortion or delivery, to aid in expulsion ofthe placenta. and during the puerperium. For these purposes PGE is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 50 pg. per kg. of body weight per minute until the desired effect is obtained. Subsequent doses are given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range 0.01 to 2 mg. per kg. of body weight per day. the exact dose depending on the age. weight. and condition of the patient or animal. PGE;, is similarly useful when administered in equivalent doses.  
  PGE PGA and PGF are useful as hypotensive agents to reduce blood pressure in mammals. including man. For this purpose. the compounds are administered by intravenous infusion at the rate about 0.01 to about 50 pg. per kg. of body weight per minute or in single or multiple does of about to 500 pg. per kg. of body weight total per day. POE- PGA and PGF are similarly useful when administered in equivalent doses.  
  PGE PGF and PGFZfl are useful in place of oxytocin to induce labor in pregnant animals, including man. cows, sheep. and pigs. at or near term. or in pregnant animals with intrauterine death of the fetus from about 20 weeks to term. For this purpose, the compound is infused intravenously at a dose 0.0] to pg. per kg. of body weight per minute until or near the termination of the second stage of labor. i.e.. expulsion of the fetus. These compounds are especially useful when the female is one or more weeks post-mature and natural labor has not started, or 12 to hours after the membranes have ruptured and natural labor has not yet started. PGE PGFM, and. PGF are similarly useful when administered in equivalent doses.  
  PGF PGF and PGE are useful for controlling the reproductive cycle in ovulating female mammals. including humans and animals such as monkeys. rats. rabbits. dogs. cattle. and the like. For that purpose, PGFZa is administered systemically at a dose level in the range 0.01 mg. to about 20 mg. per kg. of body weight of the female mammal. advantageously during a span of time starting approximately at the time of ovulation and ending approximately at the time of menses or just prior to menses. POE and PGF are similarly useful when administered in equivalent doses.  
  As mentioned above, PGE is a potent antagonist of epinephrine-induced mobilization of free fatty acids. For this reason. this compound is useful in experimental medicine for both in vitro and in vivo studies in mammals. including man, rabbits. and rats. intended to lead to the understanding, prevention, symptom alleviation. and cure of diseases involving abnormal lipid mobilization and high free fatty acid levels. e.g.. diabetes mellitus. vascular diseases. and hyperthyroidism. PGE is similarly useful when administered in equivalent doses.  
  PGE and P08 promote and accelerate the growth of epidermal cells and keratin in animals, including humans. useful domestic animals. pets, zoological specimens. and laboratory animals. For that reason. these compounds are useful to promote and accelerate healing of skin which has been damaged. for example. by burns. wounds. and abrasions. and after surgery. These compounds are also useful to promote and accelerate adherence and growth of skin autografts. especially small, deep (Davis) grafts which are intended to cover skinless areas by subsequent outward growth rather than initially. and to retard rejection of homografts. PGE and PGB are similarly useful when administered in equivalent doses.  
  For&#39;these purposes. these compounds as well as the compounds of the invention are preferably administered topically at or near the site where cell growth and keratin formation is desired. advantageously as an aerosol liquid or micronized powder spray. as an isotonic aqueous solution in the case of wet dressings. or as a lotion. cream, or ointment in combination with the usual pharmaceutically acceptable diluents. in some instances. for example. when there is substantial fluid loss as in the case of extensive burns or skin loss due to other causes. systemic administration is advantageous. for example. by intravenous injection or infusion. separate or in combination with the usual infusions of blood. plasma, or substitutes thereof. Alternative routes of administration are subcutaneous or intramuscular near the site. oral. sublingual. buccal. rectal. or vagina]. The exact dose depends on such factors as the route of administration. and the age. weight. and condition of the subject. Especially for topical use. these prostaglandins are useful in combination with antibiotics. for example. gentamycin. neomycin. polymyxin B. bacitracin. spectinomycin. and oxytetracycline. with other antibacterials, for example. mafenide hydrochloride. sulfadiazine, furazolium chloride, and nitrofurazone. and with corticoid steroids. for example. hydrocortisone. prednisolone, methylprednisolone. and fluprednisolone, each of these being used in the combination at the usual concentration suitable for its use alone.  
  Racemic PGFZ} racemic PGF racemic PGF and racemic PGA;,. each are useful for the purposes described above for the optically active compounds. but these racemic compounds offer the enormous advantage of being available in unlimited quantities at much lower cost. Racemic PGB has like advantages and is useful for the same purposes as PGB Moreover, these racemic compounds are easier to purify since they are produced by chemical reactions rather than by extraction from biological materials or enzymatic reaction mixtures.  
  The POE PGF;,. PGAB. and PGB analogs and isomers cause corresponding biological responses and are useful for corresponding purposes as PGE;,. PGF PGA and PGB respectively.  
  To obtain the optimum combination of biological response specificity and potency. certain compounds within the scope of formulas Vllle and lXe are preferred. As discussed above. those formulas represent the PGE -type compounds and the PGF type compounds. respectively. Referring to formulas Vllle and lXe. when CH -CH=CH-A--COOR is attached in alpha configuration and. in the case of formula lXe. when the ring hydroxy is also attached in alpha configuration. the sterochemistry is typical of the known opti cally active PGE and PGFgu- According to this invention. preferred formula Vllle and lXe compounds are those wherein CH- CH=CHA-COOR and ring hydroxy are alpha. n is l and A is trimethylene. R is hydrogen and R;, is hydrogen or methyl and R is ethyl. These preferred compounds exhibit superior biological response specificity and/or potency.  
  Certain compounds within the scope of formulas Vllle to Xle are especially useful for one or more of the purposes stated above. because they have a substantially longer duration of activity than other compounds within the generic formulas. including PGE PG aCl PGF PGA and PGB and because they can be administered orally. sublingually. intravaginally. buccally. or rectally. rather than by the usual intravenous. intramuscular. or subcutaneous injection or infusion as indicated above for the uses of these known prostaglandins and the other compounds encompassed by formulas Vllle to Xle. These qualities are advantageous because they facilitate maintaining uniform levels ofthese compounds in the body with fewer. shorter. or smaller doses. and make possible self-administration by the patient.  
  With reference to formulas Vllle to Xle. these special compounds include those wherein A is (CH ),,Z-. wherein b is zero. one. 2. or 3. and Z is ethylene substituted by one or 2 fluoro. methyl. or ethyl. or by one alkyl of 3 or 4 carbon atoms. These special compounds also include those wherein R is ethyl. propyl. isopropyl. isobutyl. tert-butyl. 3.3-difluorobutyl. 4.4-difluorobutyl. or 4.4.4-trifluorobutyl. These special compounds also include those wherein A is (CH- ),,-Z as above defined. and R is ethyl. propyl. isopropyl. isobutyl. tert-butyl. 3.3-difluorobutyl. 4.4- difluorobutyl. or 4.4,4-trifluorobutyl. Especially preferred among these special compounds are those wherein R and R are both hydrogen.  
  In the case of Z, the divalent ethylene group. CH- CH is substituted on either or both carbon atoms. i.e.. alpha and/or beta to the carboxylate function. For example. Z is -CH -(.HF. -CH- FCH CH CF CHF-CHF-. CH-  
 )2- 3)2 2. a) =i). and similarly for ethyl. and for one fluoro and one methyl. one fluoro and one ethyl. and one methyl and one ethyl. Z is alternatively ethylene substituted on either carbon atom with propyl. isopropyl. butyl. isobutyl. sec-butyl. or tert-butyl.  
  Although all of the special compounds just described have the special advantages of long duration and oral. sublingual intravaginal. and rectal routes of administration. there is a still more limited group of compounds encompassed by these formulas which have these qualities in a particularly high degree. Those are the compounds wherein A is CH. ,Z, i.e.. wherein b in (CH ,Zis one, especially when Z is ethylene with one fluoro or methyl. with 2 fluoro or 2 methyl on the same carbon atoms. or with butyl. isobutyl. sec-butyl. or tert-butyl on the carbon atoms alpha (adjacent) to the carboxylate function. the compounds wherein R is -C(CH;,),,. CH CH(CH CH- CF;,. CH CHF or CH CF CH and the compounds wherein both A and R are both defined in these more limited ways.  
  Racemic PGE racemic PGFQQ, racemic PGF3 racemic PGA racemic PGB and the other compounds encompassed by formulas Vllle and Xle. are used for the purposes described above in the free acid form. in ester form. or in pharmacologically acceptable salt form. When the ester form is used. the ester is any of those within the above definition of R However. it is preferred that the ester be alkyl of one to four carbon atoms. inclusive Of those alkyl. methyl and ethyl are especially preferred for optimum absorption of the compound by the body or experimental animal system.  
