IE48207B1 - Prostaglandin activity - Google Patents

Description

BRIEF DESCRIPTION OF THE INVENTION This invention relates to the optically active compound of the formula: ~*1 13“C14R2 wherein Z is -(CH,) or -CH,-CH«CH-(CH ) -, wherein g is an ’ cis 2 £ integer from 5 to 7 inclusive, and f is an integer from 2 to 4, inclusive: C13-C^4 is ethylene or trans-vinylene: W is selected from the group consisting of: and R^ is hydrogen or hydroxyl; R^ is selected from the group consisting of: wherein R is Cjj-Cf alkyl, and £3 selected from the group I. 8 2 0 7 consisting of C^-C^ alkyl, di-(C^-C4)-alkylamino, and phenyl or phenyl substituted with one or more substituents selected from the group consisting cf C^-C^ alkyl, -OR, -SR, F or Cl wherein R is as previously defined; and R, is selected from the group consisting of: Oh CH>-.^^3 A 6 H OH CH\ /CH3 0 C — CZ XRC 6 OH H R„ — c H OH 01/ R7 ^CH2X R7 -CH CH, CH, OH H CH, CH, A ' H OH I8 -CH -CH,- CH, — C OH H - C — (CH,)p-CH H dH --CH, OH H CH.

CH, CH, / X CH, CH, \2 / 2 - C—C H OH CH, CH, CH / 2 — c — c OH H 'll 48307 (S) _^2-C~Rli .

OH Η (R) CH - C-Rn H OH CH,—C-C»C —R,n2/l I 10 OH Η H 4-,,.

CH, _C Rjj , CH2 C=v .«l2 /\ CHj OH H -CH- C —Ro y **- S HC H.C-CzC OH o CH, CHz-j^-CH-R? . -CH2- Cj- C CH. CH. ·> OH H o(i\ \7 - CH2-/< CH2=CH oh CH,-r-Rg CH3CH2 oh OH CH-CH, \ / ‘ CH, Λ Η OH H OH HU , / '·. Z OH Η OH H C,--R / / H OH OH H / Z OH Η H OH '11 - C - C Λ / Η OH H OR, OH H 0Rg H and wherein R^ is hydrogen or methyl; Rg is selected from the group group consisting ofc4~c7 alky1’ *5 is is selected selected from from the the consisting ofc3-c5 alkyl; *7 10 group consisting ofC2“C4 alkyl;r8 is selected from the 'group consisting ofC1“C2 alkyl; r9 is selected from the group consisting ofC3~C6 alkyl;R10 is selected from the group consisting ofCl-C4 alkyl;R11 is selected from the group consisting ofC3-C7 alkyl;R12 is selected from the 15 group consisting ofci-c4 alkyl; p is an integer from 0 to 3 q is 1 or 2; X is a divalent radical selected from the group consisting of: wherein is selected from the group consisting of C^-C? alkyl, hydrogen, and a phenoxy group optionally substituted with a substituent selected from the group consisting of halogen, trifluoromethyl and Cj_-C^ alkyloxy; Y is a divalent radical selected from the group consisting of: 4. • 48207 G is a divalent radical selected from the group consisting of -0- and -CH2-; m is zero or an integer from 1 to 4 inclusive; n is zero or an integer from 1 to 4, inclusive; with the proviso that the sum of m and n has the value of 1 to 4; s Is zero or the integer 1; and t is selected from the group consisting of hydrogen, chloro, fluoro, dichloro, trifluoromethyl, methoxy: the racemic mixture thereof; and the mirror image thereof.

This invention also relates to the method of preparing the above-described compounds, as well as to novel intermediates useful for the preparation of the prostaglandin compounds described herein. The present invention will be fully described with reference to the flowsheets and examples of this application.

DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention are administered in various ways for various purposes, e.g., intravenously, intramuscularly, subcutaneously, orally, intravaginally, rectally, bucally, sublingually, topically and in the form of sterile implants for prolonged action.

For intravenous injection or infusion, sterile aqueous isotonic suspensions are preferred. For subcutaneous or intramuscular injection; sterile suspensions of the compounds in aqueous or non-aqueous media are used. Tablets, capsules, and liquid preparations such as syrups, elixirs, 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. On certain occasions it may be advantageous to administer the compounds of this invention as clathrate compounds with substances such as a-cyclodextrin.

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 (1903) and Horton, Experientia, 21, 113 (1965) and references cited therein. All of the so called natural prostaglandins are derivatives of prostanoic acid: OOH X /¾ xCH ^CH ^H 1 ^CH2 CH, ^CHz 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 and racemates.

The configuration of substituents on the prostaglandin molecule are designed to be in the α-configuration if they lie beneath the plane of the molecule as drawn above and are designated with a -— bond. Those substituents which lie above the plane of the molecule as drawn above are designated β and are represented by a bond.

The compounds of this invention which have the structure as shown in formula (A) wherein R^, Z, Rg, Y, m, n, s and X are as herein above defined are said to be in the same ’configuration as the natural prostaglandins with respect to the configurations at Cg, and and are designated by the prefix nat. The enantiomer, represented by formula (B) is said to be in the mirror image or ent configuration. A substituent at drawn with a dotted line (C^—Rg) is said to have an o configuration; a solid line (C^^_Rg) indicates a β configuration. The configuration at Y and X will be expressed in terms of R and S as is understood in the art. For example, the compound represented by formula (C) is named nat-15S,16S-lla,15-dihydroxy20 1-(hydroxymethyl)-1,9-dioxo-15,-16-trimethylene-13-trans-prostene; its enantiomer (formula D) is named ent-15R,16R-lla,15-dihydroxy-l-(hydroxymethyl)-l, 9-dioxo-15,16-trimethylene-13-trans-prostene. The racemate [1:1 mixture of (C) and (D)] is named nat-15S,16S-(and ent-15R,16R)lla,15-dihydroxy-l-(hydroxymethyl)-i,9-dioxo-15,16-trimethyiene-13-trans-prostene. In a similar manner, the compounds represented by formulae (E) to (J) have the configurations shown below. - 7 48 207 racemate nat-15S,l6S -(and ent-15R,16R) ent-15R,16R (D) (Ε) racemate nat-15S,16R (and ent-15R,16S) CF) (G) racemate nat-15R,16S (and ent-15S,16R) CH) - 9 48207 racemate nat-15R,16R (and ent-155,16s) In each of the above formulae (C to JJ the hydroxy group at Cjj is named -Ila-hydroxy.

The novel compounds of this invention can be prepared by a novel 1,4-conjugate-addition procedure involving treatment of the ether blocked cyclopentenone such as (129) or (111) with a lithio-cuprate reagent such as (117), (118), or (119) prepared as illustrated in Flowsheets A thru N.

The 1,4-conjugate-addition procedure is described hereinbelow in Flowsheet N. The preparation of the various requisite 1-iodo-transl-alkenyl or L-tributy 1st annyl-trans-1-alkenyl derivative is illustrated in Flowsheets A-H and the novel and important methods of preparation of the 4-hydroxycyclopentenones embracing the 1T(hydroxymethyl)-1-oxo a chain is described in connection with Flowsheets I-M. - 48207 (1) (RgCH2-) R. CH20 >< CH, ch, / (CH2)£, FLOWSHEET A 2-) co2c2hs (2) R6-X (3) (RgCH2-X) co2c2h5 CfL, CH, \2 / (CH2)fI (6) (7) (RgCH (RgCH2-) OSi(Cll3) 3 X xii CH, \ CH / (CH2)£, (9) CH trans / _C=C . wherein F'is one or two inclusive.

CH, CH, \ / (ch2)£, (8) In accordance with the scheme as outlined hereinabove in Flowsheet A, carbethoxycyclobutane or carbethoxycyclopentane is converted to its enolate anion (2) by treatment with a strong base such as lithium cyclohexylisopropyl amide, prepared from the corresponding amine and n-butyl lithium (hexane solution) in a solvent, such as anhydrous tetrahydrofuran, at very low temperatures, such as -78°G. The resulting enolate anion (2) is then alkylated with R^3-X (3) to provide (4), the ester group of which is reduced to alcohol (5) by reaction with 2 equivalents of diisobutyl aluminum hydride, lithium aluminum hydride or the like. Oxidation of alcohol (5) with dipyridine chromium oxide complex [Reagents for Organic Synthesis”, L. F. Fieser and M. Fieser, John Wiley and Sons, Inc., New York, 4_, 215 (1974)], prepared in situ in methylene chloride solution, provides the corresponding aldehyde Γ6), which can also be obtained directly from ester (4) by partial reduction with one equivalent of diisobutyl aluminum hydride at -78°C, but the former two-step procedure is preferable. Reaction of aldehyde (6) with lithium acetylide ethylene diamine complex provides the 3hydroxy-l-alkyne (7), which is converted to its trimethylsilyl ether in the usual manner. The silylated derivative is then treated with disiamylborane (prepared in situ in tetrahydrofuran solution at ice bath temperatures from 2-methyl-2-butene, sodium borohydride and boron trifluoride ethereate) and then anhydrous trimethylamine oxide. The resulting solution and an iodine solution in tetrahydrofuran are then added simultaneously to an aqueous solution of sodium hydroxide to give the l-iodo-3-trimethylsilyloxy-4,4methylene-1-alkene (8). Also, the above sequences of reactions can be accomplished, as shown in Flowsheet A, using RgCl^X where Rg is a phenyl gTOup FLOWSHEET Β (CH3)3Si-C=C-CH2 THPO OH FT {CHj) 3Si-C-C-C - C-R-jj (9) (ID Ra (CH3)3Si<>C C.

Ra Ra f-ll HO OH FT (CH3)3Si-C=C-C-C-Ru H-C=C —? (14) (12) 'C=c Ra, 0' F -C(15) ,Λ -C -R. : t (CHjljSiO^ OSi(CH3)3 (16) (17) - 13 48207 Flowsheet B Continued THPO <4 CH, CH) -> (ch3)3si-c=c - C k k Η H (18) xi/ CIL-.(/ 'λ-ΞΟ,-Ο ·> \-/ O^CH, V V (CH,),Si-C=C—C— C-R. (20) Xi/ J OH OCCH, (CIl ) Si-C=C_c_C-R.,•>3 ft ι 11 (21) H \_ / \ H I H Ra Ra 'll (23) HO OCCH, y v -(CH ) jSi -C^C-C— C — Rj 1 ιί ή (19) HO OH 1 v A H-C=C—0—C—R (22) \!/ Ra.

-HC=C — C k H THPO A (26) ^Ra Ό V -C—R. (24) HC=C——C(11) / II (25) - 14 4820 Flowsheet B Continued (25) (28) HC=CTHP^ Wd (26) HC= HC=C HCO ORd c-U1 : Η H (31) \/ HO ORd : T -C-C — Η H C1L (32) \7 HC=C HO ORd Y_f i i 1 I Η H (29) _/v\_ S0,-0 ORd 2| j HC=C— ς 1 -ς· 'll (30) '11 H (33) 8 2 υ 7 In accordance with the scheme as outlined hereinabove in Flowsheet B, l-trimethylsilyl-3-tetrahydropyranyloxy-l-propyne (9) is treated with nbutyllithium at -78°C and then with a freshly prepared solution of zinc iodide in anhydrous tetrahydrofuran, also at -78°C. Reaction of aldehyde (10) with the resulting reagent then provides the 4-hydroxy-3-tetrahydropyranyloxy-l-alkyne (11). This reaction procedes with great stereoselectivity and the product (11) is in the erythro configuration. [For additional information concerning this reaction see the examples which follow and F. Mercier, R. Epstein and S. Holland, Bull. Soc. Chim. France, 690(1972).

The tetrahydropyranyl group in (11) is removed on weak acid treatment and the resulting erythro diolg(12) can be reblocked by treating with an II appropriate aldehyde or ketone (Ra-C-Ra) in the presence of strong acid catalyst in the usual way to give the ketal or acetal (13). Acetone is a useful ketone for this purpose and the product (13) is then a 3,4-isopropylidenedioxy-l-alkyne. It is also possible to utilize silyl blocking groups (introduced after removal of the 1-trimethylsilyl group) to ultimately give the vinyl iodides (16) or (17). Weak base treatment of (13), for example heating for about one hour in refluxing methanol with potassium carbonate, results in desilylation to give (14). The 1-alkene (14) is converted to the 2u corresponding 1-iodo-trans-1-alkene (15) by treatment with disiamylborane (prepared in situ in tetrahydrofuran solution at ice bath temperatures form 2-methyl-2-butene, sodium borohydride and boron trifluoride ethereate) and then anhydrous trimethylamine oxide. The resulting solution and an iodine solution in tetrahydrofuran are then added simultaneously to an aqueous solution of sodium hydroxide to give (15).

For the preparation of the threo derivatives, the 4-hydroxy-3tetrahydropyranyloxy-l-alkyne (11) is acetylated to provide the corresponding 4-acetoxy derivative (18). The tetrahydropyranyl group is preferentially hydrolited with weak acid to (19), which is then tosylated in the usual manner to afford the erythro-3-tosyloxy-4-acetoxy-l-alkyne (20). Solvolysis of (20) - 16 4820 under essentially neutral conditions by heating in aqueous tetrahydrofuran in the presence of an insoluble acid-acceptor, such as calcium carbonate, results in inversion of C^, furnishing the threo-3-hydroxy-4-acetoxy-l-alkyne (21) , which is then deblocked with aqueous base to give the threo-3,4-diol (22) . Diol (22) is converted to an acetal or ketal (23) [or silyl derivatives as in (16) or (17)] and thence to the 1-iodo-trans-l-alkene (16) as described hereinabove wherein Ra is lower alkyl (C^ to Cj).

For the preparation of the 16-alkoxyprostanoic acids of this invention, the erythro-4-hydroxy-3-tetrahydTopyranyloxy-l-alkyne (11) is desxlyl10 ated by methanol-potassium carbonate treatment and the resulting (25) is alkylated to give the 4-alkoxy-3-tetrahydropyranyloxy-l-alkyne (26). A useful procedure for this last step involves treatment of (25) with a molar equivalent of sodium hydride to give the 4-alkoxide which is then alkylated with the appropriate alkylating agent, for example methyl iodide. The 4alkoxy-l-alkyne (26) is then converted to the corresponding 1-iodo-trans-lalkene (27) as described hereinabove for the preparation of (15). If desired the tetrahydropyranyl blocking group in (27) can be hydrolyzed (weak acid) and the resulting free 3-ol corresponding to (27) converted to the 3-trimethylsilyloxy derivative (28), all in the usual manner wherein Ra is lower alkyl (C to Cj).

For the threo series, the tetrahydropyranyl group in erythro-4alkoxy-l-alkyne (26) is cleaved and the resulting 3-hydroxy-4-alkoxy-l-alkyne (29) is tosylated to give the erythro-3-tosyloxy-4-alkoxy-l-alkyne (30). Sn0 displacement reaction with (30) with reagents such as tetrahydroammonium formate results in inversion to the threo derivative (31) saponification of which provides threo-3-hydroxy-4-alkoxy-l-alkyne (32). Trimethylsilylation followed by the vinyl iodide conversion procedure described hereinabove furnishes the threo-1-iodo-l-alkene (33) wherein Rd is hydrogen or lower alkyl (Cx to C3).

The 15-alkyl and/or 16-alkyl derivatives of this invention can be - 17 4 8 2 0 7 prepared by substituting (CH^) ,Si-C=C-Cl[-R' $ for (9) and/or R^C-R'^ for (10) (R'5 = lower alkyl of 1 to 3 carbons) in flowsheet B.

In accordance with the procedure as outlined in Flowsheet C, an aldehyde (34) is treated with propargylic magnesium halide to form the homopropargylic alcohol (35), which is converted to its trimethylsilyl ether in the usual manner. The silylated derivative is then treated with disiamylborane (prepared in situ in tetrahydrofuran solution at ice bath temperature from 2-methyl-2-butene, sodium borohydride and boron trifluoride ethereate) and then anhydrous trimethylamine oxide. The resulting solution and an io10 dine solution in tetrahydrofuran are added simultaneously to a sodium hydroxide to give the l-iodo-4-trimethylsilyloxy-trans-l-aIkene (36), precursors for 16-hydroxy-prostaglandin.

The trimethylsilyl protecting group is removed with.mild acid and tne resulting vinyl iodide alcohol is oxidized with pyridinium chlorochromate to provide the l-iodo-4-oxo-trans-1-alkene (37), which upon treatment with a Grignard reagent (R jMgX) provides the l-iodo-4-hydroxy-trans-l-alkene, which is silylated in the usual manner to provide the silyl ether (38) wherein R is lower alkyl (C^ to C?) or lower alkenyl group (C„ to C$) and R1^, is vinyl, cyclopropyl or ethyl.

FLOWSHEET C II H—C —R (34) RUCOOH HC=C—CH2MgX vl/ OH H dC— CH — CH —R (35) (39a) R13Li ''''C'ZZX ' OSi(CHj), Ύή2 —CH —R^ (36) \1Z H X C tH, *11 (37) 1) R13MgX 2) (CHg) gSiCl \k H OS i (CHg) g ,x Cll ^13 (38) r13—C02H R^Li (39) II .

R11 C R13 H-C=C Bu.Sn 3 >?: H_C=C— CH2MgX \/ OH I , CH,—C—R '2 \ 13 (41) 1) (CHg)jSiCl 2) BUgSnH \Z OSi(CH-).

I ,3 3 •R, CH2 “C “IS (42) Kn - 19 4820 A more preferred method for the preparation of vinyllithium precursor is also described in Flowsheet C. Treatment of the requisite carboxI ylic acid (39a or 39) with the appropriate organolithium reagent (R^^Ll or I I I Rj, Li respectively), wherein and are hereinabove defined, give the corresponding ketone (40) which upon treatment with propargylic magnesium halide provides the homopropargylie alcohol (41) which is converted to the trans vinylstannyl derivative by sequential treatment with chlorotrimethylsilane and tri-n-butyltin hydride. Treatment of the vinylstannyl reagent (42) with n-butyllithium at a temperature of -10°C to -78°C generates the corresponding vinyllithium reagent.

FLOWSHEET D H—C=C-CH2— MgX H_c;c -CH,PH -C1' (43) (44) c=c < t z ;c—ch2—L—r;5 i4 (46) (45) In accordance with Flowsheet D hereinabove, the precursors for other 16-hydroxy prostaglandins are prepared by treating an appropriate aldehyde or ketone (43) with a proparglylic magnesium halide to yield the requisite homopropargylic alcohol (44). The alcohol is protected as a tritylether (45) (for secondary alcohols) or as a trimethylsilyl ether (45) (for tertiary alcohols). These ethers are then converted to the appropriate trans-vinyliodide (46) by treatment with disiamylborane generated in situ from 2-methyl2-butene, sodium borohydride, and boron trifluoride, followed by treatment t with trimethylamine oxide and then iodine and sodium hydroxide, wherein R^. - 20 48207 is hydrogen, methyl or ethyl; Z is O-CCC^H^j^ when is hydrogen and Z is I I O-Si(Cli3J3 when is methyl or ethyl; R^ is selected from the group-comCH, I 3 ai, prising lower alkyl (C3 to C^), lower 1-alkenyl (Cj to Cg), -C—R?, -C—R?; CH3 Cil“ ι I 3 wherein R? is as described above with the proviso that when is -C—R? or FH3 -C—R_, then R,, must be hydrogen, j 7 lb CH3 FLOWSHEET E CH, (S3, a) OSi(CH3)3 ;h,-ch,-ch-c=c-h 2 2 / \ SnBu, <- ;h2-ch2-ch // (50. a) ,-. 4 8 207 The preparation of the precursors for the synthesis of 16-aryloxy congeners is described in accordance with Flowsheet E hereinabove. The aryl esters (49) are prepared by esterifying the commercially available acids or by treatment of ethyl bromoacetate with the appropriate phenol. The ester v49j is carefully reduced to the aldehyde (50) which upon treatment with lithium acetylide provides the propargylic alcohol (51). Treatment of the alcohol (51j with chlorotrimethylsilane followed by tri-n-butyltin hydride furnishes the requisite vinylstannyl derivative (53). Similar treatment starting with substituted hydrocinnamaldehyde (50a) provides the respective vinylstannyl derivative (53a).

The preparation of the precursors for the synthesis of secondary 15-hydroxy congeners are described in the literature. The preparation of the precursor for 15-methyl-15-hydroxy is described in Flowsheet F hereinbelow.

In accordance with Flowsheet F, an acid chloride, wherein R$ is hereinabove defined, is treated with acetylene and aluminum trichloride to provide the vinyl chloride (55) which upon treatment with sodium iodide furnishes the vinyliodide (56). Treatment of (56) with methylmagnesium halide followed by chlorotrimethylsilane gives the requisite protected vinyliodide (57) FLOWSHEET F R.CC1 HC=CH A1C1, II / R,C-C=C ' 5 ' >1 RS-C^=C H 1 (54) (55) (56) 1) CHgMgX 2) (CH3)jSiCl OSi(CH,)_ I 0 4 -c— -Οι CH, (57) The precursors for the novel compounds of this invention which have a β chain represented by Formula K (K) -CCH2)s-y Wnwherein s, y, m, n, and X are hereinabove defined is shown in Flowsheet G and Flowsheet H.

Flowsheet G X HC=C-(CH,) -MgJ (J is Cl or Br) y » a-Wm (58) -(CH2)n(CH,) 2Jn HC=C-(CH2)s-C x —>hc:c-(ch2)x-c HO CH2-(CH2) (60) isomers are separated (CH3)3SiO --¾¾ (61) (C4H9)3SnH ξ_H d Ych2)s-c •<CH2>n (CH3)3SiO' ^2^2^(62) WiVJ' Wn H (CH2)s-C k.........J (CH3)3SiO (CH2-(CH2)n - 23 4821)7 In accordance with the scheme as outlined hereinabove in Flowsheet G a ketone (58) is reacted with a Grignard reagent (59) such as acetylene magnesium chloride (59, s = 0) or propargyl magnesium bromide (59, s = 1) to give the acetylenic alcohols (60). In those cases where X is not -Cl^two isomeric acetylenic alcohols are formed. These isomers can be separated by procedures well known to the art including fractional crystallization, fractional distillation and various chromatographic procedures. The individual isomers can then be carried through the remaining reactions outlined in Flowsheet G.

The acetylenic alcohol (60) is converted to its trimethylsilyl ether in the usual manner. The silylated derivative (61) is then treated with diisoamvlborane (prepared in situ in tetrahydrofuran solution at ice bath temperatures from 2-methyl-2-butene, sodium borohydride and boron triflucride ethereate) and then anhydrous trimethylamine oxide. The resulting solution and an iodine solution in tetrahydrofuran are then added simultaneously to an aqueous solution of sodium hydroxide to give the l-iodo-3-trimethylsilyloxy-trans-l-alkene (62). (63) in turn is readily prepared by the addition of tri-n-butyltin hydride to the acetylene (61) in the presence of bisazoisobutyronitrile followed by vacuum distillation at a high enough temperature (about 170°C) to isomerize any of the cis-vinyl tin compound to the trans-vinyl tin compound.

Certain of the ketones (67) of this invention are prepared as indicated in Flowsheet H below: - 24 48307 (67) wherein n and m are as hereinabove defined and the moiety -0 repre t, sents a phenoxy group which is optionally substituted with one or more halogen, trifluoromethyl, and lower alkoxy (C^ to C4) groups.

As indicated in Flowsheet H the reaction of an epoxide (64) with a substituted or unsubstituted phenol (65) in the presence of a catalytic amount of aqueous sodium hydroxide and a phase transfer catalyst such as methyl tricapryl ammonium chloride and the like at 70°-80°C gives the phenoxy substituted alcohol (66) which in turn is oxidized with an oxidizing reagent such as pyridinium chlorochromate in methylene chloride to give the phenoxy substituted ketone (67). This ketone (67) is then carried through the reactions shown in Flowsheet G above. - 25 4 8 2 υ 7 The other ketones (58) used in this invention are known in the literature or can be made by procedures well known to the art [G. Lardelli, U. Lamberti, W. T. Walles and A. P. de Jonge, Rec. Tray. Chem. Pays-Bas, Sb 481 (1967); Ng. Ph. Buu-Hoi, Τ. B. Loc and Ng. Dat Xuong., Bull Soc.

C'nem, France, 174 11958); and G. H. Posner, Organic Reactions, 19, 1 (1972)].

The preparation of the cyclopentenones of this invention containing the hydroxyketone feature (68) wherein Z is hereinabove defined and Rj is hydrogen or a hydroxy group can be accomplished in several ways one of which involves the conversion of the corresponding cyclopentenone containing a carboxylate function (69) to the respective hydroxyketone analog (68).

Meet of the cyclopentenone carboxylic acids (69) required for the purposes of this invention have been described in the literature or can be prepared by procedures quite analogous to those already described. Appropriate references are provided in the examples which follow. The synthesis of certain non-reference requisite cyclopentenone carboxylic acids (69) is also described herein.

The preparation of the requisite 4-hydroxy-thiacyclo pentenones (75) is described in Flowsheet I. In accordance with Flowsheet I which is 2d hereinbelow described, treatment of 2-furyllithium (70) with a ω-chloroaldehyde (71) provides the chloroalcohol (72). Treatment of the chloroalcohol (72) with ethylmercaptoacetate furnishes the hydroxyester (75) which upon hydrolysis with sodium formate/formic acid provides the 3-hydroxy-cyclopentenone (74). Treatment of the cyclopentenone (74) with sulfuric acid provides the required 4-hydroxy-cyclopentenone (75). - 26 4 8 2 0 7 FLOWSHEET 1 The conversion of the cyclopentenone carboxylic acid (69) to the respective hydroxyketone analogs (68) and the protection of these compounds for a conjugate addition reaction is described hereinbelow in Flowsheets J and K.

For the preparation of cyclopentenones of the type (79) wherein Z is hereinabove defined, the carboxylic acid (76) is converted to the acid chloride (77) by first forming the sodium salt with sodium hydride in tetrahydrofuran (THF) and then reacting the resulting suspension with oxalyl chloride in the presence of a catalytic amount of dimethylformamide (DMF). The re10 suiting acid chloride (77), dissolved in ether, is then added dropwise to an ether solution containing two to three equivalents of diazomethane to produce tbe diazoketone (78). The diazoketone can be hydrolized to the hydroxy ketone (79) by refluxing an etheral solution in the presence of a dilute aqueous solution of sulfuric acid.

Alternatively, the acid chloride (77) can be heated with two equivalents of 1,1,2-tris-trimethylsilyloxyethylene - 27 4 8 2 0 7 at 90-100° for 2 to 4 hours to produce compound (81). Compound (81) can be readily hvdrolized and decarboxylated to give the hydroxyketone (79) by treatment with dilute hydrochloric acid in tetrahydrofuran (THF).

Protection of the hydroxy ketone function of 79, suitable for a conjugate addition reaction, can be accomplished in two ways. Ketalization of 79 with ethylene glycol is accomplished by refluxing a henzene or toluene solution of 79 and ethylene glycol into a Dean-Stark trap. The resulting ketal (82) is then treated with fcrimethylsilylchloride (TMSC1) and imidazole in dimethylformamide (DMF) to give 83 which is suitably protected for a con10 jugate addition reaction.

Alternatively 79 can be protected by the reaction with a mixture of 2-methoxy-l-propene (84) and 2,2-dimethoxy-propane (85) in benzene in the presence of an acid catalyst such as p-toluenesulfonic acid to give the ketal 86 which is suitably protected for a conjugate addition reaction. - 28 Flowsheet J (83) 4 8 2 0 7 Tlie preparation of the 4-hydroxycyclopentenones of this invention (.32j wherein 2 is hereinabove defined is outlined in Flowsheet K below. The reaction of the hydroxy acid (87) with at least two equivalents of dimethylt-butyl-silylchloride in the presence of imidazole in dimethylformamide at 3?-40°C gives the bis-dimethyl-t-butylsilated compound 88. The carboxylate dir.ethyl-t-butylsilyl group can be selectively removed by treatment with acetic acid, tetrahydrofuran and water (4:2:1) to give the carboxylic acid (89). The acid chloride (90) is prepared by first treating the acid (89) with sodium hydride in tetrahydrofuran to give the sodium salt. The,result9 ing suspension of the sodium salt is then treated with oxalyl chloride in the presence of a catalytic amount of dimethylformamide. Alternatively the acid chloride (90) can be prepared directly by the reaction of the acid (89) or the dimethyl-t-butylsilyl ester (88) with oxalyl chloride in tetrahydrofuran ir, the presence of a catalytic amount of dimethylformamide at 0°C. The slow addition of an etheral solution of the acid chloride (90) to an etheral solution of two to three equivalents of diazomethane gives the diazoketone (91) which on acid hydrolysis gives the 4-hydroxy cyclopentenone (92) containing the hydroxyketone function.

Alternatively the acid chloride (90) can be heated with at least two equivalents of 1,1,2-tris-trimethylsilylethylene at; 90-120°C in the absence of a solvent to give compound (93) which is readily hydrolized and deearboxylated to give the 4-hydroxycyclopentenone (92) containing the hydroxyketone feature. Protecting of 92 can be accomplished by treatment with an ex cesi of a mixture of 2-mcthoxy-1-propene (84) and 2,2-dimethoxypropane (85) in benaene with an acid catalyst such as p-toluenesulfonic acid to give the his-ketal (94) which is suitably protected for a conjugate addition reaction. - 30 48207 Alternatively, the two hydroxyl moieties may be protected using 2 equivalents of 2-methoxypropene per equivalent of 92 in the presence of a catalyst such as chloroacetic acid to provide compounds such as S4A. Other useful protecting dihydro-2H-pyran, ethylvinylether and th-e like.

Other acid sensitive protecting group for the two hydroxyl groups are the triloweralkylsilyls (from silylchlorides), triphenylmethane (from tritylchloride or bromide), mono-p-methoxytriphenylmethane (from mono£-methoxytriphenylmethylchloride or bromide), methoxymethyl (from chloromethylmethylether) and the like.

Treatment of (88) with an oxalylhalide such as oxalylchloride or oxalylbromide is productive of the acid chloride (90). 8 2 0 7 Flowsheet Κ - 32 48207 Another preparation of the 4-hydroxycyclopentenones of this invention which contain a cis double bond in the potential a chain (109) is shown hereinbelow in Flowsheet L wherein g is as hereinabove defined. As illustrated in Flowsheet L there are three methods available to prepare the important intermediate 98. The reaction of the ω-bromo carboxylic acid (95) with oxalyl chloride in an inert solvent such as benzene gives the acid chloride (96). Addition of the acid chloride (96) in ether to an etheral solution of diazomethane (2 to 3 equivalents) yields the diazoketone (97) which can be hydrolized in a two phase system consisting of ether and dilute sul10 furic acid to the hydroxyketone (98). Alternatively the acid chloride (96) can be treated with an excess of 1,1,2-tris-trimethylsilyloxyethylene in the presence of a catalytic amount of stannic chloride in the absence of solvent to give compound (99) which can readily be hydrolized and decarboxylated to the desired hydroxyketone (98) using dilute hydrochloric acid in tetrahydrofuran. An alternate method to prepare (98) involves the reaction of the bromoolefin (100) with aqueous n-bromosuccinimide (NBS) in the presence of a catalytic amount of acetic acid to give a mixture of bromohydrins (101 and 102). Oxidation of the mixture of bromohydrins with an oxidizing agent such as pyridinium chlorochromate in methylene chloride gives a mixture of bromo20 ketone (103) and bromoaldehyde (104). Refluxing this mixture with sodium formate in methanol then gives the desired intermediate (98). Protection of the ketone function of 98 is accomplished using ethylene glycol in refluxing toluene using a catalytic amount of p-toluenesulfonic acid. The ketal (103) is then reacted with dimethyl-t-butylsilylchloride and imidazole in dimethylformamide to give the fully protected compound 104. The phosphonium salt (105) is obtained by refluxing a solution of 104 and triphenylphosphine in acetonitrile. Treatment of the phosphonium salt (105) with sodium methylsulfinylmethide in dimethylsulfoxide generates a phosphonium yield which on reaction with aldehyde 106 gives 107. Refluxing a water-dioxane solution of 107 in the presence of a phosphate buffer (PH 5 to 6) gives the cyclopenten33 48207 one (108). Treatment of 108 with chloral and triethylamine in ether gives (109) which on hydrolysis in a mixture of tetrahydrofuran and dilute hydrochloric acid at 50-70°C then gives the desired 4-hydroxycyclopentenone (110) which can be protected as described hereinabove in Flowsheet K.

Treatment of 109 with trimethylsilylchloride and imidazole in DMF gives ill which is also suitably protected for a conjugate addition reaction - 34 48207 (103) (104) [0] Br-CCH,)^ , NBS,H20 χ Br-(CH0)„-+ Br-(CH2)g ciT3co2H 7 g OH OH Br (100) (101) (102) - 35 • 48207 Flowsheet L (continued) Br- (¾) OH 0H,H+ > (98) - 36 - 48207 The reagent 1,1,2-tris-trimethylsilyloxyethylene (80) and its use for the conversion of acid chlorides to hydroxyketone (for example 96 to 98 and 90 to 92) are claimed in this invention. The reagent preparation is described hereinbelow in Flowsheet M. The reaction of glycolic acid with 1,1,1,3,3,3-hexamethyldisilazone and trimethylsilylchloride in pyridine gives bis-trimethylsilated glycolic acid (113). Addition of (113) to a tetrahydrofuran solution of one equivalent of lithium 1,1,1,3,3,3-hexamethyldisilazane amide at -78°C generates a lithium enolate which is trapped with trimethylsilylchloride to produce the desired reagent (80).

Flowsheet M HOCH2CO2H [ (CH3) 5Si]2NH, (CH;) 3SiCl^ TMSO-CH2CO2TMS pyridine (112) ¢113) (1) '[CCH3)3Sx]2N~L?,-78O H J)TMS (2) ™C1 THStf'-'W (80) The preparation of the prostaglandin congeners of this invention are described hereinbelow in Flowsheet N wherein Z is as hereinabove defined; ft R3 is hydrogen, 2-methoxypropyl-2-oxy (-OC(CH3)2OCH3) or trimethylsilyloxy; II ( I Rj is hydrogen or hydroxy; T is the radical CHjO CH3 wherein R is as hereinabove defined. R is selected from the group consisting of: -C-R, J S 5 -C-R.

/ \ CH 0Si(CHj)g H 0C(CgHs)3 CH. CH. \ / 3 C CH d\ CH \:h, ocCc6h5)3 CH z \ Z\ R& H 0Si(CH3)3/CH2—CH2X(Wq H \cCC6H5)3 -Tr H 0C(CgH5)3 S /Z -O H OC'C^rMg CH, Zh.

—C — C-—CH2—Rg -CH,-C-R.

HgC—C=C OH iCH2K EH, CH, -C^>c z\ 1 H OSi(CH3)3 H 0Si(CH.)3 -CH. -tCrR„ HC=C OH -CH—CH—R, 1 (erythro or threo); -CH-CH—R, (CHJ.SiO o 3 >7 (erythro or threo): OSi(CH3)3 CH, -CH—CH—R.

(CH.) SiO OR ό J o -CH2-CH_Y-C-R10 ; H -.CH2-C-Rg OC(CgH5); isi lSi(CH3)3 CH H I 3 ! . CH2 - C-f =C-R10 ; I H OSi(CHj)3 -C CH. —-0 -CH-CH-C-R. 2 I I 7 H Z\ ‘2 Z //' H ^€ISi(CH3)3 CH.

-CH.-CH-C-R Z j 7 .CH, 3 Uw, ?I3 ^A’s -‘VfAi ! OSi(CH3)3 wherein Rg, Rg, R?, Rg, Rg, R^Q, R^, βχ3, G, p, q, t, s, m, n, y, and X are as hereinabove defined.

In accordance with Flowsheet N the vinyliodide (114) is treated with either one equivalent of n-butyllithium or 2 equivalents of t-butyllithium at low temperature, preferably -30° to -70°C in an inert solvent, eg. hexane, ether or toluene to provide the trans alkenyl-lithium reagent (116).

Alternatively, the vinyllithium reagent (116) can be prepared by treatment of a vinylstannyl derivative such as (115) with n-butyllithium at -10° to -78°C in ether or THF.

For the preparation of the asymmetrical lithio cup-rate (117) or the like, a solution of one molar equivalent of copper (I)-l-alkyne, preferably copper (I)-l-pentyne in anhydrous hexamethylphosphorous triamide preferably one to five molar equivalents, and anhydrous ether is added to one molar equivalent of the aforementioned vinyllithium solution cooled to about -78°C. After about one hour at this temperature, a molar equivalent of the requisite cyclopentenone (120) is added. After several hours at -78°C to -20°C the reaction mixture is quenched with aqueous ammonium chloride solution and the blocked product (121) is isolated in the usual manner.

It is also possible to effect conjugate 1,4-addition with the asymmetrical lithio cup-rate (119) derived from vinyllithium (116) and cuprous thiophenoxide. A solution of vinyllithium (116) in ether at -78°C is reacted with an equimolar amount of a reagent prepared by admixture, in ether at a temperature of 0°C to -78°C, of equimolar amounts of cuprous thiophenoxide and copper (1) iodide tributylphosphonium complex. After about 30 minutes at this temperature, the lithio cup-rate (119) is treated with the requisite - 39 - 48207 cyclopentenone (120) as described hereinabove for the conjugate addition with 1-alkynyl lithio cup-rate (117).

For the preparation of the symmetrical lithio cup-rate (118) one molar equivalent of copper (I) iodide tributylphosphine complex, dissolved in anhydrous ether, is added at about -78°C to two molar equivalents of the aforementioned vinyl lithium (116) solution in hexanes, cooled to -78°C.

After about one hour at this temperature, the lithio cup-rate (118) is treated with the requisite cyclopentenone (120) as described hereinabove for the conjugate addition with the 1-alkynyl lithio cup-rate (117).

The procedures for conjugate addition involving organocopper reagents are well known in the art, see for example, C. J. Sih, et al., J. A.

C. S., 97, 865 (197S).

I All available evidence leads us to believe that the -CH=CH-R function introduced by the cup-rate process occupies a position trans to the 11-oxy function. Similarly, we are led to the conclusion that in the product (121j the two side-chains attached to Cg and are trans to each other. However, we are not certain of this configurational relationship in the product as it is obtained directly from the cup-rate process. These products may have the side-chains in a trans- or cis-relationship or they may be a mixture containing both the trans- and cis-isomers. This is indicated in the nomenclature of the compounds involved by the designation 8ε. In order to ensure a trans-relationship in (121) these products can be submitted to conditions known in the literature to equilibrate the cis-8-iso-PGE^ to a mixture containing about 90¾ of the trans product. These conditions involve treatment with potassium acetate in aqueous methanol for 96 hours at room temperature. - 40 4 8 2 0 7 FLOWSHEET Ν H R' V / nBuLi C=X _Σ_ / \ I · H (114) or tBuLi 4s Li nBuLi C_H_C=C-Cu-C=C 3 7 I \ H R* (117) Li+ \Z H X c=c X \ H J (Π6) (Bu)3 Sn H \ X -- c=c / \ H R' (115) \Z G V -SCH-C=C u< (119) Li (118) (123) - 41 207 When Τ' is removal of the blocking groups OR from (121) to give the prostaglandin congener (122) is accomplished by treatment of (121) with a mixture of acetic acid, tetrahydrofuran and water (4:2:1) at 25° to 55°C.

When Τ' is (121) can be partially deblocked to give ketal (123) by treatment of (121) with 0.6N hydrochloric acid in tetrahydrofuran at room temperature for 4 to 7 hours.

In certain cases it is possible to convert the carboxylic acid function of a prostaglandin congener into a terminal hydroxymethyl ketone function as shown in Flowsheet 2 hereinbelow wherein Z, C23-C14, and Rkis as hereinabove defined. Treatment of a prostaglandin congener (124! ir. which the 11-hydroxy group and the hydroxy groups of the 2-chain are protected with a suitable group such as acetate or a dimethyl-t-butylsilyl ether,with oxalyl chloride in benzene for 2 to 5 hours furnishes the acid chloride (125) , wherein ❖ Rj is hydrogen or a protected oxygen group. The protected 11-hydroxyl-acid chloride compound may be prepared in the manner described above in Flowsheet K.

The prostaglandin congeners (124) may be prepared by the 1,4 conjugate addition of the suitably protected cyclopentenones (76) or (87) such as(cyclopentenone 88) and the lithiocuprate (117), (118) or (119) by the proceedures disclosed herein by the examples and Flowsheet N. Addition of the acid chloride (125), dissolved in ether, to an ether solution of at least three equivalents of 42. 4830 diazomethane gives the diazoketone (126). Hydrolysis of the diazoketone using aqueous sulfuric acid and tetrahydrofuan at about 0-55*C gives the hydrozymethyl ketone analo (127). The acetate protecting group can be removed by refluxing with acidified methanol. The dimethyl-tbutylsilyl ether protecting group can be removed by treatment with aqueous hydrochloric acid in tetrahydrofuran at 25 to 60’C. 43.

Flowsheet 0 starting compounds two racemates are obtained. In appropriate instances these racemates can be separated from each other by careful application of the usual chromatographic procedures. In the more difficult instances it may be necessary to apply high pressure liquid chromatography including recycling techniques. [See G. Fallick, American Laboratory, 19*27 (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 Associate, Inc., Maple Street, Milford, Mass.] It is also possible to prepare the compounds of this invention in their optically active forms by the conversion of the optically active 4-hydroxycyclopent-2-en-l-one carboxylic acids (128) to the optically active protected hydroxy ketone analog (129) using the methods outlined hereabove in (128) (129) 48807 S. 97 In accordance with the following reaction scheme prostanoids are prepared as described by Stork in J.A.C.S. 97, 4745 (1975) and J.A.C 6260 (1975).

C — CH-rOH Treatment of the protected 4-oxycylcylopentenone (A) with cup-rate such as (117), (118) or (119) as hereinabove defined, followed by quenching with formaldehyde to provide the hydroxymethyl analog (B) which is dehydrated with reagents such as excess methansulfonyl chloride in pyridine followed by treatment of the crude mesylate with diissopropylethylamine in ether overII III night. Rj , Rj and R are as previously defined. Addition of the methylenecyclopentanone (C) to a solution of the grignard MgCCfy^Rj wherein f is as previously defined and R^ is a substituent selected from the group R^ wherein the hydroxyl group of the substituent is protected by a suitable blocking group such as 2-methoxy-propyl-2-oxy, and a catalytic amount of BUjP.Cul (BUj is tertiary butyl) followed by mild hydrolysis of the adduct provides the product prostanoid (C) wherein f, and are as previously defined. - 44(a) The bromide precursor to the grignard described above is prepared in accordance with the proceedure of flowsheet L. (b) Conjugate addition of tha vinyl cuprates to (129) followed by deblocking as described hereinabove in Flowsheet then gives the compounds of this invention in their optically aetive forms. Although in some eases two diastereoisomers will be formed, each optically active, they can be separated by chromatographic procedures as described hereinabove.

The preparation ef optically active 4-hydroxy-cyclopent-2-en-l-ones such as (128) is described hereinbelow The 4-hydroxyeyelopentenone racemates may be re-* solved into their component enantiomers (130) and (131) by derivatizing the ketone function with a reagent having an optically active center. The resulting diastereomeric mixture can then be aeparated by fractional crystallization, or by chromatography, or by high speed liquid chromatography involving, if necessary, recycling techniques. Among the 15 useful optically active ketone derivatizing reagents are 1-a-aminoxy-Y-methylpentanoic acid hydrochloride [to give (132)], (R)-2-aminoxy-3,3-dimethylbutyric acid hydrochloride, and 4-a-methylbenzyl semicarbazide. After separation of the diastereomeric derivatives, reconstitution of the keto function provides the individual 4-hydroxycyclopentenone enantiomers 20 (130) and (131). A useful procedure for the resolution of a 4-hydroxycyclopentenone racemate via an oxime such as (132) is described in the art [R. Pappo, P. Collins and C. Jung, Tetrahedron Letters, 943 (1973)]. «8207 ΗΟ* Z-C-OH II Z-C-OH II <1301 ΗΟ (131) Z-C-OH II (1321 Λη alternate procedure for the preparation of the. 4(R)-hydroxycyclopentenone enantiomers such as (130) involves as a key step the selective microbiological or chemical reduction of trione (133) to the 4(R,-hydroxycyclopentanedione (134). 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-anisylcyeiohexylmethylphosphine)rhodium (X) tetrafluoroborate in the presence of one equivalent of organic base, 'such as.triethylamine.

Conversion of hydroxycyclopentanedione (134) to an enol ether or enol ester, (13S, E.° alkyl, preferably 46. iso-propyl; 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 0.9S equivalents of benzoyl chloride or a slight excess of 2-mesitylenesulfonyl chloride, in a non-prototropic solvent at a temperature of about -10° to -15°C. Reduction of (135) with excess sodium bis(2-methoxyethoxy)aluminum hydride in a solvent such as tetrahydrofuran or toluene at low temperatures, such as -60° to -78°C, followed hy mild acid hydrolysis (representative conditions: aqueous dilute hy10 drochloric 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 (136). The ester (136), can then be hydrolized to acid (130).

For a description of these procedures in the art see: C. J. Sih, et al, J. A. C. S., 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. Ν. Y. Acad. Sci., 180, 64 (1971). (136) . - 47 48 207 Procedures for the preparation of the requisite cyclopentanetriones (133) are well-established in the art and generally involve the treatment of an ω-1-oxo long chain ester (137) with methyl or ethyl oxalate and a base such as sodium methoxide in methanol, followed by treatment with dilute hydrochloric acid in aqueous methanol to effect the dealkoxalylation of the intermediate (138). 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. Ν. Y. Acad. Sci., 180, 64 (1971); C. J. Sih, et al., A^ S^, 9S, 1676 (1973) (see reference 7); and J. B. Heather, et al., Tetrahedron Letters, 2313 (1973) for pertinent background literature.

II CH.-C-CH,-Z-CO,CH, 4 4 3 (137) -> CO,CH.

The intermediate keto esters (137) 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 (139) in the usual manner with the appropriate side-chain precursor (140, X=C1, Br, I, preferably Br or I) followed by decarbethoxylation and reesterification, all in the usual manner.

II CO2^2^5 * CHj CH (7, Na (139) II /v x2-CO2H (141) I (137) K-Z-C02C,H5 (140) V 11 /C \ ^C0,C,II.

CH. (JH - 3 2-C0,C,H. (142) The side-chain precursors (140) are commercially available where 2 is - (CH,) -. and can be prepared as described in Belgian Patent 86,215 - p (granted and opened to inspection January IS, 19“3).

Those precursors wherein Z is -(01.,)-0-01-,- can be prepared fcv :.-,/ transformation shown directly below starting with the mono-tetrahydrop/ranyl derivative (143). Thus, (143) is converted to the lithium alcoholate by treatment with butyl lithium, the alcoholate is then O-alkylated with ethyl bromoacetate to provide (144), which on de-0-tetrahydropyranylat ion , mesyla10 tion and reaction with lithium bromide gives the required (145). (These and all the above-described transformations can be effected in the usual manner well-established in the art; pertinent examples for most of the reactions car. be found in the above-cited Belgian patent 786,215.) - 49 ™ 48207 THP-0-(CH2) -OH (143) Jz THPO-(CH,) -O-CH,-CO,C,H5 ho-(ch2)5-o-ch,co,c,h5 Ψ MsO-(CH2)t-O-CH,CO,C,HS 4z Br-(CH,) -O-CH,CO,C,HS It is also possible to^re^olve the 4-hydroxvcyclopentenone racemate (146) by microbiological means. Thus, treatment of the 4-0-alkanoyl or aroyl derivatives (147, R = aryl or alkyl) of racemate (146) (preferably 1 o the 4-0-acetyl and 4-0-propionyl derivatives) with an appropriate microorganism, preferably a Saccharom ices species e.g. , 1375-143, affords preferential de-O-acylation of the 4(R)-enantiomer to give (14S), which is then separated from the unreacted 4{s)-0-acyl enantiomer (149) by chromatographic procedures. After separation, mild hydrolysis of the 4(5) derivative (149' lli provides the 4(s)-hydroxycyclopentenone (150). [See N. J. Marsheck and M. Miyano, Biochima et Biphysica Acta, 316, 365 (1973) for related examples.] - 50 48207 It is also possible to prepare the individual 4-hydroxycyclopenten ones (148) and (150J directly by selective microbial hydroxyl at ions of the corresponding 4-unsubstituted cyclopentenone (151). For example, with Aspergillus niger ATCC 9142; a selective 4(R)-hydroxylation of [151, I (CHj)^] has been reported; see S. Kurozumi, T. Tora and S. Ishimoto, Tetrahedron Letters, 4959 (1973). Other microorganisms can also accomplish this hydroxylation.

-C-R, (151) The ring system of the novel compounds of this invention allow them to be characterized as follows: - 51 4 8 2 0 7 PGE-Type PGFa-Type PGFg-Type ?GA=Type The 9o-hydroxy PGF compounds of this invention (154) are prepared by a conjugate addition reaction as described hereinabove in Flowsheet N. The initial conjugate addition product (121) (wherein Ζ, Τ', R^ and R*are as hereinabove defined) is not deblocked but dissolved in tetrahydrofuran. An excess of lithium perhydro-9b-borophenalyhydride (ΡΒΡΗ, in tetrahydrofuran is added at -78’C. After warming to 0’C., the reaction mixture is quenched with saturated ammonium chloride solution. The product (153) is isolated and deblocked with acetic acid-tetrahydrofuran-water 4:2:1 at 40’C. in the cases where Τ' is R R , and with dilute hydrochlorid acid in the OR to give the 9a-hydroxy compounds of this invention (154). See,Flowsheet P hereinbelow wherein S, Τ’ , Rg, Sj,R' and Rm are as hereinabove defined.

FLOWSHEET Ρ (153) (121) h3o+ II R% (154) The 98-hydroxy PGF compounds of this invention (156) are prepared by performing a conjugate addition as described hereinabove in Flowsheet N. The initial conjugate addition product (121, (wherein Ζ, T*, R’j, and R are as hereinabove defined) is not deblocked but dissolved in ethanol and an excess of sodium borohydride is added. The mixture is stirred for 8 hours, poured into water and the reduced products (153) and (155) are obtained. These are deblocked with acetic acid-tetrahydrofuran-water 4:2:1 at 40’C. in the cases where Τ' i with dilute hydrochloric acidin cases where Τ' is tetrahydrofuran in the to give the 9a-hydroxy (154) and 9g-hydroxy (156) compounds of this invention which can be separated by silica gel chromatography. See,Flowsheet Q hereinbelow wherein Ζ, Τ', R, R1, R3, R2 and Rg are as defined hereinabove.

FLOWSHEET Q H (155) (154) (156) - 56 48207 The 1-hydroxymethyl group of the PGF compounds of this invention can be selectively esterified by dissolving the compound (154 or 156) in pyridine and adding one equivalent of an anhydride (R^j-CO^O or the acid chloride R^jS-Cl and allowing the mixture to stand overnight to give the desired esters (157 and 158).

(R15CO)2° or , RlgCOCl , pyridine ' (R15CO)2o or |1 R15COC1 Z-C-CH2OH pyridine (156) R^5 is phenyl or phenyl substituted with one or more groups such as alkyl (C^-C^), OR, SR, F, Cl; dialkylamino:or cjjc4 alkyl, wherein R is 0^04 alkyl. The E-Series compound (122) mav also be esterified by this procedure.

FLOWSHEET a ®3θ The PGA, compounds of this invention (160) ar® prepared from the corresponding 11 hydroxy analogs (159) by treatment of (159) with dilute hydrochloric acid in tetrahydrofuran for 2 to 4 days at room teaeprature as shown hereinabove in Flowsheet R, wherein and f ar® as hereinabove defined and T” ic a moiety selected from a group consisting of: JV ©=©=§ 15 „ and Si Θ .©a wherein R^is hereinabove defined.

As shown in Flowsheet S„ hereinbelowt the eompounds of this invention wherein S’ · is . R -Ο«>Ι5=® (162 can also be prepared by selective esterification of the terminal hydroxyl group of compound (161), which is also part of this invention.

This esterfieation can be accomplished by treatment of a pyridine solution of (161) with one equivalent of aa anhydride (163a) or acid ghloride .(163b) at room temperature for 24 hours. FLOWSHEET S (K15co)2o .or (R.eC'Cl) tLb) (161a) © G5 (161) 38.

FLOWSHEET 'Τ' (164) The ΡΰΑ3 compounds of this invention (165) are prepared from the corresponding 11 -hydroxy analog (164) by treatment of (164) with dilute hydrochloric acid in tetrahydrofuran for 2 to 4 days at room temperature as shown hereinabove in Flowsheet T wherein and g are as hereinabove defined and T*’ is a moiety selected from a group consisting of: OH ft /M'S-’is and V 0 wherein R^gis hereinabove defined As shown in Flowsheet ϋ hereinbelow, the compounds of this invention wherein T is X’-S-'i's (167) can also be prepared by selective esterfication of the terminal hydroxyl group of compound (166) which is also part of this invention.

This esterification can be accomplished by treatment of a pyridine solution of (166) with one equivalent of an anhydride (168a) or acid chloride (168b) at room temperature for 24 hours. FLOWSHEET 0 S ? , A R15coci (168b) pyridine ^3^14^ R15CO)2O (liBa) or <48207 In accordance with the process of Bundy et al. 44 J.A.C.S. 94, 2123 (1972) or E.J. Corey 38 J.O.C. 38, 3187 (1973) the PGAp PGAq or PGA^j series compounds of this invention may be converted to the corresponding PGEo> PGE^ or PGE2 compound.

This conversion is accomplished by treating either the protected or unprotected PGA compounds (i.e. 160 or 165) with alkaline hydrogen peroxide to provide a mixture of isomeric 10,11-epoxides which, without separation is reduced with chromous acetate in acidic acid or by aluminum amalgum to provide after hydrolysis (if necessary) and silica gel chromatography, the 11a10 hydroxy-PGE compounds and a lesser amount of the corresponding HB-epimer. - 59a 48207 The novel compound» of the present invention have potential utility as hypotensive agents, anti-ulcer agents, agents for the treatment of gastric hypersecretion and gastric erosion, agents to provide protection against the ulcerogenic and other 5 gastric difficulties associated with the use of various non• flsplrin* steroidal anti-inflammatory agents (e.g., indomethacin, -eepirin, and phenylbutazone), bronchodilators, anti-inflammatory agents, abortifacients, agents for the induction of labor, agents for the induction of menses, fertility-controlling agents, oestrus regulators for use in animal husbandry with cattle and other domestic animals and central nervous sytem regulatory agents. Certain of the novel compounds of this invention possess utility as intermediates for the preparation of the other novel compounds of this invention.

The novel compounds of this invention possess the pharmacological activity described below as associated with the appropriate above-described prostaglandin types.

The known PGE, PGFa, PGFB, PGA and PGD compounds are all potent in causing multiple biological responses even at low 20 doses. For example, PGEp PGEj, PGAi and PGA2 are extremely potent in causing vasodepression and smooth muscle stimulation, and also are potent as antilipolytic agents. Moreover, for many applications, these known prostaglandins have an inconveniently short duration of biological activity. In striking contrast, the novel prostaglandin analogs of this invention are substantially more specific with regard to potency in causing prostaglandin-like biological responses, and/or having a substantially longer duration of biological activity. For example, the 11deoxy-PGE compounds of this invention are selective in that they 30 are at most relatively weak stimulants of smooth muscle, λ further advantage of these novel compounds lies in their increased * Trade MarK stabilities aad lengthened shelf-lives.

Therefore, each of these novel prostaglandin analogs of th|s invention is surprisingly and unexpectedly more useful than one of the corresponding above-mentioned known prostaglandins for at least one of the pharmacological purposes indicated below for the latter, either because it has a different and narrower spectrum of biological activity than the known prostaglandins, and therefore is snore specific in its activity and causes smaller and fewer undesired side effects than the known prostaglandins, or because of its prolonged activity, fewer and smaller doses of the novel prostaglandin analog can frequently be used to attain the desired result.

Another advantage of the novel compounds of this invention^ compared with the known prostaglandins, is that these novel compounds are administered effectively orally, sublingually, intravaginally, buccally, or reetally, in addition to the usual intravenous, intramuscular, or subcutaneous injection or infusion methods indicated above for the uses of the known prostaglandins. These qualities are advantageous because they facilitate maintaining uniform levels of these compounds in the body with fewer, shorter, or smaller doses, and make possible self-administration by the patient.

PGEj, PGEj, PGE3, dihydro-PGEj, PGFo, PGPg and PGA compounds, 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, Bergstrome, et al., Pharmacol.

Rev. 20, 1 (1968), and references cited herein. A few of those biological responses are systemic arterial blood pressure lowering 61. in the case of the PGA and PGB compounds as measured, for example, in anesthetized (phenobarbital sodium) pentoliniumtreated rats with indwelling aortic and right heart cannulas; pressor activity, similarly measured, for the PGF compounds; 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 compounds, as shown in dogs with secretion stimulated by food or histamine infusion; activity on the cental nervous system; decrease of blood platelet adhesiveness in the case of PGE, as shown by platelet-to-glass 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 cas« of the PGE and PGA compounds, stimulation of epidermal proliferation and I keratinization, as shown when they are applied in culture to embryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins are useful to study, prevent, control, or alleviate a wide variety of disease and undesirable physiological conditions in birds and mammals including humans, useful domestic animals, pets/ and zoological speciments, and in laboratory animals, e.g., mice, rats, rabbits, and monkeys. 62.

For example , these compounds are useful in mammals, including man, as nasal decongestants. For this purpose, the cS'GgS'Oss’l Γ compounds are used in a dose range of about lO^rsg to about 10 mg-per ml of a pharmacologically suitable liquid vehicle or as an aerosol spray, both for topical application.

PGA, PGFg and PGE compounds are useful as hypotensive agents to reduce blood pressure in mammals including man. For this purpose, the PGFg compounds are administered by intravenous infusion at the rate of about 0.01 mg to about 40 mg per Kg of body weight per minute, or in a single dosage or multiple doses of about 25 mg to 2500 mg per Kg of body weight total per day. The PGE and PGA compounds are administered by intravenous infusion at the rate of about 0.01 to about 50 mg per Kg of body weight per minute, or in a single dose of multiple doses of about 25 to 2500 mg per Kg of body weight total per day.

The PGE, PGFa and PGFg compounds are useful in place of oxytocin to induce labor in pregnant female animals, including humans, 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 PGF compound is infused intraveneously at a dose of 0.01 mg to 50 mg per Kg of body weight per minute until or near the termination of the second stage of labor, i.e., expulsion of the fetus. Similarly, the PGE compound is infused intravenously at a dose of 0.01 to 50 mg per Kg of body weight per minute until or near the expulsion of the fetus. These compounds are especially useful when the female is one or more weeks postmature and natural labor has not started, or 12 to SO hours after the membranes have ruptured and natural labor has not yet started.

S3 8 207 The PGE, PGFo and PFGg compounds are useful for controlling the reproductive cycle in ovulating female manuals, including humans and other animals. For that purpose, PGF2a, for exanple, is administered systemically at a dose level in the range of 0.01 mg to about 20 mg per Xg of body weight, 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. Likewise, a PGE compound is administered in the same fashion at a dose level of 0.01 mg to about 50 mg per Kg of body weight. Additionally, expulsion of an embryo or fetus is accomplished by similar administration of the compound during the first third or the second third of the normal mammalian gestation period. Accordingly, such compounds are useful as abortifacients. They are also useful for induction of menses during approximately the first two weeks of a missed menstrual period and thus, are useful as contraceptive anti-fertility agents. llo-hydroxy-PGE compounds are extremely potent in causing stimulation of smooth muscle, and are 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 PGE2, for example, 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 uterine bleeding after abortion or delivery, to aid in expulsion of the placenta, and during the puerperium. For the latter purpose, the PGE compound is administered by intravenous infusion immediately after abortion or delivery at a dose in the range about 0.01 to about 50 mg per Xg of body weight per minute until the desired effect is obtained. Subsequent doses axe given by intravenous, subcutaneous, or intramuscular injection or infusion during puerperium in the range of 0.01 to mg per Kg of body weight per day, the exact dose depending on the age, weight, and condition of the patient or animal.

The novel PGA, PGE and PGFg of this invention are also useful as bronchodilators for the treatment of asthma and chronic bronchitis. As such they may be conveniently administered by inhalation of aerosol sprays prepared in a dose range of about 10 ug to about 10 mg/ml of a pharmacologically suitable liquid vehicle. Relative to the natural prostaglandins, the PGA and PGE compounds in particular have the significant advantage of inducing prolonged effects.

The PGE and PGA compounds are also 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 gastric erosion or gastrointestinal ulcer formation, and accelerating the healing of such ulcers already present in the gastrointestinal tract. For this purpose, the 2C compounds are injected or infused intravenously, subcutaneously, or intramuscularly in an infusion dose range of about 0.1 mg to about 500 mg per Kg of body weight per minute, or in a total daily dose by injection or infusion in the range of about 0.1 to about 20 mg per Kg of body weight per day, the exact dose de25 pending on the age, weight, and condition of the patient or animal, and on the frequency and route of administration. These compounds may also be useful in conjunction with various nonsteroidal anti-inflammatory agents, such as aspirin, phenylbutazone, indomethacin and the like, to minimise the well” known ulcerogenic effects of the latter.