  Pharmacologically acceptable salts of these formula Vllle. lXe. Xe. Xle compounds useful for the purposes described above are those with pharmacologically acceptable metal cations. ammonium. amine cations. or quaternary ammonium cations.  
  Especially preferred metal cations are those derived from the alkali metals. e.g.. lithium. sodium. and potassium. and from the alkaline earth metals. e.g.. magnesium and calcium. although cationic forms of other metals. e.g., aluminum, zinc. and iron. are within the scope of this invention.  
  Pharmacologically acceptable amine cations are those derived from primary. secondary. or tertiary amines. Examples of suitable amines are methylamine. dimethylamine. trimethylamine, ethylamine. dibutylamine. triisopropylamine. N-methylhexylamine. decylamine. dodecylamine. allylamine. crotylamine. cyclopentylamine. dicyclohexylamine. benzylamine. dibenzylamine. a-phenylethylamine. B-phenylethylamine. ethylenediamine. diethylenetriamine. and like aliphatic. cycloaliphatic. and araliphatic amines containing up to and including about 18 carbon atoms. as well as heterocyclic amines. e.g., piperidine. morpholine. pyrrolidine. piperazine. and lower-alkyl derivatives thereof. eg, l-methylpiperidine. 4- ethylmorpholine. l-isopropylpyrrolidine. 2- methylpyrrolidine. l,4-dimethylpiperazine. 2-  
 methylpiperidine. and the like. as well as amines containing water-solubilizing or hydrophilic groups. e.g.. mono-. di-. and triethanolamine. ethyldiethanolamine. N-butylethanolamine. Z-amino-l-butanol. 2-amino-2- ethyll .3-propanediol. Z-amino-Z-methyll propanol. tris(hydroxymethyl)aminomethane. N- phenylethanolamine. N-(p-tert-amylphenyl )diethanolaminc. galactamine. N-methylglucamine. N-  
 methylglucosamine. ephedrine. phenylephrine. epimephrine. procaine. and the like.  
 Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium. tetramethylammonium. tetraethylammonium. benzyltrimethylammonium. phenyltriethylammonium. and the like.  
  As discussed above. the compounds of formulas Vllle to Xle are administered in various ways for various purposes; e.g.. intravenously. intramuscularly. subcutaneously. orally. intravaginally. rectally. buccally. sublingually. topically. and in the form of sterile implants for prolonged action.  
  For intravenous injection or infusion. sterile aqueous isotonic solutions are preferred. For the purpose. it is preferred because of increased water solubility that R, in the formula Vllle to Xle compound be hydrogen or a pharmacologically acceptable cation. For subcutaneous or intramuscular injection. sterile solutions or suspensions of the acid. salt. or ester form in aqueous or non-aqueous media are used. Tablets. capsules. and liquid preparations such as syrups. elixers. and simple solutions. with the usual pharmaceutical carriers are used for oral or sublingual administration. For rectal or vaginal administration. suppositories prepared as known in the art are used. For tissue implants. a sterile tablet or silicone rubber capsule or other object containing or impregnated with the substance is used.  
  Racemic PGE racemic PGF racemic PGF racemic PGA racemic P08 and the other compounds cncompassed by formulas Vllle. IXe. Xe. and Xle are produced by the reactions and procedures described hereinafter. As intermediates there are produced the corresponding 5.6. l 7. l S-dehydroprostaglandins Vllld. lXd. Xd. and Xld which in the free acid or salt forms are useful also for the purposes given above. The enantiomorphs of the VIII. IX. X. and XI compounds are formed either by resolution of the final product racemate or a racemic intermediate.  
  Racemic PGF Q, racemic PGF and the other PGF -type compounds encompassed by formula IX are prepared by carbonyl reduction of the corresponding PGE;.-type compounds encompassed by formula VIII. For example. carbonyl reduction of racemic PGE VI- Ile, gives a mixture of racemic PGF a. IXe a, and racemic PGF IXeB. The corresponding 5,6,17,18- dehydro PGF -type compounds. lXd. are produced in a like manner from 5.6.l 7.1 8-dehydro-PGE -type compounds. Vllld. and by hydrogenation of the acetylenic bonds are converted to the corresponding PGF -typc compounds. IXe.  
  These ring carbonyl reductions are carried out by methods known in the art for ring carbonyl reductions of known prostanoic acid derivatives. See. for example. Bergstrom et al.. Arkiv Kemi. 19. 563 (1963). and Acta Chem. Scand. 16. 969 (1962). and British Specification No. l.097.533. Any reducing agent is used which does not react with carbon-carbon double bonds or ester groups. Preferred reagents are lithium (tri-tertbutoxy) aluminum hydride and the metal borohydrides. especially sodium. potassium and zinc borohydrides. The mixtures of alpha and beta hydroxy reduction products are separated into the individual alpha and beta isomers by methods known in the art for the separation of analogous pairs of known isomeric prostanoic acid derivatives. See. for example. Bergstrom et 21]..  
 cited above. Granstrom&#39;et al.. J. Biol. Chem. 240.457 (1965). and Green et&#39; al.. J. Lipid Research. 5. I17 I964). Especially preferred as separation methods are partition chromatographic procedures. both normal and reversed phase. preparative thin layer chromatography. and countercurrent distribution procedures. They can be applied either before or after the hydrogenation of the acetylenic bonds.-  
  Racemic PGA and the other PGA -type compounds encompassed by formula X are prepared by acidic dehydration of the corresponding PGE -type compounds encompassed by formula VIII. For example. acidic dehydration of racemic PGE Vllle. gives racemic PGA Xe. The corresponding 5.6.17.l8-dehydro-PGA -type compounds Xd. are produced in a like manner from 5.6.17.18-dehydro-PGE -type compounds. Vllld. and by hydrogenation of the acetylenic bonds are converted to PGA -type compounds. Xe.  
  These acidic dehydrations are carried out by methods known in the art for acidic dehydrations of known prostanoic acid derivatives. See. for example. Pike et al.. Proc. Nobel Symposium ll, Stockholm (1966), Interscience Publishers. New York. p. 161 (1967); and British Specification 1.097.533. Alkanoic acids of 2 to 6 carbon atoms. inclusive. especially acetic acid. are preferred acids for this acidic dehydration. They can be applied either before or after the hydrogenation of the acetylenic bonds.  
  Racemic PGB and the other compounds encompassed by formula Xle are prepared by basic dehydration of the corresponding PGE -type compounds encompassed by formula Vllle or by contacting the corresponding PGA -type compounds encompassed by formula Xe with base. For example. both racemic PGE VIII. and racemic PGA Xe. give racemic PGB Xle. on treatment with base. Presumably the base first causes dehydration of the PGE to PGA and then .causes the ring double bond of PGA;. to migrate to a new position. The corresponding 5.6.l7.l8-dehydro- PGB -type compounds. Xld, are produced in a like manner from 5.6.17.18-dehydro-PGE;,-. Vllld. or 5.6.17.18-dehydro-PGA -type compounds. Xd. and by hydrogenation of the acetylenic bonds are converted to PGB -type compounds. Xld. I  
  These basic dehydrations and double bond migrations are carried out by methods known in the art for similar reactions of known prostanoic acid derivatives. See. for example. Bergstrom et al.. J. Biol. Chem. 238. 3555 (I963). The base is any whose aqueous solution has pH greater than 10. Preferred bases are the alkali metal hydroxides. A mixture of water and sufficient of a water-miscible alkanol to give a homogeneous reaction mixture is suitable as a reaction medium. The PGE -,-type or PGA;,-type compound is maintained in such a reaction medium until no further PGB -type compound is formed. as shown by the characteristic ultraviolet light absorption for the PGB -type compound. They can be applied either before or after the hydrogenation of the acetylenic bonds.  
  These various transformations of the PGE -type compounds of formulas Vllle to the PGF -type. lXe. PGA type. Xe. and PGB -type. Xle. compounds are shown in Chart A. wherein R,.&#39; R R... R.. A. and are-as defined above. The same transformation can be applied to the 5.6.17.18-dehydro-PGE -type compounds. VI- IId. as shown in Chart A-l. If desired. the 5.6.l7.l8-  
  3 ,8 79,43 7 l3 l4 dehydro-PGA -type compounds. Xd. can be converted Racemic POE and the other PGE -type Compounds to PGA -type compounds Xe. by hydrogenation by the encompassed by formula VlII are prepared by the mulprocedures of step 8 and 8a. infra. ti-step processes outlined in Charts B. C. and D.  
 CHART A c c OH H H /:duct i on CHz-CEC-A-COOR Vllle The bicyclic compound of formula Xll in Chart B is the initial reactant in these multi-step processes. lt exists in two isomeric forms, exo and endo with respect to the attachment of the CR O moiety. It also exists the tetrahydropyranyloxy group making in all four isomeric forms. Each of those isomers separately or mixtures thereof are used as reactants according to this invention to produce substantially the same final PGE type or 5.6. l 7, l 8-dehydro-PGE -type product mixture.  
  In Belgain Pat. No. 702,477; reprinted in Farmdoc Complete Specifications, Book 714. No. 30,905, page 313. Mar. 12. 1968. the reaction sequence leading to exo form of compound Xll is as follows: The hydroxy 55 wherein R is as defined above.  
 In the first step of the process (Chart B). the aldehyde group or keto group is transformed by the Wittig reaction to a moiety of the formula CR =CR C,,H-  
 in two isomeric forms with respect to the attachment of 45 XV can be effected by the procedures described in said Belgian patent. However. as mentioned above, that separation is usually not necessary since the cis-trans mixture is useful as a reactant in the next process step.  
  The process described in said Belgian pat. No. 702.477 for producing the exo form of bicyclic compound Xlluses as an intermediate, the exo form of a bicyclo[3. l .O]-hexane substituted at 3 with a protected hydroxy. e.g., tetrahydropyranyloxy and at 6 with an esterified carboxyl. When the corresponding endo compound is substituted for that exo intermediate, the Belgian Patent process leads to the endo form of bicyclic compound XII. That endo intermediate used in the Belgian Patent process has the formula:  
  toocu i I, v xxvn Compound XXVII is prepared by reacting endobicyclo-l3.l.0]hex-2-ene-6-carboxylic acid methyl ester with diborane in a mixture of tetrahydrofuran and diethyl ether. a reaction generally known in the art. to give endobicyclol3.l.0]hexan-3-ol-6-carboxylic acid methyl ester which is then reacted with dihydropyran in the presence of a catalytic amount of POCl to give the desired compound. This is then used as described in said Belgian patent to produce the endo form of hi cyclic compound XII.  
  Using this endo form of bicyclic compound XII as the starting material. steps 2 and 3 produce mixtures of endocis and endo-trans. These can be separated as described for the separation of exo-cis and exo-trans XV. but this separation is usually not necessary since, as mentioned above. the cis-trans mixture is useful as a reactant in the next process step.  
  In the Wittig reaction, (Step I). the other starting compound is an organic chloride or bromide, or iodide of the formula This can be prepared from the corresponding alcohol HOCHR C,,H ,,-C E C-R XXIX by processes already known in the art. for example. by reacting compound XXIX with triphenylphosphine and N-bromosuccinimide.  
  Acetylenic alcohols of formula XXIX are generally known in the art. for example, 3-pentyn-lol, 3-hexynl-ol. 4-hexyn-l-ol. 2.3-dimethyl-4-pentyn-l-ol. 6- octyn-l-ol. o-nonyn-l-ol. 4-undecyn-l-ol. 6-dodecynlol. S-tetradecyn-l-ol. and the like. Others where R is methyl. ethyl. propyl. butyl. or the isomers thereof can be made by reacting an acetylenic aldehyde of the formula with the appropriate Grignard reagent, BrMgR;,. These acetylenic aldehydes can be made by oxidizing the corresponding alcohol, for example, those listed above. with a Jones reagent, Collins reagent. a Moffatt oxidation or the like. The aldehyde is then reacted with BrMgR to prepare acetylenic alcohols of formula XXIX. Compounds thus obtainable include 4-hexyn-Z- ol, 4-heptyn-2-ol. 5-heptyn-2-ol. 3-methyl-4-hexyn-2- ol, 3.4-dimethyl5-hexyn-2-ol, 7-nonyn-2&#39;ol, 7-decyn2- ol. S-dodecyn-Z-ol. 7-tridecyn-2-ol. 5-heptyn-3-ol. 5- octyn-3-ol. 6-octyn-3-ol. 8-undecyn-3-ol. 6-tridecyn-3- ol, 8-tetradecyn-3-ol. and the like. Still other alkyn-lols according to formula XXIX (R hydrogen) can be made by condensing an omega-alkyl-l-ol of the formula with an alkyl halide. Ha 1 R using lithium and ammonia as the condensing agent; still others by condensing a protected halohydrin of the formula O-CHzCnH n-HaI XXXll with a l-alkyn. HC 5 CR Again lithium and ammonia can be used as the condensing agent.  
 The protective tetrahydropyranyl group can then be removed by acid hydrolysis to form an acetylenic alcohol of formula XXIX. The latter process is particularly useful where R is a halo substituted alkyl. The l-alkyn. HC E CR can be made by condensing acetylene with or sodium acetylide with an alkyl halide. R Hal where R is as given above.  
  The transformation of bicyclo-ketone-olefin XXIII to glycol XXIV (Step 5. Chart B) is carried out by reacting olefin XXIII with a hydroxylation reagent. Hydroxylation reagents and procedures for this purpose are known in the art. See. for example. Gunstone. Advances in Organic Chemistry, Vol. I. pp. l03-l47. Interscience Publishers. New York. N. Y. (I960). Various isomeric glycols are obtained depending on whether olefin XXIII is cis or trans and endo or exo. and on whether a cis or a trans hydroxylation reagent is used. Thus endo-cis olefin XXIII gives a mixture of two isomeric erythro glycols of formula XXIV with a cis hydroxylation agent. e.g., potassium permanganate. The endo-cis olefins and the endo-trans olefins XXIII give similar mixtures of two threo isomers with cis and trans hydroxylation reagents, respectively. These various glycol mixtures are separated into individual isomers by silica gel chromatography. However. this separation is usually not necessary. since each isomeric erythro glycol and each isomeric threo glycol is useful as an intermediate according to this invention and the processes outlined in Charts B. C. and D to produce final products of formulas VIIIe and Xe. and then. according to Chart A, to produce the other final products of this invention. Thus the various isomeric glycol mixtures encompassed by formula XXIV produced from the various isomeric olefins encompassed by formula XXIII are all useful for these same purposes.  
  In step 4 the other starting material is a haloalkynoic ester of the formula HalCH -C E C-A-COOR, xxxm wherein Hal is chlorine. bromine. or iodine. In effecting this step any of the alkylation procedures known in the art to be useful for alkylating cyclic ketones with alkyl halides. especially haloalkynoic esters, can be used for the transformation of XV to XXIII. See, for example, the above mentioned Belgian patent No. 702,477 for procedures useful here and used there to carry out similar alkylations.  
  For this alkylation. it is preferred that Hal be bromo. or iodo. Any of the usual alkylation bases, e.g.. alkali metal alkoxides, alkali metal amides. and alkali metal hydrides, are useful for this alkylation. Alkali metal alkoxides are preferred. especially tert-alkoxides. Sodium and potassium are preferred alkali metals. Especially preferred is potassium tert-butoxide. Preferred diluents for this alkylation are tetrahydrofuran and 1.2- dimethoxyethane. Otherwise. procedures for producing and isolating the desired formula XXIII compound are within the skill of the art.  
 This alkylation procedure produces a mixture of alpha and beta alkylation products. Le, a mixture of formula XXIII products wherein part has the CH C E CA-COOR moiety attached in alpha configuration and wherein part has that moiety attached in beta configuration. When about one equivalent of base per equivalent of formula XV ketone is used, the alpha configuration usually predominates. Use of an excess of base and longer reaction time usually result in produc tion of larger amounts of beta products. These alphabeta isomer mixtures are separated at this stage or at any subsequent stage in the multi-step processes shown in Charts B and D. Silica gel chromatography is preferred for this separation.  
  An alternative alkylation procedure is shown in steps 41:, 4b, and 4c. The alkylating agent XVII is reacted with the bicyclo-ketone-olefin XV by the alkylation procedure described above for step 4.  
  The alkylating agent of formula XVII is prepared by the series of reactions shown in Chart C. The initial reactants. BrACH- ,OH, are omega bromoaleohols which are known in the art or can be prepared by methods known in the art. For example, when A in the final product is to be trimethylene as it is in racemic PGE the necessary 4-bromobutanol is prepared by reacting tetrahydrofuran with hydrogen bromide.  