S5 8 2(17 The PGE and PGA compound» also stimulate epidermal proliferation and keratinization, and in such a capacity are useful to promote and accelerate healing of skin which has been damaged, for example, by bums, wounds, abrasions or surgeryΓ ~ The nasopressor action of the PGA compounds makes them particularly useful in speeding the adherence and growth of skin autografts, especially small, deep (Davies) grafts which are intended to cover skinless areas by subsequent outward growth rather than initially, and in re-.arding rejection of homografts.

For these purposes, these compounds 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, when there is substantial fluid loss as in the case of extensive burns or skin loss due to other causes, systemic administration of PGE 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, sublinqual, buccal, rectal, or vaginal. The exact dose depends on such factors as the route of administration, and the age, weight, and condition of the subject. Illustrative of a wet dressing for topical application to second and/or third degree bums of skin area 5 to 25 square centimeters is the use of an isotonic aqueous solution containing one to 500 mg/ml of the PGA compound or several times that concentration of the PGE compound. Especially for topical use, these prostaglandins are useful in combination with antibiotics such as gentamycin, neomycin, poly56 ayxin B, bacitracin, spectinomycin, and ewytetracycline; with other antibacterials such as mafenide hydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone; and with corticoid steroids, such as hydrocortisone, prednisolone, methylprednisolone, and fluoroprednisolone; each of those being used in the combination at the usual concentration suitable for its use alone.

The PGA compounds and derivatives and salts thereof increase the flow of blood in the mammalian kidney, thereby increasing the volume and electrolyte content of the urine. For that reason, PGA compounds are useful in managing cases of renal disfunction, especially in cases of severly impaired renal blood flow, for example, the hepatorena syndrome and early kidney transplant rejection. In case of excessive or in15 appropriate antidiuretic hormone ADH vasopressin secretion, the diuretic effect of these compounds is even greater. In anephretic states, the vasopressin action of these compounds is especially useful.

The PGE compounds of this invention are also useful as topical vasodilators.

The PGE^ compounds of this invention 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 to treat and prevent myocardial infarcts and post-operative thrombosis. For these purposes, these compounds are administered systemieally, 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 of about 0.005 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.

It is well known that platelet aggregation inhibitors may be useful as anti-thrombotic drugs. Inhibition of platelet aggregation can be conveniently measured in vitro by monitoring changes in optical density and/or light transmission in platelet rich plasma upon addiiton of suitable aggregating agents such as adenosine diphosphate, epinephrine, thrombin or collagen. Alternatively, platelet aggregation can be measured in vitro using platelet rich plasma obtained at various time intervals from animals given inhibitors by an oral or parenteral route.

The PGE compounds of the present invention exhibit the ability to inhibit platelet aggregation in vitro when tested by the following procedure.

Human protein rich plasma is incubated with modified Tyrode's solution in a proportion of 40-504 human protein rich plasma. The test compounds are added at varying concentrations and after 5 minutes incubation, an aggregating agent such as adenosine diphosphate or collagen is added. The change in optical density (light transmission) is monitored by eye and inhibition is recorded as a (-) or lack of inhibition is recorded as a (+). Test compounds are considered aetive if they inhibit adenosine diphosphate or collagen induced aggregation at a concentration of 0.025 mg/ml or less within 3=10 minutes. For example, a compound of this invention, l,9-dioxo-X5=hydroxy-X-hydroxymefchyl-13-trans-pr03tene, shows Inhibition of platelet aggregation induced by both adenosine diphosphate and collagen at a concentration of 0.025 mg/ml.

The PGE compounds of this invention also have bronchodilator activity as determined in a test using dogs anesthetized, artificially ventilated and submitted to a continuous respiratory spasm induced by pilocarpine.

Mongrel dogs of either sex weighing between 5 and 10 kg are used. They are preraedieated with morphine HCl by subcutaneous injection at 1.5 mg/Kg. An intravenous perfusion of 5§(W/V) chloralose is started 1/2 hour after the morphine injection in such a way that 60 mg/Kg are administered within minutes. After completion, a continuous perfusion of 10 mg/ Kg/hour is maintained throughout the experiment. The dogs are artificially ventilated by means of a Starling pump at a rate of 20 breaths/minute. The volume is adjusted according to the weight of the animal. [Kleinman and Radford, J. Appl. Physiol., 19, 360 (1964)]. All the measurements are made with the dogs positioned supine in a heated, V-shaped table. Curarization is obtained by succinylcholine chloride using a starting injection of 3 mg/Kg lasting 3 minutes, followed by a continuous perfusion of 0.1 mg/Kg/minute.

The respiratory spasm is induced by a starting injection of 400 mcg/Kg of pilocarpine HCl lasting S minutes. An increase or decrease in the dose of pilocarpine HCl may occur as a function of the observed effect on the airway’s resistance. A 15 minutedelay is Observed before the start of a continuous perfusion of 69. 4820 pilocarpine HCI at a dose of 4 mcg/Kg/minute to maintain a constant spasm during the test.

A metallic cannula is inserted and fixed, after tracheotomy, into the upper part of the trachea. The two cephalic veins and the two femoral veins are catheterized to inject the various agents. The femoral artery is catheterized to measure the systemic blood pressure. An esophageal balloon (11 cm x 2.5 cm) is inserted into the lower third of the oesophagus to measure the endothoracic pressure. The measurement of air flow is made with a Fleish pneumotachograph connected to the tracheal tube.

The transpulmonary pressure is measured as follows: The tracheal cannula is eguipped with a stainless steel axial tube (1.5 mm) which is closed at its distal end and projected 2.5 cm beyond the end of the cannula. Three holes with a diameter of one mm are pierced on this latter segment. This tube, which is used to measure the tracheal pressure, is connected to one of the two chambers of a Sanborn 267 B/C differential transducer. The other chamber is connected to the esophageal balloon by means of a polyethylene catheter of the same length and characteristics as the balloon’s.

The airflow is measured from the Fleish pneumotachograph by means of a Sanborn 270 differential transducer.

The tidal volume is obtained by electronic integration of the flow signal using an R.C. integrator.

The systemic and pulmonary blood pressures are gauged by means of a Sanborn 267 B/C or 1280B pressure transducer. 8 2 0 7 An electrocardiogram is taken An lead 2. Its use is to monitor a cardiac rate-meter.

All these parameters are recorded on a Sanborn polygraph. The transpulmonary pressure and the tidal volume are also dis-” played as rectangular coordinates on an oscilloscope.

The airway's resistance, expressed in cm of water/liter/ second, is measured by subtracting from the electrical equivalent of the transpulmonary pressure, a voltage proportional to the flow so as to synchronize the pressure and volume signals on the oscilloscope [Mead and Whittenberger, J. Appl. Physiol., 5., 779 (1953)].

The value of the pulmonary elastance, expressed in cm of water/liter, is obtained by means of the same principal, i.e., an electrical signal proportioned to the volume is subtracted from the transpulmonary pressure signal, in order to optimize the pressure-flow loop on the oscilloscope.

The details of this method are described by Lulling, et al. [Med. Pharmacol. Exp., IS, 481 (1967)].

The computing operations are carried out with an analogical 20 computer which allows the direct reading, cycle to cycle, of the values of resistance and elastance.

The test compounds are administered by an Aerosol® route. The micronebulizer of a Bird Mark 7 respirator is fitted on the metallic cannula just after the pneumotachograph.. The “puff of the test compound, in Aerosol® is driven by a 2 Kg/cm^ pressure, allowed into the micronebulizer just during one inspiration cycle. The aicronebulizer is fitted on the respiratory tube only during the Dpuff.° It io weighed just before and just after administration to determine the amount of test compound administered.

The * inhibition of apaams induced by pilocarpine for some of the compound· of this invention is shown below in Table A. Approximately 50 mg of the solution is administered to each dog. 8 2 Ο Τ' % Inhibition of pilocarpine induced spasm as a function of the after drug administration 60 min. 70 66 89 30 30 55 30 min. ] 06 80 74 30 45 75 5 min. o σ> 08 o co r-- tn o r*. 92 Dose mg/ml 3.2 3.2 3.2 3.2 3.2 3.2 1,9-dioxo-Ilex, 16-dihydroxy-16-methyl1-hydroxymethyl-5-cis-13-trans prostadiene 1,9-dioxo-lXa,16-dihydroxy-16-vinyl1-hvdroxvmethy1-5-cis-13-trans prostadiene 1,9-dioxo-11a,15-dihydroxy-16,16t r i me t h γ 1 en e -1 - hy dro xy me thy 1 - 5 - cis13-trans prostadiene 1,9-dioxo-15-hydroxy-15-methyl-1hvdroxymethyl-13-trans prostene 1,9-dioxo-15-hydroxy-1-hydroxymethyl prostane 1,9-dioxo-1la,16-dihydroxy-16-vinyl1-acetoxymethyl-5-cis-13-trans prostadiene Bronchodllator Activity (Pilocarpine Assay) * Inhibition of Spasm % Inhibition of pilocarpine induced spasm as a function of the after drug administration fi •d E o «3 in rt in Wf © r* 09 15 55 • e •d ε © rt © m © © eo in r* o wf © f* c •H E n o f- © σ\ © σι o © O © in tn Dose mg/ml n) rt ni rt ni rt m • rt 1 d >1 £ JJ tt 1 ι m 10 fi d fi t M >1+» X 1 0 n M d d * S n £-d •d 01 d 1 I m « 1 d d * >1 45 VSS 0 Stt X X-d 0 0Ό •d M fi d d JJ 1 sw m £ 0 * · ΰ d £ § tn d 1 j?, 0 n M fi d « SM A 0 •d 1 rt 1 H « 1 d »d * S 55 rd tt 81« 0 0 c Ή Μ «I flfl 44 1 2? 5 If s Hrl ft 1 d S fi H > © d 1 s X 1 0 w M fi Ό fi SM £ JJ d d d 1 rd 0 id id • s flfi d JJ d tt u g s s Ή Μ «1 ΟΌ44 “·? S F-l Λ 0 1 φ d 1 *rt t0 d d 1 d SS X A 0 4J M tt §,& C X d 0 d M 1 d β S η A d 1 »d tt 0 C d tt tt d C JJ 1 tt 0 Od 0 X SM 0ΛΛ •d JJ I V § C Old « • MM d JJ JJ d 1 s X 0 M d ι sw & c d fi d M 1 JJ 0 1 Λ rt d d • 1 0 d d S 75· x 1 β 5 &S d o jj 1 M 0 σι d 0 • SM d A CU © β 1 V C O> 6 « »3 U 8 2 0 7 The bronchodilator activity of some of the PGE compounds of this invention is determined in guinea pigs against bronchospasms elicited by intravenous injections of 5-hydroxytryptamine, histamine or acetylcholine by the Konzett pro5 cedure. (See J. Lulling, P. Lievens, F. EX Sayed and J. Prignot, Arzneimittel-Forschung, 18, 995 (1968)].

In the Table B which follows, bronchodilator activity for representative compounds of this invention against one or more of the three spasmogenic agents is expressed as an ed50 determined from the results obtained with three logarithmic cumulative intravenous doses.

Bronchodilator Activity (Konzett Assay) ED 50 mg/kg Spasmogenic Agent [ Acetylcholine tO 1 © rt X © to ) o rt X © © CN NO 1 o rt X to ON CN >320 to 1 © rt X CN to Λ © r © rt X W © <υ •rd g ra +j ω rt s 1 o rt X o to © © rt X XT in CM NO 1 O rt X to r- to NO 1 o rt X rr to 1 o rt X oo rr to 1 o X © rt CN © 1 © rt X © co r* fl> c rt +4 & +4 s? o P •a £ 1 ΙΛ K) 1 © X rt co © 1 © r—H X CN o NO 1 O rt X CO 00 CN NO © rt X © 0) CO to ( © rt X rf © to 1 © rt X © © CN © ι © X rt CO 00 1,9-dioxo-1la,16-dihydroxy-16-methyl1-hydroxymethyl-5-cis-13-trans prostadiene 1,9-dioxo-lla, 16-dihydroxy-16-vinyl1-hydroxymethy1-5-cis-13-trans prostadiene 1,9-dioxo-15-hydroxy-15-methy1-1hydroxymethyl-13-trans prostene I o h Ό £ i rt 1 X X o h Ό X fl) 45 £ ι ra m +J rt (/) 1 o o X X Λ O rt rt Ό X 1 Λ © * fl) rt g l,9-dioxo-15-hydroxy-l-hydroxy- ! methyl-13-trans prostene 1,9-dioxo-15-hydroxy-1-hydroxymethyl13-tTans prostene 1,9-dioxo-11a,16-dihydroxy-16-vinyl1-ace toxymethy1-5-cis-13-t rans prostadiene 8 2 0 7 οχ. σ ε VD I Ο <β I ο ΙΟ I ο TABLE B (Cont'd) \£> I Ο ΓΊ I Ο κο I ο »Η I X I ο > U X »ρ Ρ ι Φ Η I η ι η Η β >, * ΗΛΟ Η «U-Η φ I Φ ϋ C Ο Β I β) χ-Ηΐη-Η ΟΌ I Ό Μ ι .-4 <0 •8 β >1+) I Ν£ Ο σ» »*> Ο »<ο ω κ 17- 79.

PROTOCOL FOR EVALUATIOH 6t GASTRIC ANTI-SECRETORY AGENTS A. MODEL: Unanesthetized mongrel dogs weighing 10-15 Kg are used. The animals have a surgically prepared denervated (Ileidenhain) pouch which drains by gravity through a titanium cannula. These animals are trained to stand quietly in a Pavlov support. Gastric secretion is stimulated at the lowest rate giving stable secretion (25-404 of maximal) with histamine acid phosphate, 30-50 pg/Kg/hr. Under such stimulation, a stable gastric secretory output can generally be maintained for a period of at least 3 hours.

Gastric juice is collected continuously during secretory studies and pooled into 15-minute collections. Determination of collection volume, pH and titratable acidity is performed. Acid is determined by titrating an aliquot of gastric sample with 0.1 N NaOH to pH 7.0 using an automatic titrator.

Drugs are administered on a background of submaximal gastric secretory stimulation and the results compared with control secretory studies without the use of drug. Depending upon the duration of action of a particular drug, it may be possible for a single drug-secretory study to serve as its own control. The route of drug administration is oral administration into the main stomach. This route is easy to perform and does not interfere with the smooth collection of pouch gastric juice.

For Example, one of the PGE compounds of this invention 1,9— -dioxo-llc,16-dihydroxy-16-methyl-l-hydroxyraethyl-5-trans prostadiene on administration into the stomach of one of these dogs at a dose of 100 mg/ftg gives the results shown hereinbelow i-n Table D. The data in Table D is the average of four testa in ena dog. . 48207 TABLE D Volume and titratable activity of gastric juice after administration of 1,9-dioxo-lla,16-dihydroxy-16-methyl-l-hydroxymethyl~5-cls,13trana prostadiene (100 mg/Kg).

Time after administration, min. 0 15 30 45 60 75 90 105 120 Volume (ml) T/4 2.6 1.5 1.3 0.7 0.9 1.5 1.9 277'· Acid (meg/ 15 min.) 0.43 0.35 0.22 0.20 0.09 0.13 0.21 0.27 0.40 Gastric Acid Secretion in the Dog Fistula Three mongrel dogs (20-32 kg) were surgically prepared with stainless steel cannulae. These were inserted into the most dependent portion of the ventral stomach and exteriorized through the abdomen for the collection of gastric secretions.

The dogs were trained to stand quietly in a Pavlov support and were conscious during subsequent secretory studies.

TABLE E Effect of l,9-dioxo-llX,16-dihydroxy-16-methyl-l-hydroxyraethyl23 13-trans-prostene, and 1,9-dioxo-lW,16-dihydroxy-16-methyl-lhydroxymethy1-5-cis-13-trans prostadiene on the Gastric Acid Secretion3 in the Dog Fistula Preparation cumulative two-hour gastric dose u secretion0 τ r* \ i._ 4 Λ_ί'_ ' /‘-J? 1' ” d J k treatment (gg/kg X.G.) n volume (ml) acid (mEq H+) control - 20 130 i 11 17.2 i 1.6 Compound A 10 6 59 4· 19 (p <0.01) 6.9 + 2.8 fp 0T005) Compound B 10 6 76 ± 16 (p <0.05) 7.5 ± 2.1 (p <0.005) aA£ter a 26-hour fact, gastric add secretion was submaximally stimulated, beginning 45 minutes after treatment, using a constant intravenous infusion of histamine acid phosphate (40 g/kg/hr). ^Each of three dogs was treated aix to seven times with vehicle (control) and one to three times with each compound; n is the number of experiments conducted with each treatment. cTotal secretion from 45-120 minutes following intragastric (I.G.) administration of drugs or vehicle. Mean effects of treatment were compared to control means by Student's t test. Compound A is 1,9-dioxo-lltf,16dihvdroxv-16-methv1-1-hvdroxvmethv1-13-trans-prostene, and Compound B is l,9-dioxo-ll4,16-dihydroxy-16-methyl-lhydroxymethy1-5-cis-13-trans-prostadiene.

Restraint - Immersion Stress Ulcers in the Rat (Wilson) A. Induction of Ulcers Male “Sprague - Dawley Derived rats (Locke - Erickson Laboratories, Maywood, Illinois) weighing 150 to 200 g, are fasted, and provided drinking water for 16 to 19 hours prior to the of the study. At 0 time the rats are dosed orally with compound or vehicle, (approximately 0,5 ml) and then secured in a Bollman-type restraining cage. Five minutes after dosing, the animals are immersed (tail downward) to shoulder level into a 22°C water bath for 100 minutes. At the end of this period, the animals are decapitated and their stomachs promptly excised with about 5 mm each of esophagus and duodenum.

With a blunt tipped scissor the stomach is opened along the greater curvature, starting at the tip of the rumen through the glandular mucosa into the pylorus and opening the bit of duodenum along its amesenteric border. Debris is removed from stomach by rinsing in saline at room temperature and gently blotting it with gauze or filter paper. The stomach is then spread out, mucosal surface upward on a 3 x 5 file card or similar material.

B. Evaluation of Lesions With an illuminated magnifier the lesions are counted (for total lesion count) and scored (for weighted score) after the method described by G. Osterloh, et al., Arzneimittel-Forschung, (8a):901910, August 1966. The score for each lesion is given in the following table, modified from the paper.

LESION TYPE . SCORE No lesions 0 Erythema 1 Petechial Hemorrhages 2 Erosion 3 Pinpoint Dicer 4 Small Dicer (0.5-1 jhq) 5 Medium Dicer (1-3 mm) 6 Large Dicer ( 3 mm) 7 Perforation 8 S3 Very large (area) non-perforating lesions are frequently seen. These are measured as so many 3 nm diameter ulcers and scored as multiples of «7. For example, a 3mm2 diameter ulcer ia taken to have an area of 7.1 mm2, so a lesion measuring 9 x 4 mm will have an area of 36 mm2 and hence is equivalent tb“ 5 lesions with a score #7.

TABLE F Effect of Prostaglandins on StressInduced (Immersion) Ulcers in Rats Compound Dose (mg/Kg P.O.) Dicer Score [Mean + SEM (n) ] % Reduction ' Control 40 + 5 (27) A* 500 2+1 (10) 95 (p 4.001) 200 6 + 3(5) 85 (p <.01 ) B* 500 7 + 2(6) 82 (p <.01 ) 200 13+7 (13) 67 (p 4*005) 80 7 + 6(7) 82 (p <.005) 16 6 + 4(6) 85 (p 4.005) 3 15 + 11 ( 6) 62 (p 4.05) Rats were dosed by gavage with compound or vehicle and submerged into a 22#C water bath for 100 minutes. At the end of this period, animals were sacrificed and their stomachs removed and scored for ulcers.

A* is: l,9-dioxo-lla,16-dihydroxy-16-methyl-l-hydroxymethyl5-cis,13-trans-prostadiene.

B* isi l,9-dioxo-lla,16-dihydroxy-16-methyl-l-hydroxymethyl13-trans-prostene.

Indomethacin - Induced Dicers ia the gat Male Wistar rats (Royal Hart, Hew Hampton, SS.Y.), weighing 190-210 g are distributed among control and treatment groups (5 rats/group) and housed one rat per cage. During the 52 hour test period, the rats are permitted free access to foodand drinking water for the first 33 hours but are fasted overnight prior to sacrifice. Indomethacin is suspended (4 mg/ml) in a 1.5% starch-phosphate buffer solution (SPSS). Compound 8. is dissolved at 10 mg/ml in ethanol and then diluted in SPSS to 0.1 mg/ml or to a lower concentration as required. The indomethacin suspension is injected subcutaneously (10 mg/kg) and the prostaglandin suspension is given by gavage (0.5 mg/kg or less) b.i.d. on day 0 and 1. Rats receive only one dose of prostaglandin and indomethacin on day 2 and δ hours later are killed with chloroform. The stomachs are dissected, opened along the greater curvature, and rinsed briefly in tap water. They are then spread, mucosal surface facing upward and pinned onto uniform size corks (2.5 inch diameter) individually numbered on the back. The identification number for each stomach is unknown te the investigator and the stomachs are randomly graded according to the following scheme (10).

- Normal - Petechial hemorrhage, or pin-point ulcers - One or two small ulcers or hemorrhagic erosions - Many areas of hemorrhage erosion or ulcers, a few large - Massive areas of hemorrhagic erosion or many ulcers, mainly large Intestines are also removed and examined for the presence of ulcers, which are graded according to the scheme outlined below.

- Normal - Mucosa thin, petechial hemorrhage - DBlow-outs°, when intestine inflated with air - Pew ulcers. Gut more fragile than normal, tears along line of mesentery attachments! when removed - Many large perforating lesions. Adhesions. Gut hemorrhagic and very fragile. Tears readily and cannot be removed intact. Graded ia situ. 85.

TABLE G Effect of l,9-dioxo-lla,16-dihydroxy-16-methyll-hydroxymethyl-13-trans-prostene (Compound 8) on Indomethacin-'Indueed Ulcer* In Rats' Treatment* N Gastric Ulcer Score (Mean + S.E.M.) Intestinal Ulcer Score (Mean + S.E.M) Hematocrit (Mean + S.E.M.) Indomethacin (mq/kq Subcut.) Compound A (mg/kg P.0.) 10 - 10 2.9 ± 0.2 3.7 t 0.2 •33.1 ± 2.1 10 .5 10 2.1 ± 0.4 2.0 s 0.4b 40.0 ± 1.4b 10 .1 10 1.7 ± 0.3b 2.7 ± 0.2b 41.1 4 2.4b 10 .02 8 1.9 i 0.4b 3.5 ± 0.2 35.6 4 1.9 - - 10 0.3 ± 0.2b 0b 48.0 ± 0.6b The novel compounds of this invention induce the biological responses described hereinabove as associated with their particular prostaglandin types. These novel compounds are accordingly used for the above-described corresponding purposes.

These derivatives described hereinabove are also more selective in their biological action and generally induce a more prolonged effect than the corresponding natural prostaglandins. These preparations are novel, completely unanticipated and provide distinct and important advantages.

Xn addition, certain of the novel compounds of this invention are useful for the preparation of other novel compounds of their invention.

The invention will be described in greater detail in conjunction with the following specific examples.

* Treatment is B.X.O. on day· 0 and 1, and once on day 2, six hours prior to sacrifice for scoring. b Significantly different from indoaethacin-only treatment at p ¢.05.

The following examples describe the manner and process of making and using the invention, but are not to be construed ao a limitation thereon. 87.

DETAILED DESCRIPTION OF TOE INVENTION EXAMPLE 1 Preparation of ethyl 2,2-trimethylenehexanoate To a stirred solution of 27.6 g of freshly distilled N-isopropylcyclohexylamine in 200 ml of dry tetrahydrofuran cooled to -78°C is added at a fast rate 96 ml of 2.04M n-butyllithium in hexane. To the resulting solution is added dropwise 25 g of ethyl cyclobutanecarboxylate. After 30 minutes the resulting solution is allowed to warm to ambient temperature, is transferred to a dropping funnel under nitrogen and is addeddropwxse over a period of 1 1/4 hours to a solution of 54 g of n-butyl iodide in 100 ml of dry dimethylsulfoxide maintaining the temperature at 16°-20°C. Stirring is continued for an additional 30 minutes. The separated salts are removed by filtration, the mother liquor is taken to a small volume and the resulting oil is diluted with hexanes. This solution is washed with 2¾ hydrochloric acid, saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. The solvent is removed and the residual oil is distilled to .give 14.6 g (41%) of product, bp 84°-87°C (10 mm).

EXAMPLE 2 Preparation of ethyl 2,2-tetramethylenehexanoate In the manner described in Example 1, treatment of the lithium salt of ethyl cyclopentanecarboxylate with n-butyl iodide furnishes the subject product.

EXAMPLE 3 Preparation of 2,2-trimethylenehexan-l-ol To a stirred solution of 20 g of ethyl 2,Z-trimethylenehexanoate (Example 1) in 100 ml of dry toluene, in an argon atmosphere and cooled in an ice bath, is added dropwise 250 ml (2 molar equivalents) of 0.39M diisobutylaluminum hydride in toluene. The resulting solution is stirred at ambient temperature for 2 hours and then poured into excess iced 5% hydrochloric acid. The organic phase is separated and washed with 5% hydrochloric acid, - 88 4 8 2 0 7 saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 14.8 g (96¾) of oil; bp 92°-93°C (10 mm).

EXAMPLE 4 Preparation of 2,2-tetramethylenehexan-l-ol In the manner described in Example 3, treatment of ethyl 2,2tetramethylenehexanoate (Example 2) with 0.89 molar diisobutylaluminum hydride furnishes the subject product.

EXAMPLE 5 Preparation of 2,2-triaethylenehexaldehyde Chromium trioxide (61.5 g), dried in a vacuum desiccator over phosphorous pentoxide, is added to an ice cold solution of 97 g of dry pyridine in one liter of dry methylene chloride. The deep red suspension is stirred for 15 minutes at 0°C and then for 45 minutes at ambient temperature. A solution of 14.5 g of 2,2-trimethylenehexanol-l (Example 3) in 55 ml of methylene chloride is added all at once to the suspension. A black tarry deposit is formed immediately. After stirring at ambient temperature for 15 minutes the solution is decanted from the tarry deposit Which is then triturated four times with small portions of methylene chloride. The combined extracts are washed twice with ice cold 5¾ sodium hydroxide, ice cold 5o hydrochloric acid and finally with saturated sodium chloride solution, dried with magnesium sulfate and taken to dryness. Distillation gives 12.9 g of product; bp 69°C (11 mm).

EXAMPLE 6 Preparation of 2,2-tetramethylenehexaldehyde Oxidation of 2,2-tetramethylenehexan-l-ol (Example 4) with chromium trioxide-pyridine complex in the manner described in Example 5 furnishes the subject product.

EXAMPLE 7 Preparation of 4,4-trimethylene-l-octyn-3-ol To a solution of lithium acetylide-ethylenediamine complex (9.4 g) in 90 ml of dry dimethylsulfoxide, cooled in an ice bath, is added 12.94 g of 2,2-trimethylenehexaldehyde (Example 5) in 10 ml of dimethylsulfoxide dropwise, at such a rate that the temperature is maintained at 20°-25°C. The solution is stirred at ambient temperature for 12 hours and then poured into a mixture of ice cold 2% hydrochloric acid and ether. The ether layer is separated and the aqueous phase is extracted with ether. The combined ether extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation provides 13.53 g of product; bp 108°-109°C (13 mm).

EXAMPLE 8 Preparation of 4,4-tetramethylene-l-octyn-3-ol Treatment of 2,2-tetramethylenehexaldehyde (Example 6) with lithium acetylide-ethylenediamine complex in dimethylsulfoxide in the manner described in Example 4 is productive of the subject compound.

EXAMPLE 9 Preparation of 4,4-trimethylene-3-trimethylsilyloxy-l-octyne To a stirred solution of 5.3 g of 4,4-trimethylene-l-octyn-3-ol (Example 7) and 5.42 g of imidazole in 32 ml of dry dimethylformamide, cooled in an ice bath under argon atmosphere is added 4.35 g of chlorotrimethylsil20 ane. After stirring at 0°C for IS minutes, the solution is stirred at ambient temperature for 18 hours and then poured into 200 ml of hexanes. The solution is washed twice with ice cold water, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation furnishes 6.02 g (80%) of colorless oil; bp 110°-112°C (14 mm).

EXAMPLE 10 Preparation of 4,4-tetramethylene-5-trimethylsilyloxy-l-octyne Treatment of 4,4-tetramethylene-l-octyn-3~ol (Example 8) with chlorotrimethylsilane in dimethylformamide containing imidazole as described in Example 5 furnishes the subject product. - 90 48207 EXAMPLE 11 Preparation of l-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-octyne To a solution of 25 g of 4,4-trimethylene-3-trimethylsilyloxy-loctyne (Example 9), stirred under argon atmosphere at -78°C, is added dropwise 93 ml of 2.3M n-butyllithium in hexane at a rate to maintain the temperature below -40°C. After stirring for 40 minutes, a solution of iodine is allowed to warm to ambient temperature and 10% aqueous sodium thiosulfate solution is added until the purple color is removed. The organic phase is washed with dilute aqueous sodium thiosulfate solution, saturated sodium chloride solution, dried with anhydrous sodium sulfate and taken to dryness to afford the subject product as an oil.

EXAMPLE 12 Preparation of l-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-cis-octene To a solution· of 30 g of X-iodo-4,4-trimethylene-3-trimethylsilyloxy-l-octyne (Example 10) in 100 ml of methanol, under argon atmosphere is added 54 g of potassium azodicarboxylate [J. Thiele, Annalen der Chemie, 271, 127 (1892}] to this solution is added dropwise 45 ml of acetic acid over a period of about 2 hours. The solids are removed by filtration and the mother liquor is reduced to a small volume, diluted with water and extracted with ether. The ether is evaporated and the residual oil is stirred with 250 ml a of IM sodium bicarbonate solution. The solution is extracted several times with ether and the combined extracts are washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate and taken to dryness to furnish the subject product as an oil.

EXAMPLE 13 Preparation of l-iodo-4,4-trimethylene-3-trimethylsilyloxy-1-trans-octene To a mixture of 4.76 g of sodiumborohydride and 23.6 g of 2-methyl- 91 48207 2-butene in 220 ml of dry tetrahydrofuran at *5°C is added dropwise 23.8 g of freshly distilled borontrifluoride ethereate. The resulting mixture is stirred at -5°C to -0°C for 2 hours and to it is added dropwise a solution of 20 g of 4,4-trimethylene-3-trimethylsilyloxy-l-octyne (Example 12) in 20 ml of dry tetrahydrofuran. The resulting mixture is stirred at ambient temperature for 2 1/2 hours. The mixture is then cooled to -5°C and there is added 44 g of trimethylene oxide portionwise over a period of 20 minutes, maintaining the temperature at 15°-20°C, The mixture is stirred at ambient temperature for 2 hours and then poured simultaneously, with a solution of 119 g of iodine in 290 ml of tetrahydrofuran, into 1490 ml of 15% aqueous sodium hydroxide solution. After stirring for 30 minutes the organic phase is separated and the aqueous phase is extracted with ether. The combined organic phase is washed with 5% aqueous sodium thiosulfate solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 27 g of oily material. Chromatography on 135 g of Florisil* and eluting with 500 ml of hexanes furnishes 24 g of oily product which is shown to be contaminated with starting material and iodofOTm by infrared and thin layer chromatography. The material is purified by removing the trimethylsilyl group in the following manner. The crude product is dis20 solved in 350 ml of acetic acid-tetrahydrofuran-water (4:2:1) by stirring at ambient temperature for 5 minutes. The solvent is removed under reduced pressure and the residual oil containing mainly l-iodo-3-hydroxy-4,4-trimethyl ene- 1-trans-octene is applied to a 2 (flat) dry column containing 1200 g of Woelm silica gel. The column is developed with benzene, cut into oneinch segments and each segment is eluted with chloroform. Combination of the appropriate fractions affords 300 mg of iodomethane, 2,8 g of 4,4-trimethylene-l-octyne-3-ol, and 11.6 g of l-iodo-3-hydroxy-4.4-trimethylene-l-transoctene. Silylation of this material in the manner described above followed by distillation of the residual oil furnishes 13 g of pure product; bp 83°30 84°C (0.2 mm). - 92 4 8 2 0 7 EXAMPLE 14 Preparation of l-iodo-4,4-tetramethylene-5-trimethylsilyloxy-1-trans-octene Treatment of 4,4-tetramethylene-3-trimethylsilyloxy-l-octene (Example 10) in the manner described in Example 13 furnishes the subject product.

EXAMPLES 15-20 Treatment of the lithium salt of ethyl cyclobutane-carboxylate with the alkyl halides listed in Table 1 below by the procedure described in Example 1 furnishes the 2,2-trimethylene esters of the table. - 93 48207 TABLE 1 8 2 0 7 EXAMPLES 21-27 Reduction of the various esters listed in Table 2 below with diisobutylaluminum hydride all in the manner described in Example 3 above is productive of the alcohols of fhe fable. 93.

TABLE 2 8 2 0 7 EXAMPLES 28-34 Oxidation of tha aleoholc listed in Tabla 3 below with chromium triexide-gyridine complex by the procedure described in Example 5 above furnishes the corresponding aldehydes of the table. 97.

TABLE EXAMPLES 35-41 Treatment of the various aldehydes listed below in Table 4 with lithium acetylide-ethylenediamine complex in the banner described in Example 7 furnishes the hydroxyacetylenes of the table.

IS TABLE 4 100 482U? EXAMPLES 42-48 Treatment of the various alcohols listed below in Table 5 with chlorotrimethylsilane in the manner described in Example 9 furnishes the corresponding trimethylsilyloxy acetylenes of the table. 101 TABLE 5 102 Ο 48207 EXAMPLES 49-54 2η the manner described in Example 13 treatment of the various acetylenes of Table 6 below with disiamylborane, made in situ from sodium borohydride and 2=methyl-2-butene, followed by oxidation of the so formed organoborane with tri= «ethylamine oxide followed by treatment of this produet With iodine and sodium hydroxide furnishes the trimethylsilyliodovinylcarbinols of the table. 103 TABLE 6 104 EXAMPLE 55 Preparation of ethyl 2,2°trimethylene°4°gis-hexenoate A solution of„5 g of ethyl 2,2-trimethylene-4-hexynoate (Example 20) in 40 ml of dry pyridine is hydrogenated in a Parr apparatus using 600 mg of 5% palladium on barium sulfate. After one hour when hydrogen uptake is complete, Celife*· the solution is filtered through-ee-iifee and the mother liquor is taken to dryness to furnish 4 g of product as an oil.

EXAMPLE 56 Preparation of 3-tetrahydropyranyloxy-I-propyne To a stirred solution of 112 g (2.0 mol.) of 3-hydroxy-l-propyne and 260 g (3.0 mol.) of dihydropyran in 1.20 liters of methylene chloride cooled to 0°C in an ice bath, is added a solution of 20 mg of para-toluenesulfonjc acid in 100 ml of methylene chloride, dropwise. The reaction mixture is stirred at O’C for one-half hour, and at ambient temperature for one hour. It is then poured into 200 ml of · a 5% solution of sodium bicarbonate, the organic phase is separated, the aqueousphase extracted with 100 ml of methylene chloride, the combined organic phases washed with 100 ml of a solution of brine, dried over sodium sulfate, and evaporated under vacuum (12 mm)·' at 4 5°C to give 300 g of crude 7 product, which is purified by fractional distillation, bp 71°· -73°C (14 mm) to yield 250 g (89%) of a liquid.

EXAMPLE 57 Preparation of 3-tetrahydropyranyloxy°l-tritnethylsilyl-l-propyne To a stirred -20®C solution of 125 g (0.89 aol.) of 3-tetrahydropyranyloxy-l=propyns (Example 56J in 450 al of ether, under a nitrogen atmosphere, is added dropwise, over one hour, a solution of 45 al (0.89 mol.) of 2.0 M n-butyllithium in hexane. After ISO ml of dry either is added and MS. the mixture stirred at -20*C for 30 minutes, a solution of 9B g (0.89 mol.) of trimethylchlorosilane in 73 ml of ether is added dropwise. Stirring is continued for 30 minutes at -20*c and at ambient temperature for 18 hours. The reaction mixture is again cooled to -20*C, and a solution of 90 ml of acetic acid in 300 ml of ether is added dropwise, followed by *90 ml of water. It is then diluted with 500 ml of water, and extracted 3 times with 300 ml of 51 sodium bicarbonate solution. The organic phase is separated, washed with 500 ml of a saturated brine solution, dried over sodium sulfate, and ' evaporated at 40*c under vacuum (12 mm.). The crude product is fractionally distilled, bp 120·-125·ε (18 mm.), to yield 120 g of an oil.

EXAMPLE 58 Preparation of d,1-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-trlmethylsilyl-l-octyne To a stirred -78*C solution of 62 ml (124 mmol.) of a 2.0 M solution of n-butyllithium in hexane and 50 ml of dry tetrahydrofuran, under a nitrogen atmosphere is added dropwise, a solution of 24 g (113 mmol.) of 3-tetrahydropyranyloxy-l-trimethylsilyl-l-propyne (Example 57) in 35 ml of tetrahydrofuran. This red solution is stirred one hour at -78*C, then a freshly prepared solution of zinc iodide (135 mmol.) in 125 ml of tetrahydrofuran IF. Mercier, R. Epstein, and S. Holand, Bull. Soc. Chim.^France, 2., 690 (1972)} is added dropwise at -78*C, until the mixture turns yellow. After stirring an additional hour at -78*C, a solution of 21 g (250 jimol.) of n-valeraldehyde in 35 ml of tetrahydrofuran is added dropwise and the reaction mixture stirred for one hour at -78*C and 18 hours at ambient temperature. It is'.then cooled to 0*c and a solution of 12 ml of acetic acid in 65 ml of ether is added dropwise, followed by 75 al of ice-water. The 106 phases are separated and the aqueous phase is extracted twice with ether. The combined organic phases are washed 3 times with saturated sodium bicarbonate solution, until the last wash is basic, then with a saturated brine solution, dried over sodium sulfate, and evaporated to give 40 g of· yellow oil. The crude product may be purified on a 4 x 40“ dry col umn of alumina, and eluted with chloroform. I.H.s neat; 3550 (OH), 2200 (CsC), 840, 750 [(CJl^Si), cm”1.

EXAMPLE 59 Preparation of d,l-erythro-3,4-dihydroxy-l-trimethylsilyl-l10 -octyne A solution of 19.6 g (.066 mol) of d,l-erythro-3“ -tetrahydropyranyloxy-4-hydroxy-l-trimethylsilyl-l-octyne (Example 58) in 55.5 ml of ethanol, 22.2 ml of acetic acid, and 22.2 ml of water is heated at reflux for 3 hours. The cooled mixture is taken to dryness and evaporated twice with benzene. The residue is taken up in hexane, washed 3 times with saturated potassium bicarbonate solution, dried with magnesium sulfate, and evaporated to give 17.0 g of crude product IP: neat, 3500-3400, broad (two OH).

EXAMPLE 60 Preparation of d,l-erythro-3,4-i5opropylidenedioxy°l-trimethylsilyl-l-octyno' To a stirred solution of 17.0 g (79.5 mmol.) of crude d,1-erythro-15,16-dihydroxy-l-trimethylsllyl-l-oetyne (Example 59) is 33.6 ml of 2,2-dimethoxy propane at 0*C, is added 0.05 ml of 60S perchloric acid. After 30 minutes at ambient temperature, the mixture is shaken with 50 ml of hexane.and 25 ml of saturated sodium bicarbonate solution.

The hexane phase ic eeparated, dried with magnesium sulfate, and evaporated to give 19.0 g of crude product. 107 EXAMPLE 61 Preparation of d,l-£jvthra-3,4-isopropylidenedioxy-l-octyne A mixture of 19.0 g (75.0 mmol.) of crude d,l-erythro-3,4-isopropylidenedioxy-l-trlmethylsilyl-l-octyne (Example 60) with 95 ml of methanol and 3.0 g of potassium carbonate is refluxed for one hour. The mixture is cooled and evaporated at 50° C (13 mm), taken up in 250 ml of benzene, and washed with 100 ml of water. The water is saturated with salt, the organic phase separated, dried with magnesium sulfate, and evaporated to give 12 g of crude product. Fractional distillation yields 7.0 g of the subject com10 pound as a colorless oil, bp 103°-106°C (13 mm).

IR: neat; 3300 sharp (H-C=C), 2100, (C=C), 780 (erythro configuration) cm1 nmr: fiCDClj TMS ; 4.75 (dd., 1, Cic-CH-CH, J=2Hz, J=5Hz), 4.10 (m, 1, (SC-CH-CH-CH2, 2.5 (d, 1, H-C C-CH), 1.9-1.2 (m, 14, alkyl), .90 (m, 3H, CH2CHj).

EXAMPLE 62 Preparation of d,l-erythro-l-iodo-3,4-isopropylidenedioxy -trans-l-octene To a stirred 0°C slurry of 0.852 g (.023 mol.) of sodium borohy20 dride and 4.21 g (.060 mol.) of 2-methyl-2-butene in 40 ml of dry tetrahydrofuran, under an argon atmosphere, is added dropwise 4.26 g ( .030 mol.) of boron trifluoride etherate complex. A solution of 2.73 g (.015 mol.) of d,1-erythro-3,4-isopropylidenedioxy-1-octyne (Example 61) in 5 ml of tetrahydrofuran is added dropwise, the ice bath removed, and the mixture allowed to stir at ambient temperature for two hours. It is then cooled again to 0°C, and 2.88 g (.105 mol.) of dry trimethylamine oxide is added in portions over 30 minutes. After stirring 3 hours at room temperature, this mixture is poured simultaneously with a 0°C solution of 108 2.13 g of iodine in S3 ml of tetrahydrofuran into 765 ail of a 0°c 15% solution of BOdium hydroxide in water and the whole stirred vigorously at 0°C for 45 minutes. The organic phase is separated, the agueous phase is extracted twice with ether, the combined organic phases are washed with a 5ft solution ©f sodium thiosulfate, dried with magnesium sulfate, and evaporated. The crude product is chromatographed on a 2 by 40,r dry column of silica gel, be eluting with chloroform, to yield 1.2 g (25¾) of a yellow oil. 11 -1 IR: neat; 1599 sharp, 945 (C=C) , cm Α1 1! EXAMPLE 63 Preparation of d,1-erythro-3-tetrahydropyranyloxy-4-acetyloxy° -1-trimethylsilyl-l-octyne A solution of 3.0 g (13.2 mmol.) of d,I-erythro-3° -tetrahydropyranyloxy-4-hydroxy-1-trimethylsilyl-l-octyne is heated at 100°C for 15 hours with 3 ml οί acetic anhydride and 10 ml of pyridien. The mixture is evaporated to dryness, dissolved in ether, washed with sodium bicarbonate solution and water. The organic phase is dried over magnesium sulfate and evaporated to give 2.5 g of the subject compound as an Oil IR: neat; 2200 (C C) , 1730 (C=0), 830, 760 [(ClIjIjSi] , cm1.

EXAMPLE 6fr Preparation of d,1-erythro-3-hydroxy°4-acetyloxy-l-trimethy1silyl-l-octyne In the manner of Example 59, 2.5 g (7.4 mmol.) of d,1-erythro-3-tetra)iydropyronyloxy°4-aeetyloxy°l°trlmethylsll° yl-l-octyne (Example S3, in a solution of ethanol, acetic acid, and water is heated at 100°C for 3 hours. After workup, the crude product io chromatographed on a 7/§° s 22° dry column of silica gel, and eluted with chloroform to give 1.0 g of a yellow oil.

IR; neat; 3500 (OH), 1730 (e°Si, esf1. 109 8 2 0 7 EXAMPLE 65 Preparation of d,l-erythro-3-paratoluenesulfonyloxy-4-acetyloxy-l-trimethylsilyl-i-octyne To a solution of 7.S g (41.0 mmol.) of d,1-erythro-3-hydroxy-4acetyloxy-l-trimethylsilyl-l-octyne (Example 64) in 41 ml of dry pyridine is added 11.0 g (58 mmol.) of para-toluenesulfonyl chloride and the resulting solution is stirred at 25°C for IS hours. The mixture is then warmed at 40°C for one hour, and after cooling, partitioned between 500 ml of diethyl ether and 100 ml of 1.0 N hydrochloric acid. The organic phase is washed three times with 100 ml of 1.0 N hydrochloric acid, once with dilute sodium bicarbonate solution, dried over magnesium sulfate, and evaporated under reduced pressure to give an oil. The crude product is purified on a 2 x 24 dry column of silica gel, and eluted with chloroform to yield a yellow oil.

IR: neat, 1730 (C=0), 1595 (aromatic) cm \ EXAMPLE 66 Preparation of d,l-threo-3-hydroxy-4-acetyloxy-l-trimethylsilyl-l-octyne A mixture of 15.5 g (39.0 mmol.) of d,l-erythro-3-para-toluenesulfonyloxy-4-acetyloxy-l-trimethylsilyl-l-octyne (Example 65), 5.0 g of calcium carbonate, 25 ml of water and 250 ml of tetrahydrofuran is refluxed with stirring for 4 days. The mixture is cooled, 100 ml of water added and the organic phase separated. The aqueous phase is extracted with ether, the combined organic phases dried with magnesium sulfate, and evaporated. The crude product is chromatographed on a 3 x 30 dry column of silica gel, and eluted with chloroform to give 7.0 g of an oil.

IR: neat; 3500, (OH), cm EXAMPLE 67 Preparation of d,l-threo-3,4-dihydroxy-l-octyne A solution of 7.0 g (28 mmol.) of d,l-threo-3-hydroxy-4-acetyloxy30 1-trimethylsilyl-l-octyne (Example 66) in 50 ml of methanol is stirred at 110 4 8 20 room temperature for 24 hours with a solution of 6.3 g (112 mmol.) of potassium hydroxide in 50 ml of water. The mixture is extracted twice with hexane, washed with 0.5M hydrochloric acid, brine, and dried with magnesium sulfate. After evaporation, the subject compound is obtained as a yellow oil. IR: neat, 2500 broad (2-OH), cm'1.

EXAMPLE 68 Preparation of d,l-threo-5,4-isopropylidenedioxy-l-oetyne In the manner of Example 60, treatment of a solution of d,l-threo3,4-dihydroxy-l-octyne (Example 67) in dimethoxypropane with 60% perchloric acid, and fractional distillation (12 mm) is productive of the subject compound as a colorless oil, containing 15% of d,l-erythro-3,4-isopropylidenedioxy-l-octyne (Example 60), as an impurity.

IR: neat; 810 (threo configuration), nmr: δ CDCl^ TMS ; 4.2 (dd, 1, -C=C-CH-, J's - 2Hz, 6Hz), 4.1-3.9 (m, 1, -C=C-CH-CH-CH2-), 2.5 (d, 1, H-C^C-, J = 2HZ), 1.9-1.2 (m, 14, alkyl), .90 (m, 3H, C^-CHg).

EXAMPLE 69 Preparation of d,1-threo-1-iodo-3,4-isopropylidenedioxy-trans20 -1-octene In the manner of Example 62, d,l-threo-3,4-isopropylidenedioxytrans-l-octyne (Example 68) is treated successively with disiamylborane, trimethylamine oxide, iodine, and sodium hydroxide to give the subject compound.

EXAMPLE 70 Preparation of d,I-erythro-3-tetrahydropyranyloxy-4-hydroxy-1-octyne Alkaline hydrolysis of d,l-erythro-3-tetrahydropyranyloxy-4-hydroxy-l-trimethylsilyl-l-octyne (Example 58) by the procedure of Example 61 is productive of the subject compound.

Ill 48207 EXAMPLE 71 Preparation of d,l-erythro-3-tetrahydropyranyloxy-4-iiiethoxy-1-octyne To a stirred slurry of 6.0 g (150 mmol.) of a 60% oil dispersion of sodium hydride and 96 g of iodomethane, under an argon atmosphere, is added 700 ml of dry tetrahydrofuran. The stirred mixture is cooled to -20°C and a solution of 30 g (133 mmol.) of d,1-erythro-3-tetrahydropyranyloxy-4-hydroxy1-octyne (Example 70), is added dropwise, followed by 0.1 ml of methanol.

The mixture is stirred at ambient temperature for 24 hours, 10 ml of methanol is added, and evaporated. The residue is taken up in ether, washed 3 times with water, dried over magnesium sulfate, and evaporated. The crude product is purified by fractional distillation to yield 16.3 g of a colorless oil, bp 137°-140°C (12 mm).

EXAMPLE 72 Preparation of d,1-erythro-3-tetrahydropyranyloxy-4-methoxy-1-iodo-trans-l-octen In the manner of Example 62, 1.20 g (5.0 mmol.) of d,1-erythro-3tetrahydropyranyloxy-4-methoxy-l-octyne (Example 71) is treated sucessively with disiamylborane, trimethylamine oxide, iodine, and sodium hydroxide.

Chromatography on a 2 x 36 dry column of silica gel and elution with chloroform is productive of 0.80 g (40%) of the subject compound as an oil. nmr: d CDClj TMS ; 7.9-6.1 (m,2, HC=CH), 4.9-4.6 (2m, 2, c=C-CH, O-CH-O), 4.3-4.0 (m, 1, c=c-CH-CH-CH2), 3.9-3.0 (m, 6, CH2-°-CH, OCHj), 1.8-1.2 (m, 12H, alkyl), 0.9 (m, 3, -¾).

EXAMPLE 73 Preparation of d,1-erythro-3-hydToxy-4-methoxy-1-iodo-trans-1-octene A solution of 3.10 g (8.24 mmol.) of d, 1-erythro-3-tetrahydro» - 112 48207 pyranyloxy-4-methoxy-1-iodo-trans-1-octene (Example 72) in 60 ml of acetic acid, 30 ml of tetrahydrofuran, and 15 ml of water is stirred at ambient temperature for 18 hours. It is then evaporated at 70°C under high vacuum (1.0 mm), and three times with 40 ml of toluene to give the crude product as an oil.

EXAMPLE 74 Preparation of d,l-erythro-3-trimethylsilyloxy-4-methoxy-l-iodo-trans-1-octene To a stirred solution of 3.0 g (10.2 mmol.) of d,1-erythro-3-hy10 droxy-4-methoxy-1-iodo-trans-1-octene (Example 73) in 11.0 ml of dry dimethyl formamide and 1.90 g (28.0 mmol.) of imidazole cooled to 0°C is added, dropwise, 1.35 g (12.5 mmol.) of trimethylsilyl chloride. The reaction mixture is stirred a further 4 hours at room temperature. It is then poured into a mixture of 100 ml of hexane and 25 ml of water, the organic phase is separated, washed twice with water once with a solution of saturated sodium chloride dried over magnesium sulfate, and evaporated. The crude product is purified by fractional distillation to yield 2.0 g of a colorless oil, bp 82°-83°C (0.3 mm). jj IR: neat; 1602 sharp (C=C) , 840, 750 broad [CHjjjSi-], cm \ H EXAMPLE 75 Preparation of d,l-erythro-l-iodo-3,4-dihydroxy-trans-1-octene A solution of 1.40 g (4.50 mmol.) of d,l-erythro-l- 113 48207 iodo-3,4-i5opropylidenedioxy-trans-1-octene (Example 62) in 30 ml of acetic acid, 10 ml of tetrahydrofuran and 10 ml of water is stirred and heated at SO°C for five hours. It is then evaporated at 40°C under high vacuum (1.0 mm), and twice more with 50 ml of benzene. Crystallization from 10 ml of chloroform at 0°C is productive of 700 mg of the white crystalline subject product.

EXAMPLE 76 Preparation of d,1-erythro-l-iodo-3,4-bis-trimethylsilyloxytrans-1-octene To a stirred solution of 700 mg (2.40 mmol) of d, 1-erythro-1iodo-3,4-dihydroxy-trans-1-octene (Example 75) and 800 mg (12.0 mmol) of · imidazole, in 10 ml of dry dimethylformamide at 0°C is added dropwise 1.20 g (11.0 mmol) of trimethylchlorosilane. The ice bath is removed, and the mixture is stirred and heated at 50°C for five hours. It is then cooled, shaken with 50 ml of hexane and 50 ml of water, the organic layer separated and washed with 15 ml of O'.SM hydrochloric acid, 15 ml of a saturated solution of sodium bicarbonate, dried with magnesium sulfate, and evaporated. This crude product is fractionally distilled, bp 90°-92°C (0.40 mm) to yield 250 mg of a colorless oil.

EXAMPLE 77 Preparation of d,1-erythro-3-trimethylsilyloxy-4-ethoxy-liodo-trans-1-octene ' Following the procedure of Example 71, ethylation using iodoethane of d,1-erythro-3-tetrahydropyranyloxy-4-hydroxy-l-octyne for a period of 22 hours is productive of the corresponding d,1-erythro-3-tetrahydropyranyloxy-4-ethoxy-l-octyne. This intermediate is converted to d,1-erythro-3tetrahydropyran yloxy-4-ethoxy-1-iodo-trans-1-octene when treated successively with disiamylborane, trimethylamine oxide 114 4 8 2(17 iodine, and sodium hydroxide solution after the procedure of Example 72.

Acid hydrolysis by the method of Example 18 to d,l-erythro-3-hydroxy-4ethoxy-1-iodo-trans-1-octene, followed by treatment with chlorotrimethylsilane and imidazole in dimethylformamide using the procedure of Example 74, and subsequent distillation, is productive of the subject compound.

EXAMPLES 78-82 By the method of Example 58 reaction of l-trimethylsilyl-3-tetrahydropyranyloxy-l-propyne with n-butyllithium and subsequent treatment with the aldehydes listed in Table 7, below, provides the d,1-erythro-1-trimethyl10 silyl-3-tetrahydropyranyloxy-4-hydroxy-l-alkynes of the table. - 115 48207 TABLE 7 116 8207 EXAMPLES 83-87 Hydrolysis of the 3-tetrahydropyranyloxy group of the d,l-erythrol-trimethylsilyl-3-tetrahydropyranyloxy-4-hydroxy-l-alkynes listed in Table 8 below by the method described in Example 59, followed by conversion of the resulting d,1-erythro-l-trimethylsilyl-3,4-dihydroxy-1-alkyne to the corresponding d, 1 -erythro-1-trimethylsilyl-3,4-isopropylidenedioxy-1-alkyne by treatment with dimethoxypropane in the presence of perchloric acid by the method described in Example 60 followed by desilylation to the corresponding d,1-erythro-3,4-isopropylidenedioxy-1-alkyne by the procedure of Example 61 followed by treatment with disiamylborane, trimethylamine oxide, iodine, and sodium hydroxide solution by the method described in Example 62 provides the product d,l-erythro-l-iodo-3,4-isopropylidenedioxy-trans-l-alkenes of Table 8, below. 117 48207 TABLE 118 8 2 0 7 EXAMPLES 88-92 Acetylation of the 4-hydroxy group of the d,l-erythro-l-trimethylsilyl-3-tetrahydropyranyloxy-4-hydroxy-l-alkynes listed in Table 9 below by the method described in Example 63, followed by hydrolysis of the resulting d,1-erythro-l-trimethylsilyl-3-tetrahydropyranyloxy-4-acetyloxy-l-alkynes to the corresponding d,1-erythro-1-trimethylsily1-3-hydroxy-4-acetyloxy-1alkynes by the method of Example 65, followed by epimerization to d,l-threol-trimethylsilyl-3-hydroxy-4-acetyloxy-l-alkynes by the method of Example 66 followed by hydrolysis by the method of Example 67 to give d,l-threo-3,4-di10 hydroxy-1-alkynes are converted to the corresponding d,l-threo-3,4-isopropyl idenedioxy-1-alkynes by treatment with dimethoxypropane in the presence of perchloric acid by the method described in Example 68 followed by treatment with disiamylborane, trimethylamine oxide, iodine, and sodium hydroxide solu tion by the method described in Example 62 provides the product d,l-threo-3, 4-isopropylidenedioxy-trans-1-alkenes of Table 9 below. - 119 48207 TABLE 9 120 8 2 0 7 EXAMPLE 93 Preparation of l-octyn-4-ol A suspension of 24.3 g (1.0 mole) of magnesium in ml of dry ether is stirred at room temperature under nitrogen with 100 mg of mercuric chloride. The reaction is initi5 ated by the addition of 2 ml of propargyl bromide and maintained by the dropwise addition of a solution of 119.5 g (1.0 mole) of propargyl bromide and 107,7 g (1.25 mole) of valenaldehyde in 3C0 ml of dry ether. While the initial reaction is quite vigorous and is maintained at 30’C only by cooling m an ice bath it may become necessary to heat the mixture to reflux temperature after about a third of the ether solution is added in order to maintain the reaction. After the addition is complete the reaction mixture is refluxed until most of the magnesium is dissolved (several hours) and the reaction mixture is decanted from excess magnesium into 1530 ml of stirred ice-cold ammonium chloride solution. The ether layer is separated and the aqueous layer is extracted three times with 300 ml portions of ether. The Combined ether extract is washed with saturated sodium chloride solution, dried over magnesium sulfate and filtered. Evaporation of the ether under vacuum leaves about 115 g of yellow oil, which .is distilled through a 15 cm Vigreaux column at 18 mm. The freetion boiling at 81°-82°C is collected (36 g) and the higher-boiling and lower-boiling.distillates may be redistilled to yield additional product. The infrared absorption spectrum shows at most a trace of allene'(5.1 u) and gas-liquid partition chromatography shows a purity of about 981 for the main fraction.

EXAMPLES 94-97 fhe product l-alkyn-4-ols of Table 10 below are prepared by treatment of the aldehydes listed in Table 10 with 121. - 48207 propargyl magnesium bromide by the procedure described above in Example 93.

'TABLE 10 Example Starting Aldehyde Product l-alkyn-4-ol 94 n-hexaldehyde l-nonyn-4-ol 95 n-heptaldehyde l-decyn-4-ol 96 n-butyraldehyde l-heptyn-4-ol 97 3-cis-hexenaldehyde* 4-hydroxy-6-cis- -ene-l-nonyne •M. Winter, Helv. Chim. Acta, 4 6, 1792 (1963).

EXAMPLE 98 Preparation of 4-triphenylmethoxy-l-octyne A mixture of 10 g (0.08 moles) of 4-hydroxy-l-octyne (1. Crombie and A. G. Jacklin, J. Chem. Soc., 1632 (1957), also Example 93] and 30.75 g (0.09 moles) of triphenylmethyl bromide in 85 ml of dry pyridine is heated on the steam bath for 2 hours. The cooled mixture is treated with water and extracted with ether. The extract is washed successively witl ice cold 21 hydrochloric acid, saturated sodium chloride solution, dried with magnesium sulfate, and taken to dryness. Col umn chromatography of the residue on Florisil affords an oil; λ max 3.01, 4.72 (acetylenic hydrogen), 6.28, 9.65 and 14.25y (triphenylmethoxy group).

EXAMPLE 99 Preparation of 4-triphcnylmethoxy-l-hexyne A stirred solution of 9.81 g (0.10 moles) of 4-hydroxy-l-hexyne and 33.5 g (0.12 moles) of triphenylmethyl chloride in 100 ml of dry pyridine is heated at reflux for 2 hours. The cooled mixture is treated with water and extracted with a hexane-ether mixture. The extract ia washed successively with water and saturated sodium chloride solution, 122 « 48207 dried over magnesium sulfate, and concentrated. Column chro matography of the residue on Florisil gives an oil, max. 3290 (acetylenic hydrogen), 1600, 1030 and 705 cm-1 (triphen ylmethoxy group) . EXAMPLES 100-106 5 The triphenylmethoxy substituted 1-alkynes listed in Table 11 below are prepared by the method of Example 98 from triphenylmethyl bromide and the corresponding hydroxy substituted 1-alkynes, appropriate literature references to which are provided in the table. 123. “» 48207 TABLE 11 124 8 2 Ο 7 References : 1. G. Fontaine, et al., Bull. Soc. Chem. France, 1447 (1963). 2. S. Abe and K. Sato,-Bull. Soc. Chem. Japan, 29 , 88 (1956); Chem. Abstr., 50, 13737 (1956). 3. L. Crombie and A. G. Jacklin, J. Chem. Soc., 1622 (1957), 4. Nobuharra, Akio, Chem. Abstr., 70, 3219 (1969).

EXAMPLE 107 Preparation of 1-iodo-4-triphenylmethoxy-trans-1-octene To a stirred suspension of 1.78 g (0.074 mole) of sodium borohydride in 200 ml of dry glyme at -5°C under nitrogen is added 15.8 g (0.22 mole) of 2-methyl-2-butene and 16.2 g (0.11 mole) of boron trifluoride etherate, and the mixture is stirred for 2 hours at -5°C to O’C. A solution of 37,5 g (0.10 mole) of 4-trityloxy-l-octyne (Example 98) in 50 ml of glyme is added to the cold solution during 5-10 minutes, and the solution is allowed to warm to 20°c during 1.5 hours. The reaction.mixture is cooled to O’C and 30 g (0.4 mole) of dry trimethylamine-N-oxide is added during 5 minutes. Cn removing the cooling bath the temperature rises to 40°C and the mixture is kept between 30°-40°C for 1.5 hours. The suspension is poured rapidly into one liter of ice cold 15% sodium hydroxide solution during good stirring and a solution of 80 g cf iodine in 200 ml of tetrahydrofuran is added immediately. Stirring is continued for 30 minutes without further cooling and the organic layer is separated. The aqueous layer is extracted with three 200 ml protions of ether and the combined organic layers are washed successively with water, 5% godium thiosulfate solution and saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to yield 50 g of yellow oil. The bulk of the oil is dissolved in hexane and, after decantation from a gummy solid the hexane solution is percolated through a 5.1 cm diameter column of 1500 g of alumina with additional hexane. Fractions containing th® 125 - 48207 desired product are concentrated to a pale yellow oil (33 g) which has n.m.r. and infrared spectra characteristics of the desired product.

EXAMPLES 108-114 Treatment of the triphenylmethoxy substituted 1-alkynes listed in Table 12 below with disiamylborane, prepared in situ from 2-methyX-2-butene, boron, trifluoride and sodium borohydride, followed by trimethylamine Noxide, and then sodium hydroxide and iodine - all by the procedure described in Example 107 above furnishes the product triphenylmethoxy substituted 1iodo-l-trans-alkenes of the table.

TABLE 12 Example Starting Triphenylmethoxy Substituted 1-Alkyne of Exanple Product 1-iodo-tri- phenylmethoxysubsti- tuted-l-trans-alkene 108 99 l-iodo-4-triphenylmethoxy-1-transhexene 109 100 l-iodo-4-triphenyl- methoxy-l-trans- pentene 110 101 l-iodo-4-triphenylmethoxy-1-transheptene 111 102 l-iodo-4-triphenylmethoxy-4-methyl-1trans-hexene 112 103 l-iodo-4-triphenylmethoxy-1-transnonene 113 104 1-iodo-4-triphenylmethoxy-1-transdecene 114 106 l-iodo-4-triphenyl- methoxy-l-trans-6- cis-nonadiene - 126 48207 EXAMPLES 115-I24a The starting aldehydes or ketones of Table 13 below are converted to the product l-alkyn-4-ols of the table by the procedure described in Example S3. 127. 4820? TABLE 13 ΙΛ φ to ΓΜ Ρ μ ω X) < Φ Λ U ΓΙΛ (Ν • «η t·*- Φ t-. μ Tf rt (Ν μ W γΛό \Ο Φ σ> μ ι—I Ι·ιΜ β *=> Η * Λ JZ OT • Η 6 ώ «Η ZC JZ “χ υ · &α *ϋ § ~ Μ Η Φ μ ο μ · W μ Ο C£ 128 EXAMPLE 125 Preparation of 4-methyl-4-trimethylsilyloxy-l-octyne To a stirred solution of 75.4 g (0.537 moles) of 4-hydroxy-4methyl-l-octyne (Example 122), 104.9 g (1.54 moles) of imidazole, and 325 ml of dimethylformamide is added 65.2 g (0.60 moles) of chlorotrimethylsilane. After standing overnight the mixture is poured into 800 ml of hexane. The mixture is washed thoroughly with water followed by sodium bicarbonate solution and brine. The solution is dried over magnesium sulfate, filtered, and evaporated to give a liquid, p.m.r. spectrum, δ 1.26 (singlet, 3, CH_), 1.92 (triplet, 1, HC), 2.30 (doublet, 2, CH2).

EXAMPLES 126-129a The l-alkyn-4-ols of Table 14 are converted to the product trimethylsilyl ethers of the table by treatment with chlorotrimethylsilane according to the procedure described in Example 125. 129 48307 TABLE 14 130 EXAMPLE 130 Preparation of l-iodo-4-hydroxy-4-methyl-trans-l-octene To a stirred solution of 400 ml of 0.5 M bis-(3-methyl-2-butyl)borane in glyme, prepared from sodium borohydride, 2-methyl-2-butene, and boronitrifluoride etherate as in Example 107, is added 63.7 g (0.30 moles) of 4-methyl-4-trimethylsilyloxy-l-octyne (Example 125) at -10°C. The solution is stirred at ambient temperature for 2.5 hours, cooled to -10°C, and treated during 30 minutes with 158 g (2.1 moles) of solid trimethylamine oxide with cooling. The mixture is stirred at ambient temperature for 2 hours and then poured into a stirred, ice-cold solution of 15% aqueous sodium hydroxide; the stirred mixture is treated immediately with a solution of 426 g (1.68 moles) of iodine in 1100 ml of tetrahydrofuran. After 4 hours the mixture is extracted with ether. The extract is washed successively with water, aqueous sodium thiosulfate, and brine and dried over magnesium sulfate. The extract is concentrated, and the residue is subjected to chromatography on silica gel with hexane to provide an oil, p.m.r. (CDClj): δ 1.18 (singlet, 4-CH. group).

EXAMPLES 131-134a The 4-trimethylsilyloxy-l-alkynes of Table 15 are converted to the 4-hydroxy-1-iodo-trans-1-octenes of the table by the procedure described in Example 130. 131 TABLE 15 Example Starting 4-Trimethylsilyioxy1-octyne of Example Product 4-Hydroxy-l-iodotrans-l-octene 131 126 l-iodo-5,5-dimethyl-4-hydroxy-trans-1-nonene 132 127 l-iodo-4-methyl-4-hydroxy- trans-l-nonene 133 128 l-iodo-5,5-dimethyl-4-hydroxy- trans-l-oct ene 134 129 l-iodo-4-methyl-4-hydroxytrans,trans-1,5-octadiene 134a 129a l-iodo-4-methyl-4-hydroxy- trans-l-decene EXAMPLE 135 Preparation of l-iodo-4-n)ethyl-4-trimethylsilyloxy-trans-l-octene To a stirred mixture of 24.5 g (55.6 mmoles) of l-iodo-4-hydroxy4-methyl-trans-l-octene (Example 130), 13.6 g (200 mmoles) of imidazole, and 75 ml of dimethylformamide is added 10.9 g (100 mmoles) of chlorotrimethylsilane. After standing overnight the mixture is poured into 250 ml of hexane. The mixture is washed thoroughly with water followed by brine and dried over magnesium sulfate. After removal of the solvent, the product is distilled to give a colorless liquid, bp 67.5°-68°C (0.07 mm).

EXAMPLES 136-139b The l-iodo-4-hydroxy-trans-l-alkenes of Table 16 are converted to the product trimethylsilyl ethers of the table according to the procedure described in Example 135. 132 4 8 2 (J 7 TABLE 16 Example Starting l-lodo-4hydroxy-trans-1alkene of Example Product Trimethylsilyl Ether 136 131 l-iodo-5,5-dimethyl-4trimethylsilyloxytrans -nonene 137 132 l-iodo-4-methyl-4-trimethylsilyloxy-trans-1nonene 138 133 l-iodo-5,5-dimethyl-4trimethylsilyloxytrans-1-octene 139 134 l-iodo-4-methyl-4-trimethylsilyloxy-trans,trans-1,5-octadiene 139a 134a l-iodo-4-methyl-4-trimethylsilyloxy-trans-1decene 139b 134b l-iodo-4-methyl-4-trimethyl silyloxy-trans-1decene EXAMPLE 140 Preparation of 4-benzoyloxy-l-octyne To a stirred solution of 63. g (0.50 moles) of l-octyn-4-ol (Example 93) in 500 ml of pyridine is added 77 g (0.55 moles) of benzoyl chloride. After stirring for 1.5 hours the mixture is treated with 10 ml of water, allowed to stand for 15 minutes, and concentrated. A solution of the residue in ether is washed successively with ice-cold hydrochloric acid, water, sodium bicarbonate solution, and brine. The solution is dried over magnesium sulfate, filtered through Celite, and concentrated to give an oil, λ max. 3240 (terminal acetylene) and 1730 cm 1 (benzyloxy group). 133 48207 EXAMPLE 141 Stereoselective Hydrolysis of Racemic 4-benzoyloxy-l-octyne by Rhizopus arrhizus An agar slant of R. arrhizus (MUMF 1638) is used to inoculate 7 shake flasks (250 ml Erlenmeyer). Each flask contains 50 ml of a medium consisting of 2% Edamine, 2% glucose, and 0,72% com steep liquor in water with pH adjusted to 7.0. A total of 14 such flasks are incubated on a rotary shaker at 28°C. After 72 hours incubation, 50 mg of racemic 4-benzoyloxy-loctyne (Example 135) in 0.1 ml of acetone is added to each flask. After 28 hours the flasks are harvested and worked up by extraction of the whole mash with an equal volume of chloroform. The combined extracts are dried over magnesium sulfate and concentrated. The resulting oil is chromatographed on a column of silica gel with hexane progressively enriched in ethyl acetate.

From fractions 3-6 is obtained 150 mg of colorless oil, identical to 4-benzoyloxy-l-octyne, [a]23 = 5 +_ 1.0° (C=0.91, ethyl acetate). This compound has the (S)-configuration.

From fractions 13-20 is obtained 75 mg of colorless oil, identical to 4-hydroxy-l-octyne, [a]2S= -17 +. 1.0° (C=0.77, ethyl acetate). This compound has the (R)-configuration.

The strain of R. arrhizus utilized in this experiment is a higher fungus which grows steadily on a variety of artificial media at 20°-25°C. In this study of the taxonomic aspects of the culture, Petri dishes of potatodextrose, malt extract, and cornmeal agars were inoculated and incubated at ambient room temperature for 10 days. Observations of cultural and morphological characteristics are recorded in the description below: - 134 48207 Colonies on Petri dishes of potato-dextrose agar growing rapidly, covering the agar surface in 3-5 days and producing a thick, loose mat of grayish mycelium. Colony surface characterized by abundant black sporangia. Colony reverse grayish white. Colonies on malt extract agar growing rapidly, covering the agar surface in 3-5 days. Mycelial mat thick, grayish-yellow. Colony surface becoming brownish-black from masses of sporangia. Colony reverse yellowish. Colonies on cornmeal agar very thin, whitish; spreading across agar surface. Cultures transparent with relatively few sporangia produced. Visibility of micromorphology is good on this media. Rhizoids produced sparingly along stoloniferous hyphae. Generally two to three sporangiophores arose from rhizoids. Walls of sporongiophores olive brown, 14.ΟΣΟ.0 um in width at base, tapering slightly to apex; 0.5-1.5 mm in length Sporangiophores terminated by spherical sporangia, 130-225 pm in diameter. Columellae hemispherical, 3-50 pm high by 50-70 pm wide. Spores brownish when mature, 6.0-8.5 pm x 4.5-6.0 pm. Spore walls conspicuously marked by longitudinal striations.

EXAMPLE 142 Preparation of (S)-4-hydroxy-l-octyne A solution of 1.15 g (5.0 mmoles) of (S)-4-benzoyloxy-l-octyne (Ex20 ample 141) and 1.40 g (25 mmoles) of potassium hydroxide in 50 ml of 10:1 methanol-water is allowed to stand at room temperature for 24 hours. The bulk of the methanol is evaporated at room temperature, and the mixture is extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and evaporated to give a colorless oil, identical to 4-hydroxy-l->5 0 octyne [a] = +17 +_ 1.0 (C=0.77, ethyl acetate). This compound has the (S)-configuration. 135 EXAMPLES 143-148a The starting l-alkyn-4-ols of Table 17 below are converted to the triphenylmethoxy substituted 1-alkynes by the method of Example 98.

TABLE 17 Example Starting 1-Alkyn4-ol of Example Product Triphenylmethoxy Substituted 1-Alkyne 143 116 4-triphenylmethoxy-5- trans-nonen-l-yne 144 120 5-methyl-4-triphenylmethoxy-X-octyne 145 121 5-methy1-4-triphenylmethoxy-1-nonyne 146 . 124 4-triphenylmethoxy-5trans-octen-l-yne 147 141 (R)-4-triphenylmethoxy-l-octyne 148 142 (S)-4-triphenylmethoxy-l-octyne 148a 124a 4-triphenylmethoxy-Strans-decen-1-yne EXAMPLES 149-154A The product triphenylmethoxy substituted 1-iodo-l-trans-alkenes of Table 18 below are prepared from the starting triphenylmethoxy substituted 1alkynes of the table by the procedure described in Example 107. 137 Example 15 4B Preparation of 4-Trimethylsiloxy-l-octyne To a cold solution of 166g of 4-hydroxy-l-octyne [Prostaglandins, 10., 289 (1975)], and 240g of imidazole in one liter of dimethylformamide is added dropwise 202 g of chlorotrimethylsilane. The mixture is allowed to stand at room temperature for 2 to 3 days. The mixture is partitioned with water and hexane. The hexane layer is washed with brine, aried over magnesium sulfate, and concentrated. Distillation of the residue gives a colorless liquid, b.p. 38® (0.2mm).

Example 154C Preparation of l-Iodo-4-trimethylsiloxy-trans-l-octene To a stirred solution of 0.20 moles of freshly prepared bis-(3-methyl-2-butyl) borane in 300 ml of tetrahydrofuran at 0®-5®C is added dropwise a solution of 19.8g of 4-trimethylsiloxy-l-octyne in 30 ml of tetrahydrofuran. The resulting mixture is stirred at ambient temperature for several hours, cooled in an ice bath, and treated with 53g of trimethylamine oxide. The mixture is stirred several hours at 25® -40®C and then poured into 2 liters of 15% sodium hydroxide. The resulting mixture is treated immediately with a solution of 140g of iodine in 300 ml of tetrahydrofuran After 0.5 hour the organic phase is separated and the aqueous gas is extracted with ether. The combined organic layers are washed with water, sodium thiosulfate solution, and brine; dired over magnesium sulfate; and concentrated to give an oil, pmr spectrum (CDCl^)« 6.2 (d, ICH·) and 6.7 (quintuplet, •CH-). 138 Example 154D-E Preparation of 4-Hydroxy°l-Iodo—trans-1-octene A 23g portion of l-iodo°4-trimethylsiloxy-trans-1octene is dissolved in a mixture of 200 ml of glacial acetic acid, 100 ml of tetrahydrofuran, and 50 ml of water.

After solution occurs, toluene is added and the mixture is evaporated. The resulting oil is chromatographed on silica gel with hexane progressively enriched in benzene followed by acetone to give 16g of an oil, pmr spectrum (CDC1 ): 3.69 (r. CHOH) and 2.3 (s, OH) .

Example 154F Preparation of 4-0xo-l-iodo-trans-1-octene To a stirred suspension of 6.15g of pyridinium chlorochromate (Tetrahedron Letters, 1975, 2647) in 20 ml -r methylene chloride is added 450 mg of sodium acetate.

After 5 minutes, a solution of 3.64 g of 4-hydroxy-l-iodo trans-l-octene in 15 ml of methylene chloride is added in one portion. The dark mixture is stirred at room temperature for 75 minutes, diluted with 50 ml of ether, and decanted. The solid sludge is washed repeatedly with ether and decanted.

The combined solutions are percolated through Florisil. The solution is concentrated to give an orange liquid, pmr spectrum (CDC13) : 3.20 (d,j“ 7cps, “ CHCH7CO).

Example 154G Preparation of 4-Hydroxy-4-(1-propynyl)-1-iodotrans -1-octene To a stirred solution of propynyllithium at =25° is added a solution of 4-oxo-l-lodo-trans-l-octene in tetra30 139 hydrofuran. After the addition, the solution is stirred at -20· to -15*C for 30 minutes. The reaction is quenched with a mixture of hexane and ice. The aqueous phase is separated and extracted with additional hexane. The combined hexane extracts are washed successively with water and brine. The solution is dried over magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel with toluene to provide the product as an oil.

Example 154H Preparation of 4-Hvdroxv-4(1-propynyl)-1-iodo-trans-l-decene Treatment of 4-hydroxy-l-decyne (U.S. Pat. 3,950,406) by the procedures of Examples 154B, 154C, 154D, 154F and 154G is productive of the iodo-decene compound.

Example 154I-154J Treatment of the iodoalkenes of Table 4 with chlorotrimethylsilane by the procedure of Example 210H Infra is productive of the trimethylsilylether of the Table.

Table 1BA Starting Product Silylether Example Iodo Alkene 1541 154G 4-trimethylsilyloxy-4(1-propynyl)-1-iodotrans-l-octene 154J 154H 4-trimethylsilyloxy-4(1-propynyl)-1-iodotrans-l-decene 140 EXAMPLE 155 Preparation of ethyl-£-fluorophenoxy-acetate To a stirred solution of 50 g (0.29 moles) of £-fluorophenoxy acetic acid in one liter of absolute ethanol is added 10 ml of sulfuric acid. The mixture is heated to reflux for 18 hours, cooled to room temperature, and evaporated under vacuum. It is then poured onto 300 g of ice, extracted twice with 500 ml of ether, washed twice with 250 ml of a saturated solution of sodium bicarbonate, 100 ml of saturated sodium chloride solution, dried with magnesium sulfate, filtered and evaporated under vacuum giving 58 g of an oil. This is crystallized from 50 ml of hexane at -25°C to give 55 g (90%) of the subject product as colorless crystals, mp 32°-33°C.

EXAMPLE 156 Preparation of £-fluorophenoxy acetaldehyde To a stirred solution of 1.98 g (10 mmoles) of ethy 1-ja-fluoro phenoxy acetate (Example 155) in 15 ml of dry toluene, cooled to -78°C, under argon, is added, dropwise over 30 minutes, 8 ml of a 1.4M solution of diisobutylaluminum hydride in toluene (11 moles). The mixture is stirred for 2 hours at -78°C, 1 ml of methanol is added, followed by 5 ml of water, dropwise. The gel formed is filtered through Celite and washed with 100 ml of ether, portionwise. The organic phase is separated, washed twice with 25 ml of a saturated brine solution, dried with magnesium sulfate, filtered, and evaporated. The oil obtained is distilled at 71°-73°C (0.1 mm) to give 600 mg (45%) of the subject product as a colorless liquid.

EXAMPLE 157 Preparation of 3-hydroxy-4-£-fluorophenoxy-l-butyne Acetylene gas, dried by passing through a trap containing sulfuric acid, is bubbled at a moderate rate, through 5 ml of vigorously stirred tetrahydrofuran, for 15 minutes. To this acetylenic solution, is then added drop141 4 82 0 7 wise, with continued passage of acetylene, 3.5 ml of a 2.4M solution of nbutylmagnesium chloride in tetrahydrofuran (8.4 mmoles) over 45 minutes. The mixture is stirred a further 15 minutes, and a solution of 580 mg (3.9 mmoles) of £-fluorophenoxy acetaldehyde (Example 156) in 3 ml of tetrahydrofuran is added dropwise over 15 minutes. This solution is stirred for 2 more hours, with passage of acetylene, poured into 50 ml of a saturated solution of ammonium chloride, extracted twice with 50 ml of ether, washed with 10 ml of ammonium chloride solution, dried with magnesium sulfate, filtered, and evaporated. The crude subject product is purified by sublimation at 75°C (0.1 mm) for 5 hours to give 330 mg (48%) of white crystals, mp 46°-47°C.

EXAMPLE 158 Preparation of 4-p-fluorophenoxy-3-trimethylsilyloxy-l-butyne To a 0°C solution of 10 g (55 mmoles) of 3-hydroxy-4-£-fluorophenoxy-l-butyne (Example 157) in 75 ml of dry dimethylformamide and 88 g (130 mmoles) of imidazole is added dropwise, with stirring, 7.5 g (68 mmoles) of chlorotrimethylsilane. The mixture, while under an argon atmosphere, is stirred at room temperature for 18 hours, and then poured into 150 ml of hexane and 100 ml of ice-water. The organic phase is separated, washed with 50 ml of a brine solution, dried with magnesium sulfate, and evaporated under vacuum. This crude product is distilled under vacuum at 0.1 mm (bp 73°7S°C), to give 12.2 g (91%) of the subject compound as a colorless oily liquid.

EXAMPLE 159 Preparation of l-tri-n-butylstannyl-4-£-£luorophenoxy-3trimethylsilyloxy-trans-l-butene A mixture of 2.52 g (10 mmoles) of 3-trimethylsilyloxy-4-j3-fluorophenoxy-l-butyne (Example 158), 2.91 g (10 mmoles) of tri-n-butyl-tin hydride, and 10 mg of azobisisobutyronitrile is heated, under an argon atmosphere, with stirring, for 2 hours at 140°C. After cooling to room tempera30 ture, the crude reaction mixture is fractionally distilled at 180°-185°C 142 4 8 2 0 7 0.05 ran), to give 4.6 g (85%) of the subject product as a colorless liquid.

EXAMPLES 160-162 The product esters of Table 19 below are obtained by the procedure described in Example 155.

TABLE 19 Example Starting Aryloxy Acid Product Aryloxy Ethyl Ester 160 m- chlorophenoxyacetic acid ethyl-m-chlorophenoxyacetate 161 3,4-dichlorophenoxyacetic acid ethyl-3,4-dichlorophenoxyacetate 162 phenoxyacetic acid ethyl phenoxyacetate EXAMPLE 165 Preparation of ethyl-m-trifluoromethylphenoxy-acetate A mixture of 100 g (.618 mole) of α,α,α-trifluoro-m-cresol, 106 g (.632 mole) of ethyl bromoacetate, 87.5 g (632 mole) of potassium carbonate, and 1500 ml of acetone is stirred at reflux for 4 hours, and at room temperature for 18 hours. The mixture is filtered, evaporated under vacuum on a rotatory evaporator at 45°C and at 85°C (0.1 mm) to remove excess ethyl bromoacetate. The reaction mixture is taken up in 500 ml of ether, washed three times with 100 ml each of 0.1M potassium carbonate, once with 100 ml of water, 100 ml of .01M hydrochloric acid, and 100 ml of water. It is then dried with magnesium sulfate, filtered and evaporated, giving 142 g of the crude product. This is fractionally distilled at 73°-75°C (0.1 mm) to give 124 g of the purified subject product as a colorless liquid.

EXAMPLES 164-166 The product esters of Table 20 are obtained by treating the starting phenols with ethyl bromoacetate by the procedure of Example 162. 143 4 8 2 0 7 TABLE 20 Product Ester Example Starting Phenol 164 p-bromophenol ethyl g-bromophenoxyacetate 165 4-t-butylphenol ethyl 4-t-butylphenoxyacetate 166 £- methoxyphenol ethyl g-methoxyphenoxy- acetic acid EXAMPLES 167-173 Following the procedure of Example 156, the starting esters of Table 21 are treated with diisobutylaluminum hydride to provide the product aldehydes of the table.

TABLE 21 Example Starting Ester Product Aldehyde 167 163 m-trifluoromethylphenoxy acetaldehyde 168 164 g-bromophenoxy acetaldehyde 169 165 4-_t-butylphenoxy acetaldehyde 170 166 g-methoxyphenoxy acetaldehyde 171 160 m-chlorophenoxy acetaldehyde 172 161 3,4-dichlorophenoxy acetaldehyde 173 162 phenoxyacetaldehyde EXAMPLES 174-180d Following the procedure of Example 156, treatment of the starting aldehyde of Table 22 with acetylene magnesium chloride provides the product alkynes of Table 22. 144 4 8 2 0 7 Example Starting Aldehyde 174 167 175 168 176 169 177 170 178 171 179 172 180 173 180a a 180b b 180c c 180d d Product Aryloxy Alkyne 3-hydroxy-4-m-trifluoromethylphenoxy-1-butyne 3-hydroxy-4-g-bromophenoxy-1butyne 3-hydroxy-4-t-butylphenoxy-lbutyne 3-hydroxy-4-g-methoxyphenoxy1-butyne 3-hydroxy-4-m-chlorophenoxy1-butyne 3-hydroxy-4-(3,4-dichlorophenoxy) 1-butyne 3-hydroxy-4-phenoxy-l-butyne 3-hydroxy-5-phenyl-l-pentyne 3-hydroxy-5-(g-chlorophenyl)1-pentyne 3-hydroxy-S-(g-methoxyphenyl)1-pentyne 3-hydroxy-S-(m-trifluoromethylphenyl)-1-pentyne a. hydrocinnamaldehyde^ b. g-chlorohydrocinnamaldehyde^ c. g-methoxyhydrocinnamaldehyde^ d. m-trifluroomethylhydrocinnamaldehyde 1) Billman, et al., Synthetic Communications, 1., 127-131 (1971). 2) Lednicer, Joum. Med. Chem., 11, 1258 (1968). 145 48207 EXAMPLES 180e-I86e Treatment of the starting alkynes of Table 23 by the procedure of Example 158 followed by treatment of the procedure of Example 159 provides the product (E) 1-tri-n-butyltin-l-alkenes of the table. - 146 4 8 2 0 7 TABLE 23 147 4820 TABLE 23 (continued) 148 e, 4 8 2 U ι EXAMPLE 187 Preparation of l-chIoro-l-octen-3-one This compound is prepared according to the procedure of Price and Pappalardo [C. C. Price and J. A. Pappalardo, Org. Syn, 32, 27 (1952)] from hexanoyl chloride, acetylene, and aluminum chloride in 94% yield, bp S1°-S2°C (0.1 mm); λ max 1680, 1595, 941 cm \ EXAMPLE 188 Preparation of l-iodo-l-octen-3-one A mixture of 25 g (0.16 moles) of l-chloro-l-octen-3-one (Example 10 187) and 35 g (0.23 moles) of sodium iodide in 200 ml of reagent acetone is stirred at the reflux temperature for 18 hours. The cooled mixture is filtered and the mother liquor taken to dryness. The residual oil is dissolved in benzene and the solution is washed with 5% sodium thiosulfate solution, saturated sodium chloride solution, dried and taken to dryness. The residual oil is crystallized from hexane to give 26 g of a white solid, mp 35°-37°C; λ max 1670, 950 cm \ EXAMPLE 189 Preparation of 3-hydroxy-l-iodo-3-methyl-1-octene To a Grignard solution prepared from 1.05 g (0.41 moles) of magne20 sium and 6.2 g (0.435 moles) of methyl iodide in 30 ml of dry ether under argon is added dropwise 10 g of 1-iodo-l-octen-3-one (Example 183) in 45 ml of ether. The resulting solution is stirred at ambient temperature for one hour. After the addition of 75 ml of saturated ammonium chloride the ether layer is separated and the aqueous layer is separated and the aqueous layer is extracted several times with ether. The combined ether extracts are washed successively with ammonium chloride and water, dried and taken to dryness to give 9.24 g of product as an oil; λ max 2.89, 3.23, 6.24 and 10.5.

EXAMPLE 190 Preparation of l-iodo-3-methyl-3-trimethylsilyloxy-l-octene 30 To a stirred solution of 11.7 g of 3-hydroxy-1-iodo-3-methyl-l- 149 48207 octene (Example 184) and 7.4 g of imidazole in 45 ml of dry dimethylformamide is added dropwise 5.98 g of trimethylsilylchloride at 0°C under argon atmosphere. After stirring at 0°C for an additional 15 minutes, the solution is stirred at ambient temperature· for 18 hours. The reaction mixture is poured into 600 ml of hexane and the resulting solution washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and taken to dryness to furnish 14.7 g of oil. Distillation affords 13.4 g of clear oil; bp 65°C (0.05 mm); λ max 6.21, 8.00, 9.90, 10.51, 11.90, 13.2y.

EXAMPLE 190a Preparation of l-iodo-3-methyl-3-trimethylsxlyloxy-l-decene Treatment of octanoylchloride by the procedures of Example 187 followed by treatment of the resulting l-chloro-l-decen-3-one by the procedure of Example 188 followed by treatment according to Examples 189 and 190 is productive of the named compound.

EXAMPLE 191 Preparation of 4-trimethylsiloxy-l-octyne To a cold solution of 166 g of 4-hydroxy-l-octyne [Prostaglandins, 10, 289 (1975)], and 240 g of imidazole in one liter of dimethylformamide is added dropwise 202 g of chlorotrimethylsilane. The mixture is allowed to stand at room temperature for 2 to 3 days. The mixture is partitioned with water and hexane. The hexane layer is washed with brine dried over magnesium sulfate, and concentrated. Distillation of the residue gives a colorless liquid, bp 38°C (0.2 mm).

EXAMPLE 192 Preparation of l-iodo-4-trimethylsiloxy-trans-1-octene To a stirred solution of 0.20 moles of freshly prepared bis-(3methyl-2-butyl)borane in 300 ml of tetrahydrofuran at 0°-5°C is added dropwise a solution of 19.8 g of 4-trimethylsiloxy-l-octyne in 30 ml of tetra30 hydrofuran. The resulting mixture is stirred at ambient temperature for - ISO 48207 several hours, cooled in an ice bath, and treated with 53 g of trimethylamine oxide. The mixture is stirred several hours at 25°-40°C and then poured into 2 liters of 15% sodium hydroxide. The resulting mixture is treated immediately with a solution of 140 g of iodine in 300 ml of tetrahydrofuran. After 0.5 hour the organic phase is separated and the aqueous phase is extracted with ether. The combined organic layers are washed with water, sodium thiosulfate solution, and brine; dried over magnesium sulfate; and concentrated to give an oil pmr spectrum (CDClj): 6.2 (d, ICH=) and 6,7 (quintuplet, =CH-).

EXAMPLE 193 Preparation of 4-hydroxy-l-iodo-trans-l-octene A 23 g portion of l-iodo-4-trimethylsilyloxy-l-octene is dissolved in a mixture of 200 ml of glacial acetic acid, 100 ml of tetrahydrofuran, and 50 ml of water. Concentration provides the named product.

EXAMPLE 194 Preparation of 4-trimethylsiloxy-4-vinyl-l-iodo-trans-l-octene To a stirred solution of 456 mg of 4-hydroxy-4-Vinyl-l-iodo-trans1-octene and 320 mg of imidazole in 1.0 m of dimethylformamide is added 0.23 ml of chlorotrimethylsilane during 3 minutes. The mixture is stirred at room temperature for 22 hours and partitioned with a mixture of cold hexane and water. The hexane layer is washed repeatedly with water and then brine, dried over magnesium sulfate, and concentrated to give an oil, pmr spectrum (CDClj): 0.13 (s, trimethylsiloxy group) and 2.32 (d, =CHCH2) .

EXAMPLE 195 Preparation of n-butyl cyclopropyl ketone To a vigorously-stirred solution of 31.0 g of cyclopropanecarboxylic acid in 330 ml of ether is added a solution of n-butyllithium (748 mmoles) in about 750 ml of 2:1 ether-hexane during one hour at 5°-10°C. The resulting suspension is diluted with 300 ml· of ether and stirred at room tempera30 ture for 2 hours and at reflux for 2 hours. The mixture is cooled and poured - 151 48207 octene (Example 184) and 7.4 g of imidazole in 45 ml of dry dimethyIformartide is added dropwise 5.98 g of trimethylsilylchioride at 0°C under argon atmosphere. After stirring at 0°C for an additional 15 minutes, the solution is stirred at ambient temperature for 18 hours. The reaction mixture is poured into 600 ml of hexane and the resulting solution washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and taken to dryness to furnish 14.7 g of Oil. Distillation affords 13.4 g of clear oil; bp 65°C (0.05 mm); λ max 6.21, 8.00, 9.90, 10.51, 11.90, 13.2μ.

EXAMPLE 190a Preparation of l-iodo-3-methyl-3-triaethylsilyloxy-l-decene Treatment of octanoylchloride by the procedures of Example 187 followed by treatment of the resulting l-chloro-l-decen-3-one by the procedure of Example 188 followed by treatment according to Examples 189 and 190 is productive of the named compound.

EXAMPLE 191 Preparation of 4-trimethylsiloxy-l-octyne To a cold solution of 166 g of 4-hydroxy-l-octyne [Prostaglandins, 10, 289 (1975)], and 240 g of imidazole in one liter of dimethylformamide is added dropwise 202 g of chlorotrimethylsilane. The mixture is allowed to stand at room temperature for 2 to 3 days. The mixture is partitioned with water and hexane. The hexane layer is washed with brine dried over magnesium sulfate, and concentrated. Distillation of the residue gives a colorless liquid, bp 38°C (0.2 mm).

EXAMPLE 192 Preparation of 1-iodo-4-trimethylsiloxy-trans-1-octene To a stirred solution of 0.20 moles of freshly prepared bis-(3methyl-2-butyl)borane in 300 ml of tetrahydrofuran at 0°-5°C is added dropwise a solution of 19.8 g of 4-trimethylsiloxy-l-octyne in 30 ml of tetra30 hydrofuran. The resulting mixture is stirred at ambient temperature for - 150 48207 several hours, cooled in an ice bath, and treated with 53 g of trimethylamine oxide. The mixture is stirred several hours at 25°-40°C and then poured into 2 liters of 15% sodium hydroxide. The resulting mixture is treated immediately with a solution of 140 g of iodine in 300 ml of tetrahydrofuran. After 0.5 hour the organic phase is separated and the aqueous phase is extracted with ether. The combined organic layers are washed with water, sodium thiosulfate solution, and brine; dried over magnesium sulfate; and concentrated to give an oil pmr spectrum (CDCl^): 6.2 (d, ICH=) and 6.7 (quintuplet, =CH-).

EXAMPLE 193 Preparation of 4-hydroxy-1-iodo-trans-l-octene A 23 g portion of l-iodo-4-trimethylsilyloxy-l-octene is dissolved in a mixture of 200 ml of glacial acetic acid, 100 ml of tetrahydrofuran, and 50 ml of water. Concentration provides the named product.

EXAMPLE 194 Preparation of 4-trimethyisiloxy-4-vinyl-l-iodo-trans-l-octene To a stirred solution of 456 mg of 4-hydroxy-4-vinyl-l-iodo-trans1-octene and 320 mg of imidazole in 1.0 m of dimethylformamide is added 0.23 ml of chlorotrimethylsilane during 3 minutes. The mixture is stirred at room temperature for 22 hours and partitioned with a mixture of cold hexane and water. The hexane layer is washed repeatedly with water and then brine, dried over magnesium sulfate, and concentrated to give an oil, pmr spectrum (CDC1.): 0.13 (s, trimethylsiloxy group) and 2.32 (d, =CHCHZ).

EXAMPLE 195 Preparation of n-butyl cyclopropyl ketone To a vigorously-stirred solution of 31.0 g of cyclopropanecarboxylic acid in 330 ml of ether is added a solution of ιι-butyl lithium (748 mmoles) in about 750 ml of 2:1 ether-hexane during one hour at 5°-10°C. The resulting suspension is diluted with 300 ml of ether and stirred at room tempera30 ture for 2 hours and at reflux for 2 hours. The mixture is cooled and poured - 151 ’ 48207 into several portions of 1:1 ice:4N hydrochloric acid. The ethereal phases are combined and washed with brine, sodium carbonate solution, and brine.

The extract is dried over magnesium sulfate and concentrated. The residue is distilled to provide a liquid, bp-102°-104°C (80 mm), pmr spectrum (CDClj) δ 2.55 (triplet, -CH^CO-).

EXAMPLE 196 Preparation of 4-cyclopropyl-4-hydroxy-l-octyne To a stirred, refluxing suspension of aaalgum prepared from 6.2 g of magnesium and 50 mg of mercuric chloride suspended in 60 ml of ether is 10 added a solution of a mixture of 30.4 g of n-butyl cyclopropyl ketone (Example 189) and 29.8 g of propargyl bromide in 65 ml of ether during 60 minutes. After reaction at reflux temperature for an additional 30 minutes, the mixture is cooled to 0°C and treated with 35 ml of saturated ammonium chloride. The mixture is diluted with ether and filtered through Celite.

The filtrate is washed with brine, dried over potassium carbonate, and concentrated. The residue is distilled to provide a liquid, δ 0.43 (cyclopropyl hydrogens), 2.07 (triplet, HC=C), and 2.44 (doublet, C=CCH2).

EXAMPLE 197 Preparation of 4-cyclopropyl-4-trimethylsiloxy-l-octyne 20 To a stirred solution of 27.8 g of 4-cyclopropyl-4-hydroxy-loctyne (Example 190) and 33.3 g of imidazole in 130 ml of dimethylformamide at 5°C is added 24 ml of chlorotrimethylsilane during 5 minutes. The solution is stirred at ambient temperature for 17 hours and then partitioned with 600 ml of hexane and 250 ml of ice water. The hexane phase is separated and washed successively with water and brine. The solution is dried over magnesium sulfate and evaporated to give a liquid, pmr spectrum (CDClj): δ 0.12 (singlet, trimethylsiloxy group), 2.02 (triplet, HC=C), and 2.45 (doublet, C=CtL2). - 152 ο 48207 EXAMPLE 198 Preparation of 4-cyclopropyl-4-trimethylsiloxy-l-(tri-nbutylstannyl)-trans-1-octene A stirred mixture of 23.8 g of 4-cyclopropyl-4-trimethylsiloxy-loctyne (Example 191), 28 ml of tri-n-butyltin hydride, and 50 mg of azobisisobutyronitrile under nitrogen is heated to 85°C. After the resulting exothermic reaction subsides the mixture is heated at 130°C for one hour. The crude product is evaporatively distilled to give a liquid, pmr spectrum (CDClj): δ 0.10 (trimethylsiloxy group), 2.33 (doublet, =CHCH2), and 6.02 (vinyl hydrogens).

EXAMPLES 199-204a Treatment of the starting carboxylic acids of Table 24 with the appropriate alkyllithium by the method of Example 190 provides the product ketones of the table. - 153 48207 TABLE 24 Product Ketone 1 n-hexylcyclopropyl ketone n-propylcyclopropyl ketone n-hexylvinyl ketone n-pTopylvinyl ketone n-butyl-1-propenyl ketone n-hexyl-1-propenyl-ketone n-butylvinyl ketone Alkyl Lithium n-hexyllithium n-propyl1ithium n-hexyllithium n-propyl1ithium n-butyl1ithium n-hexyllithium n-butyllithium Starting Carboxylic Acid cyclopropane carboxylic acid cyclopropane carboxylic acid acrylic acid acrylic acid crotonic acid crotonic acid acrylic acid Example (4 σ» o ph cm to ο ο ο ο ο o pH cm cm cm cm cm cm 1S4 EXAMPLES 205-210E Treatment of the starting ketones of Table 25 with propargylmagnes ium bromide by the procedure of Example 190 followed by treatment with chlorotrimethylsilane by the procedure of Example 191 followed by treatment S with tri-n-butyltin hydride by the method of Example 192 is productive of the vinylstannyl derivatives of the table. - 155 48207 TABLE 25 156 - 48207 ' 210F .n-Butyl trimethylsilylethynyl baton· To a stirred solution of 14.4 9 of valeryl ehloride and 2004 g of bia^ferimathylsilylaeetylcne in 300 al of dry 5 asthylene chloride, cooled in an iea bath, is added powdered _ anhydrous aluminum chloride, portionwise, over a period of 20 minutes. The mixture is stirred for S minutes, then the cooling bath is removed and the mixture is stirred at room temperature for 4 hours. The mixture is poured into 500 ml of ice-water. The organic layer is separated, washed with water and brine, dried over anhydrous sodium sulfate and filtered through diatomaceous earth. The mother liquor is evaporated to dryness giving a brownish residue. This residue is Kugelrohr-distllled to give 16.56 g of colorless liquid at 45*c/0.3 nm which is essentially identical with the authentic product.

Example 210G 4-Trlmethylsllylethynyl-l-octyn-4-ol To a stirred suspension of 1.29 g of magensium and mg of mercuric chloride in 12 ml of ether is added 0.4 ml of propargyl bromide. The reaction is initiated after stirring at room temperature for a few minutes. The stirred mixture is cooled in an iee-water bath and a solution of 9.64 g of n-butyl trimethylsilylethynyl ketone and 3.51 ml of pro25 pargyl bromide in 13 ml of ether is added dropwise so that the mixture is very gently boiling during 40 minutes. After addition, the cooling bath is removed and the mixture is stirred at room temperature for l.S hours. The mixture is reeooled in an ice bath and 10 ml of saturated ammonium ehloride solu«* 3© tion is added. The resulting white mixture is filtered through diatomaceous earth. The clear mother liquor is washed with saturated sodium chloride solution and dried over anhydrous 157 magnesium sulfate. The solvent Is evaporated to dryness giving 10.5 g of a rod liquid. This liquid is xvgelrohr-distilled st 80*C/0.25-0.3 ». The pels yellow liquid distillate which is the desired product weighs 8.5 g, Example 2108 4-Trimethylsllylathynyl-l-octyn-4-ol trlmathylsllyl ether To a stirred mixture of 8.5 g of 4-trimethylsilylethynyl-l-oetyn-4-ol and 8.2 g of imidazole in 24 al of dry dimethylformamide is added, under nitrogen, 5.7 ml of chlorotrimethyleilana, in a slow stream, via a syringe. The mixture is stirred in an ice bath for one hour and then st room temperature overnight. The mixture is poured into hexane, washed with saturated sodium bicarbonate solution, water and then brine and dried over sodium sulfate. The solvents are evaporated to dryness giving 11.1 g of the desired product.

Example 2101 4-Trimethylsilylethynyl-4-trlmethyl«lloxy-l-octen-l»trln-butyl stannane To a mixture of 10 mg of azobisisobutyronitrile and 2.94 g of 4-trimethyl«ilylethynyl-l-oetyn-4-ol trimethylsilyl ether is added 2.85 ml of tri-n-butyl stannane via a syringe. The mixture is stirred and heated under nitrogen in an oil bath at 13 O’C for 3 hours and then cooled to room temperature. This mixture is vacuum-distilled through a short-path distillation apparatus to remove a forerun at 40*C/0,4 m. Tha yellow oil (pot residue) comprises the desired product.

Examples 210J-210M Treatment of tha acid chlorides of Tabla 1 by tha procedure of Example 210Z* with bis-trimethylsilylaeetyleno ia productive of tha ketones of Tabla 25λ. 158. 207 TABLE 25A Example Starting Acid Chloride Product Alkyl Trimethyl* eilylethynyl Ketone 210L butyryl chloride a-propyl tximethylsilylethynyl ketone 210M heptanoyl chloride n-hexyl trimethylsilylethynyl ketone Examples 2I0N-210Q Treatment of the ketones of Table 25B by the procedure of Example 210C- is productive of the 4-trimethylsilylethynyl-lalkyn-4-ol's of the Table.

Table 25B Example Starting Ketone Product 4-Trimethylsilylethynyl-l-alkyn-4-ol 210N 210L 4-trimethylsilylethynyl- l-heptyn-4-ol 2100 210M 4-trimethylsilylethynyl- l-decyn-4-ol Examples 210P-210Q Treatment of the alkya-4-ol's ©f Table 25B with chlcrotrimethylsilane by the procedure ef Example 210H followed by treatment of the resulting trimethylsilylether with trin-butylstannane by the procedure of Example 2101 is productive of alkenes of Table 25C.

TABLE 25C Example Starting Alkyn-4-ol Product Alkene 210? I10K (E)4-trimethylsilylethynyl4-trimethylsiloxy-l-tri-nbufcyletannane-l-heptene ~ 2100 210© (E) 4-trimethylethynyl-4triaethylsilyloxy-l-trin-butylstannane-l-decene 159 8207 EXAMPLE 211 Preparation of trans-1-Hydroxy-2 - (3- tri fluoromethyl)phenoxycyclopentane A mixture of 88 g of cyciopentene oxide, 150.7 g of 3-trifluoromethylphenol, 5.0 g of sodium hydroxide in 30 ml of water and 4.0 g of methyltricaprylyl ammonium chloride is stirred at 70°-80°C for 51 hours and at 25°C for 96 hours. The mixture is then diluted with methylene chloride and poured into water. The organic layer is washed with dilute sodium hydroxide solution and water. The solution is dried over magnesium sulfate. The solvent is removed giving 221.5 g of a liquid which is distilled (bp 110°-113°C 0.8 mm) giving trans-l-hydroxy-2-(3-trifluoromethyl)phenoxycyclopentane.

EXAMPLE 212 In the manner described above in Example 211 from 4-fluorophenol and cyclopentane epoxide is prepared trans-l-hydroxy-2-(4-fluoro)phenoxycyclopentane.

• EXAMPLE 213 In the manner described above in Exanple 211 from 3-chlorophenol and cyclopentane epoxide is prepared trans-l-hydroxy-2-(3-chloro)phenoxycyclopentane.

EXAMPLE 214 Preparation of 2-(3-Trifluoromethylphenoxy)cyclopentanone To a suspension of 327.43 g of pyridinium chlorochromate in one liter of methylene chloride is added 220 g of trans-l-hydroxy-2-(3-trifluoromethylphenoxy)cyclopentane in 500 ml of methylene chloride. The mixture is stirred for 2 hours 15 minutes. Another 50 g of the oxidizing agent is added and the mixture is stirred for 4 1/2 hours. The mixture is diluted with ether and decanted from a black residue which is washed with more ether. The combined solutions are filtered through silica gel. The solvent is removed. The residue is dissolved in ether and again filtered through silica-gel. The solvent is removed and the residue is distilled (bp 113°-116°C, 1.5 mm) to - 160 48207 give 188 g of 2-(3-trifluoromethylphenoxy)cyclopentanone.

EXAMPLE 215 In the manner described above for Example 214 is prepared from the product of Example 212; 2-(4-(fluorophenoxy)cyclopentanone.

EXAMPLE 216 In the manner described above for Example 214 is prepared from the product of Example 213; 2-(3-chlorophenoxy)cyclopentanone.

EXAMPLE 217 Preparation of lR,2S(and lS,2R)-l-Ethynyl-l-hydroxy-2-butyl10 cyclopentane and lR,2R(and lS,2S)-l-ethynyl-l-hydroxy-2-butylcyclopentane Into 150 ml of dry tetrahydrofuran is bubbled purified acetylene, as a solution of 2.4M n-butyl magnesium chloride (92 ml) is added dropwise with stirring over a 2 hour period. To the resulting solution of acetylene magnesium chloride is added 21 g of 2-butylcyclopentanone in 50 ml of tetrahydrofuran dropwise over 15 minutes. The solution is stirred for 30 minutes and then is poured into an ice cold solution of.saturated ammonium chloride. The mixture is acidified to pH 5 and extracted with ether. The ether solution is washed with brine and dried over magnesium chloride, the ether is re20 moved and the residue is distilled giving 14.8 g of a colorless liquid. This is chromatographed on a dry column of silica-gel eluting with benzene-ethyl acetate (19:1) to separate isomers giving lR,2S(and 1S,2R)-1-ethynyl-l-hydroxy-2-butylcyclopentane and lR,2R(and lS,2S)-l-ethynyl-l-hydroxy-2-butylcyclopentane.

EXAMPLE 218 Preparation of 1-propargyl-l-hydroxycyclohexane A stirred suspension of 121.6 g (5.0 mol) of magnesium in 1-1 of anhydrous ether is treated with 0.6 g of mercuric chloride and about 100 mg of iodine. After several minutes, 3 ml of propargyl bromide is added and if no exotherm is noted, a small amount of reacting propargyl bromide and magnes 161 - 48207 ium in ether is added. When the reaction begins, a mixture of 5.0 mol of cyclohexanone and 595 g (5.0 mol) of propargyl bromide is added dropwise at a rate that produces vigorous refluxing of the solution. (The propargyl bromide must always be present in some excess otherwise the reaction will stop. If this happens, the addition of about 1 ml of propargyl bromide will restart the reaction.) After about half of the propargyl bromide-cyclohexanone mixture has been added, another 500—750 ml of ether is used to dilute the reaction mixture. At the end of the addition, the reaction mixture is refluxed for at least 0.5 hour, cooled and poured into 4 liters of saturated ammonium chloride during good stirring. The ethereal layer is separated and the aqueous layer is washed with ether several times and the combined extract is washed twice with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the ether yields 583 g (530 g theory) of a dark oil which is distilled giving purified 1-propargyl-l-hydroxycyclohexane.

EXAMPLES 219-238 In the manner of Examples 217 and 218 described above the following acetylenic alcohols listed in Table 26 were prepared from the acetylenic Grignard reagent and ketone specified. - 162 41 8 2 Ο 7 Ο μ *ο X X X X ο Η Ό X Α Ο Ρ Ό X Α X X ο Ρ *α £ CM ω ca < x υ x X ο Ρ Ό X Α X Φ Α Ο «—4 υ χ υ C CU X χ X φ cu 0) X £ g. £ g ο 0 £ X X X ·—( r-4 Ρ Ρ Ρ Ρ υ Ο V Φ φ φ χ X ι 1 I υ υ r*4 Φ φ ι—4 ^4 X χ 8 S Ρ Τ3 X Α C Φ CU Ο OS C ω c cd ro ω « to Φ Μ Φ CM X CM χ CU • CU * Φ « φ 05 ο 05 ο 05 Α 05 X r-4 ι-Μ υ r-4 υ -( Ο rH «Η Ο rU Ό χ Ό X τι υ ό υ S υ I-U §2 § ο C X co υ χ 'S X '-τ' f-4 <—'Γ-Μ 1 CU I CU ι X » X ω ο as ο 05 Ρ es ti Κ) Η tO Ρ CM 3 CM 3 CU * ρ, *Χ *Χ as » α£ « Οί 1 ed » c ο § Ρ Λ Cu cu Φ Φ o o A x —1 cM o o υ a w w X X υ υ υ υ X X r-4 F*4 u υ X X ^4 τ-Μ CU cu X X 0 o P Ρ ρ μ 3 3 cu 0« A A to to CM CM ή) τ3 «—t ·Η X Ρ Ρ Ο ϋ r-t υ Α α ο Ea & Eh ω & ω ro «1 ro ro ro ro ε ε ε ε ε ε φ φ φ φ φ φ α φ C Φ ¢5 Φ C Φ C Φ c Φ Ό Φ Π3 Φ Ό Φ Ό φ TJ Φ Ό —I ·ρ4 r—4 ·Ρ —4 «Η ^4 ·Η «Η Ή >Ρ ·Η X P X P X Ρ X ρ χ £ X &ί p o P o Ρ ο Ρ ο Ρ ο Ρ 0 Φ -( a) <-( φ —( Φ —4 φ rH Φ ιΗ υ a U A Ο Α υ Α υ Α υ α ro o ro u ro α ro u ro ο ro ο 163 TABLE 26 (continued) 164 χ X ο μ Ό X Α X & £ 4-» ω ί r-i φ ι η) X rt φ *£ 03 Ο rt <“^ υ •β χ e Ο Λ rt <-/ X ι -C C2 rt rt Φ * e CS k ι-ι rt ? Ό X A Η φ pu ο μ CU I rt ea ρ cm c « Φ ω cu o rt ό υ c x co a rt/ rt I X w p CM 3 oi ? rt CM X X o μ Ό X £ §· μ (X Φ TS as • Φ ω cu r-l o rt Ό U 1 X I μ 1 oi μ cn 1 oi ι CM ff CM cn cm cn “rff Art/ Oi P oi 1 oi ι rt CM rt CM rt CM X © X s 0 co μ p tj ff X © A I o irt rt ( o rt X S 5? CU 0 o c μ © Cu£ I ffrt rt ~£ ι P oi © cm e ω S rt O 3 Ό rt c 'μ h μ p Ό ff χ © £ O. i 0 rt rt ι υ rt X &S? CU o o c μ © Cu£ I PU rt rt X /~»£ ι μ a ι * o 03 μ rt 0 Ό rH ff CO «rt μ « rt rt X P P Φ 4Ξ ff Φ C © 1 1 O Irt Φ 1 1 O Irt Φ 0 cu o §· μ x ff 0X0 μ x ff 0X0 o rt et 3 0 ff ff o 5 >, υ u rt ff rt rt c rt u X X «Η φ p Ψ» Φ ρ rt υ u •Η Λ ff •rt £ ff X rt rt μ CU © μ pu © jZ X X p rt PU ρ τ4 5* jj +J P 1 X o » x o Φ φ 3 © 3 Φ cn λ rt cn £ rt ε I c o X) 1 ff 0 X» ff 1 0 rt υ ι Φ X rt* ρ O ι Φ X cn ff CM c CM C CM s o cm ε © & φ co ·α ε ·η μ φ ο C Φ Α rt υ Ρ £ Φ 3 U ·Η co <λ Φ CO Φ ε ό •rt rt ε χ Ρ οο μ μ χ> « cu ε Ο 3 μ ·η CU ω Φ C οο co Φ 6 Ό •rt rt β X Ο οο μ μ £ rt CU g Ο 3 μ ·ι-ι pu 0.6 o.» 9) & <4 O Β Ό •rt ·—< ε &8 H μ «rt CUW - 165 4 8207 EXAMPLE 239 Preparation of lR,2S(and lS,2R)-l-Ethynyl-l-trimethylsilyloxy-2-hutylcydopentane To a solution of 29.4 g of lR,2S(and lS,2R)-l-ethynyl-l-hydroxy-2butylcyclopentane and 30.2 g of imidazole in 180 ml of dimethylformamide is added at 0°C with stirring 24.1 g of trimethylsilylchloride. The mixture is stirred for 3 hours. The mixture is poured into 700 ml of hexane and washed twice with water and once with brine. The ether solution is dried over magnesium sulfate. The solvent is removed and the residue is distilled (bp 64°10 72°C, 0.6 mm) to give 35.8 g of lR,2S(and lS,2R)-l-ethynyl-l-trimethylsilyloxy-2-butylcyclopentane.

EXAMPLE 240 Preparation of lR,2R(and lS,2S)-l-Ethynyl-l-trimethylsilyloxy-2-butylcyclopentane To a mixture of 45.0 g of lR,2R(and lS,2S)-l-ethynyl-l-hydroxy-2butylcyclopentane and 46.2 g of imidazole in 255 ml of dimethylformamide at 0°C under nitrogen is added 36.9 g of trimethylsilylchloride. The mixture is stirred at room temperature for 3 hours and then poured into 700 ml of hexane. Water is added, the organic layer is separated and the water layer is extracted with hexane. The combined hexane solutions are washed twice with water and dried over magnesium sulfate. The solvent is removed and the residue is distilled giving the product as 53 g of a colorless oil.

EXAMPLE 241 Preparation of 1-Ethynyl-l-trimethylsilyloxycyclohexane A 194 g portion of imidazole and 158.2 g of 1-ethynylcydohexan-lol are mixed with 500 g of dimethylformamide with cooling in an ice bath. A 152 g portion of trimethylchlorosilane is added with cooling and stirring in about one minute. The mixture is stirred for one hour and allowed to stand overnight. One liter of hexane is added. The lower layer is separated, di30 luted with water and extracted with hexane. The hexane layers are washed - 166 48207 several times with water and then combined and dried over magnesium sulfate. Filtration and then evaporation of the hexane gives 198.5 g of product which is distilled giving 168 g of the desired product.

EXAMPLE 242 Preparation of 1-Propargyl-l-trimethylsilyloxycyclohexane To a stirred solution of 55.4 g of 1-(2-propyn-l-yl)cyclohexanol [H. Gutmann, et al., Helv. Chim. Acta, 42, 719 (1959)] and 79 g of imidazole in 240 ml of DMF at 10°C initially is added 56 ml of chlorodimethylsilane during 10 minutes. The cloudy yellow solution is stirred at room temperature for 26 hours. The resulting mixture is partitioned between 1000 ml of hexane and 400 ml of water at 0°-5°C. The hexane phase is washed successively with 6 x 200 ml of cold water and 200 ml of brine. The extract is dried over magnesium sulfate, filtered, and evaporated to give 85 g of colorless liquid, i.r. (film):X240 and 830 cm (trimethylsilyloxy group).

EXAMPLE 243 Preparation of lR,2S(and 1S,2R)-1-(trans-2-Iodovinyl)-l-tri methylsilyloxy-2-butylcyclopentane To a mixture of 9.2 g of sodium borohydride and 45.8 g of 2-methyl2-butene in 350 ml of dry tetrahydrofuran at 0°C with stirring under nitrogen is added, over 20 minutes, 41.1 ml of boron trifluoride etherate. After 3 hours, to this resulting solution of diisomaylborane is added 38.8 g of 1R,2S (and lS,2R)-l-ethynyl-l-trimethylsilyloxy-2-butylcyclopentane in 40 ml of tetrahydrofuran in 20 minutes. The mixture is stirred 2 hours and then stored at -20°C overnight. The mixture is allowed to warm to 0°C and at 0°C 85 g of dry trimethylamineoxide is added portionwise over 20 minutes. After stirring at 25°C for one hour, the mixture is filtered through diatomaceous earth. The filtrate is poured simultaneously with a solution of 230 g of iodine in 250 ml of tetrahydrofuran into a stirred, cold solution of 430 g of sodium hydroxide in 1900 ml of water. After stirring for 30 minutes, the or30 ganic layer is separated. The aqueous layer is extracted with ether. The 167 48207 combined organic solutions are washed twice with a saturated solution of sodium thiosulfate and once with brine. The solution is dried over magnesium sulfate, the solvent is removed and the residue is dissolved in hexane. The hexane solution is filtered through diatomaceous earth and silica gel.

The hexane is removed and the residue is purified by dry column chromatography on silica gel eluting with hexane: 45.35 g of lR,2S(and 15,2R)-1(tran£-2-iodovinyl)-l-trimethylsilyloxy-2-butylcyclopentane is obtained.

EXAMPLE 244 Preparation of lR,2R(and lS,2S)-l-(trans-2-lodovinyl)-l-tri10 methylsllyloxy-2-butylcyclopentane To a mixture of 12.22 g of sodium borohydride and 60.82 g of 2methyl-2-butene in 450 ml of tetrahydrofuran under nitrogen at 0°C, is added 54.6 ml of boron trifluoride etherate, dropwise over a 20 minute period. The solution is stirred at 0°C for 2 hours and then at room temperature for 30 minutes. This solution is cooled to 0°C and 55.5 g of lR,2R(and 1S,2S)-1ethynyl-l-trimethylsilyloxy-2-butylcyclopentane in 50 ml of tetrahydrofuran is added. The mixture is allowed to stand in a cold room overnight. To this mixture at 0°C is added with stirring 112.8 g of trimethylamine oxide over a 20 minute period. The mixture is stirred at room temperature for 90 minutes and then filtered. To the filtrate is added simultaneously a solution of 565 g of sodium hydroxide in 2000 ml of water and a solution of 300 g of iodine in 300 ml of tetrahydrofuran. The mixture is stirred 30 minutes, the organic layer is separated and the aqueous layer is extracted with ether. The combined organic solutions are washed with saturated sodium thiosulfate solution and with saturated sodium chloride solution. The solution is dried with magnesium sulfate, and filtered through a pad of silica gel. The solution is removed giving an orange liquid which is chromatographed on a dry column of silica gel giving 59.5 g of the product as a yellow liquid. - 168 EXAMPLE 245 Preparation of 1-(3-Tri-n-butylstannyl-2-trans-propenyl)-1-trimethyisilyloxycyclohexane To a stirred mixture of 31.5 g of 1-propargyl-l-trimethylsilyloxycyclohexane and 150 mg of azobisisobutyronitrile is added 41 ml of tri-nbutyltin hydride. The stirred mixture is heated to about 80°C. The initial exothermic reaction is moderated, and the temperature is subsequently maintained at 130°-135°C for one hour.

The product is distilled to afford 56 g of colorless liquid, bp 10 150°-160°C (0.15-0.3 mm), pmr (CDCl^): 6.0 (multiplet, vinyl protons).

EXAMPLES 246-26S Using the procedure outlined above for Examples 239-242, the acetylenic alcohols listed in Table 27 are converted to their corresponding acetylenic trimethylsilyloxy derivative, these in turn using the procedure outlined above for Examples 243 and 244, were converted to their corresponding trans-2-iodovinyl derivatives or using the procedure outlined above for Example 245, were converted to their corresponding trans-2-tri-n-butylstannyl derivatives (Table 27). - 169 48307 TABLE 27 170 171 TABLE 27 (continued) 172 a 48207 EXAMPLE 266 Preparation of trimethylsilyl-2-trimethylsilyloxy acetate To a solution of 15 g (0.197 mol) of glycolic acid in 50 ml of dry pyridine is poured 32.3 g (0.2 mol) of 1,1,1,3,3,3-hexamethyldisilazine.

After stirring 15 minutes, 10.86 g (0.1 mol) of trimethylsilyl chloride is added dropwise. The mixture is stirred for one hour and then filtered from a white solid which is washed with petrolium ether. The filtrate and washings are concentrated at reduced pressure at 30°C. The residue is distilled (85°-86°, 15 minutes) to give 38 g of the title compound.

EXAMPLE 267 Preparation of tris-trimethylsilyloxyethylene To a solution of 50.98 g (0.316 mol) of 1,1,1,3,3,3-hexamethyldisilazine in 250 ml of tetrahydrofuran is added with stirring under argon at 0°C dropwise 113.3 ml (0.32 mol) of 2.4M n-butyl lithium in hexane. After addition is completed the solution is maintained at 45°C for 30 minutes. The solution is cooled to -78° and 58.7 g of trimethylsilyl-2-trimethylsilyloxy acetate (Example 266) is added dropwise. After stirring 30 minutes, 43.2 g (0.4 mol) of trimethylsilylchloride is added over 10 minutes. The solution is allowed to warm to room temperature over 30 minutes. The solvent is re20 moved at reduced pressure. The residue is mixed with an equal volume of petroleum ether and filtered from the suspended lithium chloride. The solvent is removed and the residue is distilled (70°-75°C, 1.4 minute) to give 64.65 g of the title compound.

EXAMPLE 268 Preparation of 2-[6-(chloroforniyl)hexyl1cyclopent-2-en-l-one To a suspension of 1.94 g (0.08 mol) of sodium hydride in 100 ml of tetrahydrofuran is added with stirring under argo dropwise a solution of 17 g (0.08 mol) of 2-(6-carboxyhexyl)-cyclopent-2-en-l-one in 160 ml of tetrahydrofuran. After the addition is complete, the mixture is stirred for 1 hour 15 minutes. The mixture is cooled to 0°C and 13 ml of oxalyl chloride - 173 4-8207 is added. The mixture is stirred at 0°C for 30 minutes and at room temperature for 30 minutes. The solution is diluted with 500 ml of ether and filtered through Celite. The solvent is removed from the filtrate and the residue is extracted with hot hexane twice. The hexane is removed to give 16.0 g of the title conpound.