  To illustrate the availability of the other bromoglycols of formula XXI (Chart C). consider the abovedescribed special compounds offormula VIlIe, wherein A is -(CH ),,Z, wherein b is zero, one, 2, or 3, and  
 Z is ethylene substituted by one or 2-fluoro, methyl. or ethyl. or by one alkyl of 3 or 4 carbon atoms. These omega-bromoaleohols, Br(CH ),,ZCI-I OH, are prepared by starting with the appropriate succinic acid. HOOC-ZCOOH, all of which are known or easily accessible by known methods. These succinic acids are transformed to the corresponding anhydrides by known procedures. Each anhydride is then reacted with an alkanol, for example, methanol, to give the corresponding succinic acid half ester, e.g., COOCH When Z is unsymmetrical. e.g., substituted with one fluoro, a mixture of isomeric half esters is obtained, HOOCZCOOCH and CH -OOCZ- COOH, which is separated to give the desired isomer. When it is desired that b is Br(CH )bZCH- )OH be zero, the succinic acid half ester is subjected to the Hunsdiecker reaction, thereby producing BrZ-- COOCH;,. which is reduced by lithium aluminum hydride to Br--ZCI-I OH. When b is to be one, the carboxyl group of the succinic acid half ester is changed to acid chloride with thionyl chloride, to aldehyde by the Rosenmund reduction, to alcohol with sodium borohydride. and to CH Br with PBr giving BR-CH- ,--ZCOOCH;,, which is then reduced to BrCH- ,Z-CH OH with lithium aluminum hydride. When b is to be 2 or 3. the succinic acid half ester is subjected once or twice to the Arndt-Eistert reaction to produce HOOC--CH ZCOOCH or I-IOCC-CH. ,CH- Z-COOCH;,, which is then subjected to the same series of reactions. given above to give BrCH C- H. -ZCH- ,OH or BrCH- ,CH CH -ZCH OH.  
  Referring again to Chart C, the several process steps. XXI to XX, XX to XIX, XlX to XVIII, and XVIII to XVII are exemplified in Belgian Pat. Ser. No. 747,348. Sept. 14, 1970, in the case wherein A is trimethylene. Those procedures are used when A is other than trimethylene and within the scope ofA as defined above.  
  The transformation of alkylation product XVI to primary alcohol XXII (Chart B) is carried out by acid catalyzed hydrolysis of the tetrahydropyranyl ether XVl. Such hydrolysis of tetrahydropyranyl ethers is well known to those skilled in the art. Oxalic acid is especially preferred for this acid hydrolysis of XVI to XXII. The oxidation of primary alcohol XXII to carboxylic acid XXIII (Chart B. R, H) is carried out by oxidizing XXII with any oxidizing agent which will not also at- 5 tack the acetylenic linkage in XXII. An especially useful reagent for this purpose is the Jones reagent. i.e., acidic chromic acid. See J. Chem. Soc. 39 1946). Ace tone is a suitable diluent for this purpose. and a slight excess of oxidant and temperatures at least as low as about 0 C.. preferably about -l0 to about C. should be used. The oxidation proceeds rapidly and is usually complete in about 5 to about 30 minutes. Excess oxidant is destroyed, for example. by addition of a lower alkanol. advantageously isopropyl alcohol, and the aldehyde is isolated by conventional methods, for example. by extraction with a suitable solvent. e.g.. diethyl ether. Other oxidizing agents can also be used. Examples are mixtures of chromium trioxide and pyridine or mixtures of dicyclohexylcarbodiimide and dimcthyl sulfoxide. See. for example, .I. Am. Chem. Soc. 87, 5661 (1965).  
  The acid thus formed (compound XXIII, R, H) can then be esterified by procedures already known in the art for transforming carboxylic acids to esters. For example, a diazohydrocarbon. e.g., diazomethane, advantageously in diethyl ether solution. is reacted with the acid to produce the ester. e.g., the methyl ester, by known procedures. When R is ethyl substituted with 3-chloro, 2 or 3 bromo. or I, 2, or 3 iodo, the acid is reacted with the appropriate haloethanol, e.g., B. B, ,B-trichloroethanol, in the presence of a carbodiimide,  
  dicyclohexylcarbodiimide. and a base, e.g., pyridine. This mixture, advantageously with an inert diluent, e.g.. dichloromethane, usually produces the desired haloethyl ester within several hours at about C. The other esters within the scope of R are prepared by procedures known to the art.  
  In step 6 the vicinal hydroxy groups of the glycol XXIV are modified by replacing the hydrogens with an alkanesulfonyl leaving-group, L, for example mesyl. containing up to and including 5 carbon atoms. Thus, the bisalkanesulfonic acid esters XXV (Chart B) are prepared by reacting glycol XXIV with an alkylsulfonyl chloride or bromide, or with an alkanesulfonic acid anhydride. Alkylsulfonyl chlorides are preferred for&#39;this reaction. The reaction is carried out in the presence of a base to neutralize the by-product acid. Especially suitable bases are tertiary amines, e.g., dimethylaniline or pyridine. It is usually sufficient merely to mix the two reactants and the base, and maintain the mixiture in the range 0 to 25 C. for several hours. The formula XXV bis-alkanesulfonic acid esters are then isolated by procedures known to the art.  
  The transformation in Chart D, Step 7a. of the modified glycol XXV to VIIId is carried out by.reacting XXV with water in the range about 0 to about 60 C. The resulting product is racemic 5.6.l7,l8-dehydro- PGE or an analog thereof. In making reacemic 5,6,17,l8-dehydro-PGE usually 25 C. is a suitable reaction temperature, the reaction then proceeding to completion in about 5 to 10 hours. It is advantageous to have a homogenous reaction mixture. This is accomplished by adding sufficient of a water-soluble organic diluent which does not enter into the reaction. Acetone is a suitable diluent. The desired product is isolated by evaporation of excess water and diluent if one is used. The residue contains a mixture of formula Vllld isomers which differ in the configuration ofthe side chain hydroxy. that being either R or S. These are separated from by-products and from each other by silica gel chromatography. A usual by-product is the monosulfonic acid ester of formula XXVI (Chart C). This mono-sulfonic acid ester is esterified to the formula XXV bis-sulfonic acid ester in the same manner described above for the transformation of glycol XXIV to bis-ester XXV. and thus is recycled in step 7a.  
  For the transformation of bis-esters XXV to the formula Vllld products. it is preferred to use the bis-mesyl esters. i.e.. compounds XXV wherein L is mesyl.  
  In step 8a the acetylenic linkages are hydrogenated to olefinic linkages. A suitable method is to hydrogenate over a Lindlar catalyst in the presence of quinoline. The Lindlar catalyst is percent palladium-onbarium sulfate. Methanol or like inert solvent or diluent is used and the pressure is low. advantageously slightly above atmospheric and ordinarily not above about two atmospheres. The resulting products can be isolated by silica gel chromatography. If the starting material contains both the R and S epimers. the product Vllle will also contain the R and S epimers. These also can be separated by silica gel chromatography. As shown on Chart D. the hydrogenation of Vllld (of Xd) leads to PG -type compounds depending on whether the acetylenic bonds of Vllld (or Xd) are reduced to cisCH=CH-. The above described hydrogenation gives this type of reduction of the acetylenic bonds.  
  The transformation of the protected glycols XXV (Step 7b) to 5.6.l7.18-dehydro-PGA -type compounds (Xd) is carried out by heating the formula XXV bisester in the range 40 to 100 C. with a combination of water. a base characterized by its water solution having a pH 8 to 12. and sufficient inert water-soluble organic diluent to form a basic and substantially homogenous reaction mixture. A reaction time of one to 10 hours is usually used. Preferred bases are the water-soluble salts of carbonic acid. especially alkali metal bicarbonates. e.g.. sodium bicarbonate. A suitable diluent is acetone. The products are isolated and separated as described above for step 7a and hydrogenated as in step 8a. The same mono-sulfonic acid esters XXVI observed as byproducts in step 7a are also observed in step 7b. Also. as in step 7b the bis-mesyl esters XXV are preferred. Also as in steps 7a and 8a. during production of Xd and Xe. alpha XXV gives alpha Xd and alpha Xe. beta XXV gives beta Xd and beta Xe. and in each case. alpha and beta Xd and Xe. a mixture of R and S isomers is obtained. These R and S isomer mixtures are separated by silica gel chromatography.  
  The configuration of the CH C- I CA-COOR, moiety does not change during these transformations of Charts B and D. Also the configuration does not change in hydrogenation. There fore. when the CH C g C-A-COOR, is attached initially in alpha configuration racemic 5.6.l7.l8- dehydro-PGE -,-type. Vllld. PGE -type. Vllle. 5.6.l7.l 8-dehydro-PGA type. Xd. and PGAg-IYPC, Xe. compounds are obtained. and when the moiety is attached in beta configuration. the 8-isoforms are obtained.  