EXAMPLE 269 Preparation of 2-(8-hydroxy-7-oxo-octyl)cyclopent-2-en-l-one A mixture of 6.3 g of 2-[6-(chloroformyl)hexyl]-cyclopent-2-en-lone (Example 268) and 16 g of tris-trimethylsilyloxyethylene (Exanple 267) are stirred at 90° to 100°C under argon for one hour. To this mixture is added 25 ml of dioxane and 10 ml of 0.6N hydrochloric acid. The mixture is heated at 80°C for 30 minutes. The mixture is poured into brine and extracted with ether. The ether solution is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed and the residue is chromatographed on a dry column of silica gel eluting with ether containing 2% acetic acid to give 1.7 g of the title compound (R^ = 0.45).

EXAMPLE 270 Preparation of 2-(6-carbodimethyl-t-butylsilyloxyhex-2-cis-enyl)-4-dimethyl-t-butylsilyloxy-cyclopent-2-en-l-one To 5.0 g of 2-(6-carboxyhex-2-cis-enyl)-4-hydroxycyclopent-2-en-lone and 7.5 g of imidazole in 24 ml of dimethylformamide is added 10.2 g of dimethyl-£-butylsilylchloride. The mixture is maintained at 37°C for 4 hours. The mixture is poured into ice water and extracted with hexane. The hexane solution is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed. Toluene is added and removed. The residue is distilled in a Kugelrohr apparatus (165°C, 0.S-0.1 mm) to give 4.56 g of the title compound. - 174 - 48207 EXAMPLE 271 Preparation of 1-(6-carboxyhex-2-cis-enyl)-4-dimethyl-t-hutylsilyloxycyclopent-2-en-l-one A solution of l-(6-carbodimethyl-t-butylsilyloxyhex-2-cis-enyl)-4dimethyl-£-butylsilyloxycyclopent-2-en-l-one (Example 270) in 40 ml of acetic acid - tetrahydrofuran - water (4:2:1) is stirred at room temperature for 1.5 hour. The solvents are removed at reduced pressure at 40°C. The residue is dissolved in ether. The ether solution is washed with water, brine, and dried over magnesium sulfate. The solvent is removed. Toluene is added and removed to give 3.1 g of the title compound.

EXAMPLE 272 Preparation of 1-[6-(chlorofonnyl)hex-2-cis-enyl]-4-dimethyl-t-butylsilyloxycyclopent-2-en-l-one To 59.66 g of l-(6-carboxyhex-2-cis-enyl)-4-dimethyW-butylsilyloxy cyclopent-2-en-l-one (Example 271) in 300 ml of tetrahydrofuran containing 0.5 ml of dimethylformamide at 0°C under argon with stirring is added over 20 minutes 29.2 m of oxalyl chloride in 40 ml of tetrahydrofuran. After 1.5 hours the solvent is removed at reduced pressure at 35°C. The residue is dissolved in petroleum ether and filtered through Celite. The solvent is re20 moved to give 59.3 g of the title compound.

EXAMPLE 273 Preparation of l-(8-hydroxy-7-oxo-oct-2-cis-enyl)-4-hydroxycyclopent-2-en-l-one A mixture of 59.3 g of 1-[6-(chlorofoΓmyl)hex-2-cis-enyl^-4-dimethyl-t^-butylsilyloxycyclopent-2-en-l-one (Example 272) and 101.5 g of tristrimethylsilyloxyethylene (Example 267) is heated under argon at 90°-95°C for 3 hours 10 minutes. The reaction mixture is poured into a mixture of 300 ml of tetrahydrofuran and 140 ml of 0.6N hydrochloric acid and the resulting mixture is stirred at 70°C for 2.5 hours. The mixture is poured in brine and extracted with ethyl acetate. The organic layer is washed with saturated - 175 48307 sodium bicarbonate and dried of magnesium sulfate. The solvent is removed and the residue is chromatographed of a dry column of silica gel eluting with ethyl acetate. The product bond (R^ = 0.4) is extracted to give 6.45 g of the title compound.

EXAMPLE 274 Preparation of 5-bromopentanoylchloride To a solution of 97 g of 5-bromopentanoic acid in 240 ml of methylene chloride containing 1 ml of dimethylformamide is added dropwise 76.2 g of oxalyl chloride. The mixture is stirred one hour at room temperature and minutes at 50°C. The solvent is removed and the residue is distilled twice (75°C, 0.6 minute) to give 88.2 g of the title compound.

EXAMPLE 275 Preparation of 6-bromo-l-hydroxy-2-hexanone To 191.4 g of tris-trimethylsilyloxyethylene (Example 267) containing IS drops of stannic tetrachloride under argon with stirring at 10°C is added 87 g of 5-bromopentanoyl chloride (Example 274) dropwise. After onehalf of the acid chloride is added, the mixture is stirred until an exotherm ensues. The remaining acid chloride is added dropwise maintaining the reaction exotherm at 65°C. The mixture is then stirred for 2.5 hours. The mix20 ture is slowly poured into a stirred mixture of 100 ml of 0.6N hydrochloric acid and 200 ml of tetrahydrofuran. The mixture is stirred for 30 minutes and poured into brine. The mixture is extracted with ether. The ether solution is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed. The residue is mixed with petroleum ether and cooled in dry-ice-acetone to induce crystallization. The petroleum ether is decanted and the solid is dried at reduced pressure to give 64.72 g of the title compound. - 176 4 8 207 EXAMPLE 276 Preparation of 6-bromo-l-dimethyl-t-butylsilyloxy-2-hexanone ethylene ketal A mixture of 84 g of 6-bromo-l-hydroxy-2-hexanone (Example 275), 240 ml of ethylene glycol, and 1.7 g of £-toluenesulfonic acid is refluxed in 1800 ml of toluene using a Dean-Stark trap for 1 hour 45 minutes. The mixture is cooled to room temperature and washed with saturated sodium bicarbonate, water, and brine. The solvent is removed giving 75.17 g of a yellow oil. To a 27.36 g portion of this material and 16.2 g of imidazole in 57 ml of dimethylformamide at 0° with stirring is added 20.55 g of dimethyl -t^-butylchl orosi lane. The mixture is stirred at room temperature for 1.5 hour and then poured into water. The mixture is extracted with petrolium ether. The organic phase is washed with dilute hydrochloric acid, saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed and the residue is distilled in a Klugrohr apparatus (0.5-0.2 mm, 100°-110°C) to give 35.25 of the title compound.

EXAMPLE 277 Preparation of l-dimethyl-t-butylsilyloxy-2-hexanone ethylene ketal 6-triphenylphosphonium bromide A mixture of 35.25 g of 6-bromo-l-dimethyl-t-butylsilyloxy-2-hexanone ethylene ketal (Example 276) and 26.2 g of triphenylphosphine in 68 ml of acetonitrile is refluxed 90 hours. The acetonitrile is removed at reduced pressure. The residue is washed three times with ether and dried at reduced pressure to give 53.8 g of the title compound.

EXAMPLE 278 Preparation of 2,5-dihydro-2,5-dimethoxy-2-(9-dimethyl-t-butyl silyloxy-8-oxonon-3-cis-enyl)furan A suspension of 2.3 g (0.096 mol) of oil from sodium hydride is stirred under argon at 65°C in 75 ml of dimethylsulfoxide. After gas evolu30 tion ceased (1 hour), at 0°C is added 53.8 g (0.086 mol) of l-dimethyl-_t- 177 48207 butylsilyloxy-2-hexanone ethylene ketal 6-triphenylphosphonium bromide (Example 277) in 160 ml of dimethylsulfoxide. After stirring IS minutes at room temperature, 16.3 g (0.087 mol) of 2,5-dihydro-2,5-dimethoxy-2-(3'oxopropyl)furan [United States Patent 3,952,0331] in 40 ml of dimethylsulfoxide is added. After stirring one hour at room temperature, the solvent is removed at reduced pressure at 55°C. The solid residue is extracted with an ether-petrolium ether mixture. The solution is washed with water, saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed and petrolium ether is added. After standing 30 minutes, the tri10 phenylphosphine oxide.is removed by filtration. The solvent is removed and the residue is chromatographed on a dry column of florisil eluting- first with hexane and then with hexane-ether 5:1 to give 13.2 g of the .title compound.

EXAMPLE 279 Preparation of 2-(8-dimethyl-t-butylsilyloxy-7-oxo-oct-2-cis-enyl)-4-hydroxycyclopent-2-en-l-one,7-ethylene ketal A mixture of 66.08 g of 2,5-dihydro-2,5-dimethoxy-2-(9-dimethyl-tbutylsilyloxy-8-oxonon-3-cis-enyl) furan (Exanqile 228), 26.4 g of sodium dihydrogen phosphate, 5.2 g of sodium acetate and 0.5 g of hydroquinone in 1320 ml of dioxane and 660 ml of water is stirred at reflux under argon for hours. The mixture is cooled to room temperature, saturated with sodium chloride, ana the organic layer is separated. The aqueous layer is extracted with ether. The combined organic solutions are washed with brine and dried over magnesium sulfate. The solvent is removed to give 57.5 g of an oil. To this is added 300 ml of ether, 300 ml of petrolium ether and 22 g of anhydrous chloral. The solution is stirred under argon and 23 g of triethylamine is added. After 1 hour 40 minutes, the solution is washed with water, dilute hydrochloric acid, saturated sodium bicarbonate, brine, and dried over magnesium sulfate. The solvent is removed and the residue is chromatographed on a dry column of silica gel eluting with ethylacetate- 178 48207 hexane 1:1 to give 14,55 g of the title compound (R^ = 0.4.

EXAMPLE 280 Preparation of 2-(8-dimethyl-t-butylsilyloxy-7-oxo-oct-2-cisenyl)-4-trimethylsilyloxycyclopent-2-en-l-one,7-ethylene ketal A mixture of 14.5 g (0.0367 mol) of 2-(8-dimethyl-t-butylSilyloxy7-oxo-oct-2-cis-enyl)-4-hydroxycyclopent-2-en-l-one, 7-ethylene ketal (Example 279) and 3.34 g (0.04 mol) of imidazole in 30 ml of dimethylformamide is stirred as 4.98 g (0.046 mol) of trimethylsilylchloride is added. After one hour, the mixture is poured into water and extracted with hexane. The hexane solution is washed with water, saturated sodium bicarbonate, and dried over magnesium sulfate. The solution is filtered through a pad of silica gel. The solvent is removed and the residue is dried at reduced pressure to give 12.5 g of the title compound.

EXAMPLE 281 Preparation of 2-Γ6-(4-methoxy-2,2-dimethyl-l,3-dioxolan-4-yl) hex-2-cis-enyl)-4-(2-methoxypropyl-2-oxy)cyclopent-2-en-l-one A mixture of 2-(8-hydroxy-7-oxo-dct-2-cis-enyl)-4-hydroxycyclopent2-en-l-one (Example 273), 14 ml of 2-methoxy propene, and 0.23 g of ammonium nitrate in 35 ml of benzene is added 7 ml of dimethoxypropane, p-toluene20 sulfonic acid is added in very small portions until TLC indicates the reaction is initiated. The mixture is stirred 1.5 hour at room temperature, 40°C for 15 minutes, and another 30 minutes at room temperature. To the stirred solution is added 50 g of crushed 4A molecular sieve. After 15 minutes, the solution is filtered, washed with saturated sodium bicarbonate, and dried over sodium sulfate. The solvent is removed and the residue is chromatographed on a dry column of silica gel eluting with ether-hexane 1:1. The product bond (R^ = 0.5) is extracted to give 3.44 g of the title compound. 179 48207 EXAMPLE 282 Preparation of 2-(8-hydroxy-7-oxo-octyl)cyclopent-2-en-l-one, 7-ethylene ketal A solution of 5.5 g of 2-(8-hydroxy-7-oxo-octyl)eyclo-pent-2-en-l-one (Exanple 269), 25 ml of ethylene glycol, and 0.1 g of ^-toluenesulfonic acid in 200 ml of toluene is refluxed for 40 minutes using a Dean-Stark trap. The solution is poured into saturated sodium bicarbonate. The mixture is extracted with benzene. The organic solution is washed three times with water and dried over magnesium sulfate. The solvent is removed to give 6.0 g of the title compound, EXAMPLE 285 Preparation of 2-(8-trimethylsilyloxy-7-oxo-octyl)cyclopent-2en-l-one,7-ethylene ketal To a solution of 2.2 g of 2-(8-hydroxy-7-oxo-octyl)cyclopent-2-en~ 1-one,7-ethylene ketal (Exanple 232) in 20 ml of pyridine is added 4.6 ml of 1,1,1,3,3,3-hexamethyldisilazine and,dropwise, 2.3 ml of trimethylsilylchloride. After 15 minutes, the excess reagents and solvent is removed at reduced pressure. The residue is taken up in ether and filtered through a short pad of silica gel. The solvent is removed. Toluene is added and re20 moved. The residue is dried at reduced pressure to give 2.77 g of the title compound.

EXAMPLES 284-296 By the sequence of reactions described hereinabove for Examples 268 and 269 or 270 to 273 and the protection reaction described hereinabove in Example 281, the protected cyclopent-2-en-l-ones listed in Table 28 hereinbelow are prepared from the indicated carboxylic acids. 180 TABLE 28 1 pH X 1 X I Λ~Λ iH X 1 \ r-( X 1 r~\ fM X I <—i X 1 F-t O XrH i y 1 st 1 sf st st st st I 7 δ· 1 § s § C rt g rH g pH C /-s 5s? o o o 0 0 0 0 o X X X X X X ( Q o o 0 0 © 0 © O CM •rt © •rt β •rt c •rt I Ό T3 S3 S3 C S3 0 S3 O *0 irt 1 K) to tO eo ι to Ip tO pH to cu » M • 1 * 1 - O fl) fH I pH β ip q ph μ β 1 1 I i C 1 © 1 © ι έ· ο I X X X pH © X 1 FH 1 X CM fH t xcm X x Λ Λ fl) X 0) X PM X f 44 1 X 0 1 p fl) P c P C P ) P P P P ρ X β fl) C fl) o © o © P © G © q © Ρ fl) f? n ε ι ε ι ε q ε © ε © ε © , •1-t 1 •H pH •rt © •ρ cu •rt o< •ρ ε PM S3 fH S3 1 S3 l S3 CU S3 0 S3 o S3 1 1 | 1 q 1 c ( O 1 fH 1 fH 1 ΡΜ +J CM β CM O CM © CM «-< cm y cm y CM ' β « fl) * 1 * 1 * y Μ | fl) CM I CM CM CM CM cm X CM U pm y PM ’t CU 0 1 CM X I X P 1 1 X P X C 1 1 XP X q ι y Xi—1 X Ή X«rt X X χΤ7 © χ χ q o O 0 O © 0 © o x O 0 o q ο q ο X X fl) 4= CU X CU X β x © x © χ © ι y P cu P O P 0 P © P I . P 3 Ρ ι ,»Ρ fl) o fl) ι—1 © —1 © ι . © (A| © (A| ©(All Ό fl) s »-* ι y ε y > X ε © 1 X S (Λ 1 »rt B «rt ι y{ Ϊ3| Β *rt q ι y|© P X st υ st o y| sf 1 St 1 sf ι ι Q > o f-4 '—'fH t 1 »PM '—'CM ' CM CM fl) 1 Ή Χ.Π X ι X in P 1 X X P 1 CM Ό 1 1 1 in p 1 I X P 1 i 1 in p P o ·—> X <—> C ' CU ‘—i X q ’ p*u—* q q ι 01 1 fl) I © 1 © 1 © 1 © 1 © © P- CM Ό CM CU CM 42 PM X CM CU CM X CM CU CU 1 p 1 P 1 1 «—* , 1 4J c β pH fH »H β fl) © pH X X 1 fl) CU CU X 0 s q «ρ CU o o 0 © © © t o V 1 ±J ι , q υ U) 1, w ί (Al © o X X •rt 1 •rtf •rt 1 I X u y •H © y 1© y|« y |cm u r-\ y|g ι 0 ι c PM O1 S CM O 1 1 CM P rH X X P X P CM 1 1 pH 1 1 P 1 1 P irt i q p © -β X β cu X 1 q «. CU ι q cu 0) 0) © © 0 © 0 © q © o υ rt X X δ 42 X X © X I cu © X 1 So X χ X X CM X PM X CM X o O fl) o fl) o © Ο ί O 1 O } o 43 0 X C X C X 4J X ti £ t χ χ Ul O Ui 0 Ul O μ C μ c μ q H ji X rt ι rt ι rt ι rt © rt © rt © rt 0 X O fH υ >-h O —1 y cu y cu y cu y μ 1 | 1 | 1 1 1 o 1 o < o 1 % c in C P*· O \O pH in i-i C- fH m X μ X—» © o d) o © o y · y *—»x © ι I I | 1 1 ι X 1 X ι X ι ι q CJ CM CM CM CM CM CM cm y cm y cm y PM Sf O fl) Λ mJ· in Ό r^· 00 cn O & co 00 CO CO co co 0) rt CM CM CM PM CM CM CM X PJ 181 TABLE 28 (continued) Protected cyclopent-2-en-l-one j 1 rt 1 rt O ί-3 7 5· fi o ra x rt X O 0 X I Ο CN •Η 1 53 rt I X to CU rt* S Λ & >» X 43 0 Ρ 43 V Ρ S a> •η E Ό ι 1 CN CN ' «. I CM rf 1 r—i Xrt 4) X X fi 0 « o fi fl) I P 1 rt 0) (Λ I ε «η c i 0 4) η- ι ι *—*CN CM I I 1 r* jj +j — CU fi 1 fl) fl) CN 43 a 2-[6-(4-methoxy-2,2-dimethyl-1,3-dioxolan-4-yl) hexy1]-4-(2-methoxypropy1-2-oxy)cyc1opent-2-en-1one 1 1 rt ts rt fl) X I 1 CN rf | 1 P G C ra fl) fi* 0 0 X rt 0 rt X Ό 0 1 O >? rt O 1 1 rt CN X I Λ rt +J X g fr 5 s ? δ CN X * O CN 43 1 P fcg 0 I Λ CN P 'rt §4 ) 1 rf r—rt rt C X fl) ΙΛ P fi rt t5 O 1 0) t CN CUrt 1 1 rt β rt fl) X l 1 CM •e ι 1 P § s rt CU o o X rt O 0 ΐ fr I rt. to X J g 1 1 rt CN X 1 ±5 rt P X ir 7 δ CN X * O CN .£ I P X a> x e O 1 ia §4 1 1 1—1 rt rt ) X « f* P fi rt. J cu 0 1 fl) 1 CN 43 rt 1 o 1 rt rt 0 rt X X O I rt I 57 S? rt CN ζ 1 X rt O •h S’ o ι P ”δ rt X 1 o rt 43 XP 43 0) P 6 fl) 1 6 cn •H rt Ό 1 1 rt CN CC CN N 1 1 Xi—· fl) Xrt S OXO fi C 1 p fl) rt fl) I.l B «g 1 rt fl) rf O r rt 1 CM 1 CN 1 © 1 P rt χ e 1 fl) fl) CN 43 CU e 1 fl) rt> 1 rt Carboxylic acid I 2-(7-carboxyhept-2-cis-enyl)- 4-hydroxycyclopent-2-en-l- one 2-(6-carboxyhexyl)-4-hydroxycyclopent-2-en-l-one 2-(5-carboxypentyl)-4-hydroxycyclopent-2-en-l-one 2-(7-carboxyheptyl)-4-hydroxycyclopent-2-en-l-one 1 rt* 1 rt fi fl) CN ) . » W P rt fi O fl) • & CN O 1 rt χ υ fl) X fi υ && 5 2 Ρ Ό rt X o fi 1 1 fl) © rt fi rtOtf O 1 rt | CN Nf rt ie 1 fi rt O fti ι «—> rt rt 1 I β rt fl) rt 1 XCN X 1 0) P fi G X fl) X cu o o fi rt P o ra x u o 1 X © X S ι ±3 CN Ό I Example j 291 292 293 294 295 296 - 182 48207 EXAMPLE 269A Preparation of 1-(1-methoxy-1-methylethoxy)8-[3-(1-methoxy-l-methylethoxy)-5-oxo-l-cyclopent-l-yl-2-octanone To a stirred solution of 31.2 g (130 mmol) of l-hydroxy-8-(3-hydroxy-5-oxo-l-cyclopent-l-yl)-2-octanone (Example 269) — in 190 ml of sieve dried O^Cl^ is added 47 ml of 2-methoxy propene (Eastman) followed by 0.1 ml of dichloroacetic acid. The resulting mild exotherm is maintained at 25°C by water bath cooling. After 30 min., TLC (ethyl acetate, 2,4-DNP) shows no starting material, minor spots at RF = 0.5 and 0.6, and a major spot at Rf = 0.78. After 1 hr. total time, another 0.1 ml of dichloroacetic acid is added. After a total reaction time of 2 hr., the solution is diluted with 650 ml of hexane. The solution is washed with 50 ml of saturated NaHCOj and brine, the solution is dried (K2CO3,MgSO4) and 0.05 ml of pyridine is added. The solvents are removed giving 48.4 g (97%) of Anal. Calcd for ^21^36%' C, 65.60; H, 9.44. Found: C, 65.35; H, 9.45.

PMR: δ (CDCIj), 7.06 (m, IH, enone), 4.92 (m, IH, CHO), 4.00 (s, 2H, CH2Q), 3.22 (s, 3H, 0CH3), 3.18 (s, 3H, OCHj), 2.62, 2.40, 2.16 (m's, 6H, CH2's), 1.36 (m, 20H, CH2's, CH3's). IR: (neat) 5830 nm.

EXAMPLES 296B-296N In accordance with the reaction sequence of Examples 267-273 and the 20 protection reaction of Example 296a, protection reaction described hereinabove in Example 296A, the protected cyclopent-2-en-l-ones listed in Table 28A hereinbelow are prepared from the indicated carboxylic acids. 183 4 8207 TABLE 28A Protected cyclopent-2-en-l-one 1 rt 1 C 5 C Φ 6 0 rt υ & 1 rt 1 0 X 0 1 ιη α ι S X 0 Λ Φ rt S £ 43 Φ Ε I rt φ I C S 0 X C 0 <0 X 43 U Φ 0 Ε 1 1 Ci rt 1 <*» I *-» rt S 1-(l-methoxy-l-methylethoxy-7-(5-oxo-1-cyclopenten-lyl,2-heptanone I r 1 e V *1 c tl 8· rt U X 0 1 rt J 0 1 tn ί et 1 S X 0 £ Φ rt S Λ 43 E 1 rt 1 Φ S 6 X 0 0 c Λ fi 43 fi Φ 0 fi c 1 1 rt Ci 1 rt rt S 1-(1-methoxy-l-methylethoxy-B-(5-oxo-1-cyclopenten-lyl)6-cis-octen-2-one rt t (S Φ 43 C « & rt u & 1 rt 1 0 X 0 1 in w* f* 1 rt s X 0 £ Φ Φ rt fi SO X 1 43 Ci Φ 1 fi C 1 Φ rt 43 1 CL 5?Je X nl 43 rt φ ol fi 1 ι in rt | 1 rt rt S 1 rt 1 c Φ 43 C Φ a 0 rt 0 s □ 1 rt 1 0 X ? in 1 et 1 S X 0 X 43 Φ rt Φ sc X 0 43 t II 1 c so x e o \ £ « 43 φ ul £ 1 1 s rt t 1 rt rt S s X 0 Λ 43 V rt 5 X Φ f rt Φ 1 c so X t 0 Ci X 1 43 e φ φ 6 £ ι a rt Φ *-»X 1 * rt tn| 1 ul 5 1 .1 m o rt X s 43 I φ rt rt J sc X Φ 43 43 Φ C 6 S ι a rt 0 1 rt SU X S 0 U X 1 43 rt Φ 1 E 0 1 X rt o -* 1 I m rt | 1 Ci 1 1 43 ( 1 1 1 Φ ~ c fi ** rt rt rt 0 C φ Q. Φ c. Φ CL rt >1 S c s c S 1 e rt 0 0 fi Φ Φ Φ i_ Ό rt ϋ 0 rt U >1 U rt υ S u rt U >1 υ rt Φ 1 , n rt φ □ IC 1 0 t w rt I □ ΙΦ 1 c Ci 0 «1 rt υ|φ t e ci 0 1 , c η Φ 3IA I 1 Ci 4) (0 υ rt >1 X Φ χ >1 χ S 43 c >1 43 CL Φ Ci | 1 rt X 1 φ fi I t 43 rt fi 1 Φ fi 43 rt CL 1 Φ C 43 Φ c a Φ 0 rt S X J §« Λ S X 0 Φ Λ Φ S 1 X Oi 0 1 a Φ S 1 X Ci 0 1 X Φ S 1 X Ci 0 I an s u X s § 9 2 2 Λ fi A 43 2 43 J3 X s X υ Μ Φ Λ C υ ο M 0 18 1 OH X 0 fi 1 OH X fi fi Φ □ CL I 0 X fi fi Φ □ CL 1 0 X fi β Φ □ a 1 0 X X fi 0 □ X 1 Ό 1 1 SD rt 1 1 ? Ci Φ 2-(5- 2-en- 2-(7- 2-en- VD rt ** □ tn rt *-* U A& Γ* rt ~ o 1 s Ci U m s — X 1 1 Ci * ο •Μ I « o O M h a 9 fg Φ so to SP SO SO to χ eh et et et et et Η CI Ci ci N Ci c< Ci 184 T3 © ΰ c c u a (N a i , 1 1 & & s X 0 rt 1 £ o 4J =e rt s © JS >» 5 a rt © Ai © © © >1 rt g rt >9 1 © rt fi > 5 >1 S 4> 1 © F rt 5 1 0 © © B g > 1 1 g f= s rt | gw 5? V 1 rt i rt I & rt 1 >1 0 1 55 X 0 £ © rt 1 h ??§ 0 «£ X 0 Is Ai fi © 0 g . 0 0 £ 1 Ai CM © 1 s c Π © ί g © s 1 0 rt * ** Q)| 1 rt rt' Ul S fi 1 fi rt Ai X? 5 © E I i © rt e 1 © rt a *-* c 1 0 rt © *-* 6 & to A? rt — φ —- 0 u η © 1 0 rt ι , 1 c ι e 1 0 rt | 75 rt fi -* fi 1 rt rt *“> rt rt 0 ' «—· «I *— ml e* cu 1 c β >1 1 rt 1 CM t rt| 1 © σ\ 0 1 t c 0 1 rt | e% ul 1 1 > a ul 1 l X i 0 ** ~£ > 1 X CM 0 1 £ 1 fi £7 o — *=* rt >1 1 X fi 0 © ££ >. e x © 0 Ai X «Ul 0 0 £_Ω c £ rt «© rt Al rt £ rt «Μ fi 5 £ Ai l © 1 (N 1 Ai c Ai > © 1 rt rt >i 1 5g Ai S © 1 rt rt > 1 5S © >4 Sh f X rt 1 g Ai >i & 1 rt rt >1 1 5g S.S. X 0 So Ai >t © cu rt 0 >»rt £ U a & © — rt rt >. >1 £ 1 Ai rt GJ 1 0 © © AJ o *> S *! g ? S o £ C CL 0 rt £ c 1 © rt cu £ © 1 © rt a, ε © AS. f“§ γ & Ε 1 1 rt ? O 1 rt 7 ό i © rt q, ) 0 u > a *0 © Ai U © l-roethoxy- xo-l-cyclo 1 0 XU is Ai 1 gf 1 0 rt X 1-methoxy- xo-l-cyclc >rt X U 1? IT rt X 5?s· 0 I £ m Ai | g> Ao >. X g? >rt X U 0 > £ U Ai | © rt E 1 1 0 rt x 0 * 0 ** 0 ** 0 7? 75 1 Ai 1 i u cu rt in rt m rt m rt in rt © rt © rt in 1 © 1 «ζ? I t 1 >1 ~ c 1 *=* 0 rt © X p fi rt © k *p -j X 0 b © rt >1 0 b *0 > 1 Ό © 1 ί s © 1 © rt £ >1 £ 1 A « 0 . f SH £ rt | ml © 1 « e 1 rt UFM rt © ΈΓ © 1 © 7ΊΪ 1 fi ul 1 ~ © -* c oio. Ό Ή o ΓΜ Ai 1 C Ai © 1 CM CM 1 1 4J rt 0 > 1 AJ rt rt 0 «Μ rt 1 0 CM rt 1 u ** © rt 1 >%fN i i if f3 0 rt a a © 0 £ rt ££ X c © © £ CU > 0 X rt C 1 s.g . x A CU 1 © c £ © &A 2 o Is © 4U I! g e 0« X? > X b Γϊ © 0 U b Is • § £ 5A gg u cu iA b fi s s. i £ M >1 gf SI? b £ u CU • O (8 o 1 Ό F* >i AS ** Ό A° ** P 1 0 r*» rt A ts c A 5? 7S to rt Cu • 1 1 CM 1 > CM J3 A o A & CM Φ rt Ao © rt 1 u a s o a IS is IS 6Λ & 01 6Λ KJ W w CM CM 125 • 48207 EXAMPLES 297-298 By the sequence of reaction given hereinabove in the Examples 274 to 280, the protected eyclopent-2-cn-l-ones of Table 29 are prepared from indicated Bromocarboxylic acid. 186 ί C 3ι Ο -6-oxohept-2- cyclopent-2-e -8-oxonon-2-c opent-2-en-l- c X χ χ~< ο κ χ X Φ 0 ο Ο X μ υ ι X X X b c r-l rd rd X φ •Η Ο ι (Λ tn »—ι ΙΛ rd rs) I rH rd <0 r-l X χ χ μ X rd rd μ μ χ φ μ ·Η Λ fi □ μ 3 <λ μ Φ _Ω φ £ r-l Φ CU ι, ε φ ο <-> ·η q ρ|λ I μ φ 1 4-> φ υ Η Ρ Η HOC χ χ ι χ χ ε φ CJ JZ Tf Χί X ·Η Η Ό μ > μ Φ Φ μ μ X Φ μ -fi Φ ε ι ε ι μ μ •Η ΧΌ •rl Tf φ U Ό fi * •β 1 1 φ 1 Φ Φ 1 /—.CO μ ι** I , C CT> r-t * ο ' w Ο '—* X Φ μ ι ·η| ι c c Cl- rd Φ |rd rd Φ 0 Ό ride ride Ο Ο Φ r—1 π3 Χί Χί Φ υ ι υ rd —Μ X X X Ο 0 box tan xan μ 3 φ σ3 J2 χ ϋ ι ο □mo ο Η μ μ Ο 43 43 μ 1 ca tr <υ r1 Cu r- 00 Ρ σ» σι <9 C4 ΓΊ X UJ 187 EXAMPLES 299-308 By the methods described hereinabove in Examples 268 and 269 and the ketalization reaction described in Example 282, the cyclopent-2-en-lones in Table 30 are prepared from the indicated carboxylic acid. By the methods described hereinabove in the sequence of reactions shown in Examples 270-273 and the ketalization reaction described in Example 282 the 4-hydroxycyclopent-2-en-l-ones in Table 30 are prepared from the indicated carboxylic acid. 188 4 8 2 0 7 Cyclopent-2-en-l-one I 2-(7-hydroxy-6-oxoheptyl)cyclopent-2 -en-1-one, 6-ethylene ketal 2-(9-hydroxy-8-oxononyl)cyclopent-2-en-l-one, 8-ethylene ketal 2-(8-hydroxy-7-oxooctyl)-4-hydroxycyclopent-2- en-l-one,7-ethylene ketal 2- (7-hydroxy-6-oxoheptyl)-4-hydroxycyclopent-2- en-l-one,6-ethyelne ketal 2-(9-hydroxy-8-oxononyl)-4-hydroxycyclopent-2- 1 en-l-one,8-ethylene ketal j 1 CM 4 P ro CJ a o rt υ δ- p-4 X ro © 1 . w •rt 1 O|pM f ro CM P 1 CJ tj4 0 CJ 0 c X CJ O rt ι x X X 1 P X CJ X 1 O x P * Ό Φ £§ t 1 09 rt '—, ί ro CM CJ 2-(7-hydroxy-6-oxohept-2-cis-enyl)cyclopent-2- en-l-one,6-ethylene ketal 2-(9-hydroxy-8-oxonon-2-cis-enyl)cyclopent-2- 1 en-l-one,8-ethylene ketal j 1 X X o P •o £ s- v.*, ro ro· p I Φ ·—» X rt X Φ ro ro φ o 1 ,rt W X •XX OP 1 © CM 1 1 f* P * υ φ o c o o X 1 O r-l 1 1 7 § O 1 P p *ro ro X Φ x a ι o 00 rt CJ 1 cm υ P § a O rt o & & δ έ I s '—'rt ro· ro 1 P rt» © rt X X P CJ υ ro o © o w X X O X 1 P r- © 1 1 sT- Q CJ •S § £rt 1 1 oo ro ί 1 CM 1 1 1 CM 0J Φ CM CJ CM 1 P CM c o § 1 P P c CJ § 1 P ro P c 1 1 o CJ a rt ro φ Φ rt I a o | φ a a X £ e o C a o o 1 X» CJ © •-M u υ χ CJ 1 0 rt rt υ υ S' & 0 CM CM X ϋ u X CM 1 υ X X CJ & ro- χ X P CJ rt» c C CJ £ o 0 p c CJ K rt rt X rt rt» rt s Ο- ο a o P Ό Ό X a o X c ro © § X Φ c ro X r-M ϋ X u i-M u X o rt\ X X 1 ro· 1 X 1 ro· 1 <—> r-t pH o X o rt -cis-e 2-cis- 2-cis- *. » 4/)|rt •rt 1 o ro 1 Φ ci krt . Tf i rt% acid X P c CJ a X X P a © A X r—4 ί? CJ X fc X P c CJ a & & a CJ 'x X xyhex-2 1 g 1 P a φ f CM 1 1 CM X i © P x ro X © x a 5? © © c X o X I X r-4 u •rt o X μ, o A μ, o A p CJ o A P CJ o X P o X Ρ Φ o x Ρ Φ o X Ρ Φ o o X r-4 O 1 x ro P © X X ro u ro a ro c u o ro c ϋ O ro u ro c u o ro c u o ro ro o o ro x u o ro r CJ CM 0 A t ΙΛ 1 r·* 1 1 r-M ιΛ —ι ' 1 r· · X 1 in Λ | ft rt ’ 1 X X o X P c « u CM 1 CM ι ro CM CJ 1 C CM CJ CM 2- en l c CM CJ i ro CM Φ ι P CM Ό cm a 0) —4 ε ro 299 300 301 302 303 304 m © 306 307 308 X tu —— 189 • 48207 EXAMPLE 309 Preparation of 2-(8-trimethylsilyloxy-7-oxooctyl)-4-trimethylsilyloxycyclopent-2-en-l-one,7-ethylene ketal To a solution of 2.2 g of 2-(8-hydroxy-7-oxooctyl)-4-hydroxycyclopent-2-en-l-one,7-ethylene ketal (Example 301) in 40 ml of pyridine is added 9.2 ml 1.1,1,3,3,3-hexamethyldisilazine and, dropwise, 4.6 ml of trimethylsilylchloride. After 30 minutes, the excess reagents and pyridine are removed at reduced pressure. The residue is taken up in ether and filtered through a short pad of silica gel. The solvent is removed and the residue is dried at reduced pressure to give the title compound.

EXAMPLES 310-318 By the methods described hereinabove in Examples 283 and 309, the hydroxycyclopent-2-en-l-ones listed in Table 31 are converted to their trimethylsilyl ethers shown. - 190 48207 © §· χ Ρ cu © X ο X rt ο © ι P \O © I X X X © o c rt © X rt rt X •rt X tn rt rt © © © ε c rt o μ ι X g g X o I rt oo rt I P X © X X o rt © X c rt © «rt rt rt j? X P X © P I © 00 s * X X P s •rt μ p © t c «e © I rt rt X rt X XP P © PU I © \O X o © x c o o I I rt t I X c X © O I rt CM X ι rt P •rt c trt © rt cu X o X *-< P u © X 6 o •rt X μ X P o I rt rt Γ- χ © / rt P I «rt © CM «Λ ε •rt μ © P s I © Tf rt 1 X *-»x rt P X © ff I O CO ff o © χ ff o o CO I & © O I rt CM X » rt p ♦rt ff Ul © rt PU X 0 X rt p o e o •c ?f P o I rt rt cn x ff * rt ρ I «rt © CM ΙΛ X X c © I , tnirt •rt ff OP I © CM X I p © O ff © © O rt X X O X I P X © o © rt ff X o rt I •rt rt tfl I rt ff X © X I P CM © I S p •rl C μ © p S* ι o CO rt ' O ι X CM O X c © I . tn •rt Jrt O ff I P CM © I X P cu © © ff X © o rrt X X O X I P \O © I I o © «rt C X o rt I •rt rt tfl I rt ff p CM © I ε £ •g s V §· X rt ο O 1 >> CM O •rt ff OP © CM .

I ff © o c ff © ο τ' X X O £ I P 00 © I X» g ® χ·§ rt I •rt rt P Cu I o Ol «rt o < X CM O rt ff X ° ff I © rt > . < tfl ff •rt © O I I CM CM I 1 P P ff O © o cu o o X rt O O ti £ ±.s? §5 «rt X Xrt rt «rt •rt tn tn rt rt X rt XX « £ Ρ P P © © ©ex ε -ρ •ρ μ μ ρ P I I rt co ei x •rt © μ rt p X Λ5 ei © *3· X ι * rt Φ rt ff X o P I o rt O I o s X © Ο i I CM X I I P £§ 5 & Xrt rt O •s b· &5? £2 © X ε «χ •rt «rt μ tn P rt I X 03 £ Krtp 1 i CM 6 ketal o rt tn tn rt tn vO rt tn x o tn eo © tn co rt m - 191 48207 EXAMPLE 319 Preparation of l,9-dioxo-lla,15-dihydroxy-l-hydroxymethyl-16,16-trimethylene-I3-trans-5-cis-prostadiene and 1,9-dioxo-11a,15-e£i-dihydroxy-l-hydroxymethyl-16,16-trimethylene-13-trans-5-cis-prostadiene To a solution of 1.95 g (0.00533 mol) of l-iodo-4,4-tximethylene-3trimethylsilyloxy-1-trans-octene (Example 13) in 6.5 ml of ether is added at -78°C with stirring under argon 6.66 ml (0.0107 mol) of 1.6M t-butyllithium in pentane. After 15 minutes at -78°C, the mixture is stirred at -10° to -5°C for 90 minutes. The solution is cooled to -78°C and a solution of 0.704 g (0.00533 mol) of copper pentyne and 1.75 g (0.0106 mol) of hexamethylphosphoroustriamide in 20 ml of ether is added. After stirring for one hour, 1.7 g (0.0044 mol) of 2-[6-(4-methoxy-2,2-dimethyl-l,3-dioxolon-4-yl)hex-2-cisenyl]-4-(2-methoxypropyl-2-oxy)cyclopent-2-en-l-one (Example 281) in 13 ml of ether is added. The solution is maintained at -40° to -50°C for one hour and -30°C for 30 minutes. A solution of 1 ml of acetic acid in 5 ml of ether is added followed by a saturated solution of ammonium chloride and dilute hydrochloric acid. The solution is filtered and solids are washed with ether.

The combined filtrate is extracted with ether. The ether solution is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The ether is removed giving a yellow oil which is dissolved in 60 ml of acetic acidtetrahydrofuran-water 4:2:1 and heated to 40°-50°C for 70 minutes. The solvent is removed at reduced pressure at 50°C. The residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with saturated sodium bicarbonate, brine, and dried over magnesium sulfate. The solvent is removed. The residue is chromatographed on a dry column of silica gel eluting with ethyl acetate-benzene 3:2 containing 1% acetic acid to give 0.35 g of 1,9dioxo-11α,15-dihydroxy-1-hydroxymethyl-16,16-trimethylene-13-trans-5-cis- 192 48207 prostadiene and 0.39 g of 1,9-dioxo-11α,15-epi-dihydroxy-1-hydroxymethyl-16, 16-trimethylene-13-trans-5-cis-prostadiene.

EXAMPLE 320 Preparation of 1,9-dioxo-lΙα,16-dihydroxy-l-hydroxymethyl-16viny1-5-cis-13-trans-prostadiene To a solution of 2.9 g (5.6 mmol) of (E)4-trimethylsilyloxy-4vinyl-1-tri-n-butylstannyloctene (Example 210a) in 4 ml of tetrahydrofuran at -78°C under argon with stirring is added 2.4 ml of 2.4M n-butyllithium in hexane. The solution is stirred at -30° to -20°C for 2 hours. A solution of 0.74 g (5,6 mmol) of copper pentyne and 2.3 ml of hexamethylphosphorous triamide in 18 ml of ether is added at -78°C. The solution is stirred at -78°C for 1.5 hour. A solution of 2.0 g (5.2 mmol) of 2-[6-(4-methoxy-2,2dimethyl-l,3-dioxolan-4-yl)hex-2-cis-enyl1-4-(2-methoxypropyl-2-oxy) cyclopent-2-en-l-one (Example 281) in 20 ml of ether is added. The solution is stirred at -30° to -20°C for l.S hour. To the solution is added 100 ml of saturated ammonium chloride. The mixture is extracted with ether and the ether solution is washed with dilute hydrochloric acid, saturated sodium bicarbonate, and dried over magnesium sulfate. The solvent is removed and the residue is dissolved in 90 ml of acetic acid-tetrahydrofuran-water 4:2:1.

The solution is stirred at room temperature for 2 hours. The solvents are removed at reduced pressure at 50°C. Toluene was added and removed. The residue is chromatographed on a dry column of silica gel eluting with ethyl acetate to give 0.5 g of the title compound.

EXAMPLES 321-422E By the methods described hereinabove in Examples 319 and 320, the 1,9-dioxo-l-hydroxymethylprostene derivatives shown in Table 32 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-l-one. In those cases where isomers are obtained at the or positions, only the Cl3 or C1(. — normal iso193 48207 aers are listed in Table 32; it should be understood that the corresponding or CI(.-epi isomers are also formed and are part of this invention.

In those cases where the initial conjugate addition product contains a triphenylmethoxy blocking group, deblocking is conducted in acetic acid-tetrahydrofuran-water 4:2:1 at 50°C for 5 hours. - 194 TABLE 32 1,9-dioxo-1-hydroxymethylprostene 1,9-di oxo-1 Ια,15-dihydroxy-1-hydroxy- methyl-16 ,16-trimethylene-20-nor-5cis-13-trans-prostadiene 1,9-dioxo-1 Ια,15-dihydroxy-1-hydroxy- methyl -16, 16-trimethylene-20-methyl-5cis-13-trans-prost adiene 1 1 XlO X ι O rt fc X Ό X X X U 1 t rt O 1 CN X I X U O fi © fc o fi Ί3 rt <0 X X^j X X rt 4-» rt •0 « fc ι £ tn LO rt o rt fc fc -Ρ a β ι ι rt \O tn 7 Ί§ 0 Ό fc X rt +J θ * 1 rt rt tO Ό Xrt t X » . σ» -Ρ tn * ω ·η rt e ul » . tnl l rt I 0 ul r-l 1 U ΙΛ X ‘ 1 S rt rt Λ T) X fc I CLP σι ο ι * fc to rt art 1,9-dioxo-lla,16-dihydroxy-16-vinyl-20- ethvl-l-hvdroxvmethvl-5-cis-13-trans- prostadiene l,9-dioxo-lla,16-dihydroxy-16-cyclo- propv1-1-hvdroxvmethvl-5-cis-13-tr an s- prostadiene 1,9-dioxo-11a,16-dihydroxy-16-ethyl-l- hvdroxvmethvl-5-cis-13-trans-prostadi- ene Vinyl Iodide or Vinyl Tin of Example 49 OS rt LO 199 201 198 210c V c o c 4> 1 CM fc C 0) a 0 rt υ X u 281 281 281 281 2 81 281 281 Method of Example i 1 319 ί 319 319 320 320 320 320 0) rt ε d X UJ rt CN 80 322-332 to to to 334 335 336a X Ό to to 195 TABLE 32 (continued) 1,9-dioxo-1-hydroxymethylprostene 1 X X s X Λ •rH T3 1 ω pH ΰ pH pH 1 o X 0 •rt 1 r—( t o μ 42 P X μ © 1 pH Ό 16-methoxy-1-hydroxymethyl-5-cis-13trans-prostadiene dl-erythro-1,9-dioxo-lla,15-dihydroxy- | 16-ethoxy-l-hydroxymethyl-5-cis-l3trans-prost adiene 1 £ •rt μ P M3 trt tn pH © pH 1 O X o •rt ·© (3) pH 1 0 μ 4= P & © 1 pH Ό droxy-1-hydroxymethyl-2 0-nor-5-cis-13t rans-prost adiene , 1 IA X'rt 1 4= υ| •rt μ tn P 1 PH \O X pH 42 * P tn © ι—ι £ * © © Prt M ·—1 1 pH OX© X Λ β OP© •rt © ‘rt Ό fll 'S ι X © O) X P * 0 w pH μ o ι ·© μ Ο X Λ μ λ ι Λ 1 (A £7 S η χ μ © X P Λ Ό *0 pH 1 , X X P * 0 (A ph μ o ι μ ρ X A μ 45 ι 45 1 1/1 £7 S Ssh « 5 *> Λ 2 « ΰ τ! h dl-erythro-1,9-dioxo-lla,15,16-trihy- droxy-19-methyl-1-hydroxymethyl-5-cis- 13-trans-prost adiene dl-erythro-1,9-dioxo-lla,15,16-trihy- Hrnxv-l-hvdroxvmethvl-5-cis-13-trans- 17-trans-prostatriene Vinyl Iodide or Vinyl Tin of Example 74 77 1 P) 00 00 85 98 1 Cyclopent-2-en-l-one 281 281 281 281 281 281 281 Method of Example Oi rH 319 319 319 319 <3> tn 319 Example 337 . 338 339 o K) 341 342 343 196 TABLE 32 (continued) ω e o rt VI o H &. X X rt <υ S X X o $M Ό X £ 1 1 O X O •rt •Ό 1 σι dl-threo-1,9-dioxo-1la,15,16-trihy- j droxv-1-hydroxymethyl-5-cis-13-transprostadiene dl-threo-1,9-dioxo-11a,15,16-trihy- droxv-20-nor-1-hydroxymethyl-5-cis-13- trans-prostadiene dl-erythro-l,9-dioxo-lla,15,16-trihy- droxv-l-hvdroxvmethvl-5-cis-13-trans- prostadiene dl-threo-1,9-dioxo-1la,1S,16-trihy- droxy-20-methy1-1-hydroxymethyl-5-cis- 13-trans-prostadiene J>1 1 -rl X ul X I · •rt IO b ι rt rrt 1 O £ rt +-> - 0) 2 J 2 8 rt Ό © 1 X C ox© X t rt o rt Ό rt i rt Ό ι-l rt 1 X V) cn x o * 44 h rt © p< 1 1 1 OOM © CM C Η i rt X X H Ρ X rt I O 1 rt b to Ό Ό rt dl-threo-1,9-dioxo-11a,15,16-trihy- droxy-19-methyl-l-hydroxymethy1-5-cis- 13-trans-prostadiene dl-threo-1,9-dioxo-1la,15,16-trihy- dTnxv-l-hvdroxvittethyl-5-cis-13-trans- 17-trans-prostatriene Vinyl Iodide or Vinyl Tin of Example | 69 88 1 76 89 90 91 . ..... . . . 92 Cyclopent-2-en-1-one |- [ 281 281 281 281 281 281 2 81 Method of Example cn r-4 tn cn trt to 319 cn rrt to 319 319 319 Example tO LO •g- to Ό to 347 348 349 o LO to - 197 48807 TABLE 32 (continued) 4) C 4> P V) 0 P cu rt X ί g X X s 53 £ 1 1 O X 0 •rt 53 1 © * rt 1 5? P fl) 53 C X fl) x £ ι 53 rt ra 1 P X « X o O P P cu 53 ι X (A 5 S 53 P » P © 1 rt to ·> rt 2 Jil rt »rt | > ol o t X ΙΛ 0 1 •rt rt 53 X 1 X © P * fl) ι-ί ε 1,9-dioxo-1la,16-dihydTOxy-1-hydroxymethvl-19.20-dinor-S-ci s-13-transprostadiene 1 1 IA 5?« SS 53 I xto fi rt 1 1 . rt (/) 1 rt X O X 1 Ο ΙΛ Ρ 1 53 p X o 43 C •rt rt T) p I P © ( rt © *CN 8 rt © rt rt fl) « * C o co a> X rt rt O 1 ’g •rt rt ra 53 XP 1 fi Vi © p O ·» 4) P rt 6 Cu 1,9-dioxo-lla,16-dihydroxy-1-hydroxy- methvl-20-nor-5-cis-13-trans-prosta- diene 1 » rt rt χ ΰ 5 S g f ι ra rt P X ra $8 ι ra © s (N ra l H xpI gto P rt 5J « , X ra 43 rt •rt O 53 1 ι in © I rt rt «£ rt P rt fl) si .3 S 53 53 4) ι X fi © 43 4) * 1 rt rt rt 53 1 »rt rt rt X P 43. ra P p fl) P I CU © 1 CM W X P 87 53 to •Η ra 5J rt ι o| © t rt tn » 1 5£ 75 ο o ge. rt X •8 0 4) l P C © 53 O * Xrt rt 43 53 Vinyl Iodide or Vinyl Tin of Example 107 108 109 110 144 CN rt rt 113 Cyclopent-2-en-l-one 281 281 irt CO 281 281 281 281 Method of Example 319 © rt to 319 319 319 319 © rt to Example 351 352 to in to 354 355 356 357 198 207 1,9-di oxo-1-hydroxyme thylprost ene 1,9-dioxo-lΙα,16-dihydroxy-16-methyΙΣΟ-ethyl -1-hydroxymethyl -5-cis-13trans-prostadiene 1,9-dioxo-lla ,16-dihydroxy-1-hydroxy- methyl-13-trans-17-cis-5-cis prostatriene 1 r-l t t »rt r-ι Ό X rt χ μ μ εΛ φ 0 ε μ I β. νΟ 1 -ι (ft is§ χ μ Ο μ μ ι Ό tO X *“9 4= ι , •rl (ft Ό ·Η 1 Φ £> 1 r-4 ΙΛ « 1 rd Λ ι μ 0 Φ 3 1. •rl X Τ3 Ο ι μ -σ φ * χ e γη λ φ 1,9-dioxo-1Ια,16-dihydroxy-17,17,20- trimethyl-l-hvdroxyTnethyl-5-cis- 13- trans-prostadiene 1,9-dioxo-lla,16-dihydroxy-16,20-di- methvl-1-hvdroxvmethyl-13-trans-5-cis- prostadiene (ft •A § ι3 μ » μ t-» r-l tO » rH r-l Iftl 1 >rl 1 X υ X t 0 (Λ μ ι *β r-l X X Λ X •rt μ 13 Φ t ε <5 X r-4 X * O 0 H r9 Ό »rt X Φ l 43 ts O 1 Φ X r-4 £ Ο 1 Ό ♦rt -4 Λ ό χμ 1 2 03 μ Ο » φ μ r-l 6 ft 1,9-dioxo-1Ια,16-dihydroxy-16-methyl- 1-hvdroxvmethyl-13-trans-17-trans-5- cis-prostatriene Vinyl Iodide or Vinyl Tin of Example rt o to115 J 135 136 137 138 139 Cyclopent-2-en-1-one 281 281 281 281 281 r-l 00 CM 281 Method of Example 319 319 319 319 03 r-l to 319 f 319 Example 358 359 360 361 362 to o to 364 199 TABLE 32 (continued) 1,9-dioxo-l-hydroxymethylprostene 1,9-dioxo-lla,16-dihydroxy-20-methyl1-hydroxymethyl-13-trans-17-trans-5cis-prostatriene 1 ι rt FH P X tn 45 s Ρ H g β, 1 (A s s ( P XP X t o *n μ *© ’ 1 X w Λ ·Η •ρ ol Ό ι i in M3 ι trt fH * X © 45 trt p »rt £ u X X o o •rt μ Ό Ό © t X (5 σ> 43 © f 1 «rt •rt fH Ό 1 in •rt § Ό μ I P o L cm tn f trt X I , fH (A I *rt I X υ x < © in μ 1 ££ •rt P Π trt X e S fH -Xj trt X © 1 45 β O 1 © X fH .H o ’ ”5 •tH »rt rt Ό X P I 4S (A Ch p O F © μ η ε fi, l,9-dioxo-lla,16-dihydroxy-l-hydroxy- methyl-13-trans-17-trans-5-cis-prost a- triene 1,9-dioxo-lla,16(R)-dihydroxyl-l-hydroxy- methyl-5-cis-13-trans-prostadiene l & o μ Ό X 45 © 1 C •rt © 1 »rt Si’S 0 P μ ia Ό O XH trt PU •rt 1 Ό tn ' 5 /—\ ra cn μ P M3 t •rt tn f trt 8 ‘ , trt (A trt »rt 1 1 O 0 i x in o t •rt fH *o x 1 45 Ch P F © trt £ 1 1 irt (A Λ § χ μ js μ Ρ 1 © r* 1 Vinyl Iodide or Vinyl Tin of Example σ> rrt OSI w m •rt CM tn •rt tn LfJ trt rr m rrt 148a Cyclopent-2-en-l-one 281 281 281 281 L 281 irt ¢0 CM 281 Method of Example 319 i 319 ©I trt tn Ch •rt tn 319 319 319 Example 365 366 367 368 σ> \O m 370 trt t- tn 200 Ό C Ο rt rt £-* © •O rt o a χ § +-> ro © x Σ tu s ro x LU ι X X ο Ρ Ό © X C χ © I rt Ο Ο Ρ Ρ •ΰ ΟΧ I X ΙΛ •rt C Ό Λ I Ρ a ρ ΙΛ I rt Μ •-ι μ rt «rt I I ©I Ο 1 X w o t •rt rt *0 X I X σ» p * © rt 3 I rt/ I X •rt X © 0 Ρ O C 2 · P X © rt ι +j +j P r* tn © υ q o I £ Ο © X O rt 1 rt * Ό X w o c c •rt © © I X P rt a p tn © ι g O r-t Ό X o I © z S? © +j O c c · o © rt C P f'i ro o a x c . © X I © < a-< · ' cn rI © ι x ro •rt x © ρ o u p x © t p ό tn © t ι ε w> O rt e Ό X ro o ro P •rt © +j ι X > rt fX,rt P c * © rt p t*· ro © a x ι I X I •rt X rt pox p x x l +J P tn © © ι ε ε O rt rt •Ο ΧΌ o c » rt © ro I X rt aro o © Z ro © P P fi · © © rt O P x ι ro © tn a x § .« p cn £ ι χ ι •rt X rt POX P X X t P P tn © © ι ε ε o rt rt Ό ΧΠ3 O C I rt © in ι x * rt ax X X tn o © z ro © p . pro» O © rt ο p r* ro o a x < tn cn r> r CO -= « - 201 48307 TABLE 32 (continued) © c © rt W 0 b ft ••d X X rt © ε s? o b •o X X 1 rt » 0 X 0 •rt Ό 1 Ch rt 1,9-dioxo-1la,15a-dihydroxy-16-methyll-hydroxymethyI-5-cis-13-trans-prostadiene ι nl rt rt X ω x δ . rt b © cu 1 t ΙΛ 7 S X b X rt 0 b W Ό rt X 1, X M •rt «rt I *0 ©1 1 ΙΟ in in ι rt rt * X 3 X rt rt rt © X X © P •rt b ·© Ό © ι X fi σι x © * t ·Η rt rt Ό , A OX© N O C * b© X Ό rt rt is·© 1 X cu X ι rt X rt W O 1 o b rt b Ό X CU Xrt 1 X fi M •rt © fi Ό M i O b 0 rt rt in © ι rt >»to * © rt a ι ι. •-ι \o in rt rd «id 1 ι ι ©| O b t x o in 6 fi I •rt 1 rt Ό rt X t b X σι rt rt * © © rt rt B 1 rt £ rt 1 © 8 rt © ·© 1 .rt Xrt 72 X X rt •rt X rt Ό © ΙΛ i X O d © b tn r-t cu rt U 1 * X in d © e rt 1 rt rt m b 1 rt rt © » 1 X b IO O 0 rt •rt C 1 , *0 rt in 1 rt -rt Ch c u - © 1 rt ftm Vinyl Iodide or Vinyl Tin of Example l-iodo-3-triphenylmethoxy4-methyl-ltrans-octene (U.S. Patent No. 3,876,690). 1-iodo-3-triphenylmethoxy4-ethy1-1-transoctene (U.S. Patent No. 3,876,690). l-iodo-3-tri- phenylmethoxy-4- cyclopentyl-1- trans-butene- (U.S. Patent No. 3,884,969). l-iodo-3-triph eny1met hoxy-3cyclohexyl-1trans-pentene (U.S. Patent No. 3,884,969). Cyclopent-2-en-1-one 281 281 281 281 Method of Example σι irt to 319 319 319 Example 377 378 379 380 202 ο fc a rt X X fc 0) £ X X O rt CN X *X CO P rt rt ίΛ X X O 0 fc fc Π3 Ό X X X X •H t rt tj c I ( 0) a «-Η rt LO XT) rt χ « * rt fc a x w rt o o rt rt fc t υ a ο χ I x u w ο ι c •π x rt Ό rt fc I I fc .. fc » O to H C rt Ό fi o rt rt £— rt rt CL X X £ fi fi rt -r-l rt X > > ω ifc O rt TJ rt O & χ ε p rt rt X 2 a ι X rt X fc o •fc x ο rt C fc X rt X fc rt ζ—1 rt c fc σ» to rt 42 rt rt SO ι ε o aa 9> O rt rt ι •σ χ υ tn o c x c rt rt u rt ι x » fc rt am p so l I X rt X fc o fc X ι P to rt ι £ O rt TJ X o e rt rt A-g. t rt P rt fi C · χ rt rt ρ χ ρ σ> c rt rt vo rt x a cn §·. . : — CO 00 > co I rt I X rt X P P V) rt o £ fc ι a tn ι rt (Λ I fi x P x fc O P fc I Ό »O X ·* X » . rt W Ό rt I u| β ‘ LO LO rt | O £ X X 0 x rt o Ό fc rt J Ό C Ci χ rt rt I fi I rt rt rt X fc X1-1 2 X ·»“ί O rt. ρ ω ι lo rt < I CN Ε X ι X in to P fi ι rt rt ο ε fc Ό -Η P O fc I ra .rl Ρ X X ι ι X w rt to o rt I c I rt rt rt χ O Xrt rt rt» X -Η Ό rt P W t O rt rt rt O Ε X I I X w to P fi ι rt rt ο e fc tj ·κ p O fc I -♦rt Ρ X X I I X w rt to O ' rt rt - 203 TABLE 32 (continued) 1,9-dioxo-l-Hydroxyraethylprostene f 1 λ «Η Ct TJ rt rt * P GO 1 V) rt rt 0 * 1 P r· x a rt χ 1 ι ο to x c ro X © rt ο χ P P CUP Τ) 0 1 X P tn X O rt .rt S 1 , TJ rt TO Cp t I rt * X © x rt p * © ¢0 s rt c* r-Γ © rt P ι T3 5?£® 8Λ S *β 1 *rt X ΧΌ X x ro .POP Ό C TO © o β χ p w a a rt I i • X TO a rt q rt | TO rt p P I O P O C t x rt m 0 P rt «ρ ρ ι, Ό © in 1 P rt σι ι u| *© 1 rt cm m X ' 5$ * o σι P r-l TJ * 00 X © rt 1 β *rt © X 1 rt >, o +, § s 8 hi h o 0. ft £8 i S S § ι X P a ι ,p in mJ ι rt ι tn * X rt a t rt 1 TO) rt Ρ «Ρ | ι o u| O fi 1 X rt in ο P 1 rt P rt TJ © X I P x σι ι p *© © rt CM g 1 © * 1 c © x © T? S3 a rt a rt 1 P * X W X 0 rt 0 p t s a x © ι X X TO o a c P »p rt •a x p XP P X 3 1 •ρ X tn •rt 1 ,rt > p < , β ι ,w in pj.p rt | U nX I a rt m rt 1 1 rt p rt ι 0 X OCX X rt p OP© •ρ p S TJ © X 1 P X © 1 o *O P rt (Μ T3 t © « I C © X © rt χ «Ρ r> I TJ 00 rt rt rt 1 P * X to r* χ o rt Ο P ι c a x © » X X w s&§ υ κ m X O P 55 μ is·?, 8 1 , m m W-ρ I rt » u| *X 1 a rt m rt 1 i rt P rt ι 0 X OCX x rt p OP© •P P g T3 © X 1 P X © 1 p «© P rt CM Ό t © * fi © 1 © rt X‘P -χ oo t rt rt rt P * 1 TO Γ* x p rt X p ι o a X fi I X © TO 8-g.S 'g.Sii 5 5 A TJ X rt » υ ι, a « to in S »pJ rt 1 U *X ί a rt »n rt 1 t rt p rt 1 O X O fi X X rt p OP© •rt P S TJ © X 1 P X σι ι o *© P rt CM TJ l ( X© * X B © t © rt rt.p * tO co XTO rt Xp * O TO X co rt © p * xa x a ι X O TO ο p ro POrt *O 3 P XrtP X *p l •ρ .ptn TJ Prt t P 1 , « 1,to ω Bw rt l U) *νθ I a «pm rt l | rt Prt POX O fix x top OP© •κ ρ e Ό © X t P X © 1 o * © P rt CMTJ Vinyl Iodide or Vinyl Tin of Example © in rt X 00 rt rt 00 CM 00 rt tn 00 rt ro 00 rt o 00 rt Cyclopent-2-en-l-one rt oo CM rt 00 CM rt 00 CM rt 00 CM rt 00 CM r—1 co CM r-l 00 CM Method of Example o π tn o CM tn © IM tn © CM tn o CM tn © CM tn o CM tn Example in 00 tn X co tn r- co tn oo co tn © 00 tn © © tn rt © tn 204 1,9-dioxo-1-hydroxymethylprostene 1,9-dioxo-11a,15a-dihydroxy-17,18,19,20-tetranor-16-(3,4-dichlorophenoxy)1-hydroxymethy1-5-cis-13-trans-prosta- diene 1,9-dioxo-11a,15a-dihydroxy-18,19,20- trinor-17-phenyl-1-hydroxymethyl-5- cis-13-trans-prostadiene 1,9-dioxo-1la,15a-dihydroxy-18,19,20- trinor-17-(m-trifluoromethylphenyl)-l- hvdroxvmethy1-5-cis-13-trans-prostadi- ene ό fe CM O •s μ © Ό © rt x ci *X © co ι rt rt rt Ό 1 1 ff Xrt tn o x o μ ff μ *0 © CU XX l , X cu ω rt X ff I *0 x rt ι ο μ a x p| in p » r-i © tn a e rt r-t >—'rt 1 1 © ο X 1 x rt tn O t 1 •η μ rt «0 o X ι ff X © rt P α μ © rt Ρ E 1,9-dioxo-11a,15a-dihydroxy-1-hydro xy- methvl-2-nor-5-cis-13-trans-prostadiene t rt i X w X c P ff © μ ε ρ 1 1 in en rt rt 1 1 . fe.2 O © μ » Ό in rt O *0 ff 1 1 a cm in ι rt rt * X a £ rt P rt © © 1 E ff οχ© X Xrt Ο Ο Ό rt μ ff *0 *0 P 1 ΰ © X p a « μ 1—l rt Vinyl Iodide or Vinyl Tin of Example 185 186b 186e 186d 1-iodo-3-tripheny1- methoxy-1-trans- S o. ω • * © χ ' © © A e tn © X p 00 υ * o »n 190 Cyclopent-2-en-1-one 281 281 281 281 290 290 Method of Example 320 1 1 © CM m 320 1 320 © rt tn 319 Example 392 tn σι tn 394 395 396 397 205 4820 TABLE 32 (continued) © c © P (A O μ Cu Frt X 45 P © E X X 0 μ TJ X 45 I rrt 1 O X 0 •irt T3 1 © rrt 1,9-dioxo-lla,15a-dihydroxy-16,16-di methy1-1-hydroxymethy1-2-nor-5-cis-13trans-prostadiene 1,9-dioxo-lla,lSa-dihydroxy-16,16-trimethvlene-1-hydroxymethyl-2-nor-5-cisi 13-trans-prostadiene erythro-1,9-dioxo-1Ια,15α,16-trihydroxy- 1-hydroxymethyl-2-ηοτ-5-cis-13-trans- prostadiene 1 sU 2 § τ) μ Χ+-» 54 μ rrt P ’ 1 1 tn Ό »rtl fH u| * 1 © m in ι «-ι μ * o © c «rt 1 rrt CM 1 1 O rrt X X O JG •rt P Ό © © < S C © X © * X »rt trt O TJ ι μ « o ·© P © X tn fix o λ ι μ P -· CU 44 «rt rrt 1 < . 5?.S δ v1 tj in X ,· »e fe •irt O Τ) C I » 57 Frt (rt * X 55 7 g O X © χ x c Ο O © •η μ »rt Ό Ό Ό ι X rt © 45 P * ι tn «-rt rrt O ι ι μ p X cu μ χ ι 43 O tn P KM S x p rt η © μ ©Bp 1,9-dioxo-lla,16-dihydroxy-1-hydroxy- methvl-2-nor-5-cis-13-trans-prostadiene 1,9-dioxo-lla,16-dihydroxy-16-methy1-1- hydroxymethyl-2-nor-5-cis-13-trans- prostadiene Vinyl Iodide or Vinyl Tin of Example l-iodo-3-triphenylmethoxy-5,5-diraethyl octene (U.S. Pat. 3,873,607)13 76 69 t· X 107 130 Cy c1opent-2-en-1-one i 290 290 i 290 290 1 290 I o © CM 290 Method of Example 319 319 © rrt tn 319 © rrt tn 319 319 © δ ra X w 398 © © tn o © 401 402 1 403 404 206 8207 Ό υ β (Μ Κ) UJ μ ω < Η 1,9-dioxo-1-hydroxymethylprostene 1,9-dioxo-1la,16-dihydroxy-16-methy11-hydroxyme thy1-2-nor-5- ci s-13-1rans- prostadiene 1 ·* 1 CO X r9 X * 0 Φ r*· μ C r-l -fi 4) * X-rt cm xz -a ι ι rt XrH 4J X I (ft OXO μ χ μ *3 0 0« x e t 43 Φ (ft •rt xz c •3 CP rt ι ι μ a \o μ LO rt I ι-l | to * h rt a ο ι, rt β (ft r-l rt «rt I ι μ Φ] o c > X Φ IO 0 CP « •rt 1 r-l T3 © X 1 CM 4= cn « +J ·»© O 1,9-dioxo-lla,15a-dihydroxy-2,17,18,- 19,20-pentanor-16-m-trifluoromethyl- nhenoxy-l-hvdroxymethyl-5-cis-13-trans- prostadiene 1,9-dioxo-lΙα,16-dihydroxy-16-vinyl-1- hydroxymethvl-2-nor-5-cis-13-trans- prostadiene 1,9-dioxo-lla,16-dihydroxy-16-cyclopropyl- 1-hydroxymethy1-2-nor-5-cis-13- trans-prostadiene 1,9-dioxo-lla,1Sa-dihydroxy-2,18,19,- 20-tetranor-17-phenyl-1-hydroxymethyl- 5-ci s-13-trans-prostadiene 1 1 1 «rl λι-9 »3 σι I 3 ι—ι /—> μ -rt (ft co X O rt β. μ • Φ 04 CM ΧΖ I ι CP (ft s?8 5 ο ο μ μ 3 μ Ό 1-9 1 X«W Μ 43 «rt »rt «rt U I . Ό μ (ft 1 L ·Η a ε υ| ΙΛ ' j r-l 1 ΙΛ • r* ι a Irt l-l rt Ρ X r-t μ 43 ι ο μ o c φ X « 6 ο μ x ..-ι μ x *3 φ O ι μ μ σι ρ *3 φ «Ο X β r-l CM 43 Φ Vinyl Iodide or Vinyl Tin of Example 134 186 180 194 CO © ι—1 186b Φ \£3 CO rt Cyclopent-2-en-1-one o Ci CM 290 290 290 290 290 290 Method of Example 319 320 1 320 © rt to 320 320 319 to © TT o o ir 407 408 409 410 411 207 4830 TABLE 32 (continued) 4) fi 4) P ra o P cu rt X X P 4) 1 o P 53 X X rt t o X o rt 53 1 © rt 1 1 rt * 53 © ι ra rt rt ρ * ι ra 00 rt. o rt rt P * X CU CN C 1 ι © ra XX c x cu ra 0 X p P X P 53 0 1 XX to X P ·-< rt © 1 . 53 S ra • 1. 1 ,rt 1 V lajul m · ι rt t m -tx 1 Si rt rt 3 ι x rt P 43 1 0 P O C « x ra β O P X rt P X 53 © O 1 P P © 1 53 © ·© X c rt CN X © 1,9-dioxo-15-hydroxy-15-methy1-1-hydroxvmethy1-2-nor-13-t rans-prostene 1,9-dioxo- llflf, 16-dihydroxy- 16-methyl l-homo-l-hvdroxymethyl-5-cis-13-transprostadiene 1 I ra SS iS 1 rt \© 1 , rt ra 1 rt I S'? Ό >1 ii § •?s-a \ό X ρ rt x rt 5 Ο P v P w rt 53 O rt P ι x cu o l 1 X rt w o ‘ S rt o ra 53 e p ι Ο P © χ 1 * k X rt rt rt J:fr rt o t P Q 53 g X © O X c X ι * ral Ν X Cl rt x a ι p M gg? o ora X p rt rt § raj χ5ί w X rt f ο ρ ω p P 1 53 t,rt X BlX X » 45 rt \0 P 53 «-· © ’ά έ 1 5§8 as-δ rt © X © ι p t e ©Irt© X © P rt Ο 1 rt 1 1 rt ra £§ •ss 1 1 \© tn rt rt 1 * . o © P t· 53 in X 1 X 7* rt X Ti 5 g . - x sg rt P © 1 53 C O X© XXrt o f *2 rt rt ra 53 1 P ι o ra ©Bp * o p· rt X CU Vinyl Iodide or Vinyl Tin of Example 186d 125 0£T 134 186 081 rf © rt Cyclopent-2-en-l-one 290 285 289 289 289 289 289 Method of Example © rt tn © »rt tn © r-l tn 319 320 320 319 Example 412 tn rt 5f rt rf 415 416 417 418 208 8 2 0 7 TABLE 32 (continued) 1 to 1 1 I 1 © * tO fi t © • fi co X CO rt © CO ) © I rt X rd tO ft 1 rtI i rt t t—· 0 1 rt »8 0 ft I o © O rd fi 0 ι rt © rd U ε 8 ε x ft 8 ft Q 1 0 X O C w O ft rt © Xm U 1 έ z 1 O j= 2 S ι X b X x p > C b V) 1 rt rt b ft ft ft ft © ft o Ό X ι *8 l ρ ι , L> b rt X ι rt X X X X © X b W X O ft X © O 1 C p □ ©I p £ Ul X s b rt © b ft I b 0 ι o X *8 i ft •a *ft m •a Xrt rt b X Xrt *8 Xft ι Xft l © *8 0 x x « C fc — X a r £ X b ft C ft .H ft X ft ε x X X £ *8 •8 © rt 1 X O •8 I.X ι Elft 8 i ,x ί cUti o Π3 X © a ah 8 © a © b 1 1 C LH 1 ft in i ε in ι 8 •o M3 rd © rt ι ft r* X ft x X rt 1 ft • rd tf) • ft X • rd X .£ « Ο T3 a 1 fi 3 .1 O ss I O I rt £ fi rt b rt rt b b rd b b rt o rt rd o b ft o ·© rt o *a | 1 X M 1 fi ft 1 S >· ’ t= X o ο 1 o O ft » o ft X O ft X X X rd b X b to x b ι x b ι o 0 ι ft o ft rt O ft ft O ft ft rl rd l ft 1 ι , ft 1 1 ft 1 J *8 *8 X rt *8 © M *8 © m *a © tn I 1 ft C 1 CM ft 1 1 C4 fi 1 CM fi O © 0 rt σ» * ©I © · rt © · rt • b b ·© ι • σι b • © b rd ftrt rd rt 1/) rt rd X rd rt ft b o © *8 O •H •a c Ο -H X © •a >-t t- © CO \O \O Ό o co eo co H rl CL rt rt rt rt x x e cc© •,d «Η X > > UJ © c 0 4 c © Cn σι © © CM eo 00 CO 00 1 CM CM CM CM rt fi © ft O Rd υ X u ft o © 8 rd O ft o © © © £ ε CM CM rt rt rt fi to to to to © X S ω © rd ft © o rt CM ts rt CM CM CM rt fi fi* fi fi X U4 - 209 48207 TABLE 32 (continued) «Μ. 1 rt X X A I X 0 fc Ό X £ 1 rt 1 0 X Φ o c rt φ Ό A 1 « 0 0 - fc rt a I ι n 0 c rt 10 1 fc XP X 1 0 m fc rt *0 * X » £rt •fc ol •ϋ ι ι tn 0 1 rt rt * X «£ rt p rt φ Φ US X X -fc ο o *o rt fc 10 Ό Ό P 1 X n 0 £ 0 * ι fc rt «ρ a AS fe» e 5. £ P Φ O rt w · rt β -fc XO X 1 0 tn fc 1 ’S.S X 0 £ C -fc 1 •o e CJ 0 1 rfc rt * X 0 £ rt 43 rt Φ u X X 0 P •fc fc »σ «σ X 0 £ * 1 rt rt -prostadiene A Em Frt Hl 0 ol rt 1 I tn ξ?Α ZZ Ό P . rt © •e CJ 1 1 « 0rt C «fc X Φ ‘£ rt β 43 Ό rt Φ fi rt E 43 ι ι m 0X0 X X fc ο o a rt fc 1 •0 fl B 1 xc 0 £ « - 1 fc rt rt 43 ν n rt c i? Lm X rt P j? 01 «Β tn 1 1 0 rt b ·· £ fi 43 rt Φ rt Ε Φ f xc 0 X φ X Ort 0 fc Ό rt «0 fi Ό XP t £ 0) 0 ι 0 ‘rt fc rt ι a Pei rtrt γ ol s? Lrt X X R £ ±f P Έ, « £ 1 Φ HOC *0 Ci φ i ι «fc 0 rt T3 rt X fi ‘£ P β ρ n rt Φ 0 rt I fc ι x a 0 X t X 0 « 0 fc c rt Ό fi Ό X fc t £ P 0 1 1 * rt <*) rt I rt Vinyl Iodide or Vinyl Tin of Example rt o rt CN a © rt CN σ © rt CJ rt in rt »O tn rt Cyclopent-2-en-1-one rt CD CN rt « CN rt 00 ci rt 0 CJ rt 0 CN Method of Example o CJ O CJ co © Cl m 0 rt m fit rt m Example « < C| c< * a Ci Ci « U Ci Ci a ci Ci «* H Ci ci For cleavage of the TMS-C=C-group see. Example 772(B). 210 EXAMPLES 423-445 By the methods described hereinabove in Examples 319 and 320, the 1,9-dioxo-1-hydroxymethyl prostene derivatives shown in Table 33 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-l-one.

In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table 33. Xt should be understood that the other diastereoisomer is also formed which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the 6-chain (the chain containing Cjj....C^ etc.) to that of the respective nat and ent forms of the listed diastereoisomer; both of these diastereoisomers are claimed in this invention as well as their component enantiomers. - 211 48207 TABLE 33 1,9-dioxo-1-hydroxymethylprostene and its diastereomer ρ μ μ ρ tj © ι χ ρ w 45 1 β •η ο rt -d cm μ 1 * Ρ ΙΛ © 1 r-l Η Κ) F F (Η ΰ 00 F rrt rrt y) I rrt f ·Η 1 » r- ϋ| Ο rrt 1 X ι ιη 0 © ι •Η fi rrt Τ) © X ί -rt 43 © χρ 1 ι © X ζ-ι £ X ρ rt ο « β μ μ β © Ρ Ό © 1 © Χ·ρ Ό Ρ 45 Ό c ι ι rt RJ \D rrt 4J '—'.rrt J V) p * μ o ra in ο μ q q q, 1 X I X rrt | Ο 1 -H μ μ τ> Ό Ο rt χ β Ρ 45 ·Η « η μ ο ό ρ μ 1 ι Λ α© Ο 1 rrt CM Μ F * β q © ra rrt rrt μ rrt f P 1 CO » o rrt tn X 1 rrt O © 1 . •h q «λ TJ © irt 1 rrt υ © X 1 - 45 in rrt ρ 1 1 © rrt r~>. £ X P rt 45 β μ p ©P © © E Ό Ρ X q f X rt x 0 a—'.rrt H pi · TJ © rt h© X β C|h 45 © 1 0 1 1 X Irt «rl o » *5 irt © rt TJ β p ι © ω © *^ o * χ μ Ή 45 Λ 1 p I /-% © w cn fi e \o .η ra rd μ μ * Ρ Ρ 02 ι 1 ΙΛ \O Μ rrt rrt ί , * ί ρ in ω β I rrt «rrtl ©1 1 ©1 Ό 5*? tn § 84 s-P X 02 ΧΛ a© 43 P rrt irt © * T) £ W l X m m x rrt rrt O ι. * μ p q tj © rain X β Bjrrt 42 © 1 © © c X ( © O rrt »rt •rl 1 TJ TJ © rt ι β P © © w Frrt O rrt X μ 1 42 0/—' P 1 W © w A© £ 'jrtl rrt .H Ul * μ » 02 p in in ι ι H © Ifll 1 ,·* S pi * ral β in μ © rrt Pl ( I TJ x*n β X rH rt O i Α—' μ rrt i TJ X 02 X42 \O A P rrt ·Η © F*q E cn ι X in in x rrt rrt O ι, * μ p a ό Λ rrt X β{ιΗ 45 1 © o q X 1 © O rrt .H •Η 1 Tl •port ι q p © © tn F Frt 0 rrt X μ ( 45 (X /-rt Ρ 11 02 © W \O £ irt| rrt »rt Ul f μ » 02 p w in ι < rrt a© Wf » ,-*4 B p * raj q tn μ| © rrt Pl > tj xw β X rrt rt ο ι A—* μ rrt 1 TJ X cn ΧΛ a© 45 P rrt irt © ftj ε cn ι x in in x rrt rrt O ι ,· μ p a rt rrt X q rrt 45 nat-(and ent)-1,9-dioxo-lla,15-dihydroxy- 15,16-trimethylene-17,18,19,20-tetranor- l-hydroxymethyl-13-trans-5-cis-prostadi- ene 1 © ra μ μ Tl P X © ’ , 45 P W •rrt 1 «cl | tj © u 1 CM 1 m * m rrt ©) 1 Frrt ΙΛ 5« § rrt rrt μ 1 F P 0 t* 1 X rrt tn Ο ι rrt •ri © 1 Π3 q ή 1 © X © rrt 42 f X P rrt 45 © ι p £ © X Pl Ε X a ra o © ©ι ρ μ q B *© © T3 © Χ·Η c p-r-q τι ra > » ra A-ΆΟ rrt p 1 rrt 1 ifl p| f μ o ra in ο μ q|r-i q q. Vinyl Iodide or Vinyl Tin of Example 246 in rt* CM 243 tn rtf CM 251 r- *f CM 248 Cyclopent-2-en-1-one of Example 281 281 281 281 281 281 1 281 Method of Example © rrt tn 320 319 319 319 1 319 320 Example 423 424 in CM M· 426 r* CM 'fl- 428 6Zt 212 8 207 1,9-dioxo-1-hydroxymethylprostene and its Diastereomer nat-15S,17R-(and ent-15R,17S)-1,9-dioxo- 11a,15-dihydroxy-15,17-dimethylene-l- hydroxymethy1-13-trans-5- ci s-pros tadiene t o X X X © o c rt rt © 0 rt 1 © 0 © ff rt • © P rt ι—1 V) 1 X O /-'Χ μ OS W cu X © 1 , rt E (fl I *· ·Η ·Η 1 62 0 υ| ιΛ ι 1 rt X in 1 rt 1 ρ * tn Cm c © rt rt ι μ 0 X P C X 1 rt o tn * μ ri 1 0 1 W Xrt XXX rt -rt x *0 +-» cn I © 55 & 1 , ·. X p a o rt rt p Cjrt Ό nat-1SS,16R-(and ent-15R,16S)-1,9-dioxo- 11a,15-dihydroxy-15,16-tetramethylene-1- i hydr oxymethy1-13-trans-5-cis-prost adi ene 1 I © O rt ff X t « ° © ·μ rt ff 0 0 © rt 1 rt P © X w • X p rt p μ 1 © cu s' i «ι 5 83 A © 1 62 P in in ι ι rt \O (Λ iris ff in μ © rt ρ t 1 0 xm ff X rt rt ο ι μ rt 1 *0 X cn xx Ό X P rt rt © * 0 ε m t x in m X rt rt 0 ι ,· μ p a 0 rt e-ι χ e|rt x nat-15R,16S-(and ent-15S,16R)-1,9-dioxo- 11a,15-dihydroxy-15,16-trimethylene-16- (3-trifluoromethylphenoxy)-17,18,19,20- tetranor-l-hydroxvmethy1-13-trans-5-cis- prostadiene nat-15R,16R-(and ent-15S,16S)-1,9-dioxo- 11a,15-dihydroxy-15,16-trimethylene-16- (3-trifluoromethylphenoxy)-17,18,19,20- tetranor-l-hvdroxvmethyl-13-trans-5-cis- prostadiene Vinyl Iodide or Vinyl Tin of Example 249 250 252 tn m CM 254 1 255 Cyclopent-2-en-l-one of Example 281 281 281 281 281 281 Method of Example © tn 319 319 319 320 Q CM tn Example © tn 1—t tn ’i- 432 433 434 in tn 213 TABLE 33 (continued) *O ro n © c © P TO O ct P rt © χ ε X 0 P © © P X TO o rt Ρ rt *0 *3 X X To ι p rt rt 1 O X o rt TJ t © ι 1 ο 1 ι ·Η x a p -g o rt o rt •ρ ι ro p TJ © « TO 1 C p o © © P P -rt © CX rt X Ρ t , 1 X < TO rts P © rt, & © cm ol \0 ε *· ι .ρ © in * P rt | tn p · w in ι co G »—1 SO rt rt 1 .rt - p P *X P G in r-l 1 © rt 1 tn 1 /—s rt •ο χ χ ι C X X rH CO o o X p ro x 1 TJ © P tn xx © ό x a fi rt rt Ο X -TJ P x. οί l o p in in 3 p ι—1 rt rt Ό 1 . -M-ί x P 8 I X © rt b-ι ro ι ro q|rt ' rt © nat-15R, 16R-(and ent-15S,16S)-1,9-dioxo11 ,15-dihydroxy-15,16-trimethylene-16(4-fluorophenoxy)-17,18,19,20-tetranor1-hydroxymethyl-13-trans-5-cis-prostadiene 1 1 Ο ί 1 rt X \O P 'O o H 0 (? •rl J G P Ό © CO TO ι G Ρ O © © P P — rt © rt X Ρ 1 . ι χ t to I P © rt 05 © CM ©| SO B - 1 «—ι rt os in - P 1-4 1 cn p * to in i co e rt %£ rt rt 1 rt - p P| *X P c in rt I ©|rt » tn ! rts rt TJ XX I G X X rt rt O 0 X '-'PCX 1 TJ © P cn xx © so x a ε rt rt o X -Ό P x as ι o o tn in r-% ρ rt rt X Ό i * © X p a ι x © rt rt tn ι G Cjrt *—'rt © 1 1 Ο 1 1 rt X so P TJ O r-l O rt rt ι fi P Tj © rt TO ι ro ρ o © © P P -τ« © a rt X P 1 , 1 X 1 TO r-, p © rt tn © cm ©J © S * ι rt rt © tn * P rt ι cn p * to m ι « G rt ι© rt rt I ,rt - P P - X p C IO r-4 1 © r-ι ι 1 /rt rt TJ X X 1 C X X rt « Q Ο X p ro x I TJ © P Cd XX © ό χ a S rt rt o X -TJ Ρ X Cd I © o tn m rt ρ rt rt A *O ι - ϋ X pa ι x © ro Η tn ι g C,rt 'rt © III, o -TO X © Tt O rt ©1 rt 1 1 Ό © ΙΛ © © TO - rt fi rt χ ro » X P /rt P P tn © > x £ tn rt rt rt - P 1 05 P rt in « X rt X X » ,rt P sL’| ° ι X *0X0 GXP rt O *P ρ χ I TJ X 05 X l © χ x rt ro rt rt 1 © -TJ Ρ ‘H tn ι o tj TO TO C nJ rt rt rt P 1 , -TJ TO P « 1 0 rt rt o P ro|r-i cm a Vinyl Iodide or Vinyl Tin of Example \0 m CM 257 i 258 259 260 Cyclopent-2-en-l-one of Example 281 281 281 281 281 Method of Example © rt tn 319 1 320 320 © rt tn Example 436 X tn ro oo tn ro 439 440 -. 214 8 2 0 7 1,9-dioxo-l-hydroxymethylprostene and its diastereomer 1 I 1 . 0 - rt X © ft OH υ| •rd > 1 8 © to 1 fi « © © rt - r-i c rt X « ( X b ft ft oi © 1 x E eo rt ft ft *> b ι Qi ft ft tO 1 X ft X £ I .ft ft ft * © Crt 6 ©ft X ι X 8X0 C x b CO O 8 v-' b X 1 8 X CO X ι © X X rt C rt m-ι © * 8 b ft V) 1 O 8 m m fi « rd rt rt ft i*8 rt w a I o fi rt © b fijrt ΓΜ ft nat-16R,17S-(and ent-16S.17R)-1.9-dioxo- 11a,16-dihydroxy-16,17-trimethylene-20- methvl-1-hydroxymethyl-13-trans-5-cis- prostadiene 1 Ο ι X © I , ο n w •rd I ft] 8 © ©| 1 C l © © to • ft t rt x tn 1 X c Zrt ft fi tn © b x e ft rt ft t * b to cn b ft 1 1 rt X ft 1 .ft X ft *x fi bO ft © ft © t E 8 X X CXX ig g ι 8 8 ei X X © X X X c ft ft 1 © » 8 ft ft ei ι ι 8 \O © ft co ft ft X ft ι ·χ w fc a fc P 8 i—4 fl) fc C Ή Ε Λ nat-16R,17S-(and ent-16S,17R)-1,9-dioxo- 1la,16-dihydroxy-16,17-1 rime thylene-16- (3-trifluoromethylphenoxy)-18,19,20-tri- nor-1-hydroxymethyl-l3-trans-S-cis- prostadiene 1 ο 1 ft X Ό b O ft ft •rd 1 1 8 © O 1 , ι fi cm rt © © ft ft © ϋ| ft X ft 1 » £ -ΙΛ __. jj en ι cn © ft m X E i fi ft ft /rt fi b X b cn ft x ft \0 1 O » ft X fi to 1 .ft © ft ft *X · Cho cuft ©|ft rt x t X X 8 XX ft fi X ft © fi Ο © E b £ X ι 8 Ο X ei X b o © x X o b c ft ft 3 8 © *8 ft Sft ei 1 Vinyl Iodide or Vinyl Tin of Example 261 262 263 264 265 1 Cyclopent-2-en-1-one of Example 281 281 281 281 281 Method of Example 319 320 320 320 320 Example 441 442 443 fi fi fi 445 215 48307 EXAMPLES 446-530E By the methods described hereinabove in Examples 319 and 320, the 1,9-dioxo-1-hydroxymethyl prostene derivatives shown in Table 34 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclppent-2-en-l-one.

In those cases where isomers are obtained at the or positions, only the or C^-normal isomers is listed in Table 34; it should be understood that the corresponding or C^-epi isomers are also formed and are part of this invention.

In those cases where the initial conjugate addition product contains a triphenylmethoxy blocking group, deblocking is conducted in acetic acid-tetrahydrofuran-water 4:2: 1 at 50°C for 5 hours. - 216 4 8 2 0 7 1,9-dioxo-1-hydroxymethylprostene 1,9-dioxo-11a,15-dihydroxy-1-hydroxymethyl16 , 16-trimethylene-20-nor-13-transprostene 1,9-dioxo-1Ια,15-dihydroxy-1-hydroxymethy1- 16,16-trimethylene-20-methy1-13-trans- prostene 1,9-di oxo-1Ια,15-dihydroxy-1-hydroxymethy1- 16,16-trimethylene-20-ethyl-13-trans- prostene 1,9-dioxo-1Ια,16-dihydroxy-16-cyclopropyl- 20-ethvl-l-hvdroxymethyl-13-trans- prostene 1 o o c CN d) 1 P rt tn X P β fc •H CL > P 1 ΙΛ 0 S rt (3 ι fc XP X p O tO fc rt •σ ιXrt £ X rt £ Ό P I 0) so ε rt X * X d p rt fc rt «β 1 X o £ X 1 O rt rt k Ό rt 1 X 寜 *P --ι σ 1 rt X §· fc CL O rt ο ω x e □ Q 1 P \O W rt O 1 fc χ αχ 1 Ο (Π fc fi Ό «1 x fc £ P rt V to 1 rt r rt rt * X S £ rt P rt 4) u X X o o rt fc Π3Ό σΐ£ ·» frt rt 1 rt X £ P § s?S Ο di fc P Ό tn X P £ fc 1 CL rt P ι tn o fc fc P •σ r Xto £ rt l· •σ ο I fi ΙΛ ¢) rt rt * X δ £ rt P rt σ ι ε O rt X fc O p rt t Ό Ό 1 rt 0 *» *0 rt rt 1 rt X £ P □ ε 5? o fc Ό X £ I rt 1 X d) X « O di fc P Ό (Λ >, p £ fc rt CL tJ I· 1 tc 0 C rt fi * fc 0 p rt 1 rt to 1 rt O t X rt O rt fi TJrt 1 > 0 P *0 rt rt rt 1 1 P X Ϊ x p O fc fc h3 i X in £ C rt fi Ό fc 1 P to » rt to * 8 i' rt rt rt X 1 £ O p X ω .2 •σ χ t o 0 fc *o rt X ι £ gi ί X 0) £ 1 Ρ Φ <-« σ fi ό ε o Vinyl Iodide or Vinyl Tin of Example σι -3- o LD 51 193 I- 195 CN 0 rt 13 210a • t*·. Cyclopent-2-en-1-one 292 292 292 _ .j 292 292 292 292 292 292 Method of Example σι ι-Η tO Oi •-H to 319 320 1- 320 L _____________ | 320 319 320 0 rt to Example 446 447 448 449 450 451 452 453 454 217 4820 TABLE 34 (continued) 1,9-dioxo-1-hydroxymethylprostene 1 vO fl) rt fi 1 © X X ra o o P P 53 (X X? til 3 g ι P in p rt 1 *tO β «-ι rt 1 rt rt ) X Si •Sg ? fr rt 53 I X p X P 1 X rt © o ι X R-l P 53 © 1 X X 1 i—4 1 rt X X P © 1 \O © 7 § s?tS 88 Ό O« > 1 X ra *H C •ό ra ι P Ό P * tn a R- ί rt rt i£ X P 0 © •rd 6 •a x © o * P Rd 53 d1-erythro-1,9-di oxo-1la,15,16-trihydroxv-1-hvdroxvmethy1-20-nor-13-transprostene ra § ι P XP X rt »n p rt P 1 rt 5.ί? in © rt B * 1 a © rt CN rt 1 t rt q x X X O P rt © Τδ © X rt P 1 53 O X P X X 1 © p rt c X t © P XP © x ra 1 9 9 rt U U Ό 53 fU dl-erythro-1,9-dioxo-11a,15,16-trihy- drnxv-20-ethvl-l-hvdroxymethyl-13-trans- prostene I ra i ι P XP P rt P 1 1 rt IO X si a* fr ZJ 8 ι Ό O X X X 0 t rt rt Ό » 1 rt © X •X rt p ig P 1 X © © p rt e XI o p X P © x ra ι Ο O rd Ρ P 53Π3 Λ dl-erythro-1,9-dioxo-1la,15,16-trihy- droxv-1-hydroxyme thy1-13-trans-17-trans- prostadiene dl-threo-l»9-dioxo-lla,15,16-trihydroxy- l-hydroxvmethyl-13-trans-prostene t © 8 « 53 O X P X cu rt » P ra 5 1 9 Ό P r-l P * 1 in tn rt rt A 1 a rt χ rt fi 1 P o © χ ε ο Λ» rt λ T s © 5) * rt X 1 . 1 O rt © 1 P P xo PIC » 1 1 rt O •a cn Vinyl Iodide or Vinyl Tin of Example 77 210c tn co rf 00 85 86 87 69 88 Cyclopent-2-en-l-one 292 292 292 292 292 292 292 292 292 Method of Example © rd K) 320 © r-l m 319 1 319 . 319 i 319 © rt tn © R-l tn Example ra in in rr 455b vO m rf 457 458 459 I 460 461 CN Ό rf 218 Ό tt) β τΤ Κ) ω _□ Ο < Ε• Η tt) C η Ο Ή Cm Γ—ι ·—I X χ χω β β •Η «Η > > U X (J x rt μ x tt) ω tt) β I 0) χ μ js ιη •rt ο μ μ μ CP I I ςθ ιη a to Ο X X JZ Ο μ •Η tt) τ3 ε σι & rt ε ι Ό ο μ JZ μ X μΊ Φ •Ό ι X w § μ μ μ μ \Ο to rt X “•C a μ 1 r> o X X Ο Ο μ •η ·3 σ X ι JZ σι ι 51S I ι μ X W X ο ο μ μ Ό ί X ω § μ μ μ μ rt X «5 rt tt) rt Β i & §ε •rt *3 *3 X ι Λ σι ι s £ o μ *3 X JS o μ *3 £ © rt to 0) ε χ g μ Ό X 4= t Φ rt fi I Φ χ μ x w *3 U X > 43 tn £ § rt t - to a ·-< rt ί rt μ ι O o c X rt O *3 «rt ( *3 O I CM cn * • σι © rt IO © \O Tt I Φ s ? , *3 I S ??* o in •S § χ μ μ •rt I *3 to I rt \O ( rt μ • o a c rt «Η «μ μ ι μ O t X © O CM »rt « *3 σι £ μ Φ e & ο μ Ό X X* Ο Φ μ c *3 Φ χμ »β W «rt Ο »3 μ I CP © t rt in • β a φ rt μ rt μ ι 5 Ο CO X rt ο A »rt μ *3 Ο ι s © t· ·© rt CM 219 TABLE 34 (continued) © c © P V) 8 P< rrt X Λ P © & o μ Ό £ 1 rrt 1 0 X o •rt Ό 1 © rrt 1,9-dioxo-1 lot, 16-dihydroxy-17-methyl-1 hydroxymethv1-13-trans-prostene rrt 1 rrt X 42 P © s © i fi © 4) CM P j to s?8 8 δ Ό (Λ Μ TJ Ρ ‘ 1 I \ο tn rrt rrt F t 0 rrt rrt X th 42 1 P II TJ O ι μ © TJ * X Ηβ 1 £ 1 rrt t rrt p © 1 © © g SS TJ cx, X * 42 tn •rt e T) « ι μ aO p rrt I Ftn 8 rrt rrt I rrt rrt ι X s X P 0 © γ “S rrtTJ > © fi> CM C 1 © X w ’g ° ι tn 5 g ι μ ss Ό 1 1 © %o s a p rrt μ rrt TJ ( X S-f 0 rrt •rrt 1 TJ rrt 1 X © js * P rrt © 1,9-dioxo-lla,16-dihydroxy-1-hydroxymethyl- 13-trans-17-cis-prostadiene 1 rrt 1 rrt £ © £ © 1 fi aO © rrt P 1 V) &2 8? TJ (rt •rl μ TJ P 1 t a© tn rrt rrt * ( 8 Τ' rrt X rrt Λ J P §1 78 ©*O *X rrt JS 1,9-dioxo-1Ια,16-dihydroxy-17,17,20-tri- me thy1-1-hydroxymethyl-13-trans-prostene 1,9-di oxo-1Ια,16-dihydroxy-16,20-dimethyl- 1-hydroxvmethy1-13-trans-prost ene 1,9-dioxo-lla,16-dihydroxy-17,17-dime thy1- l-hvdroxvmethyl-13-trans-prostene 1,9-dioxo-1Ια,16-dihydroxy-16-methyl -1- hvdroxvmethyl-13-trans-17-trans-prosta- diene Vinyl Iodide or Vinyl Tin of Example 144 ΓΜ rrt rrt 113 139a 115 ί 135 136 137 138 © tn rrt © β 0 t H 1 β © l CM 1 P β © & 0 rrt υ X υ 292 292 292 292 292 292 CM © CM 292 292 292 Mrt o © rrt tj a O ts •c g ρ X J) Ci) Ξ © rrt tn 319 319 © rrt tn 319 319 319 © rrt tn © fH tn © rrt tn Example 472 473 7 Τ’ U) c* ’t 476 b- b- 478 © r- ra· © co T* 481 220 1,9-dioxo-1-hydroxymethylprostene 1,9-dioxo-11a,16-dihydroxy-20-methy1-1- hydroxvmethy1-13-trans-17-trans-prosta- diene 1 rt I rt X X ft © E © I C o © ft +J 1 V) P X b O CU b ι 8 rt X C X « ft b 8 ft 1 1 M3 tO rt rt » 1 ft X ft x 1 ft o © X E O X ft X 8 O 1 b © 8 * X ft £ 1,9-di oxo-11a,16-dihydroxy-17,20-dimethyl- 1-hydroxymethyl-13-trans-prostene 1,9-dioxo-11a,16-dihydroxy-l-hydroxymethyl- 13-trans-17-trans-prostadien'e t & o b 8 X X 1 τ—ι 1 X X o b 8 X © X fi •H © 8 ft 1 rt zrt O cc b fL ο ι ft w a § ft b ft ft I i o to X ft O 1 ft ft 8 X ι X © ft * P ft £ 1,9-dioxo-lla,16(S)-dihydroxy-l-hydroxy- methyl-13-trans-prostene 1 © X fi X © 1 ft ft 8 1 fi ft ft X W X P ft b © &, 1 1 O rt CM C 1 fi X b X ft O 1 b Γ 8 ft X 1 X rt 3 § 1 b \O ft ft t *to a »-· ft > ft ft t X o x X ft o © •η ε 8 X » X © o * b ft8 1,9-di oxo-1la,15 a-dihydroxy-1-hydroxy- methyl- 13-trans-prostadiene Vinyl Iodide or Vinyl Tin of Example cn fi rt 150 151 152 153 154 fi co fi ft 1-iodo-3-tri- phenylmethoxy- 1-trans-octene (U.S, Pat. No. 3,873,607) Cyclopent-2-en-1-one 292 i CM © CM 292 292 292 292 292 292 Method of Example © to 319 319 319 319 319 1 319 319 Example PM CO fi 483,484 485 486 t-> co fi 488 489 490 221 TABLE 34 (continued') 1,9-dioxo-1-hydroxymethylprostene 1 rt 1 rt X X P © o c CM © 1 P X w SS μ cu 0 1 X w 5 § 0 μ ι P a 1 ιλ m rM rt ii rt X 1 P o © X 6 O X rt X 0 O ι μ © 0 * X rt X f rt 1 X X P © 1 © © fi CM © X « s ε X w 5S 0 μ 1 P a < lo tn rt rt * 1 a 74 rt X rt X 1 P 0 tt S£ •Ρ X 7 ε © 0 rt jq X p § rt 0 I 0 tt rt fi A © 0 P rt (Λ S A ’! £ μ rt P 0 1 ι tn a rt m ι rt rt * X « a x rt p Π X X o o •rt ft 0 0 t X © X A J. rt rt 1,9-dioxo-1 lot, 1 5a-dihydroxy-17,17- dimethy 1- 1-hydroxymethyl-13-trans-prostene rt 1 rH X p e 1 tt \© fi rt © j -μ feS ο μ μ cu 0 1 X W £§ 0 μ » P β I m m rt rt 53. rt X 1 P ε g O X rt X 0 O ι μ © 0 * X rt X Vinyl Iodide or Vinyl Tin of Example l-iodo-3-tripheny1methoxy-1trans-nonene (U.S. Pat. No. 3,873,607). l-iodo-3-tripheny lmethoxy1-trans-decene (U.S. Pat. No. 3,873,607). l-iodo-3-triphenylmethoxy4,4-dimethyl-ltrans-octene (U.S. Pat. No. 3,873,607) . l-iodo-3-tri- phenylmethoxy- S,S-dimethyl-l- trans-octene (U.S. Pat. No. 3,873,607). l-iodo-3-tri- phenylmethoxy- 4-methyl-l- t rans-octene (U.S. Pat. No. 3,876,690). © c 0 i rt 1 fi © > CM 1 P c © cu o υ X υ 292 i 292 292 292 292 Method of Example 319 319 i 319 © rH tn © rt tn Example 491 492 tn © 494 tn © 222 8 ’-i ϋ 7 ra μ ι p tn © rrt Ρ 1 I rrt © I © X C rrt © I P X W S 8 S ? X ra g TJ frt ii Ή X P O © x e O X •rrt x TJ O » μ © TJ * X rrt X Γ © rP £ ι X 2-5 Ό X X45 42 » •rl rrt Ό t ‘ τ’ a X tn p rrt c * © © a λ c rrt O © rrt rrt P ι O tn oxo χ υ μ ο ι cu •ρ X TJ rrt © μ F o rrt q © tn Gt rrt I I © rrt CM X -43 Ό P rrt © gg μ μ ό ό X x 43 45 •Ρ I TJ rrt I I a i-i F © © a 43 q rrt O © rrt rrt p I © (0 O X o χ υ μ ο ι q< •rl tn I •a rrt ϋ) ι ι fi © H « f ο μ rrt β P •P q μ rt ρ μ ι P © t cm in * rl CO | rrt rrt ι X s?£ o © £o •η μ •a ό ι X a 43 in ι - ι a i-* & I © o x X o © O rrt β •rrt O © •a xp I u V) © ι P • γ*. μ rrt rrt p* TABLE 34 (continued) •H © Tl fi r4 O -rl CU w h e ra l-rt rrt X χ χω c β •rl ·Η > > ) X O •rl X ©2 HOC Ρ X I © · /—' I 4J rrt Ρ P © tn © ι ora© I £ rrt o cu x ο ή ϊκ ι * •a xx ra · x Ο β P fi W b•rl © © ra _♦ CO ι χ ι μ . . © · Xrrt β o • x © z p H β 3 · © X P © cu ι ra Ό •rl x μ o p x I P tn © ι ε ο ρ tj χ o ra o c x μ •Ρ © Ο P I X I I o ra n £ o. © • ra· CO 00 • oo © © t q · ι X ι © O •P X rrt p 2 μ ο X q ρ χ x © ♦ /—» ι p © CUP © tn © χ ι ra ao t 6 o ra O rrt rrt q tj χ o ra o q x μ •p © © p I X I t 3 rrt CU1*5 rrt A—'tn © ι q · I X I © o •Ρ X rrt ρ 2 μ ο X fi P X X © . /-A I p © Cu P © tn © χ ι rax ι £ ο ω cu © o Frt rrt C F •a x 0 ra · ra· ο c x μ cn eo •p © o p «oo t X » ι © * rrt CUtn rrt A—'tn o © rrt •a cu ο ε x ra Ρ X © UJ © tn © »P tn © © ra· - 223 -18 2 0 7 TABLE 34 (continued) 1 1 fc cn gs rt fc -a rt 1 1 o to CN rt * 1 0 rt rt X ι £ s?S g §. Ό X X P rt T? 0 X i £ 8 > I/) r-l r—4 I * rt 8 X r-l rt rt fi 1 tt) 0 oX O 8 O rt fi rt ϋ Φ TJ X p ι u cn 0 ι 0 •00 fc rt rt fit 1 rt 1 rt X £ rt § 1 tt) in fi rt 4) ι rt X 55 x o 5S TJ fc ι rt tStA rt rt • 1 o rt rt X rt £ ι rt o « X s O >> rt X TJ O 1 fc 0 £ rt£ 1 © CN tt) I fi rt tt) P 0 4) fc S CL 1 1 in in rt fi 1 co X fc X p 2 to TJ rt X ) £ T* rt X TJ £ 1 P β ο s & * X 5 g rt *8 1 X 0 £ X I 0 rt »rt I TJ rt t X 0 £ • P rt tt) 1 o CN 1 • X 0 X rt,g 00 0 ’’ijS* t 1 rt rt 1 1 £&· o o fc fi tt) •8 tt) fi X£ 4) £ CLP rt o w TJ fc p 1 O fc 8 S CL in rt ι rt L-t W. • ι ,cf a &l« rt t fci rt 0 PI 1 rt R ο ι to X fc rt O O t rt fi rt TJ S x 1 fc £ 0 P +- • 8 tt) rt P £ ό A CN Ό • rt 0 » rt rt »£ rt P e rt X ι X &8 u TJ £ X l £ rt rt 1 TJ X 1 * 8 O in c rt tt) *£ tt) 8 CL C rt ( tt) rt 0 p I rt in Ο ι p X fc fc ο O fit rt fi 1 Ό co in 1 fc fi 0 ρ n • tt) fc rt Ρ p t © CN * | 0 X rt X • O 00 fc 1*S. X £ rt 1 1 rt fci, fc O 8 TJ C fi X tt) fl) £ £ P rt fit in ?gs 8 O CL in fc ι rt £ in 8 Pj| rt t fc rt Ο P I rt 1 O .» to X fc rt OOP rt C rt TJ 8 X ι fc£ 0 P P * tt) 8 rt P £ t ο 1 CN X • X 2 g • TJ co X rt £ • 1 r* rt rt 1 o c fc tt) 8 Ό £ fi X fit tt) £ rt 4J rt χ «Λ TJ P o 1 O fc fi £ fit in ι , ι , rt P| tn 8 euS rt l fc rt 0 P| 1 rt | o t to X fc rt O O ) rt fi rt TJ co χ I fc £ 0 Ρ P • tt) tt) rt >> ε Vinyl Iodide or Vinyl Tin of Example ltd)· 1 Xr-I fi o rt X X tt) z fc Ο Ρ X rt £ fi CD · rt. ι ρ 8 £ ρ 0 to tt) CL ι rt 0 ι e o w o- 0 O rt rt fi · tj x u rt · sr O C X fc W co rt tt) U rt · CO t £ 1 1 3 * rt fit 0 rt '—'CO . -ι o a) m fc rt p CN Ρ X U rt 1 rt O tO rt C tt? 1 !?) rt ι—1 O rt 1 Gt TJ X cn g •2 5 5 8 ι 4) fc ω rt 6 +j · tt) 1 fi i rt tt> rt X u Xrt 4) o £ rt 0 <0 +j in t © fl) rt rt 0 £ X 1 rt ι £ m to Ρ β β) t tt) 8 rt o e fc cl *α .η ρ ε O fc I 3 •Η Ρ X X ι ι χ ω r-l to o 0 in rt 0 00 rt rt 00 rt CN 00 rt ω g I rt 1 C tt) 1 CN 1 fi o CL O ϋ X u CN 0 CN CN 0 CN CN 0 CN CN 0 CN CM 0 CN CN 0 CN CN 0 CN Ifc O 8 ΈΪ £ rt +> x tt) GJ Z 0 rt to 0 r—i to 0 rt to O CN to © CN tn O CN to O CN to V CL £ rt X £ © © ιΛ rt O ω CN © in to © in Ν’ o in in o in 0 © ω 224 Q C rt O rt Crt H § rt M rt X χ χω c β • rS rt > > I © » 04 X - X © O rt μ -13 oo x -< 43 • I Γ- rt X O Q β HOC •3 XZ β X d « xz X μ rt x w s a μ cp LO tt) I rt ε in • ι, β a dl« .-ι ι μ rt ςο μ I rt I Ο ι to χ μ rt ο ο ι •H C rt •3 λ x ι μ x © μ μ • ο fl) r-ι +j ε CM I * X © X rt o - μ co -3 rt X X b X X o μ o β - fl> ,XX 4) ιΛ χ: rt υ a El I to X μ rt Ο Ο ι • rt β rt 13 « X ι μ x © μ μ * φ φ rt μ e I ι X O X CM 0 * μ © *3 rt X -X oo i O I CM χ -43 © > X X rt X I o X e X Φ O X μ d 4) *3 ρ β X μ 4) ο μ rt 3 W τ) rt I Mm a m in o μ .. d μ ι . . μ V) a El § r-* ι μ rt \o μ J rt I ο I tO X μ rt O O I •rt β rt 3 rt X ι μ xz © μ μ * tt) 4) rt μ ε x o rt c tt) ι fl) β XX 4) X dμ Ο O tn μ μ o Τ3 ο μ Xrt d -•Si T-3 S o t μ LO 9j- μ rt - I -to to a ^rt rt I I rt \D rt I rt X O I X X μ μ Ο O tt) •μ c ε *3 rt X ι μ χ © μ ο - 4) μ rt μ *3 μ ι μ ω β ο « cm μ - μ © » rt to - rt t rt rt I X XX χ μ S3 ε *3 X X X X Ο •η μ *3 ι X a 43 LO I I 4) o xz X d 4) O t β rt X 4) *3 rt μ > ι tn μ o ο μ c d μ μ ι r X O 43 CM ) • rt © t oo x rt β 1 2 ££ O rt μ X *3 43 fl) χμ p X fl) 4) ¢5 ε μ «3 o tn ι μ ο a ο μ ΙΛ 3 d rt rt ί -Μμ «η 3 ‘rt β rt μ rt rt μ μ » ι ,μ ο ε ι χ *rt to Ο X rt rt X L *3 rt χ ’ J * © μ o • ο μ rt c 13 I I •ri rt μ x μ X i μ Ο 0) cm ε © >? 'Ί ε 13 7£ X « X rt Ο ι μ <—» *3 rt X X X β •ri tt) *3 X a & φ LO X β rt Ο Φ -43 μ a μ hi rt tt) ο rt ε μ I I ,d o dl χ X in Ο ι β •ri X « •e rt μ ι ι μ _ μ f - o to • c 514 319 295 l-iodo-3-tri- 1,9-dioxo-lla,15a-dihydroxy-1-hydroxyphenyl methoxy- methyl-trans-prostadiene - 225 48207 TABLE 34 (continued) 226 ο ρ cu © X rt Ο * c co © rt χ - ο, © rt x S •5 I © O X ε P X o ci Ο Ρ I Ρ O w a 3 c Xrt 3 x Md P •P -rt P a ρ ι ι p tn a in 6f I R Rd I p Rd p © ι ο ε OCX X Λ X O p p •rd c P a © a i cu x © I x *o l rt CM rt © Ud a o •H © a c rt ο ·ρ cu I X « P X © UJ Rd © I fi rt © X P c 2 •Ρ O > P > CU a tn X rt 5 P a o ι fi vO I Rd I rd X cu © o c P © CUP O ra Rd o U P X cu υ ι ι ra VO C rt « I P £7 a ι X p X o rt β rt © ι ε o x x x .2 8 a a » x © x • V • © g.

X X § 2 ρ a a x xx X ι •rd rt a ι I rt a x in c rt © *x © a cu c rt | © rd Γ- P ι rt ra O I 0 X P P o o c. a ra ι P © p * © rd rd * X CM fi © I © fi XX © X CUP Ο O ra P P O a ο p x 3 οχ rt I •p Ud ra a >-< c ι 'p ra a ρ p in ρ p rt I I * ε tn a v—'rt rt I I rt t*» rt I rt X O I X X P P o o © £52 a rt X I P X © p o * © P rd p a © . · c X X © X fi P o © ra P X P a cu p x x cu X X I •P o w a x c ι p ra a © p m e p rt ι 1 • CUM a '-r'rt rt t t rt C* rt I rt X O I X X P p o o « § g. f P X © P o a © P rt p a CM ι ι i Xtn X rt O I P rt a χ xx x p a i s? ns a a b rt x I I O rt X I © O rt fi •ρ X © a c p I X w © X p A p p rt © CU •rj ·*» »* © CM tn « < o tn * ca © tn in - 227 48207 TABLE 34 (continued) 1,9-dioxo-l-hydroxymethylprostene 1,9-dioxo-lla,16-dihydroxy-16ethynyl-l-hydroxymethyl-20-ethyl13-trans-prostene 1,9-dioxo-lla,16-dihydroxy-16-(1p ropvny11 -1-hydro xyme thyl-13-transprostene 1,9-dioxo-lla,16-dihydroxy-16-(1propynyl)-l-hydroxymethyl-20ethyl-13-trans-prostene Vinyl Iodide or Vinyl Tin of Example © 1—4 CM 1541 154J Cyclopent-2-en-l-one 292 292 292 Method of Example © CM tn 319 1 319 Example * U o tn in Q © tn in tu © tn in 227a 8 2 0 7 EXAMPLES 531-553 By the methods described hereinabove in Examples 319 and 320, the 1,9-dioxo-l-hydroxymethyl prostene derivatives shown in Table 35 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-l-one.

In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table 35. It should be understood that the other diastereoisomer is also formed which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the β-chain (the chain containing C^j....C^ etc.) to that of the respective nat and ent forms of the listed diastereoisomer; both of these diastereoisomers are claimed in this invention as well as their component enantiomers. - 228 4 8 2 Ο 7 TABLE 35 1,9-dioxo-1-hydroxymethylprostene and its diastereomer nat(and ent)-1,9-d ioxo-1 la ,lS-dihydroxy15,16-tetramethylene-17,18,19,20-tetranor-1-hydroxymethyl-13-trans-prostene 1 X 1 X 0 1 b b 8 0 X C X •h b 8 ft © I 1 C M3 © © ft CM ft * * « a © p r-i «-4 b rt · ft ι co ι O rt rt x 1 € o © fi •h fi b 8 © ft l rt » © χη • X rri rt ft 1 | © rt /rt, Ε X ft fi X fib ft © ft © © E 8 ft X C I X ra x o '·—'.rt b ft *8 rtk© X fi|rt X nat-15S,16R(and ent-15R,16S)-l,9-dioxo1la,15-dihydroxy-15,16-1r imethy1ene-1hydroxymethyl-13-trans-prostene 1 0 X 1 o rt •ri t 8 © 1 fi © © * rt rt X © 1 X fi ft © w © ft E rt rt rt O A b b cC ft ft LA 1 1 rt \O rt »,rt e ft * ra Clin b ©[rt ft 8 xn § X—» b rt I 8 X Oi XX M5 X ft rt .rl © *8 E ca « X LA LO X rt rt O 1 * b ft ΰ 8 ra rt x C[rt x 1 0 X I © rt •rt 1 8 © ι C © © rt* X © 1 X fi ft © Ci © ft \O E rt rri «rl 0 * b b OS ft CU LA t 1 rt Ό rt 1 ,rri C ft * fi fi IA b ©[rt ft 1 1 8 xn fi X rt ra ο ι · b rt l 8 X CA XX \O X +-> ·—( ·ι—Ι © *8 6 CA ι X LD LA X rri rH © 1 « b ft © 8 ra rt x filrt £ 1 X X b o o b fi 8 rt X b X ft .rl © © 8 ft fi 1 1 © LA O ft rri CM rt * * 0 S © b rt rt ft rri * | ι oo rt 0 X b •rl rri ft 8 » ι ι © n © fi rri a © ί rH rH r-l 1 X X z-a.X X ft ft ft fi © © ©Ie e •o ’fc i? S V g >\O 8 1 .rri X ft -X rain l CH « nat-(and ent)-l,9~dioxo-lla,15-dihydroxy- 15,16-pentamethylene-17,18,19,20-tetra- nor-1-hydroxymethy1-13-trans-prostene t o X O 1 •rt rri 8 1 1 © © c A © rt rri © i X c © W ft ft r- © rt rri Ε O •rt b OS 8 pu LA < » rt t-» rt I P ft A fi ClLA b © rrt ft 1 L 8 xn fi X rri rt Ο 1 ' b rt 1 8 X OS XX X X ft rri .rri © • 8 E CA I X LA LA X rri rri © ι * b ft a 8 rtjrri X ch x Vinyl Iodide or Vinyl Tin of Example 246 LA fi CM 243 n fi CM 251 247 248 cn fi CM Cyclopent-2-en-l-one of Example 292 292 292 292 I 292 292 292 292 Method of Example 319 320 319 319 319 319 320 © rri n Example 531 CM to m 533 fi n LA lA n LA 536 537 538 229 8 α ο 7 Ό C ra © c © P tn ο μ μ © cu e rrt O X © χ μ P © © P £ tn x « X -H Ο T3 P Ό tn X p X Ή 1 1 o X o • H TJ 1 © rrt 1 1 O X X x O I •rl rrt TJ 1 1 © © q • ¢) rrt rrt 1 X /-% X © os p q Γ» © © rrt g P * .rt tn qs tj o tn * μ rrt r-* cu J .rrt } p * cn film C Qjlri rt » μ T3 X P q x ι rt 0 cm AP μ rrt 1 TJ 1 co χ-* X X X rrt .rl x • TJ P ω ι © tn m E rrt rrt X 1 * X P|CJ 0 rt ρ—· μ cl· TJ nat-15S,16R-(and ent-15R,16S)-1,9-dioxo- 1 Ια , 15-dihydroxy-15,16-tetramethylene-l- hydroxymethyl-13-trans-prostene 1 1 O rrt X 1 O © •rl q Ό © 1 rrt © X fX rrt P © 1 © c —a € © OS rt P \o μ tn rrt ρ o * © μ OS P CU m ι ι rrt © «Λ| ρ|Ί § q m μ ©|rrt p| tj xto q X rrt ra ο ι Art μ rrt 1 TJ X co XX © X P rrt «rl © •TJ ε V) 1 X in in X TT 2 p a tj «rrt x q rrt x 1 1 O 1 I P X © © tn o rrt CM O ♦η ι * μ T3 © © CU 1 q rrt 1 © © * tn • rrt CO fi rrt X rrt TO ι χ * μ z-s P x P fii © rrt 1 ao ε ι m rrt «rt /—% rrt • μ x » CO Ρ X rrt ΙΛ 1 Ο X rrt © fi X 1 .rrt © P P · X © c in cu £ © rrt r-l X I X X Ό XX p e X ρ μ rt o © tj a-' μ e x ι ό ο x CO X μ ι © X O rrt rrt ·Η 3 1 • το «-4 μ OS I Mrt o in in ·η β rrt rrt μ « ι · ρ μ pi a p © « «-ι m © q β rrt A-* P © t 1 O 1 1 P X ao © tn o rrt CM O •hi · μ TJ © © cu 1 β rrt 1 © © F (Λ • rrt 00 β rrt Xrrt Λ ι x f μ /-% P X P CO © rrt | AO g 1 to ι—l «Η /—% rrt f μ χ i CO P X rrt m ι ο x rrt © C X 1 ,Η © P C IO g £ & TJ XX P c χ ρ μ ra o © tj μ 6 x 1 TJ o X os χ μ ι AO X O rrt rrt irt 3 1 • TJ rrt μ OS I Mrt o tn m «w rrt rrt μ rt ι , * Ρ μ pa ι p © ra rrt tn © β fi rrt Op© I O 1 1 χ © μ O rrt o •η ι q tj © ra ι e μ ©Op • rrt © © rrt xp q 1 X 1 © /-% Ρ © P OS © cm tn © g - o r-< «Η © H • μ rrt ft co p · tn, in ι co c rrt © rrt «I I ,rrt · μ P, · r·· m_>| q m «π ι ξ, ι-ι ι tn l /—> rrt TJ χ X I q x x ή ra ο ο x a-* μ q x ι «a © p ω xx © © x q< g rrt ·Η Ο X • tj μ X OS 1 o p in tn 3 μ rrt rrt rrt *a 1 , fIW X PS J X rt rrt ra I q rrt A»/rrt 1 O 1 I x ao μ O rrt o •η ι q •a © co ι q μ Ol O P 2 Tx® § Λ-S i » CO © CM g © £ H rrt «Η © »4 • μ rrt 1 W p * 2 in ι co £· rrt © rrt Λ 1 .rrt · H 4_>J · χ P fi in rrt » ©rrt | 1 /-% Γ* TJ X X » β X X rrt ra ο ο X A_/ μ fi X ι -3 § ** os xx y © x cu ε rrt ·Η O X • Ό μ * cs ι ο o in tn 3 χ ^rt rrt rrt *8 1 , f ' PS ι ra (rrt ra 1 cH Vinyl Iodide or Vinyl Tin of Example 250 252 253 254 255 256 257 Cyclopent-2-en-1-one of Example 292 292 292 292 292 CM © CM 292 Method of Example 319 319 © rrt tn 320 320 319 © r-l tn Example © tn in 540 541 542 543 544 545 230 8 2 0 7 TABLE 35 (continued) § © c © P TO o p P a © rt £ X O X © P p © © £ P X TO X rt o rt P TJ TJ X To X p 1 rt rt 1 o X o •P TJ 1 © rt 1 0 1 } X sO P O rt O «ρ ι e tj © w ι e p © © P © * rt © c rt χ P © ι χ ι p /-, P © TO 05 © CM 0 so £ * P rt rt © a - P rt 1 W P · TO m ι 00 c rt rt 03 | rt - p pi - P·» +-> C tn rt 1 © b-ι ι tn 1 /rt rt Tj X X 1 C X X rt 3 ο ο x '—'PCX l T © P W XX © so x a ε rt rt Ο x -TJ P X C5 l O 0 m in rt p rt rt X TJ 1 , - U X p a ’ x ro b-ι tn ι c[rt *—· rt 1 Ο 1 1 X © P O rt o rt 1 C tj © « ι C P © © P © -rt © q rt χ P © 1 X 1 P /rt P © TO cn © cm o © £ * P i-η .η © a - P rt | cn p * to tn » fi rt sO rt rt 1 ,rt - p p -X P cm <-h » © rt ι tn 1 /rt rt TJ X X I e x x rt « ο ο x ρ e x 1 TJ © P 05 XX © © x a ε rt rt 0 X -TJ Ρ X 05 ι Ο O m m rt ρ rt rt x TJ 1 - o X p a ι x λ H m ι C rt rt nat-15S ,17R-(and ent-15R.17S)-1,9-dioxolla ,15-dihydroxy-15,17-trimethylene-19,- 20-d inor-1-hydroxymethyl-13-trans-prost- ene I 1 t o - P X © To o rt O rt I P tj © a 1 C 1 © © TO -rt q rt x rt 1 X p /->pp 05 © » x e tn rt rt rt - P 1 05 P rt in ι x rt χ a 1 rt P P - © c Jin ε ©Jrt x TJ x o G X P « o tj ' ρ χ 1 tj χ cn X « X X rt rt rt 1 -Ό P cn ι o m in C rt rt rt 1 , -TJ P rt 1 © rt rt © C q|rt CM © nat-16R,17S-(and ent-16S,17R)-l,9-dioxo- 11a,16-dihydroxy-16,17-trimethylene-20- j methyl-1-hydroxymethyl-13-trans-prostene 1 © O J C X © © O C4 P rt 1 TO TJ © o ι c p © © a * rt 1 «Ρ X TO > x fi /-s p rt cn ω P X S P rt rt 1 * ρ tn cn p r-i \Q » ( rt X rt 1 rt X P -x C © P © {rt © Tj X X C X X rt Ο O V-' P P 1 TJ TJ cd X x XXX t—4 ·<Η I -TJ rt 05 1 1 2 rt x », *x pa p CJ rt © GH e 1 1 Ο 1 rt X © P o rt p © rt 1 1 S TJ © O © 1 C CM P © © - TO - rt © O rt Xrt p t x * a ζ-, p oo r Oi © rt To χ ε u c rt rt «rt rt * p X P cn ρ x p © > O J rt x c tn I rt © rt P -X ι q © a rt ©frt rt X I X X TJ XX P C X P © « ο © ε srt p s χ ι TJ 0 X cn χ ρ o X X O P rt rt 3 TJ -TJ rt χ 05 I· A \Q sO rt J rt rt Pl rt 1 - P I p a » p np m o ch fi Vinyl Iodide or Vinyl Tin of Example oo in CM ' 259 260 261 262 tn sO CM 264 Cyclopent-2-en-l-one of Example 292 292 292 292 292 CM © CM CM O CM Method of Example 320 320 319 319 o CM tn 320 320 Example © ro LO 547 548 549 550 551 CM in m 231 8 2 υ 1,9-dioxo-1-hydroxymethylprostene and its diastereomer nat-16R,17R-(and ent-16S,17S)-1,9-dioxo1 la , 16-dihydroxy-16,17-t rimethylene-16(3-trifluoromethylphenoxy)-18,19,20-tri- nor-1-hydroxymethyl-13-trans-prostene Vinyl Iodide or Vinyl Tin of E xamp1e 265 1 o c o t f—1 ( c © o «-* 1 CU CM £ « « X ff UJ o cu <4-1 o o υ X u 292 ί 1_ Method of Example 320 Example tn Lfl LO 231a 8 3 0 7 EXAMPLES 554-637G By the methods described hereinabove in Examples 319 and 320, the 1,9-dioxo-1-hydroxymethyl prostene derivatives shown in Table 36 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-l-one.