  Resolution of the final product racemates or the racemic intermediates are carried out by procedures known in the art. For example. when a final compound of formula Vllle. lXe. Xe. or Xle is a free acid. the dl form (racemate) thereof is resolved into the d and 1 forms (the natural and unnatural configurations) by reacting said free acid by known general procedures with an optically active base. e.g.. brucine or strychnine. to give a mixture of two diastereoisomers which are separated by known general procedures, e.g.. fractional crystallization. to give the separate diastereoisomeric salts. The optically active acid of formula VIII to XI is then obtained by treatment of the salt with an acid by known general procedures. Alternatively. the free acid form of the intermediate dehydro compounds Vllld. lXd. Xd. or Xld is resolved into separate d and l forms and then esterified and transformed further to the corresponding optically active form of the final product Vllle to XI as described above.  
  Alternatively. glycol reactant XXIV. in exo or endo form. is transformed to a ketal with an optically active 1.2-glycol. e.g.. D-(-)-2.3-butanediol. by reaction of said l.2-glycol with the formula XXIV compound in the presence of a strong acid. e.g.. p-toluenesulfonic acid. The resulting ketal is a mixture of diastereoisomers which is separated into the d and l diastereoisomers. each of which is then hydrolyzed with an acid. e.g.. oxalic acid. to the original keto compound. now in optically active form. These reactions involving optically active glycols for resolution purposes are generally known in the art. See. for example. Chem. Ind. 1664 (196]) and J. Am. Chem. Soc. 84. 2938 (I962). Dithiols may be used instead of glycols.  
  The novel PGE PGF;,, PGA and PGB -type compounds of formula Vllle to Xle wherein R is alkyl of one to 4 carbon atoms. inclusive. preferably methyl or ethyl. are preferred over the corresponding PGE PGF PGA;,. and PGB -type compounds in which R;, is hydrogen for the above-described pharmacological purposes. For convenience the compounds of the invention where R, is alkyl will be referred to as l5-alkyl analogs even though the number actually will be greater or less than 15 depending on whether the number of methylene groups in A is greater or less than three.  
  These lS-alkyl prostaglandin analogs are surprisingly and unexpectedly more useful than the corresponding IS-hydrogen compounds for the reason that they are substantially more specific with regard to potency in causing prostaglandin-like biological responses, and have a substantially longer duration of biological activity. For that reason. fewer and smaller doses of these l5-alkyl prostaglandin analogs are needed to attain the desired pharmacological results.  
  Although the above-mentioned l5-alkyl compounds are produced by the methods outlined above in Charts A-D. the preferred methods are set forth in Charts E and F as follows.  
 CHART E (Oxidation) CH -Q-ACOOR;  
 R Vllla CHART F CHg-Q-ACOOR;  
 H, bu  
 (oxidation) i s i 1 ylat ion) CH -Q-A-COOR in Chart E is shown the transformation of lS-alkyl PGF-type acids and alkyl esters to the corresponding S PGE-type acids and alkyl esters by oxidation. For this purpose. an oxidizing agentis-used which selectively oxidizes secondary hydroxy groups to carbonyl groups in the presence of carbon-carbon double bonds. Formula lXa in Chart E includes optically active compounds as shown and racemiecompounds of that formula and the mirror images thereof, and also the 15- epimers of both of those. i.e.. wherein the configuration at C15 is R rather than S as shown. Also in Chart E. A. R R and R are as defined above. R is alkyl of one to 4 carbon atoms. and both Os are ethynylene or cisethylene.  
  For the transformations of chart E. the B-hydroxy isomers of reactant [Xa are suitable starting materials when the carboxyl side chain is alpha. although the corresponding a-hydroxy isomers are also useful for this purpose.  
  Oxidation reagents useful for the transformation set forth in Chart E are known to the art. An especially useful reagent for this purpose is the Jones reagent. i.e.. acidified chromic acid. See J. Chem. Soc. 39 (I946). Acetone is a suitable diluent for this purpose. and a slight excess beyond the amount necessary to oxidize one of the secondary hydroxy groups of the formula lXa reactant is used. Reaction temperatures at least as low as about 0 C. should be used. Preferred reaction temperatures are in the range &#34;10 to 50 C. The oxidation proceeds rapidly and is usually complete in about 5 to 20 minutes. The excess oxidant is destroyed. for example by addition of a lower alkanol. advantageously. isopropyl alcohol. and the formula Villa PGE- type product is isolated by conventional methods.  
  Examples of other oxidation reagents useful for the Chart E transformations are silver carbonate on diatomite [Chem Commun. 1102 (I969)]. mixtures of chromium trioxide and pyridine [Tetrahedron Letters 3363 (1968. J. Am. Chem. Soc. 75. 422 (1953). and Tetrahedron. 18. 1351 (1962)]. mixtures of sulfur trioxide in pyridine and dimethyl sulfoxide [1. Am. Chem. Soc. 89. 5505 (1967)]. and mixtures of dicyclohexylcarbodiimide and dimethyl sulfoxide [.I. Am. Chem. Soc. 87. 5661 (1965)].  
  The novel. 15-a1ky1 PGF and&#39;-PGF -type acids and esters of formula lXa are preferably prepared from the corresponding lS-hydrogen compounds by the sequence of transformations shown in Chart F. wherein formulas IX. XXXVI]. XXXVlll. lXa(S). and lXa(R) include optically active compounds as shown and racemic compounds of those formulas and the mirror images thereof. Also in Chart F. R is alkyl of one to 4 carbon atoms. inclusive. and A. R R R are as heretofore defined and Q is ethynylene 0r cis-ethylene. Also in Chart F. G is alkyl of one to 4 carbon atoms. inclusive. aralkyl of 7 to 12 carbon atoms. inclusive. phenyl. or phenyl substituted with one or 2 fluoro. chloro. or alkyl of one to 4 carbon atoms. inclusive. and R is alkyl or silyl of the formula -Si(G )1; wherein G is as definedabove. The various G s of a -Si(G) moiety are alike or different. For example. a -Si(G)=; can be trimethylsilyl. dimethylphenylsilyl. or methylphenylbenzylsilyl. Examples of alkyl of one to 4 carbon atoms. inclusive. are methyl. ethyl. propyl. isopropyl. butyl. isobutyl. sec-butyl. and tert-butyl. Examples of aralkyl of 7 to 12 carbon atoms. inclusive. are benzyl. phenethyl.  
 a-phenylethyl. 3-phenylpropyl. a-naphthylmethyl. and Z-(B-naphthyhethyl. Examples of phenyl substituted with one or 2 fluoro. chloro. or alkyl of one to 4 carbon atoms. inclusive, are p-chlorophenyl. m-fluorophenyl. o-tolyl. 2.4-dichlorophenyl. p-tert-butylphenyl. 4-chloro-2-methylphenyl. and 2.4-dichloro-3- methylphenyl.  
  In Chart F. the final PGFg and PGF -type products are those encompassed by formulas lXa(S) and lXa(R). respectively. where both Q&#39;s are cis-ethylene.  
  The heretofore-described acids and esters of formula lX are transformed to the corresponding intermediate l5-oxo acids and esters of formula XXXVll. by oxidation with reagents such as 2.3-dichloro-5.o-dicyano- 1.4-benzoquinone. activated manganese dioxide. or nickel peroxide (see Fieser et al.. Reagents for Organic Synthesis.&#34; John Wiley &amp; Sons. Inc. New York, N.Y.. pp. 215.637. and 731). Alternatively. these oxidations are carried out by oxygenation in the presence of the l5-hydroxyprostaglandin dehydrogenase of swine lung [see Arkiv for Kemi 25. 293 1966)]. These reagents are used according to procedures known in the art. See. for example. J. Biol. Chem. 239. 4097 1964).  
  The novel 5.6.l7.18-dehydro-PGF -type compounds of formula lXa are obtained by the borohydride reduction of the corresponding 5.6.l7.l8-dehydro-PGE type compounds of formula Vllla. Here again the num bering is merely typical and will vary according to the values of A and n.  
  Referring again to Chart F. the intermediate compounds of formula XXXVll are transformed to silyl derivatives of formula XXXVllI by procedures known in the art. See. for example. Pierce. Silylation of Organic Compounds.&#34; Pierce Chemical Co.. Rockford. Ill. H968). Both hydroxy groups of the formula XXXVII reactants are thereby transformed to O-Si(G) moieties wherein G is as defined above. and sufficient of the silylating agent is used for that purpose according to known procedures. When R is the formula XXXVll intermediate is hydrogen. the COOH moiety thereby defined is simultaneously transformed to COOSi(G) additional silylating agent being used for this purpose. This latter transformation is aided by excess silylating agent and prolonged treatment. When R in formula XXXVll is alkyl. then R in formula XXXVlll will also be alkyl. The necessary silylating agents for these transformations are known in the art or are prepared by methods known in the art. See. for example. Post. Silicones and Other Organic Silicon Compounds. Reinhold Publishing Corp.. New York. N.Y. (1949).  