In those cases where isomers are obtained at the C^g or positions, only the C^g or C^-normal isomers are listed in Table 36; it should be understood that the corresponding C^g or Cepi isomer is also formed and is part of this invention.

In those cases where the initial conjugate addition product contains a triphenylmethoxy blocking group, deblocking is conducted in acetic acid-tetrahydrofuran-water 4:2:1 at 50°C for 5 hours. - 232 4 8 2 0 7 © c © Ρ tn Ο Η CU rt X X Ρ © £ X X ο μ 0 X X 1 ι Ο X ο •Ρ 0 © 1—« 1,9-dioxo-IS-hydroxy-1-hydroxymethyl-16, 16-trimethylene-20-nor-5-cis-13-transprostadiene l,9-dioxo-15-hydroxy-1-hydroxymethyl-16, - 16-trimethylene-20-methyl-5-cis-13-trans- prostadiene 1,9-dioxo-15-hydroxy-1-hydroxymethyl-16, - 16-trimethylene-20-ethyl-5-cis-13-trans- prostadiene 1,9-dioxo-16-hydroxy-16-cyclopropyl-20- ethy1-1-hyd roxymethyl-5-cis-13-trans- prostadiene 1 rt © ff rt © Xrt X 0 P ff © P 1 Ul Ο p cm μ 1 cu r—4 1 X Ul .5 § > μ t P Ό 1 rt IO I rt X ». X Ul O rt μ u| 0 1 X in X ι 1 rt Ό X rt X 1 P o © rt X 0 O ι μ © 0 * X rt X 1 rt X ftrt O 0 μ rt CU P o tn rt o υ μ X cu υ ι ι tn \o e rt ff ι μ X P X i O to μ »-i 0 1 . X ui X rt rt o 0 1 ι in © t rt rt * X a x rt P rt © A £ X X o o •η μ 0 0 ι X © X © r—1 rt © 1,9-dioxo-lS-hydroxy-l-hydroxyme thy1-16,- 16-trimethylene-13-trans-5-cis-prostadiene 1,9-dioxo-16-hydroxy-1-hydroxymethyl-16- 1 yinyl-5-cis-13-trans-prostadiene 1 fe o •5 > © rt £ P 1 Ul vff O ι-ι μ 1 CU X 1 X Ul O ff μ rt 0 μ XP X I ι to in rt rt 1 . 1 Ul O rt ‘ X o O 1 «η in 0 1 1 rt © X •X rt P 1 © io h 0 ΰ © X ff 1 X © rt 1 .p 0 rt 0 Vinyl Iodide or Vinyl Tin of Example | 49 1 © Lf) 51 193 195 192 13 210a 74 Cyclopent-2-en-l-one 287 287 287 287 287 287 287 287 I 287 Method of ! Example 319 © rO 319 320 320 © CM to 319 320 - 319 Example 554 SS5 \O ΙΛ LO 557 558 559 560 561 562 233 8 20 7 > , Ο rt X *3 μ «β Φ μ ( ιη Ό Ο rt μ t d § •3 μ χ μ χ Λ © χ -χ rt μ I X » X ιη ο β μ rt ό μ χμ χ I •rl tO 13 rt I 1 . M3 «Λ © » — rt X 1 λ 2 Ο -Μ β μ Φ φ X Ε »η μ Χ2 χ χ λ μ ο μ φ μ ιη ι ,-3 ο r-< χ μ *3|χ d CM I I X w X β ο rt μ μ •3 μ χ ί χ to rt rt Ό I . ι ιη \Ο »rl | rt υ| - I ΙΟ ΙΟ rt I I rt Ο X Ζ ο μ •μ Φ »3 Ε I X © X 8 . τ3 φ X β I X Φ ' | rt -3 ι rt rt 4J X in ,Ρ Ρ 4-> μ φ d ι in X P X rt ο μ μ μ •3 ι XtO X rt rt I . •3 mJ t rt \O o I X O X χ μ ο φ © o - μ rt 3 ι X Φ •3 * τ rt μ X μ X ω t-> Ο φ μ Ε d X' TABLE 36 (cont inued) o tn Ό O • rt Φ 3 C —' se & rt rt Η X χ χω fl fi rt rt > > Ο Φ 3Ϊ rt μ X Φ ω rt I ι in X P X rt ο μ μ μ 'rt » xcX ·“< rt I *3 in I P so rt ι-i μ • μ ΙΟ I rt tO I rt Ο I , X in O rt Ό I I V) © I * I—( rt X fl) I X S εμ Φ fl) rt .β ε μ 4-> X μ X X « Ο μ μ in ,*3 Ο «-•ι μ •3IX d I X X Φ I fi rt Φ I rt X*3 X rt Ο μ μ O rt r-ι μ - μ ιο ι CM I I X «Λ § § μ μ -3 μ rt rt Ό I . ι in so rt o ‘ , X in O rt I μ Φ ε χ X rtj μ -3)13 ο μ .η Φ *3 E t X © X - Φ . β •3 Φ X£ rt +J _ ι in ι μ p 571 319 287 76 dl-erythro-1,9-dioxo-11α,15,16-trihydroxy-l-hydroxymethyl-5-cis-13-trans-prostadiene 234 8 2 0 1,9-dioxo-1-hydroxymethylprostene dl-threo-1,9-dioxo-15,16-dihydroxy-20methyl-1-hydroxymethyl-5-cis-13-transprostadiene dl-threo-1,9-dioxo-15,16-dihydroxy-20- ethyl-1-hydroxymethy1-5-cis-13-trans- prostadiene dl-threo-1,9-dioxo-15,16-dihydroxy-19- methy1-1-hydroxymethyl-5-cis- 13-1rans- prostadiene dl-threo-1,9-dioxo-15,16-dihydroxy-1-hy- droxymethy1-5-cis-13-trans-17-trans- prostatriene 1,9-dioxo-16-hydroxy-l-hydroxymethyl-5- cis-13-trans-prostadiene 1 cn ·—t x © X c +J © © rt X +J O tn P O a p x cu X l ι ω rt C ι ra X p X P O 1 P tn a rt X ’ . x ra 1 rt \o o | 1 ι in ο I x P o o a rt ι a cn ι * o rt CM l,9-dioxo-16-hydroxy-l-hydroxymethyl-18,- 19,20-trinor-5-cis-13-trans-prostadiene 1,9-dioxo-16-hydroxy-1-hydroxymethyl-20- nor-5-cis-13-trans-prostadiene 1 X X o P a X X 1 © rt c 1 © rt rt x·© fi rt P P © ra ε o 1 P r- CU i—4 1 ι ra x 5 O t-l P P a ι x*n X rt 1 t , vO ra rt rt 1 1 ©1 Ο ι x tn o i rt rt a x 1 X © P * © rt ε 1 X X o P a X X 1 © rt C 1 © rt »rt x a X ra P P © ra ε o 1 P o Cl, CM 1 ι ra X c x ra o P £ a ι X tn X rt 1 1 , vo ra rt rt 1 ©! O 1 x in ο I •H rt a x I X © P * © rt ε Vinyl Iodide or Vinyl Tin of Example © co 06 191 ΓΜ cn 107 108 109 o rt 144 112 1 1 C © 287 287 287 287 287 I 287 287 287 287 287 Method of Example © r—1 m © tn cn tn 319 σι i—4 tn 319 319 cn rt tn 319 © rt tn © s’ 572 573 574 in r* «Λ 576 577 1 I 578 © in 5 80 581 235 TABLE 56 (continued) 1,9-dioxo-1-hydroxymethylprostene 1 X X o fc 0 X £ 8 fi rt 8 l rt rt 0 X rt £ P P V) 8 O I fc © fi. CN 1 1/)1 X C x rtl O fc rt +JI 0 1 xto £ rt l 1 0 WI Ή .rtl 1 Ul o » x in O 1 •rt rt 0 X 1 £ 0 rt • ϋ rt g 1 I rt «rt X0 £ « rt rt 8 W 1 O © fc Γ4 fit 1 1 rt in X fi £ W rt fc 8 rt ε ι 1 IO 0 rt 7 i. srsl SJ, 0 » X rt £ X l £ 0 rt rt 8 u X X 0 0 rt fc 0 0 ) X 0 £ 8 • k fi rt rt 1,9-dioxo-l6-hydroxy-1-hydroxymethyl-13trans-17-cis-5-cis-prostatriene 1,9-dioxo-16-hydroxy-16-methyl-1-hydroxymethyl -5 -cis- 13-trans-prostadiene 1,9-dioxo-16-hydroxy-17,17,20-trimethy1- 1-hydroxymethyl-S-cis-13-trans-pros tadi- ene 1 X £ 1 8 rt fi > 8 rt ·Η X0 £ rt P P 8 in £ O rt fc 0 fi l 1 , o in IN rt • UJ 0 1 rt 0 1 X W X c o « fc fc 0 rt X · £ tO 1 rt 0 I trt ι X O £ X rt O 8 s I ι X 0 O fc rt 0 1 X £ I 8 rt fi 1 8 rt rt X0 £ rt p P g s rt fc TJ fit 1 1 x in s • rt x fc rt rt 1 1 Xto X rt O ' I fc tn rd £ ι 1 0 0 1 lrt rtt I X 0 £ X rt O 8 rt £ 0 X t X 0 O • fc rt 0 1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy- methyl - 1 3- t rans - 1 7- t rans-5- ci s-prost atriene 1 Xrt X fc 0 P fc rt 0 P X in λ 2 1 fc rt fi 1 1 . rt cn X •'Ί I £ u| rt I 8 0 ε » ι in © C cn rt 1 fc X4J X t Ο X fc rt 0 r X m £ fi i rt 0 fc rt rt 1 1 o IO X rt o t rt rt 0 X ι £ 0 fc 8 • 8 fi rt ε 8 Vinyl Iodide or Vinyl Tin of Example to rrt —H 0 to SII 135 0 to rt 137 138 0 to rt 149 Cyclopent-2-en-1-one 287 287 287 _ 287 287 287 287 Z8Z 287 Method of Example 0 to 0 to 319 319 319 0 to 0 rt to 319 319 Example 582 to oO 0 584 0 co 0 586 587 CO co 0 0 oo 0 © 0 0 236 8207 -σ χ X xra χ η ο ι μ rai Ρ © © β g © X'H X μ Ο Ρ μ « Τ3 ρ X ω X Ο ι μ ι—ι CU ι I X ra Ο 1 X ΙΛ Ο ι © ι ri ι—t I X Ο X X ο © •rrt g TJ X ι X © ο μ ι Ό ΙΛ X I X ra ι C © ra η μ ι ρ ο ι a ra ι ra © nJ g X X o μ TJ X X I © rrt C J © X'H x tj O nJ μ P TJ ra X P χ μ I CU /—·> I , cd ra o x tn O rrt © g X X o μ Ό X X I © Ή C » © Χ·Η X O o ra μ p tj ra x P χ μ > cu /“\ l co ra β © ra r-ι μ ι p ο ι X tn o rrt Xtn ι Oi O I x m Ο ι X X o μ TJ l © Ή β © Χ·Η X TJ o ra μ ρ TJ ra x Ρ χ μ I cu a ι in ra rrt C ι ra ο μ x P ο ι •η tn x x o μ TJ X X > rrt © I β rrt © x id js *5 p ra © P g ra ι o © μ CM CU μ μ tj +j x L χ tn o t x in ο ι •rl rrt TJ X I X © P x β ι © ra X β I © ra X β cu ra η μ μ ρ ρ 1 ι «-, 33 tn tn ι c· ι χ «ο ox©* τ> o c tn ox© •rl p p ι © o o rrt £ Ο Z rrt zj tn tn ι oo . X OX©* tj o β tn ox© •rrt ρ β ι © o o ri g q Z 237 8 2 0 7 rt 8 X fi X ' ω o b cu ι rt S rt 4 b rt 8 X rt X ft ft rt So b mH ft X X o b 8 X X I © rt C 1 © TABLE 36 (continued) b «Η I 8 υ X 1 X LA ι ι ϋ rt LA X rt X t ft O 1) •rt X 8 O ι b © 8 « X rt X r** ff rt ra - b t*- +U »A X rt X ’ . o rt b rt ©I X I x n t I a »in X rt X I ft © E O X rt X 8 O I b cn 8 * X rt X © rt I 0 \O b rt x, t ι X rt X ff O rt b b 8 +-> X i X LA 1 I in rt rH «ri I I ©I 0 I X LA 0 I rt rt 8 X ι X cn ft © Uh 8 O rt © 8 C rt O ·-* c. rt E— £ ra rt rt X X XCL2 C ff •rt rt > > ra · © i 1 ra · © 1 1 CU /—' X rt V} cu ‘ X rt rt K CU8 ff r* CU8 ff • © •rl I fi • © • rt 1 rt co © b fi b cn © b LA b ft * ft • * ft A ft x to Γ¢0 ι X ι Ο X rt 8 Ο X O X X ί X O X 8 O O X rt © * x c to x © © to cu ε ra x ω X i ff rt © X X X © · CUft ff o rt © © Z b ε ft ft ( © ♦ /-A I fi O ft O • ‘ · - rt cn ι X rt O X c 8 O rt Ο X b .η ft ft ι © r-ι ε rH CU \O —rrH | X rt G I © rt X X cux © z c n- . © · /rt , fi ft ft o t © ra cn is O (U © to Ο X i 8 O rt Ο X ff .η ft ra l © b rt ε -b • © ¢/5 r• co © a to - 238 4 8 2 0 7 Ρ I ο tn fi rt X Ρ «-ι ω ι ε χ χ X X ο ο Ρ Ρ TJ TJ © X X C A Α © χ c Ρ ο © a —ι a « , Ό Ο i/ι, ι C a υ rt - X Ρ C rt © ©I a ι ι in I © χ ε x x o x p o op© xtj ro A X © t A rt a in · rt ι p TJ o ι rt c Ch © ro - X P rt © P ρ ©1 P I ι in O I CM rt - X CO A rt P I © ?g O X P o TJ P © XTS C X X © • x Ti a > tj rt P rt TO X o X P © a ο o to I rt c τ» u rt - X P -I © p cn p rt © gg X X o o P P Tj *o © X X C X X © I ( rt a r-l TJ in ro r—1 f—c P 1 X TO O P o X C P o © a rt a 1- T> o TO r—I C cn © ro s XP rt © p J. I in TJ © □ c A rt a u « rt X i Ρ © ι CC < p>, XX •—I -r-l > > • ro ι zj ro —' cc CO © rv ro tn © □ o tn I X I x O X 0X4-< t-> c I © © - ε a. t) ι X O X 3 O O X cn o Ch ZJ ' ro co rt © co ι c * rt © tn x p x c · © © o x az cn so • CJ o s—> ro oo rt © co I c * rt © tn X P x c · © © o x az X rt [/1 a © c •κ x ro POP P I P I \0 I tn ι »—ι ' uj ι χ ι oo Ο X rt © * TJ Ο X C ο χ p ro rt p c x · i © © © o >-< ε ax z a Ch • lO cn cn =J ro I © tn q I © rt I P Xrt © x x o / P rt | l © rt rt ( ε - j TO tn x c ι x ro ο ρ ρ TJ © P ο ε ι ro rt rt XX I P X UJ p o x-/ ch tn 239 TABLE 36 (continued) © q © P ω o μ cu X X © £ X 0 μ TJ X X 1 rrt i o X o • H Ό 1 © l-rt l,9-dioxo-15a-hydroxy-15-methyl-20-ethyll-hydroxymethyl-5-cis-l3-trans-prostadiene 1 ι m ra ι μ rrt ρ X © X P P 1 © s g. • X © o rrt μ • TJ oo χ rrt X • 1 © r- rrt fi rrt 1 © 1 X’H X X TJ χ o rt o q p μ © ra TJ X o x cu μ χ o cu t μ ι a 2 2 tn 3 fi rrt rrt ra ι (μ μ O i ,P x cd ι O I to •trt © rrt *0 rM I 1 1 1 © μ w F 0 1 rrt q υ 1 1 ra tn μ -rt P » . © ra Ρ ·π ι ©I © I CM W F | © rrt rrt X -X 00 P rrt © r-’g. rrt X 1 o X μ X TJ o X μ X •a ι © XrH fi X 1 © ι X’^j a χ tj in o ra rrt q P ι © ra OXO x cu μ ο ι cu •μ © ι TJ rrt ΙΛ ι ι q © μ ra f ο μ rrt fi p 1 1 ra w μ ι P rrt © X P X 1 P o © CM £ * X © X rrt O f μ 00 TJ -Η X «X b- 1 © rrt rrt β t 1 © X X«rl X X TJ ο σ λ μ q p TJ © ra XX o x cu μ t o cu a ε ι in o ra rrt μ C ι x ra ο ι, μ x oJp Ο ι • rl © tn T5 rrt rrt »11, © μ ra f ο ·Η rrt fi O| 1,9-dioxo-15a-hydroxy-17,18,19,20-tetra- no r- 16-£- t-butylphenoxy-1-hydroxymethy1- ] 5-cis-13-trans-prostadiene 1 t ra rrt μ X p X © P V g © X CM X • o © μ rrt TJ F X eo x rrt I © Frrt fi b> 1 © rrt X ·μ 1 X Ό χ o ra x q p o © ra μ X O tj cu μ χ x cu X X 1 t o ra a x q in p « •^ © μ ι ε ρ οι.» χ ο4»η Ο ι rrt •trt Αθ 1 Ό rrt Λ 1 · ««rt 1 © μ υ| F ο I »-ι β in 1 ra ι μ rrt P X © X p P ( © © e CM X F X © 0 rrt H • T3 CO X © «-ι x q • 1 © b» rrt Ή rrt 1 TJ ι X ra X X P X O V) o q o μ © μ TJ x cu X 1 42 O W J μ q a o ra lo η μ rrt X P 1 © ίο 1 X 34*-* 0 1 I , •rl © tj rrt σι 1 I Ή © μ υ * Ο ι rrt C m Vinyl Iodide or Vinyl Tin of Example 1- iodo-3-methy13-trimethylsiIyloxy-trans-1-decene (Example 190a) 159 186 181 182 183 184 Cyclopent-2-en-1-one 287 287 287 287 287 287 287 Method of Example 319 320 320 320 320 320 © CM tn Example 609 610 611 612 613 1 rrt © 615 240 - fc CO 0 8 rt X fi -£ 8 X l rt rt rt 0 ι ι rt χ X rt X X tn ooo fc c fc 0 8 CL X£ ι . £ CL tn rt o c fc ra o fc 3 rt LD 1 i X fi. tn X O fi o fc ra fc o fc Ό rt rt X£ « £ Ο »Ο a 0 ι 0 rt *3 ι · u| O to ι X '—'io ο ι ι rt £ rt 0 rt χ t I £ 0 fc rt • 08 rt C 6 I t fc tn O C C rt rt fc fc rt rt ι tn ι • ι co 0 rt I t rt X X X £ st: e X X £ X 2 0 rt X 8 ι £ fi Ο I 8 X rt ι C tn 0 8 0 ·£ fc rt CL cl C rt O rt CL >— H £ (3 .-1 rt X X X £ fi fi I 0 O X CM £ • ι rt rt I 8 • rt. fi oo rt 8 'ϊ S^S X fc X£ CL £ +-1 I O rt rt fc fc I O fc O 3 I X rt to ο M-I rt •rt «rt t . 0 fc tn I fc Ή 0 I ,U • E| V fc ul O » c 0 •rt I fc rt fc X I £ © fc CM 8 cn X rt x • o co fc rt 0 I X δ”? 8 O rrt C fc I 8 0 rt. rt X-rt 'S £ X rt I C fc a 8 tn 0 £ o rt fi. fc ι X CL O X + χ ο tn O £ fi •rt fc rt 0 8 fc ι e fc 0 I . I J X X s s 0 8 Χ·Η £ Tl -t fi^eo -rt X’S £ rt I fc rt tfl » o X fc X CL S i * i £ fc •rt fc 0 I ι tn a •-t 0 » , rt cn I .rt o u X I O 0 •rt » 0 fc I o © fi • t CL rt •rt fc fc fc rt tn » s-/ rX X 8 · O C 0 O £ 8 •rt fc fc · I 8 U O rt ε O 2 ι tn rt O X fc £ CL fc I 8 tn ? § 0 fc rt fc I I Xtn X rrt O ’ . fc tn 0 Ή I 0 fc rt O I fi Ο I X CJ O I •rt rt 0 X I £ 241 TABLE 36 (continued) 1,9-dioxo-l-hydroxymethylprostene 1,9-dioxo-15a-hydroxy-16,16-dimethyl-lhvdroxvmethvl-2-nor-5-cis-13-transprostadiene 1,9-dioxo-15a-hydroxy-16,16-trimethylene- l-hydroxymethyl-2-nor-5-cis-13-trans- prostadiene erythro-1,9-dioxo-15a,16-dihydroxy-1-hydroxymethyl-2-nor-5-cis-13-trans-prosta- diene 1 X X o μ tt 0 C X tt X £ 1 0 rt rt i P X ui χ s ο μ μ ρ* 0 ι X ui X ff •rt (0 0 μ 1 P \O ( rt tO A rH a L· LO Ul r-4 «rt 1 1 tt O 1 x in o •rt μ 0 o 1 ff © 1 • CM rt ( 1 rt 0 X tt X μ P X tt p 6 I X X o X I P Ul tt ff S rt ι μ \O P rt 1 1 to fe3, O ui μ «π i 0 tt| x » x in 1 1 a μ m o rt ff t 1 O CM X i O rt rt X 0 X 1 P © tt tt • EC rt X « I X rt O 0 0 μ μ rt X 0 P P X Ul fe4? g tt rt ft, 1 CM 1 rH X X 4-> tt 0 tt μ ·η 0 0 X rt X p ι tn t-i o 1 μ X CU X » O U) μ c 0 « χ μ X P 1 1 \D tO rt rt 1 1 . Ο tn X rt o tt| rt t 0 in 1 1 © μ • o rt fi 1,9-di oxo-16-hydroxy-16-methy1-1-hydro xy- methyl-2-nor-5-cis-13-trans-prostadiene I fe 8 t 0 Ul X ff X rt ι μ rt p I 1 rt t*» Xw «5 1 P U) tt ff E rt t μ \0 P rt 1 l to feT o u> μ ·η 0 ο X ι x m 1 1 \0 μ tt rt o c « ff © Ο 1 rt x cm μ 0 1 p rt r-Ι CO 0 X P 1 x u> © Ρ Ο a α) μ rt ε cu Vinyl Iodide or Vinyl Tin of Example 1 rt X c tt 1 X ·Η &0 tt O rt » c z μ in tt P n+J · z—s ι in υ p to ι o rt o 1 X CU \0 Ο x rt * 0 0 X · tO Ο X X V3 I*' .rt Ρ P *00 1 tt tt 3 * rt ε ε to ι- 76 © \O 74 107 130 134 Cyclopent-2-en-1-one 288 ί ! 288 2 88 288 288 1 288 j 288 00 00 CM Method of Example 319 319 319 319 1 © rt to 319 319 319 Example 623 624 625 M? CM 0 627 628 629 630 241a 8 2 0 7 a © Ε , a e - rt Η eT \Ο rc X X U4 i SS CO < Η • X CM Ο ι Η xa X X Ο X μ ι a © χ « c χ X © I X ·Η ρ Ο ε μ © a cu χ I X Ο I CM ι-ι * I © © X Ε ΗΧΟ « Ο ·Η co ε a r-l Q) Ctf •X Ρ x cu tn Η Η Ο * X Η ΓΜ X CU I Ρ I χ © ra χ ε e ο ο ra μ μ μ a ο ρ X 3 ι χ rt © I tp rt Ο rt I © μ ra ι—< p ·Η J I I , ©I O El I X I LD O \C 1 rt rt rt a ι x j μ x ©op ~§ g I X © X c o © μ ·ι-ι a a x ra X P ι ra rt O ι μ rt cu X I c ra •rt c > 2 ι μ \0 P rt I ι m X « X m ι ι Ό μ rt o I E O I X ΓΜ O I rt rt X i x rt 1 P rt ra ι o rt μ x fu © I o ra £§ ο H rt P ο I X© © ra P rt ι © X X P o t μ o a CM X -X © I «—4 r—( - I oo .

I X rt X μ p ι © X ι x in O I μ μ a o X c X I I CM vO I rt r4 I X O X X P o © •rt E X © X E Q © μ rt rt a a 241b χ s? ° o a μ x a x © x « E X rt o I I rt οι-ia ©Xrt rt E P ι © ra oxo x cu μ ο ι cu E * X © CM c -rt i © a xx ra X CU P Ο Ο W μ μ o a ο μ x 3 cu X r* ‘ ι © ε 7 5? S μ *a © X rt X * I CO rt © rt I c A/rt © CM rt rt I xa X C rt X © P ο x ra H CO a χ μ X X cu X O I I ra OPE © © rt rt s μ o cU ί i x © X Ε O © μ ·η a a X « X p ι ra v£3 rt t ι © £7. o ra μ ·κ a oi X I X © ( I μ o c μ ©I • O « c © rt x f a rt w I I ·«-( © μ © A ο ι rt e © t o X CM Ο I rt rt a x » X © P A © rt E 4-8 2 0 7 TT X X ft X b *o X X I ri I Ο Φ X c Ο Φ rt ft •ο n I 0 σι b »a rt I Trt I X « e e x « £ b ft ft t> I I rt vo rt ?.·> Xrt x ul 0 I b ut *0 I Xrt £ X I £ VO ft rt φ a> ι e c o Sn X Xrt 0 0 *0 rt b 0 ΌΌ ft ι xn σ> £ o *1 h rt rt CU b ft 0 Φ 8 C rt ο -η a HE* E 0 rt rt X x χω e fi o rt N CU © TABLE 36 (continued) V c I c Φ I X I ft c Φ CL rH u X u x (N X CO CM ΓΟΟ (N X CO rw ΓΟΟ CM ft © rt 0 £ ε ft 0 QJ X £ ω © (S rt © n rt σ\ rri V rt CU υ x rt io « □ X rt vo * Cd x rt vo X x rt vo O x rt vo ‘For the cleavage of the TMS-C=C-bond see, Example 772(B). 242 2 >7 EXAMPLES 638-660 By the methods described hereinabove in Examples 319 and 320, the 1,9-dioxo-l-hydroxymethyl prostene derivatives shown in Table 37 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-l-one.

In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table 37, It should be understood that the other diastereoisomer is also formed which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the β-chain (the chain containing C^. ...C^ etc.) to that of the respective nat and ent forms of the listed diastereoisomer; both of these diastereoisomers are claimed in this invention as well as their component enantiomers. 243 4 8 2 0 7 TABLE 37 φ s φ μ (Λ Ο Ο. h rt Φ X g X Ο X +J X w ο « μ ·<η 3 Ό X X <Λ β Φ Ο rt rt rt Η CM Φ β Ο I rt I Φ β rt Φ CM ι Ε μ ω β . φ Ψι β. Ο £ X rt CM e rt χ ω oo to Ό I I X X rt X - ο ό μ rt Ό X I Φ Srt β I Φ 3 μ ·η X Ο 3 X Ρ rt I ·Η μ >ο μ «λ rt +J Ο ι ι μ Ο © CM X CM I ο * ΙΛ rt © β 3 rt rt - μ σι οο μ - rt I rt I Κ) I Φ rt —, β I , 4-> Φ W) Clrt rt φ|χ υ| χ > μ ιΛ Ρ υ ’ rt S rt ' rt χ ι. μ χ μ μ μ rt Φ φ ρ|μ ε Ο \D μ cm rt ιΛ Φ fijrt β ΙΛ Tf \D - 244 4 8 2 0 7 τ © □ G ο μ μ ο {X £ <-> Ο X ο χ μ Ρ © Ό C Ο ·Η ί—I ~Η ί η <-< ro χ χ X q c χ •rt -rt > > 245 820 TABLE 37 (continued) 1,9-dioxo-1-hydroxymethylprostene and its diastereomer nat-15R, 16S-(and ent-15S,16R)-1,9-dioxo15-hydroxy-15,16-trimethylene-16-(3chlorophenoxy)-17,18,19,20-tetranor-lhydroxymethy1-13-trans-5-ci s-prostadiene , . 0 c X I © . o r-ι Ή •HI ι T3 τι μ ra I | Q P ’ © » C ra • f© rt o rrt r-1 Η H I ι ι P q 1 ,_, © © > * cn fi p ra > © © 1 ·Η ' η π ο υΙ * XCM I : cn x -in in p © t Π © rrt ra . ε f c +j .h oo ra . c μ rn μ ’ ©P -P 1 I b- i- XI © rrt tn STA7 Α-ΊΛ X-rt t rrt X X OS 1 Ο X © X C p rrt X © © - Ο X E os μ q. x in ό p * rrt χ Η p 1 ,Λ O fj p(| rrt TJ ra in χ x Clrrt U χ rt 1 P ο ι ra P o -a μ •h > q tj ο ι. ι cm ra © *·η f© υ| rrt rrt 1 ι ι m r-% © 1 w c ra b- © c rrt rrt it, » χ μ Cd 43 P in ρ ι r-ι a tn 1 , ε rrt Ρ ·Η I e μ ? © P X I X TJ x p q rrt © rt * E a—'tn X 1 rrt x OS ι 0 b* X μ rrt X TJ F P X w μ x in tj ι rrt Xrrt © t ,X 1 G ρ ι μ © rt in O ·«-, fil·-· G TJ 1 t ra O P X ·Η V) 0 Tj 0 •η ι μ tj o q t cm ral *© u| rrt rrt 1 ι ι m /-> © 1 OS C W b* © c rrt rrt 01 * χ μ CC X P tn ρ ι rrt © tn 1 , E r-l p ·Η 1 G μ rrt © P X X TJ X P st§ a—· in X I rrt X W P b~ χ μ rrt X TJ -OX w μ χ in TJ ι rrt Xrrt © 1 ,X 1 fi ρ ι μ © rt in O «ri G|rrt C TJ nat-16R,17S-(and ent-16S ,17R)-1.g-dioxo- lS-hydroxy-16, n-trimethylene^O-methyl- l-hvdroxvmethyl-lS-trans-S-cis-prostadi- ene 1 1 1 Ο «Ρ »w x xtj OG rt •H.P P TJ © ra ι e p © ι μ fo q rrt CM 1 . ι ι w| /Ή © »H J w fi y| b- a ι rrt rrt ΙΛ - X 1 co 4rt ra © P fi rrt a ra i,g μ Ρ ·Η p fi μ ι a|p fo l rrt TJ b· 1 fi rrt rrt rt - X ’-rt© X l rrt ρ os ι a b· X 6 rrt X X -OX OS μ o © tj μ rrt X TJ t ,45 x p J ι x a rt© ι c fi|rrt rrt © I I © ο «Η 1 G X μ·1© •rl t a tn ora 7 ·—gp © « ·££ f %o μο rrt rrt μμ ι · ’ q /—% © ® 1 > oS fiiMra b* © -Ηϊ rrt rrt©Cj| * x^‘ cn © p co | ,-i a '“‘ra • .e »g q I μ χμ a P ι ο 1 © b% fitn q PH ©rrt c3 fX 1 a—· © q-> cn ι X£ x rrt X P © f O ©2 os μ Sx © TJ ox rrt Xfcg Ρΐ’ΐ °tj Vinyl Iodide or Vinyl Tin of Example 258 259 260 i 261 262 tn © CM 264 Cyclopent-2-en-1-one of Example 287 2 87 287 i 287 287 2 87 287 Method of Example 320 320 319 319 320 320 320 Example tn in © 654 in m © 656 657 658 © tn © 246 <= 4 82 1)7 246a 8 20 I rt © I C X © X P 0 TO P p Ό P x a 5 i 7 S \O P TJ o I CM OJ I * rt rt X * P TABLE 38 (continued) © U-i •a o .η © TJ fi rt 2S & ra rt rt x χ χ ω c c rt rt > > I I rt p I TO X o X P o a P I Τ» TO •M rt P TJ P ι t so tn rt rt - I Lrt rt rt X si rt 1 O X X X O P rt © ό ε » X a x g P & TJ I X TO i TJ P I P s£J I rt tn — in ι rt rt ί X o X X P 0 © rt e & OJ o ·· P rt T3 » X O X I I rt ro I P x to x o o P p a TJ I X w g TJ P ε o © _ p c ι Ό © rt Xrt TJ X TJ T3 X © X C rt © Ό P i to SO P © © ρ ε ΐ & Λ.δ TJ TJ © © CM fi I © X P X TO o o P P tj a X I X TO rt fi Ό ro t P sO P rt | - tn in »-i rt | I rt O X * ·* O P rt © tj ε ι X a x * o rt p I TJ 0 © P X I X X g TJ X © X fi rt © T3 P I w sO O rt p * a r-l X a tn © fi © O P CM TO I O && O 1 P TO •gs iiS TJ t I to i—t r—I t I P o © x e O X rt X TJ o ι P a tj * X rt X o a p < TJ TO X fi X « rt P TJ P I t tn rt * I in r-i rt X I X O P X © ο ε rt X TJ X 1 £ a p Ό rt X I X O ' - 249 l ο X b X CU l 8 rH ffl t ft X ω X o O b b Cu 8 i Η» in § b ι ft vO ι r-H X Ε X X s X £ X o b © X C £ © ι ft rt tn I o X b X CU X © X c o © b ft 8 tfl X P £ b I cu O I b cn 8 A X X £ © ι G vO I rft O I X b o o rt G 8 «ft I 8 cn ι * o rH CM O b b ft 8 l Xrt 45 rt I I Ό b «ft O i.s X b O b •ft ι 8 O I CM cn * t © X G X © O ft b V) 8 O X b 45 CU l I 8 tn § O b X b ο I •ft rt rH I I cn b * O rt q O b X £ X £ b © X G ·—I © I b X « X O O b b & I X tn Ύ s \O b © ι © o G CM © ι b ?S O b b CU 8 ι X tn •Ϊ s \O b O rt X rt O I •ft rt 8 X I X cn b O rt X rH Ο ι © ι © O G CM © I b ?S O b b CU 8 ι X 2 4= s t fi \O b rt ft I I O rt X rt O I rt r8 X I £ cn ft © rt e X £ ft © ι O © CM C 1 © rt ft X W 45 p ft b © CU ε ι ι tn § ι b Xb X · o rt b rH 8 « ££ I 45 vp b rH © t S O X X X o o •ft ft 8 8 ι X cn 45 * J X b © ε x X o b X •ϊ s rt © I rt x8 X fi o b ft tn 8 O X b £ CU I I , «ρ O I x f'O rH •ft I tn o Uh 8 O •ft © G ah O -ft G - H s fi X x^ - 250 4820 TABLE 38 (continued) 1,9-dioxo-1-hydroxymethylprostene 1,9-dioxo-16-hydroxy-16-methyl-l-hydroxymethyl-13-trans-prostene 1,9-dioxo-16-hydroxy-17,17,20-trimethyl1-hydroxymethyl-13-trans-prostene 1,9-dioxo-16-hydroxy-16,20-dimethyl-lhvdroxvmethyl-13-trans-prostene rt 1 i—l X £ fc 8 8 ε ra •H 8 0 p 1 tn X o rt fc * fi X 1 •-η « J CS X rt X fc P fc fc 1 0 0 Xrt £ l 1 rt \£> X rt £ 1 P O 8 s i. •Η X 0 O 1 fc © 0 • X rt £ 1 5? 0 fc 0 8 X c £ 8 1 »H rt 0 1 rt rt P X 55 A P fc fc 8 CL ε ι 1 w so C rt rt 1 fc X fc X ι O X fc rt 0 l X w S ι rt \0 fc rt +-> 1 1 o tO X rt o » 0 X 1 £ © P • ¢) ·-< ε 1,9-dioxo-16-hydroxy-20-methyl-l-hydroxy- 1 methy1- 13-1rans-17-trans-prostadiene 1,9-dioxo-16-hydroxy-16-methyl-l-hydroxy- methvl- 13-trans-prostene 1 X £ 1 rt t r-H X £ P 8 ε •rl 8 0 C 1 8 © fc CN V) • O X fc rt fi i 1 X tn * 5 o rt fc fc 0 P X 1 £ 0 1 rt \O 1 «—ι rt I X O £ X P O 8 •η ε 0 X t X © o • fc rt 0 1,9-dioxo-16-hydroxy-1-hydroxymethyl-13- trans-17-trans-prostadiene 1,9-dioxo-16(R)-hydroxy-1-hydroxymethyl- 13-trans-prostene 1,9-di oxo-16(S)-hydroxy-1-hydroxymethyl- 13-trans-prostene Vinyl Iodide or Vinyl Tin of Example 0 0 136 137 138 139 1 . © rt 150 151 152 153 154 Cyclopent-2-en-1-one 284 2 84 284 284 284 *3· CO CM 284 284 284 rf CO CM 284 Method of Example © r- tO © to 319 © 0 j 319 319 319 319 © to 319 © to Example , Tt © 0 © xO 696 697 co © sO © © 700 701 702 703 704 - 251 4 8 2U 7 1,9-dioxo-1-hydroxymethylprost ene 1,9-dioxo-16-hydroxy-20-ethyl-1-hydroxy- methyl - 1 3-trans-17-trans-prost adiene t-0 1 73 l o . S , X . x o 1 £ 1 73 >· I x 1 ι I --1 ! 1 i x X O μ 3 1,9-dioxo-lSa-hydroxy-20-methyl-1-hydroxy- methyl-13-trans-prostene 1,9-dioxo-15a-hydroxy-20-ethyl-1-hydroxy- methyl -13-trans-prostene 1,9-dioxo-15a-hydroxy-16,16-dimethyl-1- hvdroxymethyl-13-trans-prostene 1,9-dioxo-15a-hydroxy-17,17-dimethyl-1- hvdroxvmethyl-13-trans-prostene Vinyl iodide or Vinyl ’fin. of Example w cc rt rt 1-i odo-3-1 r i pheny1methoxy-l-t ransoctene (U.S. Pat. No. 3,873,607). 1-iodo-3-tri phenylmethoxy-1-transnonene (U.S. Pat. No. 3,873,607). l-iodo-3-triphenyl- methoxy-1-trans- decene (U.S. Pat. No. 3,873,607). l-iodo-3-triphenyl- methoxy-4,4-di- methyl- 1-trans-octene (U.S. Pat. No. 3,873,607). 1-iodo-3-triphenyl- methoxy-5,5-dimethyl- 1-trans-octene (U.S. Pat No. 3,873,607). c o 1 c o rj 1 CM rt cc ~T co •“I 284 284 284 1- 284 Ο Φ 3 CM ο ε X rt •Μ X CJ “ cr. ro Ci tn © t-H to © to © tn © tn o cm rt MJ L-O © Γ- 3 O r 707 oo © P-- © © r- 710 252 TABLE 38 (continued) 1,9-dioxo-1-hydroxymethylprostene l,9-dioxo-15a-hydroxy-16-me thyl-1-hydroxymethyl- 13-trans-prostene 1 X X ε TJ X X 1 1 rt X X +-> © 1 so © rt q 1 © XP X TO ε ε τ> a X ι X TO a S IO P rt p t > O tn X rt ο I rt rt TJ X 1 X Oj p - © ε 1,9-dioxo-15a-hydroxy-17,20-tetrano r-16- cyclopentyl-1-hydroxymethyl-13-trans - prostene 1,9-dioxo-15a-hydroxy-16,20-pentanor-15- cvclohexvl-l-hydroxymethyl-13-trans- prostene 1,9-dioxo-l5a-hydroxy-18,20-trinor-17- cvclohexvl-1-hydroxymethyl-13-trans- prostene Vinyl Iodide or Vinyl Tin of Example l-iodo-3-triphenylmethoxy-4-methyl1-trans-octene (U.S. Pat. No. 3,876,690). 1-iodo-3-tripheny1methoxy-4-ethyl-Itrans-octene (U.S. Pat. No. 3,876,690). l-iodo-3-triphenyli methoxy-4-cyclo- pentyl-l-transbutene (U.S. Pat. No. 3,884,969). l-iodo-3-triphenylmethoxy-3-cyc1ohexyl-l-trans-pentene (U.S. Pat. No. 3,884,969). 1-i odo-3-tripheny1methoxy-5-cyclo- hexyl-l-trans- pentene (U.S. Pat. No. 3,884,969). Cyclopent-2-en-1-one ro co 284 284 ro 00 CM ro oo CM Method of Example 319 319 319 OJ rt m Ch tn Example 711 712 tn ,—ι r-· 714 1 715 253 7 CO ii x x X £ O ft ft © ε X X £ X ) Ο Ο b ΙΑ 8 rt X I 45 Ο I X 4= ft © ε I LA © rt C I © X ft X I £ σι ft * © rt £ © Ο I , 45 rH V) CU U G rt X fi ft q © oo © © G “ ε cu © hi I I Hl X ι X rt O Xrt © · £ x q * ft rH © LA © rt ft CM £ tn © rH I rt O to x I ® J £ rH rt O ft I CU 8 © tn ο ε co ι ft ft rt © X ft £ « ft O © b ε cu I I LA Vi O b rt 8 rt X I £ I X a 45 in ft rt © ι ε o x x x o o rt b 8 8 ι X σι £ §ΰ b ι ft M © rt ft I I rt O X CM 45 A ft σ» 92 rt £ « x rt O * b r- 8 rt X I 45 X I X O I b X 8 X x 2 G t © * ’S LA CU rt 0 ι b O O X 3 © O rt G rt Uh © 8 I ,ft » σι > O a\O b rt rt CU I b O © C G fi © b ft ft tn © O ft b I CU O I CM (Λ A G σι fi rt ft a ft 1 © G ft fi ι b O ft I o b b o cu b G ft fi © b ft ft rt X U · x^ _2 c? X rt 8 fi ft tn » o ι fi X X X UJ O *—1 o © b ε 8 X X £ 4= p ι b d 8 lA X rt 45 I I o rt X J O X •ft X 8 O > G cn © a 45 rt CU r- © rt £ I X X X X p O b ft 8 8 X X45 45 > I rt a < LA X rt X I o O G X © O 4= rt CU 8 O ι ε σι ρ * b rt £ σι «-η rt X CO ft rt © a ε X X rt X I o X b X 8 O X b «*= 8 ι Xrt 45 I I X a x LA o rt q ι © O 45 X CU O rt rt X 8 ft » 3 Ol 43 rt ft| - 254 4 8 2 0 7 TABLE 38 (continued) 1,9-dioxo-l-hydroxymethylprostene 1 1 rt r-ι μ x ρ x © P 4-t CJ X CM X * O © μ rt a * X co χ; rt 1 a rt X 1 7 fr X O X G o © μ X © a cu G X X © X x p ι o ra «X p © ρ μ rt © Cm ι ε » Ο ι , ra X cUc 0 ι ra .μ ο μ a rt p l I 1 © μ © * O rt c ι l,9-dioxo-15a-hydroxy-17,18,19,20-tetranor-16-m-chlorophenoxy-1-hydroxymethyΙΙ 3-t rans-prost ene 1,9-dioxo-15a-hydroxy-l7, 18,19,20-tetranor-16-m-1 ri fluorophenoxy-1-hydroxymethyl- 13-trans-prostene 1 rt ι μ x P X 0) o ρ μ ι a © x CM X » © rt rt 1 * rt* co X rt X a O X fi © rt fl) fi 1 X © X CUP X O W p £ o μ ° μ a rt p, XX 1 χ υ ra i'-g s © ι μ rt P 1 A 1 o tn © X ' rt O « i •rt VO rt a rt X 1 © μ p * o © rt c ε 1,9-dioxo-15a-hydroxy-l8,19,20-trinor-17- nhenv1-1-hvdroxvmethyI-13-trans-p rost ene 1,9-dioxo-15a-hydroxy-18,19,20-trinor-17- (m-tri1fuoromethyIphenyl)-1-hydroxymethyl- 13-trans-prostene 1 X rt i μ ι O © G rt •rt | μ ip P X 1 X © P CM © a ε © >* rt X CO S r-ι a l X XX X 1 O rt μ ι a z— X rt X X 1 G © a © c © χ © 7 SS O X o χ ο μ O X CU •rt Ρ 1 a © ra t ε C © ι ,ra a cj μ rt rt· P 1 CM 1 i—4 X X P X X o μ a X •v © rt fi I © X x a o ra μ p a ra χ μ fi 2 Prf I © ra 7 S ο μ X P O 1 •rt © a 1 1 © μ A o rt C Vinyl Iodide or Vinyl Tin of Ε x amp 1e 183 M· 00 081 185 186b ! © © co P98t 1 - iodo- 3- t ri pheny 1 - methoxy-1-trans- octene (U.S. Pat. No. 3,873,607). Cyclopent-2-en-1-one 2 84 At co CM 284 284 284 At CO CM 284 © oo CM Method of Example o IN © 320 320 o C4 tn © CM © 320 320 j 319 Example tn <-M 724 725 X 727 728 © X 730 255 0' tt, Ci O I co U4 CO Hi o μ CU x cu I o in μ rt CU I I X tn X C o 0 μ μ 0 *-> X ι X tn o § f—ι μ ι p X I x tn 0 μ X O X c ( I O tt •η ε 0 x I X © o α μ R-. 0 i<0 tt χ I I fi co . LO tt A > a +j m Ο X -· Z 0 O X O X X · χ μ X o o c μ ι 0 CM X I X rt » X a X LO P r-l tt ι ε O X X X o 8 •η μ 0 0 ι x © x tt ε x x feis tt I tt rt fi I tt X P X V) o o μ μ CU X ‘ X W rt c 0 tt t μ \O P r—I I a tn rt μ ι o o c X I O CM rt I 0 rt I X © X ? © o c χ tt p P tt cn £ 8 » μ 0 P· X g X rt ο μ μ 4-» 0 1 xtn X rt i ( a μ in o rt c I I O CM X I O rt rt X 0 x P © tt • e rt X o μ X X I r-l I tt X C X tt O p μ ω 0 Ο χ μ χ cu I t ο μ X p ο I •h tn I tt rt fi X tt X p P tn tt o ε μ I cu tn Xrt * L vO §7 o ' rt si 0 P ‘ P ©. tn tt I fi X tt X rt O 0 μ tt 0 p X Ϊ X P ω ff Cu tt j μ o p rt ui X C X « ρ μ tt P ε » ι r\O rt rt | I Ul X c X rt ο μ μ ρ t Xtn X I I \o μ rt O ό ί X CM O t rt rt 0 X I X © P a tt rt ε x rt X • P Ca ¢) rt £ a X CM X I O χ μ X 0 O X μ x 0 I Xrt *? :k & S rt ff tt O X X CU tt ο I ff rt tt © μ p a ο μ rt fi cu 256 4820 TABLE 38 (continued) j 1,9-dioxo-1-hydroxymethylprostene l,9-dioxo-15a-hydroxy-2,17,18,19,20-pentano r-16-m-1 ri f1uorome thylphenoxy-1-hydToxymethy1-13-trans-prostene 1,9-dioxo-16-hydroxy-16-vinyl-1-hydroxymethyl-2-nor-13-trans-prostene 1,9-dioxo-16-hydroxy-16-cyclopropyl-1-hydroxvmethy1-2-nor-13-trans-prostene 1,9-dioxo-15a-hydroxy-2,18,19,20-tetranor17-Dhenvl-l-hvdroxymethyl-13-trans-prost- ene 1,9-dioxo-15a-hydroxy-2,18,19,20-tetranor- 17-(m-1 rif1uorophenyl)-1-hydroxymethyl- 13-trans-prostene 1 fc O § 0 fc rt fc 1 8 rt fc X CM 8 • ε © X rt X • O 00 fc rt 0 • X CM £ 1 i x«-· X I O /—* fc rt 0 X x e £ 8 1 £ 8 a A fi 0X8 rt χ p ι O W Ο £ O X P fc O 8 fi •H E 1 * -ι X p 1,9-dioxo-16-hydroxy-16-ethynyl -1-hvdroxymethy1-13-trans- prostene 1,9 -dioxo - 16-hydroxy-16- etfiyny1-1-hydroxymethy1-20- nor-13-trans-prostene Vinyl Iodide or Vinyl Tin of Example 180 761 00 Cl X) o 00 Γ-Η 8 \D 00 0 £ CO t—4 2101 210P Cyclopent-2-en-1-one S9E 285 285 0 00 CM 0 00 CM -1 285 284 284 Method of Example 320 319 o CM 0 320 319 319 I 320 320 Example 741 742 743 •31 ”3· X 745 1 746 746A* * CQ £ X 25c a tl θ 7 © β α rrt ρ X ra X Ρ X ρ X © q Ο £ » μ χ ra τ χ c χ ο β χ μ μ ι Ό Ο —· ι X ι Ο χ •rrt XX TJ β Η I X ο © X ' - rt Ο ^rt © ΓΜ Ο X μ χ © •α ο β χ μ © χ TJ Ρ I X ω © X Ο rn ι μ I rrt Ρ, Ο χ C •rrt C Λ tj £. μ ι q ρ © ο » • μ tn rrt I © A-> rrt fi I X © © X P rrt P tn X E &?· μ o ra Ό μ β χ-a rt x χ μ ι tn O X X •frt C X TJ X P « q © cr> Ο ι * μ © -+ qrM - 256b 18 3 0 7 EXAMPLES 747-769 By the methods described hereinabove in Examples 319 and 320, the 1,9-dioxo-l-hydroxymethyl prostene derivatives shown in Table 39 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table 39. It should be understood that the other diastereoisomer is also formed which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the β-chain (the chain containing C13C14 etc.) to that of the respective nat and ent forms of the listed diastereoisomer; both of these diastereoisomersare claimed in this invention as well as their component enantiomers. - 257 48207 σ PA J CC ~ ft lA O rt q X X rH X A O sO ft cu ft rH © X £ ft X O £ C I -ft \O ft i I © ο o q X Ol © rH • C I rt © rH I rt X ft Lc ft q ft © © © ε ε x fi X q ft ρ fi ft ft 'r-' © 8 X sts i · cn co ©lx · £ H) 8 ft «Η § §« X I ft J5 ft ft ft fi © © c ft ε x ε ο x rt x 8 ο ί b cn 8 * X rt £ I I z“\ rH cA ι MO © «-η q A © OS rt LA X rt £ I ft ft © C £ © rt © b C 8b© S 1 p fi \O tn 'rt rt O PS A ft Ό IA PU t*H rH I • ι tnj CA X q in X fi rt o b ι b bl ft 8 ι fi X« ql-ff rt \D © Uh 8 O • ft © C ah rt Η X X X UJ q q c © Uh cu o ι ι O X X X O O •ft b 8 8 ι x cn £ A | zrt © es q \O © rt rt • X CS 45 © la ft q rt © © ι ε b b ·η tn q b p © b b -. 1 8 Ό I t rt ft CA I ft p X I rt x tn «Oft CA b I LA 8 rt rt X x I ,£ £ b ι b rt Ila © ch g - 25S 48207 TABLE 39 (continued) tj § © fi © P TO o P P- P rt © X § 5 s s δ S.S TJ Ό j? to t P rt rt 1 O X o rt TJ 1 Ch ·—1 t O i X X o x rt o TJ P ι TJ σι X *X rt 1 » rt S © x C rt β) cd X © tn x c rt P © 1 . © P p| £ in CM O © Ό P 1 0 Ό Ρ» ι c rt tnl 3-c »ΙΛ rt, 1 rt pi co l Ρ» χ χ ι r-i x tn -Qrt to P 1 m rt rt X X » ,X X P 1 P ro in © cirt ε nat-15S,16R-(and ent-15R,16S)-1,9-dioxo15-hydroxy-15,16-tetramethylene-1-hydroxymethyl-13-trans-prostene 1 o X O 1 •Η X TJ X 1 1 Oj rt * 1 rt © 1 fi /rt © © 05 rt ιΌ X © rt A p - p TO 05 © 0 tn 6 P rt Λ 0 < , Ρ i Ρ P TO! C © C ©|p 31 ό © a C rt 1 ro -tn JrtlO rt 1 rt 1 CO 1 rt \O X X rt χ A -OP to P © in τι g rt χ χ 1 .X x pIt o ro in p C|rt T) t 1 O rt J x p ro OPP© •HIPC Ό tn © © ι X-/ P 4J OJ 1 1 TO - Ό © 0 rt rt cm P 11*0 /-- © Οι ι os c ·-» tn Ό © * fi rt rt oo ro - Xrt p CO X * P in p r* ι rt © rt to 1,8 1 rt plrt rt | C P Xrt © P X X ι Ο X TJ Ό C P C rt © © 3 -χ ε '-'in 0 χ t rt rt X to 1 X p Ό XX P rt χ ρ Ό * O © X Q5 Ρ ε μ? in Ό ο ι rt χ P rt « .X o « ρ] ι fi P ro in »-* o cirt tp q ---1 nat-15R, 16R-(and ent-15S,16S) -1,9-dioxo- 15-hydroxy-15,16-trimethylene-16-(3-tri- f luoromethyIphenoxy)-17,18,19,20-tetra- nor-l-hydroxymethyl-13-trans-prostene nat-15R, 165-(and ent-15S,16R)-1,9-dioxo- 15-hydroxy-15,16-trimethylene-16-(4- fluorophenoxy)-17,18,19,20-tetranor-l- hydroxymethyl-13-t rans-prostene O P 1 O 1 O fi X X rt X O 1 ‘ J /rt © P CO fi O Ό © C rt rt 3 * X P co X 4-» © in p © fi rt © P © ι ,e » p Ρ Ή © m fi P CM p © P * P ι cn 0 TJ Ό rt 1 fi rt * TO rt -oo fi in ή ro 1 rt - p 05 t r- p \© Xrt 1 rt χ ι tn * O /rt rt 05 Ρ X 1 in TJ X »-i rt X O X 1 ,X fi X P l © P rt in X © fi rt 0 g Vinyl Iodide or Vinyl Tin of Example 250 252 253 254 255 256 257 Cyclopent-2-en-1-one I of Example 284 284 284 284 284 284 284 Method of Example 319 319 319 320 320 319 319 Example 755 756 757 758 759 760 761 259 8 2 ο Ί Product Prostanoid 1 m X c •r-l > 1 3 X xz 4-> o ε X X o μ 3 X X 1 X X O μ 3 X X 3 S' © ι—4 a ι—r i—1 Ο Φ X C O O •H +J 3 tn ι Q © μ - CM t tn ’. c *-» rt rt μ β1<-> tn X c • rd > 3 r—4 1 l—1 X X M Φ ε X X 0 μ 3 X X X X ο μ 3 X X • r-4 3 l ω '_ζ 3 0 Γ—4 1 Ο Φ X β ο φ ·*—* +-· 3 tn ι Ο © μ - CM r-4 1 t tn • C w rt rt μ β|μ tf) U m l rt X β • r-4 > 1 3 r—1 1 r—4 X X μ Φ ε χ X ο μ 3 X X I ^4 4 X X ο μ 3 X X •rrl 3 t S' 3 r-4 φ * C a φ 4—1 rt rt 3 ι rt Ο μ X tn ° s rt μ 3 χ, 1 t © tn * c ·—i ct3 ι μ * μ μ I rt tn βΗ nat.-1,9-dioxo-11a:16(5)-dihydroxy-I-hydroxymethyl-16-vinyl-5-cis , 13-trans-prostadiene dl -1.9-dioxo-lla .16fRI-dihydroxy-1-hydroxymethyl-16-vinyl-13-transprostene 1 tn § μ μ tn r—1 1 rt X β rt > t 3 4—4 1 rt X 5 Φ e X X o μ 3 X X 1 4—4 1 fe o μ 3 X X rt 3 ΐ-\ w 1 3 rt s 1 O X o rt 3 4) 1 β © Φ * μ rt tn • , ° rt μ 3 cm dl-1,9-dioxo-11α,16(R)-dihydroxy-1-hydroxymethyl-16-vinyl-5-cis, 13-trans-prostadiene in I rt (j| 1 3 1 rt X c rt t 3 I X X μ 0) ε X X o μ 3 X X 1 t X X o μ 3 X X rt 3 t r-C W ' Cyclopentenone of Example o © rt Ό © Cl © Cl 296M 296-0 296-0 296J 296J Example < © o r» 769B u © 3 r> 769D 769E 769F 769G 769H 260b •J 8 2 ϋ 7 EXAMPLE 769A-769H Conjugate'addition of the vinylstannane of Example 210(a) by the procedure of Example 320 or 772A is production of the optically active or racemic prostanoid of Table 39A.

The listed confounds are separable by silica gel dry-column chromatography or H.P.L.C. techniques into the individual 16a- or 16B-isomers. - 260a 8 2 0 7 1,9-dioxo-1-hydroxymethylprostene and its diastereomer nat - 15R, 16S-(and ent-15S, 16R)-1,9-dioxo15-hydroxy-15 ,16-trimethylene-16-(3chlorophenoxy)-17,18,19,20-tetranor-lhydroxymethyl-13-trans-prostene , 0 X ι Ο rrt •rt 1 1 tj tn μ 1 Art o © ι c • © rt i—1 rrt μ O ι ι p G <^ © © © ω g ρ p © © » w rrt rrt O p - Xcm μ ωχ * q ω ρ © ι , rrt © rrt U) 1 E F c rt ή co rt 1 e μ ·—ι μ I © p * P ι b I Ό s£3 rrt tn c rrt 1 rrt PJ -r~s 1 '—' LT) > rrt 1 rrt X X Cd ι Ο X © X C P irt X © © • Ο X £ Cd H q 5s in Ό Ο X rrt χ μ O 1 .χ ° μ P I (rt Ό rt in χ X cl·-· U JZ , Ο ι X »rt Ο Ό © •Η 1 C TJ O © 1 CM P © · ra *© o rrt rrt μ 1 1 q —. © 1 ω G « S.2 § cd c p ω ρ ι r-ι © in ι. e —< Ρ ·Η 1 G -rt © P X » X TJ b p § ig a—»in X ι -ι χ OS 1 o b χ μ -π χ q F o X ω μ x ω q ι r-l X rrt 1 ιΛ Λ pH μ rt in ο G|r-< fi nat- 15b. 17S- land ent-15R, 17R) -1,9-dioxo- 15-hydroxy-15,17-trimethylene-19,20-di- nor-l-hydroxymethy1-13-trans-prostene 1 t o rrt x is O X •rt P © © ι ε © 1 © • o g rrt CM © ι » P © ra cd c p b· © μ rrt rrt q F X 1 w X ra ©PC rrt © rt ι ,e μ Ρ -rt P Chi ©Ip m 1 rrt Obi C rrt rrt rt X ^© X 1 rrt P ω < 2 b X E rrt X X • ox Cd μ O \o tj μ rrt xtj ι ,X is P 1 43 rt © ι fi|rrt i—I t I O rrt x is O X •rt P T3 © © 1 © *O G rrt CM © ι t P r—% © ra WCO b © μ rrt rrt q F X I ω X ra ©PC rrt © rt ι .6 μ ρ .η p G * ' ©Jp m 1 rrt TJ b k G rrt rrt rt * X '—'AO X t rrt P cd 1 © b X £ rrt X X • OX cd μ o © © μ rrt XTJ ι ,x X P 1 X rt© ι C|rrt rrt 1 1 O *rt 1 X μ rrt ο P 1 •rt ι μ τ tn o 1 q © 1 irt f© μ rrt rrt p © ι ι ι G © o © cd G cm b © · ra rrt rrt © O * X rrt H ω x * q © p 00 I rrt © rrt VJ 1 ,E 1 G P .rt /-a rt r μ χ μ © P X p ι Ο I © b G G rrt © rrt rt f 4^ ι A—/ © qrrt 1 rrt irt ω » xg b XX P rrt X P © • o © £ cd μ £ X © TJ o X rrt X μ O I .X Ο μ P I 3 Ό W © rrt X c|rt X l l O «rt · X μ rrt ο P ι •η ι μ tj tn o I a-> g © » ‘rt Λ i 0 tn c cm·»; © P eo ’ rrt © rrt ra 1 ,e '5 P .rt «—%? g ΰ g;q a->© qr· 1 rrt rrt Cd ι Xt b X Xd rrt X P 2 F. O © 5 cd μ £ © Ό o 5 rrt χ μ g 1 ,4- 2© P 1 rt © rrt >» Clrrt MrtX Vinyl Iodide or Vinyl Tin of Example co ιΛ CM © ιΛ ΓΜ o © CM rrt © ΓΜ CM © CM tn © CM T· © CM in © CM © c o r~-1 1 © C rrt © q t e r%j n ι X rt J c © Um q o o 'J τ co ΓΜ τ co ΓΜ Tj- co CM rt- 00 CM 00 CM 5T 00 CM T 00 CM M 00 CM Method of Example σ ΓΜ tn O CM tn © 1—I tn © r-( tn © CM tn o CM tn O CM tn O CM tn © ί rt X LJ ΓΜ ο b tn © b © b ω © b © © b b © b 00 © b © © b 260 EXAMPLE 770 Preparation of 1-9-oxo-15(S)-acetoxy prostanoyl chloride To a solution of 0.5 g of l59-oxo-15(S)-acetoxy prostanoic acid in 10 ml of benzene at 0°C with stirring is added 0.5 ml of oxalyl chloride.

The mixture is stirred at room temperature for 2 1/2 hours. The solvent and excess oxalyl chloride is removed at reduced pressure. The residue is dissolved in hexane and filtered. The solvent is removed giving the title compound.

EXAMPLE 771 Preparation of l-l,9-dioxo-15(S)-acetoxy-1-hydroxymethyl-prostene To a solution of 11.9 mmol of diazomethane in ether at 0°C with stirring is added dropwise a solution of 2.99 mmol of _l-9-oxo-15(S)-acetoxy prostanoyl chloride (Example 770) in 10 ml of ether. After 10 minutes the solution is warmed to room temperature and the solvent and excess diazomethane is removed in a stream of nitrogen. The residue is stirred at 55° C in 15 ml of tetrahydrofuran containing 5.75 ml of 2M sulfuric acid for 30 minutes. The mixture is poured into water and extracted with ether. The ether solution is washed with saturated sodium bicarbonate, brine, and dried over magnesium sulfate. The ether is removed and the residue is chromatographed on a dry column of silica gel eluting with hexane-ethyl acetate 3:2 to give the title compound.

EXAMPLE 772 Preparation of .1-1,9-diaxo-15 (S)-hydroxy-l-hydroxymethylprost ane A solution of 0.41 g of l_-l,9-dioxo-15(S)-acetoxy-l-hydroxymethyl prostane (Example 771) ill 8 ml of methanol containing 1 ml of water and 0.19 ml of concentrated sulfuric acid is refluxed for 5 hours. The methanol is removed at reduced pressure and water and tetrahydrofuran is added. The - 261 8 2 J 7 mixture is then refluxed for 1 hour. The mixture is poured into dilute sodium bicarbonate and extracted with efher. The ether solution is washed with and dried over -magnesium sulfate. The solvent is removed giving 0.34 g— 5 of the title compound. 262 EXAMPLE 772A Preparation of 1, 9-dioxo-llt<. 16-dihydroxy-16-trimethylfcllylethynyl-l-hydroxymethyl-13-trans-prostene To a solution of 9.2g of E l-tri-ji.“butylstannyl-45 trimethylsilylethynyl- 4-trimethylsilyloxy-octene (Example 210 I) in S.2 ml. of distilled tetrahydrofuran (from LiAlH4) at -78°C is added, dropwise, 5.2ml of 2.0 M n-butyllithuim (in hexane). After 15 min. at -78°C, the bath temperature is raised to -40°C to -30°C for 1.5 hrs. The solution is cooled to -78°C 2o and a solution of l.Sg of pentynyl copper in 4.2 ml of distilled hexamethyl phosphoramide and 3 ml.of dry ether is added. The solution is stirred at -78° for 1 hr.

To the above cuprate solution at -78° is added a solution of 2.0g 1-(1- methoxy -1- methylethoxy) -8- (5-oio-l cyclopenten-l-yl)-2-octanone (Example 269A) in 5 ml of dry ether. After stirring at -78°C for 10 min., the solution is stirred at -40 to -30°C for 1 1/2 hrs. The solution is briefly warmed to -25°C and then cooled to -78’C and 1.1 ml of gl. acetic acid is added dropwise. The solution is poured into ether (70 ml) and saturated aq. ammonium chloride (NH4 Cl) (70 ml) and stirred for 15 min. at ambient temperature.

The organic phase is separated and the aqueous layer is extracted twice again with ether (50 ml). The organic ' phases are combined, washed with 54 cold aq.HCl (50ml), three times with saturated NaCl (50ml), dired over Mg S04 , and concentrated In vacuo to a viscous oil.

The oily residue is diluted with acetic acid tetrahydrofuran- water (4:2:1) (70ml) and this solution is stirred vigorously at 40°C to 44°C for 1 hr. Toluene (50ml) is 30 added and the solution is concentrated in vacuo. An additional 263. portion of toluene (50 ml) is added and concentrated. The toluene addition and concentration is repeated two or more times to remove traces of acetic acid.

The residue is dissolved in methanol (40 ml) anil the lower phase (mostly tetrabutylstannane) is discarded. The methanol solution is extracted twice with heptane (40 ml). The combined heptane solution is extracted with methanol (10 ml) and the methanol fractions are combined and concentrated in vacuo to an oily residue. 1C This residue is dissolved in ethyl acetatehexane-acetic acid (60:40 :1) (10 ml) and applied to a drycolumn of silica gel (Woelm: 550 g - 69 χ 1 1/2). The dry column is developed with the above solution and a 200 ml fraction is collected.

The column is cut into 1 segments and 540 mg of the title compound is isolated. 264, 8 2 0 7 EXAMPLE 772B Preparation of 1,9-dioxo-llg, 16-dihydroxy-16-ethvnyl-lhydroxymethyl - 13 - trans- prostene To a solution of 1,9-dioxo-llat 16-dihydroxy-16trimethylsilyl ethynyl-l-hydroxymethy1-13-trans-prostene {400 mg) in dimethyl formamide (11 ml) at ambient temperature is added 400 mg. of potassium fluoride dihydrate. After 90 min. the solution is diluted with either (60 ml) and washed three times with 30 ml water and once with 30 ml of brine.

The aqueous extracts are acidified with dilute HCl and extracted with ethyl acetate (2 x 30 ml). The organic phases are combined, washed with water (30 ml), brine (30 ml), dried over Mg so4 and concentrated in vacuo to provide 303 mg of a viscous oil.

The viscous oil is disolved in a small amount of ethyl acetate-hexane (3:2) and applied to a dry column (of silicagel (Woelm: 225g, 54 x 1). The column is developed with ethyl acetate-hexane (3:2). The column is cut into 1 segments and the portions containing the product are eluted off of the silica-gel with ethyl acetate to provide 160 mg of the title compound. 265. 8 2 0 7 EXAMPLE 772C Preparation of 1,9-dioxo-lla,16-dihydroxy-16metnyl-l-hydroxymethy1-13-trans-prostene A. To a stirred solution of 75.5 g (150 mmol 5 total vinylstannane; estimated 120 mmol of trans-isomer by CMR) of E-l-tri-n-butylstannyl-4-methyl-4-trimethylsilyloxy1-octene in 120 ml of THF at -78° initially was added 60 ml of 2.0 M n-butyllithium in hexane during 5 min. so that the ta^erat was <-60°. The light amber solution was warmed to -40° during min. and maintained at·that temperature for 2 hr. The solution was recooled to -78° for use in paragraph C. 63·) To a well-stirred 17.25 g (132 mmol) sample of copper pentyne was added 48 ml (about 43.1 g, or 264 mmol) of freshly distilled hexamethyl-phosphorous triamide. After 20 min. 300 ml of ether 1- was added. The resulting clear, light yellow solution was cooled to -78° for 60 min.

C. To the vinyllithium solution prepared in paragraph A at 78°, initially was added the precooled solution of copper complex prepared in paragraph B via double tip needle technique during 10 min. so that the tenperature was <-65°. The resulting light amber solution was stirred at -78° for 60 min.

D. To the stirred solution prepared in paragraph C at -78° initially was added a solution of 23.07 of (60.0 mmol) of 1-(1-roethoxy-l-methylethoxy)-8-[ 3-(methoxy-l-methylethoxy) 25 5-oxo-l-cyclopen-l-yl]-6-octanone in 50 ml of ether during 1C min. so that the tsnperature was <-65°. The syringe and septum bottle were washed with 10 ml ether. After 5 min. the light amber solution was warmed to -40° during 10 min. The solution was stirred at -40° for 1.5 hr and then allowed to warm to -20° during min. and then recooled to -78°. The reaction was quenched by addition of a solution of 14.4 al (about 240 mmol) of gl HOAc in 100 ml ether. The precipitate which formed was stirrable with a magnetic stirrer on this scale. 266 £. The mixture above was transferred with the aid of washing with 750 ml of ether into a stirred, icecold mixture of 48Q ml of N/l HCl and 240 ml of satd NH^Cl.

The mixture was stirred vigorously at 0-5’ for 5 min. The aqueous phase was separated and extracted with 350 ml of ether. The-eombined organic phases were washed successively with 2 3C240 ml of ice-cold N/l HCl, 240 ml of half-satd brine, 240 ml of 1:1 satd brine-satd NaHCO3, 240 ml of half-satd brine, and 3 X 240 ml satd brine. The solution was dried over MgSO4, filtered through a small pad of Celite, and concentrated in vacuo at ca 30° to give 108 g of mobile light yellow liquid.

F. The materials from paragraph E resulting from this run (60 mmol-scale, 108 g) and a similar run (57.7 mmol-scale, 103 g) were combined. This material (211 g) was treated with a solution prepared from 940 ml of gl HOAc, 470 ml of THF, and 235 ml Of water. The resulting solution was stirred at 40-43° for 60 min. Some (n-Bu)4Sn was not dissolved. The mixture was diluted with 600 ml of toluene. Then 600 ml of distillate was removed via rotary evaporator at about 30°.

The flask which contained the solution was set up for standard vacuum distillate (dry-ice acetone cooled receiver). The solution was diluted with 600 ml of toluene. Then 600 ml of distillate was removed (bath at about 30°, 0.1 mm). The solution was diluted with 600 ml of toluene. Then the volume of the solution was reduced to about 1000 ml. The solution was diluted with 600 ml of toluene. Then the volume was reduced to about 500 ml. - The solution was diluted with 300 ml of toluene (total toluene used was 2700 al). This solution was evaporated to give 194 g of a mixture of colorless (n-BuJ^Sn and a dark amber oil. 267 R 2 Ο 7 G. The material from paragraph F was placed, with the aid of repeated hexane wash, on the top of a pad of 385 g of Mallinckrodt SilicaAr CC-7 silica gel contained in a glass column; dimensions 5.8 X 30 cm. The column was washed 5 with 2500 ml of hexane to remove stannane material. The column was then washed with 4000 ml of ethyl acetate, taking care to wash all hexane-insoluble material in flask and on column sides onto the top of the silica gel. The first 3250 cc of ethyl acetate eluate yielded 77.4 g of amber oil on evaporation. The last 750 ml of eluate yielded 0.1 g of amber oil (total = 77.5 g) .

H. Chromatography. To a 5.4 cm diameter column filled with 2:1 heptaneethyl acetate was added 970 g of * Mallinckrodt SilicAr CC-7 silica gel. The column stood over15 night; dimensions 5,4 X 98 cm. This column was used to purify most of the material from paragraph G (71.0 g).

The material (71.0 g) was dissolved in 250 ml of 2:1 heptane-ethyl acetate and 50 ml of ethyl acetate (required to produce solution). The solution was developed . on the above-described column. Elution was carried out under slight nitrogen pressure to produce a flow rate of about 3-4 S/hr.

Fractions which emerged from the column were examined by TLC with the solvent system 20:1 EtOAc-MeOH. Plates were developed by spraying first with 2,4-DNP solution and then cupric acetate solution and charring.

' The column was eluted with heptane-ethyl acetate block gredients according to the following schedule: 268. 8 20 Batch Volumn Solvent Ratio 1 7 2:1 heptane-EtOAc 2 7 5:3 3 12 3:2 '4 2 4:3 5 2 10:9 6 4 1:1 7 2 3:2 EtOAc-heptane B 2 2:1 9 6 3:1 10 12 3:1 - increased to pure EtOAc Fractions collected were of appropriate size (about 1500-2000 ml) and were pooled according to TLC as above. The product emerged from the column corresponding to solvent batches 6-10 above to provide 16.9 g of product.

EXAMPLES 772D-772AAA Conjugate addition of the indicated vinylstannane or vinyliodide with the indicated cyclopentenone of the following table by the procedure of Examples 772A, 772B, 772C or the procedure of Examples 319-320 is productive of the optically active racemic prostanoid of Table 39A.

The listed compounds are separable by silica gel drycolumn chromatography or H.P.L.C. techniques into the individual 16a- and 16B-isomers. 269. .70 8 2 0 7 TABLE 39A (continued) 271. 8 2 Ο ? Ό Φ C < σ' η u: c < Η jcllq 272 8 2 0 7 TABLE 39A (continued) 273 .1 y ζ ο ο C CD fc Ε Ο fc & fc υ Ο fc CL fc Ο Φ 0 C rt 2Έ C rt (0 fc r-l cn >« rt c >» rt C > Φ c c φ jj c Φ G* rt u is u Θ rt CL , >0 '53 rt rt §Λ S. rt >1 I , 7&S °15 2 rt φ fcl fc rt rt fc η ι r tt CN f* P* CN S*» F* CN δ* ·? CN F* P* 274 8 2 0 7 is (ύ t-3 CQ < Η Ρ U Έ μ & μ ο φ Φ 0 CM β τ> C ο C W ιο Ρ rt W X rt C >Μ c > φ c ο c φ Ρ C φ α ο φ Μ £ α & Μ ί* Ci Γ* t Ci « t* r* 275 8 2 0 7 JClk) 275A 8 2 01 TABLE 39Λ (continued) 275B I 8 2 0 7 275C 8 2 0 7 TABLE 39Λ (continued) £ CM Γ» CX E re x tc ¢) C Δ I υ II u ι eφ £ 0) CP fi > fi © »rt υ μ ο &4 « f75D EXAMPLE 773 Preparation of l,9-dioxo-lla,16-dihydroxy-l-hydroxymethyl-20-homo-5-cis-13-trans-prostadiene, 1-ethylene ketal To a solution of 3.58 g (7.0 mmol) of l-iodo-4-triphenylmethoxy-ltrans-nonene (Example 112) in 8.0 ml of ether is added 8.9 ml of 1.6M tbutyliithium solution (14.1 mmol) with stirring under argon at -78°C. The solution is allowed to warm to -30°C over a 2 hour period. The solution is recooled to -78°C and a solution of 7.0 mmol of copper pentyne and 2.9 ml of hexamethylphosphorous triamide in 20 ml of ether is added. After 1 hour, 3.28 g (7.0 mmol) of 2-(8-dimethyl-t-butylsilyloxy-7-oxooct-2-cis-enyl)-4trimethylsilyloxycyclopent-2-en-1-one,7-ethylene ketal (Example 280) in 5 ml of ether is added. The mixture is stirred at -30°C for 2 hours and at 0°C for 30 minutes. The mixture is poured into 150 ml of saturated ammonium chloride and extracted with ether. The ether solution is washed with dilute hydrochloric acid and dried over magnesium sulfate to give 6.0 g of an oil.

A 3.0 g portion of this oil is stirred in 40 ml of tetrahydrofuran-0.6N hydrochloric acid 5:1 for 5 hours at room temperature.

The mixture is poured into water and extracted with ether. The ether is removed and the residue is heated in 70 ml of acetic acid-tetra20 hydro furan-water 4:2:1 at 60°C for 4 hours. The solvent is removed at reduced pressure. Toluene is added and removed. The residue is chromatographed on a silica gel column eluting with ethyl acetate giving 0.1 g of the title compound.

EXAMPLE 774 Preparation of l,9-dioxo-ll«,16-dihydroxy-16-methyl-l-hydroxymethyl-5-cis-13-trans-prostadiene,l-ethylene ketal To a solution of 3.4 g (6.75 mmol) of (E)-4-trimethylsilyloxy-4methyl-l-tri-n-butylstannyloctene (Example 210b) in 3.5 ml of tetrahydrofuran with stirring at -78°C under argon is added 2.8 ml (6.75 mmol) of 2.4M n- 276 48207 butyllithium in hexane. The solution is maintained at -20° to -15°C for 2 1/2 hours. A solution of 0.89 g (6.75 mmol) of copper pentyne and 2.2 g of hexamethylphosphorous triamide in 25 ml of ether is added at -78°C. After 1 hour, a solution of 2.3 g (5.0 mmol) of 2-(8-dimethyl-t-butylsilyloxy-7oxooct-2-cis-enyl)-4-trimethylsilyloxycyclopent-2-en-l-one,7-ethylene ketal (Example 280) in 20 ml of ether is added. The solution is stirred at -45°C for 30 minutes and at -45° to -20°C over 30 minutes. To the solution is added 3 ml of acetic acid followed by saturated ammonium chloride. The mixture is poured into water and extracted with ether. The ether solution is washed with dilute hydrochloric acid, saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed and the residue is stirred in 75 ml of tetrahydrofuran containing 15 ml of 0.6N hydrochloric acid and 1 ml of acetic acid at room temperature for 5 hours. The solution is saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate solution is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed and the residue is chromatographed on a dry column of silica gel eluting with ethyl acetate containing 0.5% acetic acid (1000 ml) to give 0.65 g of the title compound.

EXAMPLES 775-868E By the methods described hereinabove in Examples 773 and 774, the 1,9-dioxo-1-hydroxymethylprostene derivatives shown in Table 40 are prepared by the indicated method from the indicated cyclopent-2-en-l-one.

In those cases where isomers are obtained at the or C^g positions, only the Cl5 or C^g-normal isomers are listed in Table 40; it should - 277 . 48207 be understood that the corresponding C^g or C^-epi isomers are also formed and are part of this invention. - 278 48207 I , (ft I rt ,i—1 X © rt X I P o tn © μ ι j* Ό μ X Q © X G G ι ι © 1—4 I CM x X t 43 X © P O G © μ © ι *0 rh rt X X A X X © •η p e ό © © » g rt © rt 53 rt μ rt * p p β ι w rt \0 O rt rt μ i A CU Ο Ο I x rt m ° 1 s •rl rt rt ia χ μ I X P O> P » * o © rt E rt rt p ι © I ω rX χ ι X rt o Ο X fi μ χ © Ό p rt X © X X g X ι ι P rt O © l CM ι X I rt X © A OC© μ © C 53 rt © X Xrt χ x *2 rt P rt 53 © P I B (ft © rt p ι—ι μ μ aP cu a ι ι rt \O ο \o μ X rt P o » ι Xrt 1 X ι I ©ρω A © rt rt β ©| X rt μ (ft co 53 rt P χ υ © χ ι fi ι © rt | © » rt e x x © XXrt O P X μ © X 53 f P xo © X CM I rt ί rt 53 © a I G © © © G rt rt © * Xrt a x 5? O rt O χ μ μ ο ρ cu rt l I Ό o (ft I rt fi © *rt • © μ rt ·-» P X © s § rt X53 X (0 I P rt 1ft i 0 X μ X G< ο ι μ «η 53 G £2 rt P 53 ι I © \O «—4 rt 1 . a (ft rt a .η rt rt u|p rt | © I © fi o . rt © X G c © x . o rt 53 « > X © ι x A\O P rt r-l © o CM I I (ft rt P > « ι © © rt ι tftlrt Xrt ρ X ©I© 0 I X μ © » © Xrt fi X X © rt X rt 53 Ρ X ι © 43 © S P rt X © A X I 85 rt T) © ( X c ox© X I rt O rt 53 rt I © Ό rt p t X « © X o A Ρ μ rt © CU I rt X ( Girt O 53 μ ra cu P o (ft ι-ι O υ μ S'* (ft g . μ x P χ i o © μ »-ι 53 ι, X (ft X rt rt rt Ο rt 53 I P I © © © ( fi • X © a x g rt p © rt © rh ι e x o XX X X Ρ O 0 © rt μ ι 53 53 rt • X * Ch X © rt rt © TABLE 40 0) Uh 53 O • rH © C rt & fi rt rt X X χω G G rH ·γ4 > > G © CU o rt © X o > CU o e x « p x © X cu E rt X UJ - 279 48207 1,9-dioxo- 1-h ydroxymethylprostene dl-erythro-1,9-dioxo-lla,15-dihydroxy-16methoxy-l-hydroxvmethvl-5-cis-13-transprostadiene,1-ethylene ketal l,9-dioxo-lla,16-dihydroxy-16-ethyl-l-hy- droxymethyl-5-cis-13-trans-prostadiene,1- ethylene ketal dl-erythro-1,9-dioxo-11α,15-dihydroxy- 16-ethoxy-l-hydroxymethy1-5-cis-13- trans-prostadiene,1-ethylene ketal dl-erythro-1,9-dioxo-11α,15,16-trihydroxy- i-hvdroxvmethvl-20-noT-5-cis-13 -trans- prostadiene,1-ethylene ketal fci 8 § 0 fc Xfc 5Λ fc rt fc > . I rt £ ·Η rt U| • 1 rt ΙΛ 1Λ d rt (- fc • rt 8 6 X£ rt £ rt fc 8 1 8 C ο ε 8 X Xrt O X X •Η O £ 0 fc fc I 0 8 © X 1 ·£ rt rt| · 1 rt 8 O > C fc rt 8 £ Xrt fc £ 0 Xfc 8 fc 8 fc 8 g tfl 1 1 o rt O fc 0 pi fi £ . O V) fc e 0 a X fc £ fc •rt t fc 0 fc rt 1 S £ * rt rtl 0 ι- rt rt 0 fc -. (. 8 3 rt £ rt X rt £ 8 1 fc fi 0 8 8 χ e ή o X X •rt X £ 0 O fc 1 fc 8 © 0 1 • X rt rt£ · 1 P 8 O rt fi fc 1 8 £ rt rt fc X0 X£ rt fc fc fc 8 8 rt ι , v O rtl© fc 0p4 fi 1 X · X rt © fi fc rt 0 fc Xfc 5Λ fc rt fc 1 1 ι w £ ««-J rt 8 • 1 rt 0 0 rt rt 1 fc • rt 8 a x^d rt £ rt fc 8 1 2 C 0 6 8 X Xrt O X X •rt O £ 0 fc fc 1 0 8 © X + ·£ rtrt | * 1 rt 8 O i fi fc rt 8 £ fc £ 0 X fc rt fc 8 fc 8 B rt ι ι © rt © fc 0 rt fi Vinyl Iodide or Vinyl Tin of j Example N Γ 210c r- 83 84 85 86 Cyclopent-2-en-1-one 2 80 2 80 280 2 80 280 280 280 Method of Example 773 774 i 773 773 0 r-- r-·» 773 773 Example <ϋ 0 CO r- 783b 784 785 786 1 787 788 280 482 07 TABLE 40 (continued) 4> e o μ (A O H CM rt X X μ fl) ε χ X ο μ 3 X X t ι—I 1 Ο X Ο •r9 3 I © rt dl-erythro-1,9-dioxo-lla,15,16-trihydroxy1-hydroxymethyl-5-cis-13-trans-17-transprostatriene,1-ethylene ketal dl-threo-1,9-dioxo-1Ια,15,16-trihydroxyl-hvdroxvmethyl-5-cis-13-tTans-hydroxymethyl,1-ethylene ketal dl-threo-1,9-dioxo-1Ια,15,16-trihydroxy20-nor-1-hydroxymethyl-5-cis-13-transprostadiene,1-ethylene ketal dl-erythro-1,9-dioxo-11a,15,16-tTihydroxy1-hydroxvmethvl-5-cis-13-trans-prostadiene,1-ethylene ketal dl -threo-1,9-di oxo-11a,15,16-trihydroxy- 20-methyl-l-hydroxymethyl-5-cis-13- trans-prostadiene, 1-ethylene ketal dl-threo-1,9-dioxo-lla,15,16-trihydroxy- 20-ethvl-l-hvdroxvmethyl-S-cis-13-trans- prostadiene,1-ethylene ketal dl-threo-1,9-dioxo-lla,15,16-trihydroxy- 19-methy1-1-hydroxymethyl-5-cis-l3- trans-prostadiene,1-ethylene ketal dl-threo-1,9-dioxo-1Ια,15,16-trihydroxy- 1-hvdroxvmethvl-5-cis-13-trans-17-trans- prostatriene,1-ethylene ketal Vinyl Iodide or Vinyl Tin of Example 87 © 3 00 co 3 © 00 © © © 92 t Cyclopent-2-en-l-one 280 280 280 I- 280 1 1 280 280 280 280 Method of Example 773 773 773 773 773 773 773 773 Example 789 790 791 792 793 794 795 3 © 281 1,9-dioxo-1-hydroxymethylprostene 1,9-dioxo-lla ,16-dihydroxy-1-hydroxymethyl- 5-cis-13-trans-prostadiene,1-ethylene ketal 1,9-dioxo-11a,16-dihydroxy-1-hydroxymethy1- 19.20-dinor-5-cis-13-trans-prostadi ene 1-ethylene ketal rt tt X c tt Ρ M tt 0 g.3 X Ul o o μ μ 0 ft X 1 £ 10 Λ g ι μ fe? ο to μ 0 ι, X «ο £ Ml rt o| 0 1 ι tn 1 r-l -Μ μ d • OP a c tt rt rt •-ι μ 1 P tt o i fi X © tt O CM rt rt · X 0 © £ 1 rt p © * tt • 00 1 rt rt rt 1,9-dioxo-lla,16-dihydToxy-l-hydroxymethyl- 20-nor-5-cis -13-trans-prostadiene,l- j ethylene ketal 1,9-dioxo-lla,16-dihydroxy-l7-methyl-l- hvdroxvmethyl-5-cis-13-trans-pTostadi- ene,1-ethylene ketal 1,9-dioxo-lla,16-dihydroxy-20-methyl-l- hvdroxymethyl-5-cis-13-trans-prostadi- ene,1-ethylene ketal I t rt ·Η ι 0 rt β) X p £ (0 P o tt μ « Λ Ο 1 CM Ul t fi feS O P μ ι 0 tn X Μ £ 1 ,rt rt Ul cd 0 MP 1 U tt \O 1 A ι-ι in • 1 tt 9 rt fi rt X tt i—f JZ rt 1 p X O tt A x e p •S fe? 0 O rt ι μ · © 0 tt • X-fi rt A tt μ © CM 1 i rt Ul X 5 j* Λ ρ μ tt Ρ \0 rt ·—1 1 ,rt ι υι cd XM P X Ott ο ι & μ in 0 1 tt XM 6 £ ΧΦ M £ rt 0 P X I © £ \O e P rt g, tt a o rt «-ι μ * rt 0 tt ι X fi Q £ tt X M O rt 0 •H 1 cd 0 rt P 1 X «Λ © £ O * ρ μ rt tt ft Vinyl Iodide or Vinyl Tin of Example 107 108 1 109 110 144 112 | i 113 139a Cyclopent-2-en-1-one 280 280 280 280 280 280 280 280 Method of Example 773 773 773 773 773 773 773 773 Example 797 798 799 800 801 1 802 803 804 282 TABLE 40 (continued) a G © p ra 0 μ q rrt X X P g δ- ε © X X t rrt t o X o •rt © 1 © 1,9-dioxo-lla,16-dihydroxy-1-hydroxymethyl13-trans-17-cis-5-cis-prostatriene,lethylene ketal I rrt I rrt © X rt •5 S g 2 ι q © 1 rrt w 1 fi X rt χ μ O P μ ι © tn Xrrt X ' 1*3 •rt in rt © .rt P ι O| a © 1 44 rrt in * ι a a τ e rrt x a irt j- rrt » P X o © X χ ε p .2 ??? ©On ι μ * © © a * X fi r-ι χ a 1 ♦rt μ t p ra 1 fi © rt ο, μ * P b 1 rrt Κ) * rrt b t , rrt W rrt ι ·Η rt x op X I 0) Ο in 44 μ ι -rt rrt a X X G bx a Τ P rrt S j 2 4 °Λ.2 Λ 1 ,® rrt Λ © χμ 7 x ra ' xj o ©» a μ a q 1,9-dioxo-lla,16-dihydroxy-16,20-dimethyl- 1-hydroxymethyl-13-trans-5-cis-prosta- diene,1-ethylene ketal 1,9-dioxo-lla,16-dihydroxy-17,17-dimethyl- 1-hvdroxvmethyl-5-cis-13-trans-prosta- diene ,1-ethylene ketal l,9-dioxo-lla,16-.dihydroxy-16-methyl-l- hvdroxvmethvl-13-trans-17-trans-5-cis- prostatriene,l-ethylene ketal 1,9-dioxo-lΙα, 16-dihydroxy-20-methyl-1- hvdro xvmethy1-13-trans-17-trans-5-ci s- prostratriene.l-ethylene ketal 1 rrt » ‘ X rrt © X «5 X P p tn © 9 S £ ι q © » rrt tfj O p μ ι © tn X X ι .rrt •rt tn rt © «rt P ι o a © 1 44 rrt in * • ι a a rrt G rrt χ a rrt X rrt t P X Ο © X X Ε P oxa •rt X I © OH » μ * © © a * X fi rrt χ a Vinyl Iodide or Vinyl Tin of Example 115 135 © tn rrt 137 138 139 149 i OSI Cyclopent-2-en-1-one 280 280 280 280 280 280 280 280 Method of Example 773 773 tn b b , 773 773 773 1 773 773 Example 805 806 807 808 608 810 811 812 283 <υ ro ε ρ •Η ω ·? 8 Ο 0 CM I * TO S rt ro ι Ρ s?V o tC P rt TJ I rt x to ro X rt P rt ©I© TJ I x ι in Α ι © rt rt fi * X © ax—* rt p x rt ω XJ ι ε p ox© x x · Ο O rt •Η P * TJ TJ © I X c σι x © x © X G 8.8 TJ P x y x ro I P rt TO I X' 0 O 1 . P TO Ό rt X © X I rt m Ό l l TO Ό C I X o © P 1 TJ rt X * X © ι c rt © I rt x*5 x ro o P ρ TO Tj O X P X 0 rt I TJ TO I rt I X o © P I Ό rt rt © I rt x·© x ro o p p TO TJ o X p X 0 rt I TO OT ω p •rt p Ό I rt tC TJ fi 0 O rt E H-if-.ro O © •-H TJ 0 0 Ϊ -c ro P X © UJ rt X I rt ο ι X TO O C rt ro TJ P I P rt TO| rt rt I I ©I ο I rt x in ro ο ι p rt rt © TJ XX ι X Oi P « * © s rt g © a «. rt TO rt «rt j ©I Ο I rt x in ro o I P rt rt © TJ XX I X σ> p © • © p rt g © rt rt X X G 1 *» G 1 © to ro - © TO X C 0 X G 0 ro x 0 « rt P · © rt p Ρ Ρ « Ό p P PI·* P 1 1 rt 33 tc 1 rt tc | '-'X tc I ι X «1 fc» OX©* O X T, o c tc TJ o ox© O X rt P P · rt P ι © © O 2 rt B o Z rt g rt 33 tC Ό rt CO - 284 J TABLE 40 (continued) 1,9-dioxo-1-hydroxymethylprostene © t c rt © 1 «ft rt *0 X Λ 4= b b tn © 0 ι b O ft l » tn X G X « O b b ft 0 i XM 45 rt •ft 1 •0 W 1 .ft ο © ΙΛ 1 rt ΙΛ * 1 B rt rt X rt J2 t b 0 © x ε 0 X •rt X 0 O ι b Ch 0 * X rt 45 1-ethylene ketal 1 * rt © X G £ © b rt © *0 ε g •rt b 0 (fl I O O b rt ft * 1 \O tn 7 § X b x b O t b « •0 rt X 1 , £ « •rt »rt 1 0 U| I t s in m ι rt rt rt fi • X b SSS 7 § « 0 X G X X © O O rt •rt b X -0 0 £ ι Xb O> 4= © A I 1 rH rft rt 1,9- dioxo-1 la, 15ct-dihydroxy-17,17- dimethyl- 5-cis-13-trans-prostadiene,1-ethylene ketal 1 © rt C 1 © rt rt X0 £ rt b b gs I b «5 ft rt ( t tn 5?§ O b b b 0 1 x«n 43 »“· •ft 1 , 0 tn 1 rtl 3 ©1 in ι rt rt ΙΛ fi a » b a rt © rt >>44 rt JS t b © O © G x ε © ° Xt* rt 5? X 0 O £ 1 b b Ol 0 © * X l rt £ rt l,9-dioxo-lla,15a-dihydroxy^l6-ethyl-l- hvdroxvmethvl-5-cis-13-trans-prostadiene, 1-ethylene ketal Vinyl Iodide or Vinyl Tin of Example. ' l-iodo-3-triphenyl- methoxy-1-trans- I decene (U.S. Pat. No. 3,873,607) . l-iodo-3-triphenylmethoxy-4,4-dimethyl -1-transoctene (U.S. Pat. No. 3,873,607). 1-iodo-3-triphenylmethoxy-5,5-dimethyl- 1-transoctene (U.S. Pat. No. 3,873,607). l-iodo-3-triphenylme thoxy-4-methyl1-trans-octene (U.S. Pat. No. 3,876,690). 1-iodo-3-triphenylmethoxy-4-ethyl1-trans-octene (U.S. Pat. No. 3,876,690). Cyc1opent-2-en-1-one 280 280 280 280 280 Method of Example 773 Hl b- Hl Γ- r- 773 773 Example 820 821 822 823 824 285 Ο c <υ μ <Λ Ο μ CM rt X X μ Φ ε χ X ο μ 3 X X I ι—4 Ο X ο Ή 3 © irt 1,9-dioxo-lla,15a-dihydroxy-17,20-tetranor -16- cyclopentyl-1-hydroxymethyl-5-cis13-trans-prostadiene,1-ethylene ketal 1,9-dioxo-11α,15a-dihydroxy-16,20-penta- no r-15-cy c1oh exy1-1-hydroxymethy1-5-cis- 13-trans-prostadiene,1-ethylene ketal 1,9-dioxo-lla,15a-dihydroxy-18,20-trinor- 17-cyclohexyl-1-hydroxymethyl-5-cis-13- trans-prostadiene,1-ethylene ketal 1 1 μ tn O 3 .5 άι 3 rt I U|h ο ι rt CM ΙΛ μ • t Φ © rt X rt X 1 X Φ χμ» c X Φ Φ ο ε rt μ X X 3 X X χ ο μ £ v » rt 3 P 3 Xrt ι X a » φ IS) rt fi rt 1 Φ * ι—1 rt a xo rt μ rt rt fi μ ι Φ (ft O CM O χ ο μ O rt CM rt O P 3 x tn ι υ β © ι rt μ rt rt μ t Φ rt fi 1 Φ rt rt X'O X rt μ μ Φ (ft ε 8 ι μ 3 CM rt > 1 (ft X β x rt ο μ μ μ 3 I XtO X rt rt k 3 Vinyl Iodide or Vinyl Tin of Example I l-iodo-3-triphenylmethoxy-3-cyclopentyl-l-trans- ] butene (U.S. Pat. No. 3,884,969). 1-iodo-3-triphenylmethoxy-3-cyclohexyl- 1-trans- pentene (U.S. Pat. No. 3,884,969). 1-iodo-3-tripheny1- methoxy-5-cyclo- hexyl-l-trans- pentene (U.S. Pat. No. 3,884,969. 1-iodo-3-triphenyl- methoxy-6-cyclo- pentyl-l-trans- hexene (U.S. Pat. No. 3,884,969). 1-iodo-3-methy1- 3- trimethylsilyl- oxy- trans- 1-octene (Example 125) Cyclopent-2-en-1-one 280 280 280 I L____ 280 280 Method of Example 773 773 773 773 tn r- c- Example 825 826 827 828 829 286 TABLE 40 (continued) © fi © P TO 0 P 0 t-4 X X P © & X o P TJ X X 1 rt 1 0 X o •rt TJ σ» rt » © CM 1 rt I X W «§ l ( m tc rt rt t 1 .Ή X TO rt X .rt P o o © P k X tj ω X k © X rt c •rt x © TJ X l P X 8 © X m 6 +* rt x © * X 1 β O rt p * rt TJ © 1 X c QA © X P .rt Q r-l TJ •rt r rt TJ rt p 1 X TO O *P P rt © 0 rt * X © X CM 1 P * X © O X 1 rt 0 rt * P * CO C3 © rt X G *x « X t »rt rt rt Ό ι ι ro X X P X X TO 0 O 0 PGP TJ © 0 XX I X 0 TO HOC tj p ro I O P a 3 p m «-i · rt tc * I rt β (=4 '. rt 1 TO rt © .rt 1 rt ©| Ο ι I Ή x P m ro Ο ο ι p •rt C rt © *0 « XX 1 P X OPP© r © © q rt p g © 1,9-dioxo-Ila,15a-dihydroxy-17,18,19,20tetranor-16-phenoxy-1-hydroxymethy1 - 5 cis-13-trans-prostadiene,l-ethylene ketal 1 rt ι X o x CM P » I © cn X ι rt X rt oo S © rt TJ G * X © r- χ ·η rt ι Ό ι «-ι ro X k P X X TO O X P POP TJ G 0 X © I XX W •rt 0 G •a o « ι e p a ο p in P t rt χ tc * k rt rt Γ TO] rt lO «Η 1 1 rt © O k ι rH χ P in ro 0 O i P «Η C Γ1 © Ό ro xx ι Ρ X cn p p © * © © G rt p g © 1,9-dioxo-1Ια,15a-dihydroxy-17,18,19,20- tetranor-16-jo-t-buty Iphenoxy-1-hydroxy- methy 1-5-cis- 13- trans-prost adiene, 1-ethylene ketal rt ι X © k X CM x p * X © σι Ο ι rt p rt *TJ * 00 X © rt X G - 1 © P— r4 «rt rt v *a ι X rt X X P X O TO O G o POP T3 X 0 X 0 » X X TO •Η X G tj o ro , X P a ρ p in © ι rt e tc ι 1 .rrt a w .Lt rt J TO J rt \o Ή , 1 rt © 1 Ο Ρ 1 rt χ ρ in ro ο ο 1 P •rt G τ» © tj ro Xx ι P X cn ρ p © . - « © G rt p ε © Vinyl Iodide or Vinyl Tin of Example I © tc G 1 © rt ι υ Xrt © cn m rt 186 181 182 183 Cyclopent-2-en-1-one 280 280 280 280 280 280 Method of Example 773 774 774 774 774 774 1 ........,,.1 Example 830 831 832 tc tc 00 834 835 287 © ο β Ο τ UJ X CQ < Η a β a ρ ω Ο μ q rrt X X Ρ a ε χ X ο μ © χ X ί η 1 Ο X ο •rl © 1 © I o X © X ι «—1 O rrt • μ · oo © a rrt X C • x a b 1 -«rt rrt rrt © 1 1 rt X X P x x tn o o o μ c μ © a q XG I x q w •irt O C © μ rt ι ο μ a n P ω χ ι rrt a tn • 1 rrt rrt O CM 1 , © rrt 1 10 P rrt © ·Η 1 a 1 rrt O|X O I 1 X μ ΙΛ a Ο Ο ι β •rl fi n a © rt Xrrt ι μ χ X © P P X • o a p n P S a 1,9-dioxo-lla,15a-dihydroxy-17,18,19,20- tetranor-m-trifluorophenoxy-l-hydroxy- methy1-5-cis-13-trans-prostadiene,1- ethylene ketal 1,9-dioxo-lla,15a-dihydroxy-17,18,19,20- tetranor-16-(3,4-di chlorophenoxy)-1-hy- dro xymethyl-5-cis-13-trans-prostadiene, ethylene ketal 1 •#rt μ ι p tn 1 rrt © 1 ! cm ra * «frt Jrrt © art W t P Fin a CO | 44 rrt «~t ι X a X X fi X p a o a «-< μ e X χ p a •μ μ ι © © rrt I x * a x © in ι fi rrt rrt a • 1 © a rrt © rrt X rt rrt q p ι a ra oxo χ q μ ο ι q •irt b J © rrt ΙΛ 1 1 c © μ rt * ο H rrt fi p I I & ρ © ι X ο X 1 CM 1 rrt f rrt f © ι a rrt q Frrt a CO X’p rrt G © ι a rt XX P x q ra O «-rt O μ χ μ © x q XP 1 x a w •irt E fi ©os ι μ μ a ο p in 3 ( rrt rrt tn • M-l pH rrt a «κ i.s r-ι μ ra p rrt P «rt a ι i.ow ο ε ι x '-'in a 0 t 1 . fi •H b n a © rrt χη 1 t X X © μ ρ x «OOP rrt β β a 1 1 •rt rrt μ x P X ι p a 8 £ a rrt Ο X * μ p oo © a rrt X 1 1 X Frt S?rrt a 0 1 fi μ a © rrt © x fi s «rf a P © X ra ι q o a X h in X q rrt ο 1 *x ra a μ g was w g μ 1 ,P 0 fil I x 0 rrt ♦irt b 1 , © rrt ΙΑ «Ρ ι ι ©frt © μ op f ο ι a W q tn 44 1 rrt £4 P x a 84 © F X a vs W ·Η 1 © 0 ra •8 8 •rl ra vs js 8 w 1 *tn a rrt rrt 1 , rrt ra! 1 © S V 0 in •rl 1 © μ o © c • 1 W CM ene ketal Vinyl Iodide or Vinyl Tin of Example 184 180 185 186b a © co rrt © © oo w l-iodo-3-triphenyl- jiiethoxy-1-trans- octene (U.S. Pat. No. 3,873,607). Cyclopent-2-en-1-one , 280 1 i 1 280 280 280 280 280 297 Method of Example 774 774 774 774 774 774 tn b b Example 836 837 838 839 840 841 | 842 288 8 2 0 7 TABLE 40 (continued) 1,9-di oxo-1-hy dro xymethylprostene 1,9-dioxo-lla,15a-dihydroxy-15-methyl-lhydroxvmethyl-2-nor-5-cis-13-trans-prostadiene,1-ethylene ketal 1,9-dioxo-1la,15a-dihydroxy-16,16-dimethyl1-hydroxymethyl-2-nor-5-ci s-13-1 ransprostadiene,1-ethylene ketal •rt rtrt fc rt fc U fc ι ι 8 £ 0 £ rrt 1 • fc 8 £ O C rt fi 8 1 1 rt O rt fc fc X 8 0 £ 1 Xfc rt 5 g ® 0 o 0 0 fc 0 1-4 0 rt •Xfc a £ rt rt 1 O rt rt fc 1 1 fi o 8 I X fi tn o 8 C •H rt rt 0 X fc ι £ fc © fc L • 8 0 E rt erythro-1,9-dioxo-1Ια,15a,16-trihydroxy- l-hvdroxvmethvl-2-nor-5-cis-13-trans- prostadiene,1-ethylene ketal 1 rt 1 X* O 1 fc rt &§ £ H •rt fc fc 1 fc 0 r-l I rt rt £ ι rrt W 8 • «rt Ι^ί 5 V1® rt 0 fi • t 8 a fc rt rt o x rt ci £ 1 1 fc ON D χ ι o rt rrt •rt X · 0 £ 8 1 fc fi © g 8 7 s?1 O 0 fc 8 fc rt fc 0 O £ X fc fc £ fi erythro-1,9-dioxo-11a,15a,16-dihydroxy-16- methoxv-1-hydroxymethyl-5- cis-13-trans- prostadiene 1-ethylene ketal 1,9-dioxo-lla,16-dihydroxy-l-hydroxymethyl- 2-nor-5-cis-13-trans-prostadiene,1- ethylene ketal Vinyl Iodide or Vinyl Tin of E xamp1e 185 1-iodo-3-triphenylmethoxy-5,5-dimethyl octene (U.S. Pat. No. 3,873,607). 13 £ r·'* 69 •t r- 107 ί Cyclopent-2-en-1-one 297 297 297 297 297 1- 297 1 297 ί Method of Example 773 773 773 773 0 r-. 773 ι 773 i Example 0 N CO N 00 0 N CO £ N CO 847 848 849 289 Ο Ρ fi c ο ο © «Τ © < Η 1,9-dioxo-1-hydroxymethylprostene rt 1 rt X X w tt § e μ 1 P \O rt «0 ι—1 | r—1 TO X ,p X U) tt O ·η Lrf μ u 0 tt Xm c A 1 tt .η μ »-i 0 0 X t fi X \0 1 P rt M tt • 1 1 a rt r-i rt is. · rt X tt 1 P C O tt tt X E rt 0X0 rt X TO 0 Ο P ι μ ω © 0 O • χ μ rt x ft 1 rt J ι X rt f—1 X . X U) rt p C fi tt TOP ε μ tt 1 P |rX Ό 1 r-i tn tt 1 rt c X ι , tt X U) rt O rt X μ υ|χ 0 1 Ρ Χ«Λ tt X 1 1 rt μ ·-» 0 o · I C tt \0 1 c rt CM tt « ( rt a ι-ι 0 rt X rt rt X p 1 P w O tt o X e μ ο X ft rt χ 1 0 Q 71 ι μ 6 © 0 TO • χ μ rtX P t rt t un fi • 1 P © rt tt H Xi! 00 p tt Ig § £ fe£ • ox cm μ p t 0 tt X X 1 X X rt Ο 1 A μ rt tt 0 t e X X tt £ Xm rt O 0 0 c fi ι tt p Sfi tfl un ft o •-ι ι μ •uO ft a ·-« ι rt 1 U) rt μ c i 0 fi o c μ X TO P Ο P l •η fi tn 0 tt rt • ft ' . © 1 Ul A © rt rt CM oj 1,9-dioxo-11a,15a-dihydroxy-2,17,18,19,- 20-pentanor-16-m-trifluoromethylphenoxy- 1-hvdroxvmethvl-5-cis-13-trans-prostadi- ene,1-ethylene ketal 1,9-dioxo-1la,16-dihydroxy-16-vinyl-1-hy- 1 droxvmethvl-2-nor-5-cis-13-trans-prosta- j diene,1-ethylene ketal 1,9-dioxo-lla,16-dihydroxy-16-cyclopropyl- 1-hvdroxvmethvl-2-nor-5- cis-13-trans- prostadiene,1-ethylene ketal 1,9-dioxo-11a,15a-dihydroxy-2,18,19,20- tetranoT-17-phenyl-l-hydroxymethyl-5- cis-13-trans-prostadiene,1-ethylene ketal Vinyl Iodide or Vinyl Tin of Example © tn r—4 134 186 180 194 198 186b Cyclopent-2-en-1-one 297 297 297 I 1- 1 297 297 297 ________ i 297 Method of Example 773 tn r** 774 ’tt r· t·. 773 774 774 I Example 850 851 852 853 854 855 9S8 290 8 2 0 7 TABLE 40 (continued) - T ————-.......η 1,9-dioxo-1-hydroxymethylprostene 1,9-dioxo-lla,15a-dihydroxy-2,18,19,20tetranor-17τ(πι-trif luorophenyl) -1-hydTOxymethvl-5-cis-13-trans-prostadiene,1ethylene ketal 1,9-dioxo-lla,15a-dihydroxy-2,18,19,20tetranor-17- (jj-methoxyphenyl) -1-hydroxymethvl-5-cis-13-tTans-prost adi ene,1-e thy1ene ketal 1,9-dioxo-15-hydroxy-15-methyl-1-hydroxymethyl-2-nor-13-trans-prostene,l-ethylene ketal 1,9-dioxo-lla,16-dihydroxy-16-methyl-l- 1 homo-1-hvdroxvmethvl-5-ci s-13-trans- I prostadiene,1-ethylene ketal 1 1 rt Γ> 1 rt rt 1 X ra rt X C rt p rt p © H © g P fi 1 l © © rt rt fi 1 I . © X ra rt Xrt X o ©|x μ i +j 53 © © X t ι X rt rt rt X * 53 X © I P fi \O © © rt g rt * χ μ a χ p rt o rt rt μ p ι 53 ra oxo XX % o cu rt rt 1 53 l· ra 1 2 £ σι e ra * ο μ rtX P 1,9-dioxo-11a,15a-dihydroxy-17,18,19,20- tetranor-16-phenoxy-1-hydroxyme thy1-5- cis-13-tTans-prostadiene,1-ethylene ketal 1 O 1 CM rt 1 • 1 rt cn X’rt rt x rt A O P co fi ra rt © p αχ μ x cu cu rt rt 1 I X ra XX G X P rt ο © μ μ Ε ρ •ο 0 ι X μ X Ο r-f rt 3 1 ,rt •o rt ra rt ι «Η rtjp art © © © μ 1 fi rt P © A I I © a e r· ρ rt ( X © rt O X rt ί 1 rt Ρ X O 1 © X x μ ε ρ ο ο χ © rt fi χ ι 53 TO 0 rt ρ μ * ό ρ·ρ © A © X fi r-l PX © Vinyl Iodide or Vinyl Tin of Example 186e 53 SO CO 1—1 125 130 134 186 180 Cyclopent-2-en-l-one 297 297 310 298 298 298 298 Method of Example 773 773 773 773 773 774 © ra X U4 857 858 859 098 861 862 © sO co 290a © C •Η ft c ο u ο fi UJ J CO ¢- 1,9-dioxo-1-hydroxymethylprostene o £ o » X £ ι 0 rt ai ι b rt tn X P G £ .ft ft > t t cn 2 § ι b X b X ι o Hl b rH 0 » . X v> £ rt rt rt ©1 03 0 r b ι in © Ο ι £ rt rt « X © B £ G rt ft © rt © rt t ε x ο X £ X X b o o © rt b ι 0 0 rt 1 X * cn £ © * t G rt rt © 1 rt X ft 0 t b tn ft G o rt rt b U b X I υ hi 1 rt \O t , rH Ul Irt 1 rt rt X © b X 1 © Ο ΙΛ 4 b ι 0 rt © X X G 4? £ © .ft ft rt 0 © X I £5 rt X © Ο ι 3 b rt rt 0 * rt X © « £ C O 1 © X rt rt 0 1 0 rt o rt 0 £ ft ι O « Ol £ P * j b rt rt ft 1,9-dioxo-lla,15α-dihydroxy-1-homo-18,19,- 20-trinor-17-phenyl-l-hydroxyniethyl-5-cis- 13-trans-prostadiene,1-ethylene ketal 1,9-dioxo-Ila,I5a-dihydroxy-1-homo-18,19,- 20-trinor-17-(m-trifluorophenyl)-1-hydroxy- methyl-13-trans-5-cis-prostadiene, 1- ethylene ketal t 1 * | rt σι x x rt X £ A O ft oo b © rt 0 1 1 Χ·“· O £ * £ l © o rt G £ I © 1 zrt °rl rt rt 0 t X rt X G ft X © rt O £ O b ft b 0 X ft X X I , £ Ο ω •Η £ ·Η 0 ft υ 1 © 1 B £ tn rt ι. ι rt pm rt 3 1 rt rt r*· b rt rt ft 1 I < o b H) rt x o rt rt o G « b •H -ft rt © 0 b X44 1 b 42 Oi ι b © a© © e rt rw £ © 1,9-dioxo-1la,16-dihydroxy-16-ethynyl-1- hvdroxvmethvl-5-cis,13-trans-prostadiene,1- ethylene ketal 1 rt ft i tn rt O i b •S.?· ί s © ft ( ί \O Hl rt rt ’ *, X W X ’ft o © b ι 0 in rt X < fi £ b ft •ft o © 0 G ftS 1 1 VO O © rt rw G A | © 3 rt rt rt xx rt ££ 1 ft ft O © © x ε ι O Xrt •ft x · 0 O © ι b c σι 0 © A X»b rt 42 0 Vinyl Iodide or Vinyl Tin of Example 194 00 Oi rt 186b 186e 0 \D OO rt 2101 210P 1 i © c 0 1 rH 1 c © 1 rw 1 ft G © ft 0 υ X i_> 298 298 298 298 298 280 2 80 1 Method of Example 773 774 ί , 774 1 H) Η» H- 773 774 774 Example 864 865 998 867 868 86 8A* 868B* 290b TABLE 40 (continued) 1,9-dioxo-1-hydroxymethylprostene t TO rt G BS ί M © rt 1 * Ό TO rt «rt rt ι o] ro X p χ m © O 1 X P rt TJ χ © XX G Λ P © •rt © rt TJ 1 X ι Ο X Ό CM P rt 1 © * rt 1 3 ΧΉ rt A * rt p © 1 © C 0 X © X X *rt OOT, .η ρ rt TJ TJ P 1 X TO 0 X P * I P rt rt 0 |--- ----------- 1,9-dioxo-lla,16-dihydroxy-16-(1-pTopynyl)1-hvdroxvmethvl-5-ci s,13-1 ran s-p ros t adiene,1ethylene ketal 1,9-dioxo-lΙα,16-dihydroxy-16-(1-propyny 1)1-hvdro xvmethyl-20-ethyl -5-cis,13-transprostadiene,l-ethylene ketal Vinyl Iodide or Vinyl Tin of Example O' © rrt CM rt ’C' in rt XT in rt Cyclopent-2-en-l-one 2 80 i 280 280 Method of Example •M- 773 773 Example 86 8C* © co Ό OO 3898 ! 290c EXAMPLES 869-891 By the methods described hereinabove in Examples 773 and 774, the 1,9-dioxo-1-hydroxymethyl prostene derivatives shown in Table 41 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cycIopent-2-en-l-one.

In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table 41. It should be understood that the other diastereoisomer is also formed which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the 8-chain (the chain containing C13' ',t'14 etc·) t0 that t^ie respective nat and ent forms of the listed diastereoisomer; both of these diastereoisomers are claimed in this invention as well as their component enantiomers. - 291 48207 TABLE 41 1,9-dioxo-1-hydroxymethylprostene and its diastereomer 1 Λ O cd fc fc 0 fc X 8 1 £ fc W 0 © § 1 CM fc 0 · +J rt © 1 • rt 0 ,-1 a *rt td rt 00 1 ,fc rtrt cn 1 8 1 · -H Ltf oxo X rt ι 8 0 I 0 C rt 8 I 8 0 fi rt rt I 8 X X © rt £ £ • Xfc w g? os sr. C cd P 8 8 fc fc C fc 0 8 0 8 Xrt C fc £ 0 rt » ι cd '—'£ rt +j 1 .rt t «rt +j 1 · fc o cd|0 O fc fiH fi fi nat-(and ent)-1,9-dioxo-lla,16-dihydroxy16,17-tet ramethylene-18,19,20-tTinor-1h vdro xymethyl-S-cis-13-trans-prost adiene,1-ethylene ketal i O X ) 1 o rt rt rt 1 0 0 8« 1 fi fc © 8 tn • rt O rt X fc 1 £ fi j*· fc 1 w 8 tn «ο e c rt rt Cd • fc fc ei fc fc 0 1 1 rt £ 0 ) rt rt fc * 1 .*2 Sl0 (rtl« ©lrt .h +j 1 0 8 0 X 1 £ fi X 0 rt Ο 1 8 •rt fc rt fi »0X8 « X£ ·-< £ £ fc X rt rt 8 £ • 0 E fc W ι X 8 0 0 X » rt rt g rt fci a 0 o firt χ fi Girt £ 8 nat-15S,16R-(and ent-15R,16S)-1,9-dioxo- lla ,15-dihydroxy-15,16-tTimethylene-l- hydroxymethy1-13-trans-5-cis-prostadi- ene,1-ethylene ketal nat- 15S, 16S- (and ent-lSR, 16R)-1,9-dioxo- lla, 15-dihydroxy-15,16-tri methylene-1- hvdroxymethyl-13-trans-5-cis-prostadi- ene,1-ethylene ketal 1 X « » X fc rt Ο O 0 fc fi « 0 rt fc X fc «η £ fc p rt 8 fc 0 fc fi J 1 , 0 © tn ΰ © t rt rt 0 rt * 1 r oo tn O rt fi X * « Ο X fc rt rt fc rt 0 » t cd I 8 0 +-> © fi rt 8 • 8 t· £ rt rt rt 1 X X 8 z—x, £ £ fi +->+» 4-> 8 C S O rt 8 ε ε x 'rt X£ 0 fc X fc S7S ? '-'£ TS rt 1 ,rt X * fc *£ 8 rt 0 » c fi rtrt 8 Vinyl Iodide or Vinyl Tin of Example 246 245 0 N CM 243 251 247 Cyclopent-2-en-1-one of Example 280 © 00 CM 280 280 280 280 Method of Example 773 774 773 L 773 773 773 Example 869 870 871 872 1 873 874 292 r-l Τ- ω χ co t— 1,9-dioxo-1-hydroxymethylprostene and its diastereomer 1 ι rt χ μ X J ra O rt o μ μ h © p q χ a ·. χ p ra •rt 1 © © o a| 1 CM 1 in · ιΛ r-l © » • r-l tfl 3» § r-l rrt μ 1 * P O b 1 χ © M © Ο i © rt •η a ι p © c τ a 1 a X44 © w X * χ p a rrt X a C ι p £ a ZT, a Xrrt P g X X C rt ρ x a ρ μ p c © a © a X ι § ν·ίΤ V—i \O r-ι a p| · μ a λ Ιιλ o © eH c © nat-15S,17R-(and ent-15R,17S)-1,9-dioxo- lla, 15-dihydroxy-15,17-dimethylene-1-hy- droxymethyl- 13-trans-S-cis-prostadiene,1ethylene ketal » 1 1 rrt OX* χ x a o 1 £ © rrt a © 1 © ι a © © C rt * a p rrt rrt W 1 P <-aX μ os p q b a ι, rrt s ra • © © I 02 © o| IA 1 1 rrt b ΙΛ 1 .rrt I pi ra fi tn fi Oil—, rt ι μ © XP fi X I rt O tn rrt a—» μ rrt a ι © ι P cn Xrrt a b X XX © © X ·© p o co ι a c ιλ in s a rrt © X © ι , * X X P CJ p X rt © μ p Cl© © a 1 1 o © X 1 1 o a © © c © ©art 1 © P © X ra * x p © Ρ μ ι a q r·» £ ι , ω rt ral © μ © © ρ υ • φ ι PS p in in ι © © w ¢3 © c in μ rt a © ρ P t ι a © χιη x fi x © rt ο ι a 'w μ © C ι© X a cd xx © © X p X ©©ax *© ε p ω ι x a in in X i © © O rrt ι * μ ·» p a © a rt © x fi fi © x a 1 t 0 © X 1 1 o a © © fi Ή ©art 1 © P © X ra *X p © ρ μ ι a q <—a g 1 , oS rt ral © μ © p U • a ι cd p in in ι ι © © w ΛίΤ S r fi in μ rt a © ρ p ι ι a © xm χ fi x © rt ο ι a α© μ © c ι © X a to XX © © χ μ x © © a x *© ε p co ι x a in ω χ ι © © o © ι . * μ * p s © a rt © x fi c|© X a 1 ’ I ο ι ι ra X © © © ο «Τ CM O| © 1 * 1 © a © in ι C © » © a * ra F© 00 fi © X © rt ι χ * μ OP b P oi a © ι © © Ε ι tn rt © © <—«© μ * μ χ ι a co ρ x © x tn ι ο X _ © © c x a i ,© a p c ρ ·χ a a β in q £ © al© © χ x ‘(XXX © XX O p e χ ρ μ a rt o a © ι a—' μ g x© I © p X * co χ μ ι a © X o © fi © © 3 1 a f© © μ © cs ι μ os in tn © fi rt rrt © μ rt P ι f +j μ ra ρ» ι ρ p rt © to a μ q |rrt A-' P q Vinyl Iodide or Vinyl Tin of Example 248 © -sf CM o in CM 252 253 ---1 254 Cyclopent-2-en-1-one of Example 280 280 280 280 280 . 280 Method of Example '1774 i 773 773 tn b b 773 774 Example 875 © b co 877 878 879 o 00 co 293 TABLE 41 (continued) 1,9-dioxo-1-hydroxymethylprostene and its diastereomer 1 1 , 6 ι ι ml X sO © -H 0 rt CM ©1 •HI * 1 •a © © in I G rt ι © © in * rt 00 c rt Xrt a IX * P ,-v p r* «j CO © r-l 1 rt so g ι tc rt ι—1 Ή rt. rt p « P X 1 « cn p x x in ι ο x rt sO β X © I ,rt © P G p *X © © c m 0 S «τ* © rt rt x X 1 X X 4= •a xx ο p x +□ p © « p © *a k Srt p g Xrt ι *a ο x * Cd XP 1 © sO X Ο β rt «Η S 1 © κ TJ rt P rt G 1 Ofi in ω ·η c « rt «π p S p , «,ρ μ to p a t p p a rt tc © p. Gjrt'rt +j e, nat-15R,16S-(and ent-15S,16R)-l,9-dioxo1la,15-dihydroxy-15,16-trimethylene-16(4- fluorophenoxy)-17,18,19,20-tetranor1-hvdroxvmethy1-13-trans-5-cis-prostadiene,1-ethylene ketal 1 , rl O 1 1 X so P 1 o rt Ο Ή •rt 1 G *2 •a © « «β ι G Ρ P © © P TO Art © O rt X Ρ P 1 X 1 0 Η* P © », cn © CM TO Ό £ rt rt CD ©J a P rt 1 co p «in in t °o ι rt © rt TO ι ,-> * e p * Γ*· rt rt β in rt ρ rt © rt | Ρ P 1 /rt 1 © Ό X Xtc X G X X rH rt ο ο ι © ’rt p G rt c I Ό © X © X XX X rt sO X 0 Ρ X rt rt o © χ *Ό Ρ E P ed ι ο X © in in fix ι rt rt rt O rt | ft ψ| p « pi a ι *a © «rt rf >, e G «-· '—'X © 1 1 © » J rt X sO P *© o rt o ro rt ι G P •a © rt to I G P p © © Ρ P Art © 0 rt XP 1 . 1 Λ 1 TO z-s Ρ Ο ‘H 05 © CM ©I so B · , rt rt © m a p rt 1 cn p * to in , oo c rt SO rt βί I rt * P p Ar- p rt elm ή ι rt SH » tc p 1 /—» rd © -Q χ χ 1 44 G x χ r* rt ο ο X © Ρ β X fi , T, © p © cn xx © r* s© λ 0 e x rt rt Ο XX a a ρ χ p OC ι o © © in m ή P t rH 43 Ό rt , A © X A p a ι x © rtlrt tc ι G eh © nat- 15R, 16R- (and ent- 15S, 16S)-1,9-dioxo- Tla,15-dihydroxy-15,16-trimethylene-16- (3-chlorophenoxy)-17,18,19,20-tetranor- 1-hydroxymethyl-13-trans-5-cis-prostadi- ene,1-ethylene ketal Vinyl Iodide or Vinyl Tin of Example m in CM 256 257 258 259 Cyclopent-2-en-1-one of Example 280 280 2 80 i i 280 I o « CM Method of Example rt t-» X 773 1 773 1 774 774 i ι ......... , ,.,-1 -, Example 881 882 883 884 885 294 8 2 0 7 1,9-dioxo-1-hydroxymethylprostene and its diastereomer III o * w X © rt o rt υ| rt 1 1 3 Φ 3 ι c ι © φ tf) Art C rt χ rt ι χ μ /-> μ μ cn ο ι rt x e tn « rt ·Η rt μ • μ ι φ ci μ «-ι χ 3 1 X rt X χ Φ I,rt μ fi μ * Φ Φ C3 6 ή ©Η X X ι X X 3 X ο μ C X μ Φ rt ο Ο ι *—> μ χ·ι 3 X * ci X ι Φ X X rt fi rt rt 1 φ a 3 μ ·η 3 1 o 3 3 3 β rt rt ι—ι ·Η μ 1 ·3 W μ a 1 Ο co »-1 ο μ fi|rt CM cm nat-15S,17S-(and ent-1SR, 17R) -1,9-dioxo- lla,15-dihydroxy-15,17-tTimethylene-19,- 20-dinor-1-hydroxymethyl-13-trans-5-cis- prostadiene,1-ethylene ketal 1 Ο ι X © t , O CM tf) •rt 1 rt 1 3 Φ Φ fi 1 © Φ 3 A ρ—1 | rt X tf) • fz e /-> μ rt cs φ μ rt r- 6 μ rt rt .rt » μ α μ tn φ 3 μ rt 44 © 1 1 rt X rt φ 1,1-* x c μ ·Χ Φ fi ko μ rt ©|rt © X t ε x 3 x xp c X X Φ rt ο o t rt / μ μ .-ι l 3 3 * 3 X X Φ χ χ x t= rt rt 1 Φ • 3 rt .h OS I 1 3 \O rt rt rt rt X μ 1 »X tf) μ a μ o rt rt φ μ fijrt ε λ 1 O 1 χ © ι, Ο CS Λ •ri I «ri I 3 Φ Ol l β 1 © Φ 3 • rt 1 rt χ ω ι X C r, μ rt 3 φ μ rt X Ε P rt rt ·η ι μ • μ tn ο 3 μ rt χ © 1 1 rt X rt Φ J ,rt X β Ρ X Φ fi © μ rt Φ rt Φ X t ε χ 3 χ χμ fi X X Φ rt Ο Ο 1 *-9 μ μ rt ι 3 3 * PS X X φ χ χ χ c rt -rt 1 © A 3 rt rt ci ι ) 3 xO 3 rt rt rt rt X μ 1 , · X (ft μ a μ o rt Η © μ e|w ε cm 1 rt ι ι μ O t »H « x © μ o O rt μ μ •Η 1 1 CM 3 φ Ο 1 . 1 fi CM (ft © Φ a.H • rt © U) rt Xrt I IX «3 /-, μ 3 1 OS Φ ^-1 (Λ χ ε i c rt ·Η rtx rt Α μ X μ 3 Ρ κ μ © ι ο J. rt X β to rt 1 .rt φ rt rt μ *x ι μ fil© CMrt Φ ©jrt rt XX 1 XX 3 xx μ φ fi X μ Φ fi to ο © ε φ > μ E x rt ι 3 Ο X X 3 X μ ρ χ χ χ ο μ μ rt rt 3 3 Φ A 3 rt X ι CC 1 X rt LO © rt 1 Α rt rt μ rt φ I Α μ ι β μ) a ( μ Φ rt rt 3 Ο rt fi |rt ·—’ β 3 rt ι ι μ Ο 1 rt tf) χ © μ ρ ο η μ μ •Η ι ι Cu 3 Φ ο ι. 1 β CM (ft © Φ -·Η Art © Oj rt X rt 1 1 X A3 . /-» μ 3 1 3 φ rt tf) χ ε ι c rt ·Η /“\ Λ α μ χ μ 3 μ χ ρ © » ο · rt X fi 3 rt ) rt Φ rt rt μ| ·Χ ι P fi © CMrt φ Srt rt XAi f XX 3 XX p φ fi X Ρ Φ c rt Ο Φ Ε Φ ‘—'MS Xrt l 3 Ο X X os χ μ ρ x X χ Ο _μ P rt rt 3 3 © A 3 rt X 1 os ι m x *-< ©©•Hl · rt rt M rt φ I Α p 1 fi μ a ι μ Φ rt ·-( tn ο ·η filrt χ-z fi 3 Vinyl Iodide or Vinyl Tin of Example 260 261 262 263 © CM 265 1 Cyclopent-2-en-l-one of Example 2 80 1 280 280 280 280 280 Method of Example 773 773 1 t. X. 774 _ 774 774 j Example 886 887 3 3 3 889 890 ri © 3 295 EXAMPLES 892-975E By the methods described hereinabove in Examples 773 and 774, the 1,9-dioxo-hydroxymethyl prostene derivatives shown in Table 42 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where isomers are obtained at the C15 or positions, only the CJ5 or C^g-normal isomers are listed in Table 42; it should be understood that the corresponding 0^^ or C^-epi isomers are also formed and are part of this invention.