  Referring again to Chart F the intermediate silyl compounds of the formula XXXVllI are transformed to the final compounds of formulas lXa(S) and lXa(R) by first reacting the silyl compound with a Grignard reagent of the formula R ,,MgHal wherein R is as defined above. and Hal is chloro. bromo. or iodo. For this purpose. it is preferred that Hal be bromo. This reaction is carried out by the usual procedure for Grignard reactions. using diethyl ether as a reaction solvent and saturated aqueous ammonium chloride solution to bydrolyze the Grignard complex. The resulting disilyl or trisilyl tertiary alcohol is then hydrolyzed with water to remove the silyl groups. For this purpose. it is advantageous to use a mixture of water and sufficient of a water-miscible solvent. e.g.. ethanol to give a homogenous reaction mixture. The hydrolysis is usually complete in 2 to 6 hours at C.. and is preferably carried out in 30 an atmosphere of an inert gas. e.g.. nitrogen or argon.  
  The mixture of 15-5 and l5-R isomers obtained by this Grignard reaction and hydrolysis is separated by procedures known in the art for separating mixtures of prostanoic acid derivatives. for example. by chromatography on neutral silica gel. In some instances. the lower alkyl esters. especially the methyl esters of a pair of 15-5 and l5-R isomers are more readily separated by silica gel chromatography than are the corresponding acids. ln thos cases. it is advantageous to esterify the mixture of acids. separate the two esters. and then. if desired. saponify the esters by procedures known in the art and described herein.  
  The novel IS-alkyl PGA-type acids and esters of formula Xa are prepared from the lS-alkyl PGE compounds. Vllla. heretofore described. by dehydration as shown in Chart G. For this purpose. a dehydrating agent is used which removes the hydroxy group from the alicyclic ring in the presence of a hydroxy group on a tertiary carbon atoms. Formula Vllla includes optically active compounds as shown and racemic compounds of that formula and the mirror images thereof. and also the IS-epimers of both of those. i.e.. wherein the configuration at C15 is R or S and that of the carboxyl side chain is a or ,8.  
  Dehydration agents useful for the transformation to PGA -type compounds set forth in Chart G are known in the art. Any of the known substantially neutral dehydrating CHART G cHa- -A-comi Vllla 0 CH2-Q-A-C00R1 &#34;Reagents for Organic Syntheses&#34;. John Wiley &amp; Sons. Inc.. New York. 1967. Preferred dehydrating agents are mixtures of at least an equivalent amount of a carbodiimide and a catalytic amount of a copper (ll) salt. Especially preferred are mixtures of at least an equivalent amount of dicyclohexylcarbodiimide and a catalytic amount of copper (ll) chloride. An equivalent amount of a carbodiimide means one mole of the carbodiimide for each mole ofthe Formula-Vllla reactant. To ensure completeness of the reaction. it is advantageous to use an excess of the carbodiimide. i.c.. 1.5 to or even more equivalents of the carbodiimide.  
  The dehydration is advantageously carried out in the presence of an inert organic diluent which gives a homogeneous reaction mixture with respect to the Formula-Villa reactant and the carbodiimide. Diethyl ether is a suitable diluent.  
  It is advantageous to carry out the dehydration in an atmosphere of an inert gas. e.g.. nitrogen. helium. or  
 argon.  
  The time required for the dehydration will depend in part on the reaction temperature. With the reaction temperature in the range to C.. the dehydration usually takes place in about 40 to 60 hours.  
  The Formula-Xa product is isolated by methods known in the art. e.g.. filtration of the reaction mixture and evaporation of the filtrate. The product is then purified by methods known in the art. advantageously by chromotography on silica gel.  
  The conversion of Formula-Villa and Formula-Xa compounds to Formula Xla compounds is effected with base as described above in connection with Charts A and A-l.  
  The formula Vlll and X compounds produced according to the processes outlined in Charts B. C. and D and discussed above are all carboxylic acid esters. wherein R is not hydrogen. Moreover. when these compounds are used to produce compounds of formulas IX and XI according to the processes outlined in Chart A and discussed above. corresponding R esters are likely to be produced. especially in the case of the PGF;; compounds of formulas IX. For some of the uses described above. it is preferred that these formula Vlll to X! compounds be in free acid form, or in salt form which requires the free acid as a starting material. lt is also sometimes desirable to have the free acid or salt forms of the acetylenic compounds of the 5,6,17,18- dehydro-PGE -type (Vlld) and the 5,6.l7.l8-dehydro- PGA -type (Xd) compounds. as well as the 5.6.17.18- dehydro-PGF;,-type (lXd) PGB -type (Xld) compounds and which are derivable therefrom by the processes outlined in Chart A-l. because these free acids and salt forms have properties like those of the corresponding hydrogenated (olefinic) compounds and are useful for the same purposes detailed above.  
  The formula lXe. Xle. lXd. and Xld R,-esters are easily hydrolyzed or saponified by the usual known procedures. especially when R, is alkyl of one to 4 carbon atoms. inclusive. Therefore it is preferred when the free acid form of compounds lXe. Xle. lXd. and Xld is desired. that R by such alkyl. especially methyl or ethyl.  
  On the other hand. the formula Vllle. Xe. Vllld. and Xd&#39;products are difficult to hydrolyze or saponify without unwanted structural changes in the desired acids. There are two other procedures useful to make the free acid form of formula Vllle. Xe, Vllld. and Xd products.  
 and 5,6,l7,l8-dehydro-.  
  One of those procedures is applicable mainly in preparing the free acids from the corresponding alkyl esters wherein the alkyl group contains one to 8 carbon atoms. inclusive. That procedure comprises subjecting the alkyl ester corresponding to formula Vllle. Xe. Vllld. or Xd to the acylase enzyme system of a microorganism species of Subphylum 2 of Phylum Ill. and thereafter isolating the acid. Especially preferred for this purpose are species of the orders Mucorales. Hypoereales. Moniliales. and Actinomycetales. Also especially preferred for this purpose are the species of the families Mucoraceae. Cunninghamellaceae. Nectreaceae. Moniliaceae, Dematiaceae. Tuberculariaceae. Actinomycetaceae. and Streptomycetaceae. Also especially preferred for this purpose are species of the genera Absidia. Circinella. Gongronella. Rhizopus. Cunninghamella. Calonectria. Aspergillus. Penicillium. Sporotrichum, Cladosporium. Fusarium. Nocardia. and Streptomyces.  
  Examples of microorganisms falling within the scope of those preferred orders. families. and genera are listed in U.S. Pat. No. 3.290.226 and details of the process are disclosed in German Offenlegunsschrift No. 1.937.678. reprinted in Farmdoc Complete Specifications. Book No. 13. No. 6863R. Week R5. March 18. 1970.  
  This enzymatic ester hydrolysis is carried out by shaking the formula Vllle. Xe. Vllld. or Xd alkyl ester in aqueous suspension with the enzyme contained in a culture of one of the abovementioned microorganism species until the ester is hydrolyzed. A reaction temperature in the range 20 to 30 C. is usually satisfactory. A reaction time of one to 20 hours is usually sufficient to obtain the desired hydrolysis. Exclusion of air from the reaction mixture, for example. with argon or nitrogen is usually desirable.  
  The enzyme is obtained by harvest of cells from the culture, followed by washing and resuspension of the cells in water, and cell disintegration, for example, by stirring with glass beads or by sonic or ultrasonic vibrations. The entire aqueous disintegration mixture is used as a source of the enzyme. Alternatively and preferably, however, the cellular debris is removed by centrifugation or filtration. and the aqueous supernatant or filtrate is used.  
  In some cases, it is advantageous to grow the microorganism culture in the presence of an alkyl ester of an aliphatic acid, said acid containing 10 to 20 carbon atom. inclusive, and said alkyl containing one to 8 carbon atoms. inclusive. or to add such an ester to the culture and maintain the culture without additional growth for one to 24 hours before cell harvest. Thereby. the enzyme produced is sometimes made more effective in transforming the formula VIIIe, Xe. Vllld, or Xd ester to the free acid. An example ofa useful alkyl ester for this purpose is methyl oleate.  
  Although, as mentioned above, most of the R esters encompassed by formulas Vllle. Xe. Vllld, and Xd are not easily hydrolyzed or saponified to the corresponding free acids, certain of those esters are transformed to free acids by another method. Those esters are the haloethyl esters wherein R, is -CH CCl They are transformed to free acids by treatment with zinc metal and an alkanoic acid of 2 to 6 carbon atoms, preferably acetic acid. Zinc dust is preferred as the physical form of the zinc. Mixing the halo ethyl ester with the zinc dust at about 25 C. for several hours usually causes substantially complete replacement of the haloethyl moiety of the formula Vllle, Xe, VIIId, or Xd ester with hydrogen. The free acid is then isolated from the reaction mixture by procedures known to the art. This procedure is also applicable to the production of the free acid form of the formula IXe, XIe, IXd, and Xld compounds from the corresponding haloethyl esters thereof.  
  As described above, the alkylation of cyclic ketone XV to ketone XXIII (Chart B) usually produces a mixture of alpha and beta alkylation products with respect to the CH C i CACOOR or the moiety. Also as described above, those two isomers lead to different final products, alpha leading to the PG -series and beta leading to the 8-iso-PG -series. If a compound in one or the other of those series is preferred, there are two methods for favoring production of the preferred final product.  
  One of those methods involves isomerization of the final product of formula VIIIe or formula VIIId. Either the alpha isomer of formula VIIIe or VIIId, or the beta isomer of formula VIIIe or VIIId is maintained in an inert liquid diluent in the range to 80 C. and in the presence of a base characterized by its water solution having a pH below about until a substantial amount of the isomer has been isomerized to the other isomer, i.e., alpha to beta or beta to alpha. Preferred bases for this purpose are the alkali metal salts of carboxylic acids, especially alkaloic acids of 2 to 4 carbon atoms,  
 e.g., sodium acetate. Examples of useful inert liquid diluents are alkanols of one to 4 carbon atoms, e.g., ethanol. This reaction at about 25 C. takes about one to about days. Apparently an equilibrium is established. The mixtures of the two isomers, alpha and beta, are separated from the reaction mixture by known procedures, and then the two isomers are separated from each other by known procedures, for example, chromatography, recrystallization, or a combination of those. The less preferred isomer is then subjected to the same isomerization to produce more of the preferred isomer. In this manner. by repeated isomerizations and separations, substantially all of the less preferred isomer of the formula VIIIe or formula VIIId compound is transformed to more preferred isomer.  
  The second method for favoring production of a preferred final formula Ville or formula VIIId isomer involves any one of the intermediates of formuulas XVI, XXII, XXIII, XXIV, or XXV (Chart B). Either the alpha form or the beta form of one of those intermediates is transformed to a mixture of both isomers by maintaining one or the other isomer, alpha, or beta, in  
 an inert liquid diluent in the presence of a base and in range 0 to 100 C. until a substantial amount of the starting isomer has been isomerized to the other isomer. Preferred bases for this isomerization are alkali metal amides, alkali metal alkoxides, alkali metal hydrides, and triarylmethyl alkali metals. Especially preferred are alkali metal tert-alkoxides of 4 to 8 carbon atoms, e.g., potassium tert-butoxide. This reaction at about C. proceeds rapidly (one minute to several hours). Apparently an equilibrium mixture of both isomers is formed, starting either isomer. The isomer mixtures in the equilibrium mixture thus obtained are isolated by known procedures, and then the two isomers are separated from each other by known procedures, for example, chromatography. The less preferred isomer is then subjected to the same isomerization to produce more of the preferred isomer. In this manner, by repeated isomerizations and separations, substantially all of the less preferred isomer of any of these intermediates is transformed to the more preferred isomer.  
  The final formula Vllle, IXe, Xe, and XIe compounds and VIIId, IXd, Xd, and Xld compounds prepared by the processes of this invention, in free acid form, are transformed to pharmacologically acceptable salts of neutralization with appropriate amounts of the corresponding inorganic or organic base, examples of which correspond to the cations and amines listed above. These transformations are carried out by a variety of procedures known in the art to be generally useful for the preparation of inorganic, i.e., metal or ammonium, salts, amine acid addition salts, and quater nary ammonium salts. The choice of procedure depends in part upon the solubility characteristics of the particular salt to be prepared. In the case of the inorganic salts, it is usually suitable to dissolve the acid in water containing the stoichiometric amount of a hydroxide, carbonate, or bicarbonate corresponding to the inorganic salt desired. For example, such use of sodium hydroxide, sodium carbonate, or sodium bicarbonate gives a solution of the sodium salt. Evaporation of the water or addition of a water-miscible solvent of moderate polarity, for example, a lower alkanol or a lower alkanone, gives the solid inorganic salt if that form is desired.  
  To produce an amine salt, the formula VIIIe, IXe, Xe, XIe, VIIId, IXd, Xd, or Xld acid is dissolved in a suitable solvent of either moderate or low polarity. Examples of the former are ethanol, acetone, and ethyl acetate. Examples of the latter are diethyl ether and benzene. At least a stoichiometric amount of the amine corresponding to the desired cation is then added to that solution. If the resulting salt does not precipitate, it is usually obtained in solid form by addition of a miscible diluent of low polarity or by evaporation. If the amine is relatively volatile, any excess can easily be removed by evaporation. It is preferred to use stoichiometric amounts of the less volatile amines.  
  Salts wherein the cation is quaternary ammonium are produced by mixing the formula Vllle, IXe, Xe, XIe, VIIId, IXd, Xd, or Xld acid with the stoichiometric amount of the corresponding quaternary ammonium hydroxide in water solution, followed by evaporation of the water.  
  The invention can be more fully understood by the following examples and preparations in which the parts are by weight and solvent ratios are by volume unless otherwise specified.  
 All temperatures are in degrees centigrade.  
  NMR spectra are recorded on a Varian A-6O spectrophotometer on deuterochloroform solutions with tetramethylsilane as an internal standard (downfield).  
  Mass spectra are recorded on an Atlas CH-4 mass spectrometer with a TO-4 source (ionization voltage ev).  
  For convenience the formulas are given in the natural configuration, it being understood, though, that the compounds produced, unless otherwise specified, include the enantiomorphs.  
 Example 1-Racemic PGE methylester (XXXIX) Part A-l Endo-bicyclo[3. 1 .0]hexan-3-ol-6-carboxylic acid methyl ester A mixture of endo-bicyclo[3. 1 .0lhex-2-ene-6- carboxylic acid methyl ester (103 g.) and anhydrous diethyl ether (650 ml.) is stirred under nitrogen and cooled to -5 C. A one molar solution (284 ml.) of diborane in tetrahydrofuran is added dropwise during 30 minutes while keeping the temperature below C. The resulting mixture is then stirred and allowed to warm to 25 C. during 3 hours. Evaporation under reduced pressure gives a residue which is dissolved in 650 ml. of anhydrous diethyl ether. The solution is cooled to 0 C., and 3 normal aqueous sodium hydroxide solution 172 ml.) is added dropwise under nitrogen and with vigorous stirring during 15 minutes, keeping the temperature at 0 to 5 C. Next, 30 percent aqueous hydrogen peroxide (94 ml.) is added dropwise with stirring during 30 minutes at 0 to 5 C. Then, 500 ml. of saturated aqueous sodium chloride solution is added, and the diethyl ether layer is separated. The aqueous layer is.  
 washed with four 200 ml. portions of ethyl acetate, the washings being added to the diethyl ether layer, which is then washed with saturated aqueous sodium chloride solution, dried, and evaporated to give 1 g. of a residue. This residue is distilled under reduced pressure to give 69 g. of a mixture of the methyl esters of endobicyclo[3.l.0]hexan-3-ol-6-carboxylic acid and endobicyclo[ 3. l .0]hexan-2-ol-6-carboxylic acid; b.p.  
 .8695 C. at 0.5 mm.  
  Part A-2 Endo-bicyclo[3. l .0]hexan-3-ol-6-carboxylic acid methyl ester tetrahydropyranyl ether The 2-ol and 3-ol mixture (66 g.) obtained according to Part A-l in 66 ml. of dihydropyran is stirred and cooled at l5-20 C. during addition of 3 ml. of anhydrous diethyl ether saturated with hydrogen chloride. The temperature of the mixture is then kept in the range to 30 C. for one hour with cooling, and is then kept at for 15 hours. Evaporation gives a resi-&#39; due which is distilled under reduced pressure to give 66 g. of a mixture of the methyl esters-tetrahydropyranyl ethers of endo-bicyclo[3.l.0]hexan-3-ol-6-carboxylic acid and endo-bicyclo[3.l.0lhexan-2-ol-6-carboxylic acid; b.p. 96lO4 C. at O.l mm.  
 Part A-3 Endo-6-hydroxymethylbicyclo[ 3.1 .0 lhexan-3-ol-3 tetrahydropyranyl ether A solution of the mixture (69 g.) of products obtained according to Part A-2in 300 ml. of anhydrous THPO CHO  
 diethyl ether is added dropwise during 45 minutes to a stirred and cooled mixture of lithium aluminum hydride (2l g.) in 1300 ml. of anhydrous diethyl ether under nitrogc. The resulting mixture is stirred 2 hours at 25 C., and is then cooled to 0 C. Ethyl acetate (71 ml.) is added, and the mixture is stirred 15 minutes. Water (235 ml.) is then added, and the diethyl ether layer is separated. The water layer is washed twice with diethyl ether and twice with ethyl acetate. A solution of Rochelle salts is added to the aqueous layer, which is then saturated with sodium chloride and extracted twice with ethyl acetate. All diethyl ether and ethyl acetate solutions are combined, washed with saturated aqueous sodium chloride solution, dried, and evaporated to give 61 g. of a mixture of the 3- tetrahydropyranyl ethers of endo-6- hydroxymethylbicicyl-[3.1.0]hexan-3-ol and endo-6- hydroxymethylbicyclo[3.1.01-hexan-2-0l.  
  Part A-4Endo-bicyclo[3.1.0]hexan-3-ol-6- carboxaldehyde 3-tetrahydropyranyl other A solution of the mixture (34 g.) of products obtained according to Part A-3 in 1000 ml. of acetone is cooled to -l0 C. Jones reagent (75 ml. of a solution of 2| g. of chromic anhydride, 60 ml. of water. and 17 ml. of concentrated sulfuric acid). precooled to 0C.. is added dropwise with stirring during 10 minutes at l0 C. After 10 minutes of additional stirring at l0 C.. isopropyl alcohol (35 ml.) is added during 5 minutes. and stirring is continued for 10 minutes. The reaction mixture is then poured into 8 l. of an ice and water mixture. The resulting mixture is extracted 6 times with dichloromethane. The combined extracts are washed with aqueous sodium bicarbonate solution, dried. and evaporated to give 27 g. of a mixture of the tetrahydropyranyl ethers of endo-bicyclo[3.l.0]hexan-3-ol-6- carboxaldehyde (XL) and endo-bicyclo[3.l.0]hexan- 2-ol 6-carboxaldehyde.  
 Part B 3-Hexynyll triphenylphosphonium bromide To a solution of 130 g. (0.81 moles) of l-bromo-hex- 3-yne in 250 ml. of benzene is added 236 g. (0.9 moles) of triphenylphosphine. The resulting solution is heated with stirring in a heating bath of C. for 24 hours. Stirring is continued at room temperature for 24 hours, then the reaction mixture is allowed to stand for 48 hours. An oil precipitated. The supernatant solution is decanted, the oil stirred in 200 ml. of benzene. The oil is again allowed&#39;to separate and the supernatant solution separated. The oil is dried under vacuum at room temperature. the oil solidifies while drying. The decanted solutions are combined and heated at 80 C. bath temperature for 48 hours, workup as above resulted in a second batch of solid material making a total yield of 210 g. of 3-hexynyl-ltriphenyl-phosphonium bromide.  
  Part C-Endo-6&#39;-Hept-l-en-4-ynyl-bicyclo[3.l.0lhexan-3- ol-3tetrahydropyranyl ether (XLI) THPO 105 g. of the phosphonium salt of Part B is stirred in 1200 ml. ofdry tetrahydrofuran under a nitrogen atmosphere. The reaction flask is cooled in an ice-methanol bath. 150 m1. of a 15.1 percent hexane solution of nbutyl lithium is added dropwise. When the addition was complete. stirring is continued for 20 minutes. Then a solution of42 g. of aldehyde XL in 150 ml. tetrahydrofuran is added dropwise with stirring over a period of 15 minutes.  
  The ice-methanol bath is replaced by a heating bath and the reaction mixture is heated at 60-70 C. bath temperature for 3 hours. The reaction mixture is allowed to stand at room temperature overnight. The solvent is removed under reduced pressure. The residue is treated with 500 ml. benzene and filtered; the solid is washed with 500 ml. benzene. the benzene solutions combined and evaporated under reduced pressure. The resulting oil is triturated with 500 ml. of Skellysolve B (technical hexane). filtered and the resulting solution evaporated under reduced pressure to give 37 g. of a yellow oil. The oil is chromatographed using 1500 g. of silica gel. The column is developed with seven 1500 ml. portions of 1:1 benzene-Skellysolve seven 1500 ml. portions of benzene, five 1.500 ml. portions of benzene containing percent ethyl acetate. five 1.500 ml. portions of benzene containing percent ethyl acetate. and three 1500 ml. portions of ethyl acetate. Fractions l2l8 are combined to give a total of 12.9 g. of tetrahydropyranylether XLI as a colorless oil. fractions 19-26 are combined to give a total of 13.5 g. of the corresponding alcohol XLIl as a colorless oil.  
  Part D -Endo-6-hept-l-en-4-ynyl-bicyclo[3.1.0]hexan-3-ol (XLll) XLI I 12.8 g. of tetrahydropyranylether XLI is dissolved in 300 ml.. of methanol. 600 mg. of oxalic acid is added and the solution heated under reflux for 1.5 hours. The methanol is evaporated under reduced pressure. the resulting residue dissolved in 300 ml. of methylene chloride. washed with 100 ml. of saturated aqueous HaH- CO and dried over Na. ,SO Evaporation of solvent results in 11.2 g. of crude alcohol XL&#34;. The alcohol is combined with alcohol XLll obtained in Part C and used for Part E without further purification.  
  Part E-Endo-fi-hept-1-en-4-ynyl-bicyclo[3.1.0]hexan3- one (XLlll) XLl ll Qw- A solution of 23.7 g. of alcohol XLll in 720 ml. of ace tone is cooled to -5 to l0C. 48 ml. of Jones reagent is added dropwise over a period of minutes maintaining a reaction temperature of 0 to 5 C. When the addition is complete. stirring is continued for 10 minutes at 5 C. 24 ml. of isopropanol is added and stirring continued for 10 minutes. The green solution is poured into 5 liters of water and the aqueous solution extracted with five 1 liter portions of methylene chloride. The combined extracts are washed with 750 ml. of saturated aqueous NaHCO two 750 ml. portions of saturated aqueous NaCl. and dried over Na SO Evaporation of solvent under reduced pressure yields 18.2 g. of a brown oil which is chromatographed using 800 g. of silica gel. The column is developed with four 800 ml. portions of Skellysolve B containing 2.5 percent ethyl acetate and twelve 800 ml. portions of Skellysolve B containing 5 percent ethyl acetate. Fractions 9-14 are combined to yield 5.3 g. of ketone XLlll as a colorless oil. NMR:  
 1 H at 5.4 5.98 (multiplet). l H at 4.7 5.28 (multiplet). 2 H at 2.75 3.08; 9 H at 1.4 2.758, 3 H at 0.9 1.38 (triplet).  
  Part FEndo-( 6-heptl -en-4-ynyl )-2-( 6-carboxyhex-2-yna-yl)-bicyclo[3.1.0]hexan-3-one methyl ester (XLlVa) A solution of 8.1 g. of ketone XLlll and 34.4 g. of methyl 7-iodo-hept-5-ynoate in 300 ml. of dry tetrahydrofuran is stirred at room temperature under a nitrogen atmosphere. A solution of 7.16 g. of potassium tbutoxide and 6.67 g. of dicyclohexyl-l8-crown-6 (Pedersen. J. Am. Chem. Soc. 89. 7017. 1967) in 450 ml. of dry tetrahydrofuran is added dropwise over a period of 1.5 hours. Stirring is continued for 10 minutes. then ml. of 1N l-lCl is added followed by 900 ml. of saturated aqueous NaCl solution. The reaction mixture is extracted with three 750 ml. portions ether. the extract washed with two 450 ml. portions of5 percent aqueous Nil- 5 0;; and 450 ml. of saturated aqueous NaCl solution. and dried over Na SO The solvent is removed under reduced pressure to give 34 g. of a brown oil which is chromatographcd using 1 kg. of silica gel. The column is developed with ten 1 liter portions of Skellysolve B containing 2.5 percent ethyl acetate. ten 1 liter portions of Skellysolve B containing 5 percent ethyl acetate. and ten 1 liter portions of Skellysolve B containing 10 percent ethyl acetate. Fractions 21-24 are combined to give 1.6 g. of keto-ester XLlVa as a colorless oil.  
 NMR:  
  2 H at 4.7 5.98 (multiplet). 3 H at 3.638 (singlet). Mass spectrum:  
 peaks at 326 (M*). 311 (m-15). 295 (M-3l).  
  Part G-Endo-6-( 1.2-dihydroxy-hept-4-ynyl)-2-(6- carboxyhex-2-yn-a-yl)bicyclo[3.1.0]hexan-3-one methyl ester (XLV)