In those cases where the initial conjugate-addition product contains a triphenylmethoxy blocking group, deblocking is conducted in acetic acid-tetrahydrofuran-water 4:2:1 at 50°C for 5 hours. tt fi tt Ρ -4Λ Ο μ ft rt X X Ρ tt £ X ο μ 0 χ X I rt 1 Ο X ο •Η 0 1 © irt 1,9-dioxo-1Ια ,15-dihydroxy-1-hydroxymethy 1 16,16-trimethylene-20-nor-13-transprostene,1-ethylene ketal 1,9-dioxo-11α,15-dihydroxy-1-hydroxymethyl16.16-trimethvlene-20-methyl-13-trans- prostene,1-ethylene ketal 1,9-dioxo-lla,15-dihydroxy-l-hydroxymethyl- 16.16-trimethylene-20-ethyl-13-trans- prostene,1-ethylene ketal 1,9-dioxo-lla,16-dihydroxy-16-cyclopropyl- 20-ethvl-l-hvdroxymethyl-13-tTans- prostene,1-ethylene ketal 1 tt o c CM tt 1 P rt V) rt ft ι ω 5 § 1 M X » o to μ rt 0 ι Xrt A rt x 0 P 1 2 tt 6 rt rt X TO • X P a o tt rt μ rt 0 1 X tt O X c X 1 tt o rt rt rt » x 0 rt X ι xp © X « * P t rt tt rt 1 rt ft 8 ft ( O rt rt · O tt X c υ ο ι P \O (Λ rt o ι μ X ft X I o ui s § χ μ X P rt 1 0 tn 1 rt Ό ι rt rt * Xrt a x fi rt p p rt tt tt ι ε x o X X X tt O P fi •η μ tt 0 0 rt 1 X X © X X A 1 p rt rt tt 1,9-dioxo-lla,15-dihydTOxy-1-hydroxymethyl- 16.16-trimethvlene-13-trans-prostene, 1-ethylene ketal 1 rt rt rt XP X tt P x tt £8 0 x χρ X tt1 1 rt rt 1 · fe| 83 0 Ul £8 1 Ul Ό fi rt rt * μ a p rt 1 rt tn 1 rt O 1 X rt O X rt c 7 > © I •VO rt rt Vinyl Iodide or Vinyl Tin of Example © ’tr OS 51 tn © rt 195 192 13 rt o rH CM Cyc1 opent-2-en-1-one 309 309 309 309 © o en 309 309 309 Method of Example eo I-A ΓΆ tn Γα r-A 773 774 774 774 773 tn PA. fA. Example 892 893 894 895 968 897 898 899 297 TABLE 42 (continued) © G © P (ft ε (X rt X X P g X X s 5) X X 1 rt 0 X o •P 53 1 σι rt dl-erythro-1,9-dioxo-11a,15-dihydroxy-16methoxy-1-hydroxymethy1-13-trans-prostene,1-ethylene ketal I vO rt 1 1 X P χ ω O o μ μ 53 CU X I X w 3 S ι μ © P rt 1 A © B rt | rt rt > X Ο X rt χ P rt o © p rt E © 5J ΧΛ5 ι X σι o © * μ g rt 53 © 1 Xrt O X X μ ι x X rt p p 1 © X X ’ μ x rt © O A ι x © rt p fi 53 © © 1 X A X © p G μ © 53 P X ra X P ή μ μ & Ρ ι ι ra 2 g * μ © Ρ rt » A© d rt | rt μ » 0 o G X ι o o •rl CM Ό 1 rt 1 rt rt σι XP *x © rt p 34 1 © p e © μ X c X X Φ port X μ X μ 53 x © XP I X © rt 1 J Ό rt rt © ι C X © X P o ra μ o Ό μ X CU X t •rl ra μ G ρ co » μ Ό P rt 1 A© © r-l rt 1 a rM B X rt X rt P 1 © ο ε X 1 o © •Η CM 55 1 rt 1 «-I ra Ch X P *X © rt P fi 1 © Ο E © μ x c X X © port χ μ x μ 53 X © χρ 4 X © rt 1 1 Ί3 rt rt dl-erythro-1,9-dioxo-lla,15,16-trihydroxy- l-hvdroxvmethvl-20-ethy1-13-trans-prostene, 1-ethylene ketal dl-erythro-1,9-dioxo-lla,15,16-trihydroxy- 19-methvI-1-hvdroxvmethyl-l3-trans-prostene, 1-ethylene ketal dl-erythro-1,9-dioxo-11a,15,16-trihydroxy- 13-trans-17-trans-prostadiene,1-ethylene ketal . dl-threo-1,9-dioxo-1la,15,16-trihydroxy-1- hydroxymethyl-13-t rans-prostene,1-ethylene ketal Vinyl Iodide or Vinyl Tin of Example r*. r«. X i | 83 1 84 © cq 98 87 69 Cyclopent-2-en-1-one 309 o © 60S 309 309 309 Ch © © 309 Method of Example 773 773 773 773 773 .. .. .1 773 773 773 Example 900 901 902 903 904 905 906 907 298 8 2 0 7 1,9-dioxo-1-hydroxymethylprostene dl-threo-1,9-dioxo-1Ια,15,16-trihydroxy- | 20-nor-l-hydroxymethyl-13-trans-prostene, 1-ethylene ketal dl-erythro-1,9-dioxo-lla,15,16-trihydroxy- | 1-hydroxymethy1-13-trans-prostene,1-ethylene ketal 1 I O «-i CM * ι a X fi x a 0 p μ ra © o χ μ x q •Η 1 μ ra P c rt © μ rl P • t in to ι—1 © • 1 a © © X © X ι p o a g s. •Η X © O © ι μ ns C7) © P * X a © X 44 1 1 O rrt a a ι fi μ © a X X© P X X t P x rM a P © e a t 1 X P X w O O μ μ © q b* 1 X ra •rl fi μ rt ρ μ 1 P © 1 © tn * © ω ι © © • X ¢5 X © P © a © ι ε 1 X X o μ © 1 X ra £ § μ μ Ρ Ρ I I «ο tn © © • 1 in © © © X rt *X P a p a © a 44 Ί* a o x fi χ o a q μ © •rl © X © XX 1 X P cn ι a * © | © 1 © I © * oxa axe μ p a X a p p S ra 1 1 O © cn μ © © q dl-threo-1,9-dioxo-1Ια,15,16-trihydroxy- 1-hydroxymethyl-13-trans-17-trans- prostadiene,1-ethylene ketal (- © X X P a ε s? o © μ rt © p x a X 44 1 © a x S 2 x a X 1 •rl © © * ι a v0 C © a * P a ra © o © μ λ Λ ο I χ ra o c •rl « © μ 1 P cn ι * tn rM © 1,9-dioxo-1Ια,16-dihydroxy-1-hydroxymethyl- 19 ,20-dinor-13-trans-prostene,1-ethylene ketal Vinyl Iodide or Vinyl Tin of Example 88 76 cn oo © cn © cn CM σ> b © © 108 Cyclopent-2-en-1-one σ» o tn 309 309 309 309 309 309 cn o tn Method of Example 773 773 tn b b 773 773 773 773 773 Example 806 606 910 911 912 913 914 915 ] 299 TABLE 42 (continued) 1,9-dioxo-l-hydroxymethy1pro st ene 1,9-dioxo-1la,16-dihydroxy-1-hydroxymethyl18,19,20-trinor-13-trans-prostene,1-ethylene ketal 1,9-dioxo-1la,16-dihydroxy-1-hydroxymethyl-20nor- 13-trans-prostene,1-ethylene ketal 1 X X o b 0 x»~! 42 « ι ft rri © 1 Ai rri X © 42 G b © fi g X 45 rri © 1 1 Xrri X * O © b G 0 © Xft 42 W .ft O 0 b 1 CU © » rri W a « rri b rt b 1 1 o tn X rt O 1 •ft rt 0 X 1 42 © b * fi rt £ 1 X X o b 0 X0 42 rt ι b rt © 1 44 rt X © £ G ft © » 42 o b cm © &A o © b C 0 © X b £ «Λ .ft O 0 b cu © i rt (Λ a § rt fri rri ft 1 1 O tn X rt O 1 •ft rri 0 X ι £ © ft A © rt s 1,9-dioxo-11a,16-dihydroxy-20-ethyl-l-hydroxymethyl-13-trans-prostene,1-ethylene ketal t rt b © © rt 1 b © 42 CM b 1 © rt ί b © fi C g © ι b © w rt O 1 b X ft X J o in £ s X b 42 b l,9-dioxo-lla,16-dihydroxy-l-hydroxymethyl-13- trans-17-cis-prostadiene,1-ethylene ketal 1,9-dioxo-1la,16-dihydroxy-16-methyl-1-hydroxy- methyl- 13-trans-prostene, 1-ethylene ketal 1 rt rt rt 1 ft rt © X44 42 b © SS b X ft 42 I ft © © CM I Ι-» A rri © - G t-. © rt ft r ω X o X b O ft b ι 0 tn £§ •ft b 0 ft 1 1 \D tn rt rt A 1 3 rt rt >» 8 g O X •ft X 0 O t b © 0 rt £ Vinyl Iodide or Vinyl Tin of Example 601 © rri 144 112113 G © tn rri 115 135 136 1 1 Cyclopent-2-en-1-one 309 σ» © to cn © m 309 309 309 309 60£ © © tn Method of Example K) Γ*· Γ-* 773 773 773 1 773 j 773 tn IX 773 773 Example 916 917 00 rt © 919 920 ________ 921 922 tn CM © 924 300 8 2·) 8 C 8 4J M O fc fi rt X £ fc 8 ε fc 0 fc 0 X £ 1 rt 1 O X O •rt 0 1 © 1,9-dioxo-11a,16-dihydroxy-16,20-dimethyll-hvdroxymethyl-13-trans-prostene,1-ethylene ketal 1,9-dioxo-lla,16-dihydroxy-17,17-dimethyl1-hydroxymethy1-13-trans-prostene,1-ethylene ketal 1,9-dioxo-1Ια,16-dihydroxy-16-methyl-1-hydroxy- methyl-13-trans-17-trans-prostadi ene , 1-ethylene ketal 1,9-dioxo-1Ια,16-dihydroxy-20-methy1-1-hydroxy- methyl- 13-trans-17-trans-prostadiene,1-ethylene ketal 1,9-dioxo-1Ια,16-dihydroxy-16-methyl-1-hydroxy- methyl-13-trans-prostene,1-ethylene ketal 1,9-dioxo-lla,16-dihydroxy-17,20-dimethyl-1- hydroxymethyl-13-tTans-prostene,1-ethylene ketal 1,9-dioxo-11α,16-dihydroxy-1-hydroxymethyl-13- 1 trans-17-trans-prostadiene,l-ethylene ketal 0 Vinyl Iodide or Vinyl Tin of Example r-» 0 rt 138 139 149 150 151 152 Cyclopent-2-en-1-one 309 309 309 309 © © 0 309 © © 0 Method of E xamp1e 773 773 0 c- 773 773 0 f- r- 773 Example 925 926 927 928 929 930 rt 0 © 301 8 2 0 7 TABLE 42 (continued) © G © P TO s 0 rt £ P g ?? s *a X X 1 rt ό X o rt T, 1 © rt 1,9-dioxo-1la,16(R)-dihydroxy-1-hydroxymethy113-trans-prostene,1-ethylene ketal 1 rt X X P T, Xrj X rt l P rt © X* ρ G ft © TJ X X X X rt P •a © | i /rt rt tn * SH © Ό G rt © * P a w rt O rt p I 0 O 1 X TO 5§ Τ, P 1 P © J rt rt © 1 c X © X «Ρ 0 X Ρ Λ *a p X © X < 1 r** rt * 1 © •P G X © X 23 © rt ι p © TO CM O 1 P 5?^ O TO 3S X p X P rt 1 TJ Γ* , lP Ό ι rt TO a § rt p rt P 1 1 0 tc X w 0 1 rt rt *O Xrt ι X rt © P P • © © rt fi X 1,9-dioxo-1 Ια,15a-dihydroxy-1-hydroxymethyl-13trans-prostadiene,1-ethylene ketal 1,9-dioxo-lla,15a-dihydroxy-20-methyl-l-hydroxy- methyl-13-trans-prostene,l-ethylene ketal X § P tj χ «ρ X rt 1 P rt © J X rt X © X G P © © iP 1 X © X CM P 1 © X ' 3 P © TJ G X © X p rt TO Ό O t P β 0 ΙΛ 1 rt TO a § rt p rt p 1 1 o tc X rt O 1 •rt rt •e k· f X © P A fl) rt fi rt rt P 1 © rt X 1 rt © X G X © P rt g£ rt p TJ © 1 1 \O Ή rt * A © Ό C rt © ι P X « s s S ? X TO 5 § TJ P t P β A 1Λ tc rt rt * 1 o © X fi 0 X rt X Ό O f P © TJ * X rt X Vinyl Iodide or Vinyl Tin of Example to ιΛ rt 154 rt 00 XT rt l-iodo-3-triphenylmethoxy-1-trans- octene (U.S. Pat. No. 3,873,607). 1-iodo-3-triphenylmethoxy- 1-trans- nonene (U.S. Pat. No. 3,873,607). 1-iodo-3-triphenyl- methoxyτ1-transdecene (U.S. Pat. No. 3,873,607). 1-iodo-3-tripheny1- methoxy-4,4-dimethyl-l-transoctene (U.S. Pat. No. 3,873,607). Cyclopent-2-en-1-one 309 309 © © tc 309 309 309 309 Method of Example 773 773 773 773 ί 773 773 773 Example 932 tC tc © tc © 935 936 937 938 302 Λ 8 a ί) 7 a c a Ρ tn 0 μ q X χ Ρ g s? 0 μ © χ X 1 rM 1 O X o •K © 1 q 1,9-dioxo-lla,15a-dihydroxy-17,17-dimethy1l-hydroxymethyl-13-trans-prostene,1-ethylene ketal l,9-dioxo-lla,l5a-dihydroxy-16-methyl-1-hy- droxymethyl-13-trans-prostene,1-ethylene ketal 1,9-dioxo-1Ια,15a-dihydroxy-16-ethy1-1-hy- droxymethyl-13- trans-prostene,1-ethylene ketal 1,9-dioxo-1Ια,15a-dihydTOxy-17,20-tetranor- 16-cyclonentyl-l-hydroxymethyl-13-trans-prost- ene,1-ethylene ketal 1,9-dioxo-lla,15a-dihydroxy-16, 20-pentanor-15- cvclohexvl-1-hvdroxymethyl-13-trans-pTOStene, 1-ethylene ketal Vinyl Iodide or Vinyl Tin of Example l-iodo-3-triphenylmethoxy-5,5-dimethy1-1-transoctene (U.S. Pat. No. 3,873,607). l-iodo-3-triphenylmethoxy-4-methyl1-trans-octene (U.S. Pat. No. 3,876,690) . 1-iodo-3-tripheny1methoxy-4-ethyl-ltrans-octene (U.S. Pat. No. 3,876,690). l-iodo-3-triphenyl- methoxy-4-cyclo- pentyl-l-trans- butene (U.S. Pat. No. 5,884,969). 1-iodo-3-triphenyl- methoxy- 3-cyclohexyl- 1-transpentene (U.S. Pat. No. 3,884,969). Cyclopent-2-en-I-one cn © tn 309 309 309 cn © tn Method of Example 773 773 773 773 773 Example 939 o 5J· © 941 942 943 303 TABLE 42 (continued) 1,9-dioxo-l-hydroxymethylprostene 1,9-dioxo-lla,15a-dihydroxy-18,20-trinor-17cyclohexyl-1-hydroxymethyl-13-trans-prostene, 1-ethylene ketal 1,9-dioxo-1Ια,15a-dihydroxy-19,20-dinor-18cyclopentyl-1-hydroxymethyl-13-trans-prostene, 1-ethylene ketal 1,9-dioxo-1Ια,15a-dihydroxy-15-methy1-1-hydroxymethyl-13-trans-prostene,1-ethylene ketal 1,9-dioxo-lla,15a-dihydroxy-15-methyl-20-ethyl- 1-hydroxymethyl-13-trans-prostene,1-ethylene ketal 1 1 fc fc M O O ss. fc » fc in 8 fi fc rt 1 fc © fc CM 1 • 0 © rt rt I • rt co χ rt £ • fc X 8 rt 6 1 X & o O fc fc 0 0 X XX £ » •pi rt rt 0 ι rt 1 X fc δ» X 8 0 O £ rt fi • 8 8 £ C rt fi 8 rt O «1 1 fc X Ο O £ X S fc O rt 8 •H 1 fc O 1 fc e 8 8 fc fc 1 M © o (N fc • fi © 1 rt ω 00 § rt fc • fc X I rt 0 I rt X I X rt O X ss ££ 0 & l O a 0 0 rt X • £ rt a ι « rt rt p rt I 8 ι X£ O X X O 8 O C fi •fc 8 8 0 £ rt ι fi X © ι £ ·£ fc rt rt 8 Vinyl Iodide or Vinyl Tin of Example 1-iodo-3-tripheny1methoxy-5-cyclohexyl-1-transpentene (U.S. Pat. No. 3,884,969). 1 ------- 1 l-iodo-3-triphenylmethoxy-6-cyclopen tyl-l-transhexene (U.S. Pat. No. 3,884,969). 1-i odo-3-methyl3-trimethy1silyloxy-trans-l-octene (Example 125) 1-i odo-3-methyl 3-trimethylsilyloxy- trans- 1-decene (Example 190a) 159 981 Cyclopent-2-en-1-one 309 3091 309 i 309 309 © © 0 Method of Example 773 773 i 0 b- b- 773 1 N- Γ*. X 774 Example 944 0 N © 946 I*» N © 948 © rf © 304 8 2 0 7 © C © ft in o b ft rri X £ ft © g X X o ft 0 X £ 1 rri 1 0 X o •ft 0 1 © 1,9-dioxo-11a,15a-dihydTOxy-17,18,19,20tet ranor-16-p-bromophenoxy-1-hydroxymethyl-13-trans-prostene,1-ethylene ketal rri i rt ο 1 ft CM X © * X 44 © O rri fri © *0 C 00 X © rri J5 rri * » X X rri £ rri | ft » X © X X » X O rri OCA b © © 0 £ G X ft © 4= rri ft •ft x ω 0 ft O ι 3 b a £ ft ΙΛ 1 , 1 rri ft| y) * 1 . C a ft « rri 1 fri rri © ft 1 rri J ο ι tn X b rri O O 1 •ft C rri 0 S X ι b £ © ft ft A © © rt ft £ rri ι rt O 1 ft CM X © a X 44 © O rt b © •0 G oo x © rt 42 rt • « X X rt £ ft t ft X O rt O G * b © © 0 45 G X ft © £ Xft •ft X w 0 Ο O » £ b 8 ft ft in © t rt £ tn 8 c4§ rri 1 fri rri © ft 1 rt i Ο ι tn X b rt Ο Ο i •ft G rt 0 rt x 1 b 45 © ft ft * © © rt ft £ rt ι rt o ft CM t © a X44 © X rt o © Ab c 00 0 © rri X rt *45 X Γ-- t rf! rri rri ft 1 1 © fe X rt 0 O » bG© 0 © G X45 © 42 ft ft •ft O tn 0 b O ι O b a ft in 42 I •ft © w • ’ ι £ 8 ft© rt | b rri © ft o t tn X b rt ο O 1 •ft G rt 0 rt X t b *G © ft ft * © © rri ft £ 1,9-dioxo-lla,15a-dihydroxy-17,18,19,20- tetranoT-m-trifluorophenoxy-1-hydroxy- methyl- 13-trans-prostene, 1-ethylene ketal 1,9-dioxo-11a,15a-dihydroxy-17,18,19,20- tet ran or-16-(3,4-di chlorophenoxy)-1-hy- droxymethy 1-13-trans-prostene, 1-ethylene ketal 1,9-dioxo-1la,15a-dihydroxy-18,19,20-tri- nor-17-phenvl-l-hydroxymethyl-13-tran s- prostene,1-ethylene ketal BLE 42 (continued) Vinyl Iodide ot Vinyl Tin of Example 181 182 183 184 180 00 rri 186b < H Cyclopent-2-en-1-one I 309 1 © © tn © o tn 60S 309 309 309 Method of Example 774 774 774 774 774 774 774 Example 950 ft in © 952 tn in © 954 955 956 305 8 2 0 7 ra A l-l X X P I I rt rt Ρ X P X ι p o © .t. σ» x ra rt o P a μ © 00 53 44 rt S» I X © X I β Xrt© C I rt μ x rt X X XP X β © rt © I *0 x rt i δ» © X β rt ο © eft! A g ό cq X ra ο ι G •rl X CO to rt μ ' .» P μ ι A O © rt fi rt TABLE 42 (continued) X X c c rt rt > > o © rt g B* x ra P X © (U Z X rt g* ?S 0 © μ rt X XX X P I © rt I I rt X * X © o c μ © Ό rt X3 X rt rt P 5) W I O Β μ © A rt | * w ϋ fi o . X © O rt rt I ό μ I o Ch fi ra ft g °·: rt μ μ ρ Pl·” I rt S3 © © ι ' rx ι χ «ο ox©* O fi © 0 X © •rt P P · I I rt rt j? © s s ε p ι ra © o rt μ ι A X « x ra •σ μ rt © 55 rt I I a μ © o rt fi a cm ra rt I p rt rt © I XX o x X P © O © fi rt ε © Xrt I X X Ch p X a μ p rt *o © rt X » X rt P X © fi I P rt © A g © £ G Ό © I P © ra rt O a μ Ό A rt I ι ra fr S ο μ μ ρ » ΧΛ X rt I •β μ ι Ο a β © ι rt ΓΜ ϋ rt X I Ρ Ο © rt χ e ra Ο χρ rt X © 0 X ι μ d 5> © A X C rtX « © < X xi A 53 rt i ~ μ © © P A +J · /-* ι © υ ρ x ‘ ι o rt o .Xiao Ο X rt a ό o X · © Ο X X W X H p p · oo I © © » * rt S 6 'rt © rt © X fi X ν Ρ Ρ © ra ε ο ... μ μ a •rl a μ Ό Ρ rt f I © Xrt x J ο μ μ ο fi X I X CM rt I 53 rt i£ © p rt e p &.S rt O ι μ © O 53 fi X X © 0 X X rt I >, 53 rt X I I P σι © © » C I rt © rt © I fi X © X £ ’ >> rt X I P X'© X I O rt h * 5J © X C X © rt P μ ra Ρ p r μ © A rt I a W rt μ A p a ι rt © A x rt X I P © ε >?£ x ra x o P • μ © x CM rt © CM \O o © cn - 306 4 8 2 0 7 TABLE 42 (continued) 1,9-dioxo-1-hydroxymethylprostene threo-1,9-dioxo-lla,15a,16-trihydroxy-lhydroxymethyl-2-nor-13-trans-prostene,1-ethylene ketal erythro-1,9-dioxo-11a,15a-dihydroxy-16- methoxv-1-hydroxymethy1-2-nor-13-trans- prostene,1-ethylene ketal 1 X x d p ro 0) p μ © © P G TJ © X rt X X 1 X rt P 1 © X t X rt 0 P © TJ c X © X P •rt TO TJ o 1 P Ό 0 rt 1 * TO 5 § rt p 1 P O l X m O rt •rt 1 •a P ι O © G * 1 rt CM l,9-dioxo-lla,16-dihydroxy-16-methyl-l- hvdroxvmethyl-2-nor-13-trans-prostene,- 1-ethylene ketal 1,9-dioxo-1Ια,16-dihydroxy-16-methyl-1 - hvdroxvmethvl-2-nor-13-trans-17-trans- prostadiene,1-ethylene ketal 1,9-dioxo-1Ια,15a-dihydroxy-2,17,18,19,- 20-pentanor-16-phenoxy-1-hydroxymethyl- 13-trans-prostene,1-ethylene ketal 1,9-dioxo-11a,15a-dihydroxy-2,17,18,19,- 20-pentanor-16-m-trifluoromethylphenoxy- 1-hvdroxvmethvl-13-trans-prostene,1-ethyl- ene ketal 1,9-dioxo-lla,16-dihydroxy-16-vinyl-l-hy- droxvmethvl-2-nor-13-trans-prostene,1- ethylene ketal Vinyl Iodide or Vinyl Tin of Example 69 74 107 130 134 186 180 194 ί Cyclopent-2-en-1-one i 1______________ 1 312 312 312 312 312 1 312 312 312 Method of Example tc r- r* 773 773 tc pA 773 774 774 773 Example 964 965 996 967 896 969 970 971 306a TABLE 42 (continued) j 1,9-dioxo-1-hydroxymethylprostene 1 rt ft tt o fi μ tt ftp O VI 73 2 S'? ι ω 5 § ι μ XP X 1 o tn μ <-» 0 6 o •rt fi 0 1 1 CM Ό « *rt rt rt TO A XP tJJS o rt P rX rt tt 1 E tt ο X e X X tt .2 2~ 7 XP © X tt • ι μ rt rt rt © 1 cm tn • rt © 1 rt rt • X 00 X rt P rt • tt ol CM S P 1 X tt X κχ X o ο μ tt μ 0 is 0 X tt XX X » X •rt rt X 0 1 P 1 rt tt a x > ΙΛ fi rt rt tt · • X tt a ft c rt | tt rt p* P 1 rt (A 0 1 0 χ μ μ O O ft •rt fi t 0 TO tf) μ € © P TO • tt μ rt p P 1 C P © μ tt CM 0 X © X tt rt 1 fi • rt tt ¢0 I rt rt /-χ X a rt X CM XP 1 fi tt X tt I X X rt O ft A μοβ) 0 μ c XO tt X □ P rt rt V) 0 M-ι O ι rt μ a μ ft LO Ρ 1 rt 1 .« e-S'S r-ι ι μ rt Χ P 1 rt 1 0 » **? χ μ rt ο ο ι •rt C rt 0 fi X ι μ x © P p A tt tt rt P g rt 1 fi ώ fe35 CM Ο iX A p © 0 tt rt ϊ»> fi • χ tt co 1 rt rt rt X • I X CM » p 1 rt tt Ott· μ x tt 0 ft C X X tt χ X P ΐί o tn 0XO ι ρ μ J!§? rt 1 , «ft a<5«S r-ι ι μ rt pA P I rt μ q ι »n χ μ Ο ο μ rt fi rt 0 » X ι μ x © P P • « φ rt Ρ S Vinyl Iodide or Vinyl Tin of Example 00 © rt X \O 00 rt tt \0 co rt 186d Cyclopent-2-en-1-one 312 i 312 312 312 Method of Example 774 774 | 773 tn PA Ρ* Example 972 973 974 975 . j 1 306b Ό a C CM u a Ό 0 © Ό C Ο -μ © h >1 * c c CL E rt x ω a c I © I c a I CM I P c a a o © υ x u a Ό © ο α χ ε jj rt a x £ w X tt ξγ © ι CM σ» © © «3· b b CU © CM σ> © © m b es ffi in © © CM in © es o © es © es © © © b b K P* et ffi in b es •For the cleavage of the TMS-C=C-linkage see, Example 772(0) 307 EXAMPLES 976-998 By the methods described hereinabove in Examples 773 and 774, the 1,9-dioxo-l-hydroxymethyl prostene derivatives shown in Table 43 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table 43. It should be understood that the other diastereoisomer is also formed which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the 6-chain (the chain containing C^j. ...C^ etc.) to that of the respective nat and ent forms of the listed diastereoisomer; both of these diastereoisomers are claimed in this invention as well as their conponent enantiomers . 1,9-dioxo-hydroxymethylprostene and its diastereomer nat-(and ent)-l,9-dioxo-lla,15-dihydroxy15,16-tetramethylene-17,18,19,20-tetranor-1-hydroxymethyl-13-trans-prostene,1ethylene ketal nat-(and ent)-1,9-dioxo-11α,16-dihydroxy- 16,17-tetramethylene-18,19,20-trinor-l- hydroxymethyl-13-trans-prostene,1-ethyl- ene ketal nat-15S,16R- (and ent-15R,16S)-1,9-dioxo- lla, 15-dihydroxy-15 ,16-trimethylene-1- hydroxymethy1-13-trans-prostene,1-ethyl- ene ketal 1 1 o © X i is O © X •rt 1 P © a a * c os a © * © * © x a l x c /—.pa w ω p \© g ra © .rt o * μ μ os p q ΙΛ 1 1 © W if.g C in μ a © p ι ι © X© g §7* '—μ μ © I© X Oi xx Ό X P © .rt a © *© s d w ι X p in in X a tl s * p rt © rt rt © χ c c © x a nat-15S, 16S-(and ent-15R,16R)-1,9-dioxo- lla ,15-dihydroxy-15,16-trimethylene-l- hydroxymethyl-13-trans-prostene,1-ethyl- ene ketal nat-(and ent)-l,9-dioxo-lla,15-dihydroxy- 15,16-trimethylene-17,18,19,20-tetranor- 1-hydroxymethyl-13-trans-prostene,1-ethyl- ene 'ketal Vinyl Iodide or Vinyl Tin of Example ’ 246 245 243 . 243 251 247 Cyclopent-2-en-1-one of Example 309 309 309 ί 309 i 309 309 Method of Example tn b b 774 ι 773 773 773 773 E xamp1e b σι 977 978 979 086 981 . 309 TABLE 43 (continued) 0 s 8 C 8 P 8 μ X o £ « P fc 8 8 E fc X w X nat-(and ent)-l,9-dioxo-lla,15-dihydroxyT5,16-pentamethylene-17,18,19,20-tetranox-1-hydroxymethy1-13-trans-prostene,1ethylene ketal nat-15S,17R-(and ent-15R,17S)-l,9-dioxolla ,15-dihydroxy-15,17-dimethylene-1-hydroxymethyl-13-trans-prostene,1-ethylene 1 ketal 1 1 8 ο X fi X £ © O l rt •rt rt >» 0 1 £ 1 8 fc © c 8 • 8 « rt rt rt ι X * <>£ 2 oi p c r* © © rt g fc • •rt V» Oi 0 0 0 1 fc rt H fi 1 rt | fc · vi fi 0 fi 8frt 8 1 fc rt o 0 v-' fc rt 1 0 I 0 Xrt C’ £ X irt ·Η £ • 0 fc 0 1 8 0 0 S 7,1 S? « ψ S ii e|rt 0 ja 1 1 O rt X 1 X 0 rt £ •rt 1 P 0 8 8 1 fi 1 © © rt • rt · rt X 8 1 £ fi rt. fc 8 0 8 fc £ g £ rt .rt O • fc fc OS fc fi 0 > 1 rt £ tn Af-S g|!2 V 0 X0 gg7 ’ fc rt 1 0 X ed X£ £ £ fc rt »H 8 rt • 0 e « 0 1 Xfc 0 0X8 rt rt Q £ » , · fc fc CJ 0 8 rt rt X fi fi H £ 8 nat-lSS,16S-(and ent-15R,16R)-1,9-dioxo- lla , 1 S-dihydroxy-15,16-tetramethylene-l- hydroxymethyl-13-trans-prost ene,1-ethyl- ene ketal ( t O 1 1 fc X \o © tn o rt 4 'rt p 8 Vinyl Iodide or Vinyl Tin of Example 248 249 ί 250 252 1 1 253 N 0 CN Cyclopent-2-en-1-one of Example 309 309 309 i 309 309 309 Method of Exanple 774 0 Γ- r- 773 773 | 773 774 8 rt Ϊ X ω 982 983 984 985 1 986 987 310 TJ 0) G 1,9-dioxo-hydroxymethylprostene and its diastereomer nat-15R,16R-(and ent-15S, 16S)-1,9-dioxolla ,1S-dihydroxy-15,16-trimethy1ene-16(3-trifluoromethylphenoxy)-17,18,19,20tetrancr-l-hydroxymethyl-13-trans-prostene,1-ethylene ketal nat-15R, 16S- (and ent- 15S, 16R) -1,9-dioxo- lla,15-dihydroxy-15 ,16-tri me thylene-16- (4-fluorophenoxy)-17,18,19,20-tetranor- 1-hydroxymethy1-13-trans-p rostene,1- ethylene ketal 1 ο 1 I X sO P O rt o •rt 1 fi 1 *a © « rt , G p © Φ P © «rt © G rt >>p © ι X ι P P © TO tC © CM p Ό 6 * h rt .rt © 0 A P rt I W Ρ * ΙΛ TO 1 CO C rt \O rt G I rt a p P «f*· P GW rt I ©|rt 1 tC 1 /-\rt tj χ x » G X X rt GOO Xrt s-' p G X G l Ό © Ρ P 05 XX © © SO A 0 e X rt .rt Ο X «Ό Ρ X © 05 1 Ο O G in w fi P © rt rt rt T3 rt 1 , ««p X X p a ι χ x G rt Tf k P p- rt »—*rt © nat-15R,16S-(and ent-15S, 16R)-1,9-dioxo- lla, 15 -dihydroxy-15,16-trimethylene-16- (3-chlorophenoxy)-17,18,19,20-tetranor- 1-hydroxyme thyl-13-trans-prostene,l- ethylene ketal nat-15R,16R-(and ent-15S,16S)-1,9-dioxo- lla, 15-dihydroxy-15,16-trimethylene-16- (3-chiorophenoxy)-17,18,19,20-tetranor- 1-hydroxymethyl-13-trans-prostene,1- ethylene ketal Vinyl Iodide or Vinyl Tin of Example 255 i 256 257 258 259 Cyclopent-2-en-l-one of Example 309 309 309 309 309 Method of Example 774 773 tc Γ- Ι'- 774 774 Example 988 686 990 991 CM © © 311 TABLE 43 (continued) 1,9-dioxo-hydroxyinethylprostene and its diastereomer 1 1 ) 0 * P x © tn 0 rt p rt t H 3 Φ CM t C I © Φ (A pl’xS ι χ μ /-x p p 3 Φ 1 x s « rt rt rt • H > tf P H 3 1 X rt X X 1 ,rt μ P * 4> rt fi 3 € A ©rt XP ι X© 3 X p ,X e χ μ 3 O 3 © 'rt μ X fi 1 3 x © Oi X 1 rt X X rt χ rt rt 1 X *3 μ μ 3 1 0 © 3 3 C » rt rt rt rt 1 , a3 · PSI© rt rt © fi fijrt CM © 1 1 1 0 aP X © (A O rt 0 rt ι μ 3 © PM ρ ι © © (A x § ι Λ /-> μ μ Oi © 1 X S 3 tf μ rt 3 I X rt X X 1 ,rt μ μ a © rt rt 3 ε rt © rt X μ 1 X © 3 X Ο -X c χ μ 3 0 3 © rt· μ X C I 3 X © 3 X 1 rt X X rt X rt rt I X a3 μ μ w ι ο © 3 3 fi 1 rt rt rt rt ι , *3 a μ a ι © rt rt © fi fijrt CM © 1 Ο 1 X © ι O CM μ rt ι in 3 © O ι fi μ © © CM • rt 1 rt X IA *3 p ? os © μ X Β P rt rt 1 Α μ 3 3 P rt © 1 1 rt X rt 1 ,rt X Ρ rt fi © P rt ©rt © μ ι S © 3 X X* s x x 3 ο o © *-/ μ μ fi 1 3 3 © 3 X X’-’ X X X X rt rt 1 X • 3 rt μ Oi 1 1 © © © rt 1 rt iH X rt 1 ,*X a p a ρ ο d |w ® c s|h E 4> 1 O l X © 1 O CM μ rt ι tn 3 © O ι c μ © © CM a rt 1 rt X W ι x e /-. μ rt 3 © μ X Β P rt rt 1 * μ 3 3 P rt © 1 1 rt X rt 1 ,rt X P *43 rt β © μ rt © rt V P IB© 3 X XrX fi X X rt Ο O © ' μ μ fi l 3 3 © Οί X X’?' X X X X rt rt i X • 3 rt μ Oi ι ι © © © rt | rt rt Xrt μ| a p © rt rt © fi C rt e Φ nat-16R,17S-(and ent-16S,17R)-1,9-dioxo- lla, 16-dihydroxy- 16 ,17-trimethylene-le- ts- trifluoromethy1phenoxy)-18,19,20-trinor-1-hydroxymethyl-13-trans-prostene,1- ethylene ketal nat-16R,17R-(and ent-16S,17S)-1,9-dioxo- lla ,16-dihydroxy-16,17-trimethylene-16- (3-trifluoromethylphenoxy)-18,19,20-tri- nor-1-hydroxymethyl-13-trans-prostene,1- ethylene ketal Vinyl Iodide or Vinyl Tin of Example 260 261 262 263 264 1 265 Cyclopent-2-en-1-one of Example 309 © © to 309 309 · ~ .....1 309 60£ Method of Example 773 773 3 X X 774 774 774 Example 993 994 S66 966 997 OO © © 312 8 207 EXAMPLES 999-1082E By the methods described hereinabove in Examples 773 and 774, the 1,9-dioxo-l-hydroxymethyl prostene derivatives shown in Table 44 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-l-one.

In those cases where isomers are obtained at the C.c or C,, positions, only the C,- or C,.-normal isomers are lb lo 1^ lo listed in Table 44; it should be understood that the corresponding or C1(.-epi isomer is also formed and is part of this invention.

In those cases where the initial conjugate-addition product contains a triphenylmethoxy blocking group, deblocking is conducted in acetic acid-tetrahydrofuran-water 4:2:1 at 50°C for 5 hours. 313 48207 TABLE 44 (continued) © δ ft in O b ft rri X 45 ft g fc 0 b 0 X 45 1 r—i 1 8 0 ♦ri 0 1 © rt 1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,16-trimethylene-20-nor-5-cis-13-transprostadiene,1-ethylene ketal 1 1 a ι/j 5 s ι b rt ft .CM ft rt g J>l fc-3 p 1 rt b in rt 0 1 ft Xrt © 45 X44 1 45 rt ft © fc^l pox b CM 43 0 1 ft X © © 4= G I 1 © rt ΙΛ rt a rt X © 1 Λ £ Oft© X fi rt 0 6 0 •H «ft rt 0 b ft 1 ft Ifl © i p a© μ rt rt ft 1,9-dioxo-15-hydroxy-l-hydroxymethyl-16,16-trimethvlene-20-ethyl-5-cis-13-transprostadiene,1-ethylene ketal 1 o CM 1 ι in b ι ftto O rri rt I rft υ v> « x«ft ft υ □ © ι ι Ai © in rt | © ) —< G X X © X 45 rt o ft x b © 45 0 6 ft X X © 45 X 1 I P rt © H a rt 0 © ι X G 0 45 © X 1 rt o rt 0 •Η ι rt 0 rri ft 1 X tn © 4! g a ft b rt © ft 1,9-dioxo-16-hydroxy-16-vinyl-20-ethy1-1- hydroxymethvl-S-cis-13-trans-prostadi- ene,1-ethylene ketal 1 1 Xrt 45 * < © rt G 1 © rri 1 « 1 © .ft rri 0 < rt rt ft Is 1·, O o μ ι 0 in X ’ 4= «Λ ι b p tn ft b rt © 0 t 44 X © 45 G © 1 © G m «-ι © rt Xrt 1 45 X O ft 45 X © ft oS© •ft rt k 0 b rt 1 ft * CD t © A© G rri rt © 1,9-dioxo-16-hydroxy-1-hydroxymethyl-16- vinyl-5-cis-13~trans-prostadiene,l-ethyl- ene ketal Vinyl Iodide or Vinyl Tin of Example 49 50 51 193 195 19213 rt o rt CM 1 Cyclopent-2-en-1-one fi rft tn |- 314 1 314 314 ί 314 fi rft fO 314 fi rt tn Method of Example 773 773 773 1 774 774 774 773 Γ-- r* Example 999 1000 1001 1002 tn © o rt 1004 -1 1005 © © © rt 314 I tt X fi X tt O rt X 0 p TO tt P ι w \O o rt μ ι ft X » x wi s § μ χ ρ x ‘ ι tn m »η rt I , I tfl O rt x o| O I •η m 0 l rt I rt Λ © XP • X tt rt p I tt £8 X tt o rt I 0 X XP μ ι 0 tO Xrt X 1 ι rt lfl 0 rt rt ι u rt \0 I P rt m « • ι M in rt rt X tt I X fi Ο p tt X tt rt 0 Ε X rt I X 0 © P I CM tt © I I rt I i S κ rt ο μ μ ρ 0 ι £5 ί lfl * I * P in ι tt »-i tn fi I rt tt X tfl I X .3-35 I © ι in ι © i rt I X tt l t X · X tt ti § x rt p P μ w 0 o χ μ X ft o P tt sLS X X rt Pop © μ tfl 0|X ft TABLE 44 (continued) tt tw 0 O rt tt 0 fi -t O *H ft § r-i <—ι X x xua fi c •r4 rt > > O tt rt ft ο ε X rt P X tt UJ s tn pA P> 315 207 TABLE 44 (continued) a s P w 0 μ ft »rt X X P 1 fe 0 μ © X X 1 irt 1 O X o •rt © 1 OS © 1 o CM 1 1 X ra gs μ μ © Ρ £tA© © © rt © 1 ,Ρ ι w a \0 ©44 © a * ι a ω ω c © ι a I © © O X X XXX O P p © a a © B l 1 OS X * * o a © μ fi ι © a o X© rt x © μ ι « X © p P J ι μ o © ο μ © C ft dl-erythrol ,9-dioxo-lla,15,16-trihydroxy1-hydro xymethy1-5-cis-13-trans -ptos tadiene,1-ethylene ketal dl-threo-1,9-dioxo-15,16-dihydroxy-20ί methvl-l-hvdroxvmethyl-5-cis-13-trans- prostadiene,1-ethylene ketal dl-threo-1,9-di oxo-15,16-dihydroxy-20ethvl-l-hvdroxvmethyl-5-cis-13-transprostadiene,1-ethylene ketal dl-threo-1,9-dioxo-15,16-dihydroxy-19- methvl-l-hvdroxvmethyl-5-cis-13-trans- prostadiene,1-ethylene ketal dl-threo-1,9-dioxo-15,16-dihydroxy-1- hydroxymethyl-5- cis-13-trans-17-trans- prostatriene,1-ethylene ketal © (0 ι p ω a 1 44 © x a ί s fe£ o a μ v © © J? a > fi © a I © fee O P μ ra © o χμ X ft 1 I \O ra 7 5 ο μ X P ο 1 © tc © © ί 1 1 OS w *©l © aj. 1 OS © i 1 © © * X a f § e© X rt X P o ra μ o © μ X ft X » ι ra © fi j ra χ μ X P O t μ tc © © X ‘ 1 .era© ι ©Irt so a p © ι a 1 ΙΛ 44 O χ μ rt o o c © c a © © © ι © X OS 1 4= *© p ©cm a Vinyl Iodide or Vinyl Tin of Example 88 76 89 06 © OS 92 107 108 Cyclopent-2-en-1-one 314 T· © to 314 Τ' © tc © tc TT © tc Τ' 1—1 tC 314 Method of Example 773 773 773 773 773 tc X X tc X X 773 Example ΙΛ © © © 1016 1017 1018 1019 1020 1021 1022 316 482U7 TABLE 44 (continued) © G © P TO O P 0 X f © E 5? o P T5 X X 1 rt O X o rt TJ J © rt 1, 9-dioxo-16-hydroxy-1-hydroxymethyl-18,19,20-trinor-5-cis-13-trans-prostadiene,1ethylene ketal 1 O 1 CM rt 1 X rt A XP X © P » o rt So g § P rt *a a X rt X P 1 TO rt O ι P 5?? Ο TO is X P X P 1 t \O to rt rt > 1 . O TO rt X rt rt O UP rt k © tj ω x 1 k © P © * O G rt S © 1,9-dioxo-16-hydroxy-17-methyl-1-hydroxy- methy l-5-cis-13-trans-prost adiene,1-ethylene ketal 1,9-d ioxo-16-hydroxy-20-methy 1-1 -hydroxy- methy 1-5-cis-13-trans-prostadiene,1-ethyl- ene ketal 1 ι X δ v Ό rt Bs rt © Λ3 X rt ft! ?8 β 0 N k 1 « S?s 8 p •a t xw Ό TO rt rt I t u 0 1 rt X ΙΛ G o 1 ti rt rt © •a Xr^ X © P © A © G rt £ « ) 1 rt rt £1 P P © TO 1 P © p CM 0 rt TO Bi rt Ί1 il fe-a-a 0 1 P 'λ ui ii •a ι zz X'-i Λ b £ « 5 S § op® rt P k T, TJ rt ι X * © X © a j q rt rt © J tc rt rt X P rt © * i'S x a χ ti p TO| P »rt| TJ ul X » X ΙΛ < f't Ό TO rt rt 1 ι U O f rt xx rt O rt P rt 1 © •a to x < G © rt © * P G rt P © 1 Ii •a © X ί τ rt © Λ § p rt 83 to to ? ? si »a *1 ! Ό L rt TO , 1 rt j Ο O rt X » rt O to P rt 2 © tj Τ'x ι .8* ©£ © A© fi rt B © Vinyl iodide or Vinyl Tin of Example 109 I- 1 no 144 112 113 139a 115 135 Cyclopent-2-en-1-one 314 rf rt tC rt rt tc rf rt tc rf rt tc rf rt tc314 314 Method of Example ί 773 tc r- r- 773 tc Γ- Ι'·. 773 773 773 773 Example 1023 1024 1025 1026 1027 1028 1029 1030 317 TABLE 44 (continued) 1,9-dioxo-1-hydroxymethylprostene t 1 rt ·Η x·© x « P P © tn 5 s ΰδ ι ra s § si! rt A© X rt rt . 1 (A Xrtlrt X o rt Ο 1 P H © © *0 1 X X rt X X © I X c \O p © rt © rt ih? X X P o © « •η μ ι 5> 53 <-i I X A 6 X © A « C rt rt © 1,9-di oxo-16-hydroxy-16,20-dimethyl-1-hydroxymethyl-13-tTans-5-cis-prostadiene,lethylene ketal 1 1 £5 1 © rt C 1 © rt »rt X53 X rt P P g s •rl H 53 A ( 1 x ra 5§ x μ rt p 1 1 8 ii 53 rt X ©I fi 1 rt ι © rt 1 ti rt rt © ι XX o x X P © S S § Tsk ”.85 rt 53 © I 1 Xrt χ μ 0 P μ rt 5» P χ ΰ X P ι μ rt ft 1 1 1 rt ra X£ X o| P 1 g“? » tn © fi rt rt ι μ 5?V S p X P μ rt © •rt ι x X ra ί SS <0 μ © rt p rt 1 1 X O © X X rt P ο 1 © rt rt ι 53 Xrt 1 X 0) P © A © fi rt g © 1 1 Xrt χ μ O P μ rt •rt p £g rt CU 1 1 1 rt tnl £ΐ P ( g*? t ra © c CN rt ι μ X P rt χ i rt 0 X P μ rt © 53 1 X X w ί § g © μ © rt p rt 1 1 b o © X X rt P 0 1 © •rl rt 1 53 Xrt 1 X * 0) P © * © C rt g © 1,9-dioxo-16-hydroxy-16-methyl-l-hydroxy- methy1-5-ci s-13-trans-prostadi ene,1-ethyl- ene ketal 1 t Xrt ί © rt e 1 © rt rt X*rt X rt P P g s •η μ 53 A 1 1 © ra 5g x μ rt P 1 I O 1 , μ ra 53 rt X o| X » rt ι © rt © ι P rt rt © ι XX 6 X X P © o © e •HE© •rt Xrt 1 £ s> ©ox * μ p rt 53 © 1,9-dioxo-16-hydroxy-l-hydroxymethyl-13- trans-17-trans-5-cis-prostatriene,l-ethyl- ene ketal Vinyl Iodide or Vinyl Tin of Example 136 137 138 «h © rt 149 150 151 152 Cyclopent-2-en-1-one Tf © rt © 314 314 314 314 314 314 ( [Method of | Example 773 773 1 1 773 i 1 i_ 773 ί 773 773 © X X 773 Example 1031 1032 1033 1034 1035 1036 X © © «—1 1038 318 7 TABLE 44 (continued) 319 TABLE 44 (continued) 1,9-dioxo-1-hydroxymethylprostene 1 rt 1 rt 0 X rt £ fc fc w 8 O E £ rt fi 0 1 1 W s rt « * fc X fc rt 1 1 0 s£ Ύ rt O w rt fc rt p 0 U|8 X 1 £ £ 0 1 1 8 a c 0X8 rt £ rt t fc X 0 8 £ x e fc 0 x 8 rt X I 0 O rt 1 fc · σι 0 8 • x e rt £ 8 1 5? fc 0 rt © ( C rt © Χ£ fc rt Ί s rt fi 1 1 o rt fc fc 0 fc 1 rt rt a ι ,«fl 0 W P rt rtl 8 1 0 1 X 0 8 O I c rtrt© 0 Xrt 1 £ X © fc £ • © P rt & 8 I rt O fc fc 8 0 1 Xrt £ * 1 © rt fS 1 © rt rt £ «β fc fc 8 W ι O 0 fc rt fi 1 1 ο a fc fc 0 fc 1 rt β ι. 0 W rt rtl I 1,9-dioxo-15a-hydroxy-17,20-tetranor-16- cyclopenty1-1-hydroxymethyl-5-cis-l3- trans-prostadiene,1-ethylene ketal 1 0 rt SA C rt rt «flirt P WP C rt © © ©Lx fi 1 1 0 © ο I c CN rt © • Xrt 0 £ X 7 Ο X rt fc o · 0 fc © X0 C £ X © 1 £ rt σ ι 0 0 rt rt rt 1 P 1 rt W OXO X X fc O 8 fi rt £ t 0 O W 1 rt fi © υ cs • Xfc rt υ p Vinyl Iodide or Vinyl Tin of Exanple l-iodo-3-tripheny1methoxy-5,5-dimethyl1-trans-octene (U.S. Pat. No. 3,873,607) . l-iodo-3-tripheny1jnethoxy-4-methyl1-trans-octene (U.S. Pat. No. 3,876,690). l-iodo-3-triphenylmethoxy-4-ethyl-ltrans-octene (U.S. Pat. No. 3,876,690) . l-iodo-3-triphenyljnethoxy-4-cyclopentyl-l-trans- butene (U.S. Pat. No. 3,884,969). I rt X fi 1 8 O £ rt 1 fi © W rt pS fc υ rt P 1 fc f 0 P 0 1 ( A >7 0 O rt Ο £ X rt P X 1 © © rt E £ pentene (U.S. Pat. No, 3,884,969). Cyclopent-2-en-1-one 314 314 314 314 1 1 1 314 «Ρ 0 8 g Ϊ £ rt P X 8 W 2 0 r- 773 773 i 773 773 f Example 1 1046 1047 1048 1049 1050 320 TABLE 44 (continued) 1,9-dioxo-1-hydroxymethylprostene t X © 1 ι tc frt © © 0 ι , rt C rap © © a μ a P I ι tn a ο I c χ a * X ·-· » X X «rt Ρ X ι a p X B a g fe4 μ o · © μ a X© C χ X a 1 x © a ι © lc © rt © 1 P ι © ra OXO χ x μ o a cu rt X 1 ©Ora mu § * X μ ©UP 1 1 CO tc © © I I ,© μ ra rt O © P fi a|a © 1 44 © ΙΛ ι ι a CM © fi oxa * JG «Τ σι Ρ X © a x ι Β P fefe? 8 8^ © © a X x c χ x a 1 1 © a © © ω ι rt © © P 1 x w O P 0 x c μ o a ft •rt ft 1 © 0 w ι © fi os a « • X μ «rt U P p 1,9-dioxo-15a-hydroxy-15-methyl-1-hydroxy- methy l-5-cis-13-trans-prostadiene,1ethylene ketal 1,9-dioxo-ISa-hydroxy-15-methyl-20-ethy1- l-hydroxymethyl-5-cis-13-trans-prostadi- ene,1-ethylene ketal ι in rt rt ι p μ © a P >«44 a X ρ p a ι a fi ο B a 2 83 ·© a « χ 1 © X © * 1 * b © a s?h pert Hap © x w b ft o χ Ρ μ ι μ ft S3 Ο 1 in 3 ra © © fi ι rt Ο i.H X WP ο ’ ' © ο tc © © © lit, σι μ ra © fi a| 1,9-dioxo-ISa-hydroxy-17,18,19,20-tetra- no r- 16-phenoxy-l-hydroxymethyl-5-cis-13trans -prostadiene ,1-ethylene ketal Vinyl Iodide or Vinyl Tin of Example 1-iodo-3-triphenylmethoxy-5-cyclohexyl- 1-trans- pentene (U.S. Pat. No. 3,884,969). l-iodo-3-triphenylmethoxy-6-cyclopentyl- 1-trans- hexene (U.S. Pat. No. 3,884,969). l-iodo-3-methyl-3trimethylsilyloxy-trans-l-octene (Example 125) 1-iodo-3-methy1-3trimethylsilyl- oxy-trans-1-decene (Example 190a) 159 186 I- } Cyclopent-2-en-1-one j 314 T r-M tC 314 314 314 314 ’ Method of Example 773 773 773 773 774 774 Example 1051 1052 tc LC o © 1054 1055 1056 321 TABLE 44 (continued) ί 1,9-dioxo-l-hydroxymethylprostene rt 1 1 fi fi m P μ ι tt P rt tt X Ρ X tt 1 Ρ β O tt tt CM E rt * X X © X X rt Ο P * μ © « 0 1 rt X rt •X * X 1 0) rt rt β f I tt fefes oofi μ c p 0 tt tfl xx p x ft μ i S ? in o v) rt μ β ι x fi ο ι-, μ X ft}P 0 ι « rt VO tO 0 rt RH If 1 , © μ tn * O rtl rt β tt| 1 1 fi rt μ x P X tt tt p c P tt tt 01 H « rt 0 1 a Xrt 00 X * rt » tt * rt fi X 1 tt rt Xrt I X 0 χ o rt * fi p o tt tn μ X p 0 ft μ Xrt ft X X 1 1 £ 2 a 2 5 m x fi rt ι μ l PP O 1 J X Gjto 0 I rt rt X 1, 0 rt tfl Irt 1 1 rt I fi © μ ο p * O F tt rt gm 1 ι fi rt μ X P X tt tt P fi p tt © 1 B rt © X X CM X X * O P © μ tt rt 0 1 * Xrt 0° X * rt 1 tt *rt β X | tt rt Xrt » X 0 X O fi X C p O tt tfl μ χ p 0 ft μ X Xft X χ μ ι o tn a x fi in p w μ ν μ ι e p o ' l‘ x o>n O Irt rt Ό ι , 0 RH IfllRH 1 1 rt rt © μ tt p A O ( tt rt fiin X 1,9-dioxo-15a-hydroxy-17,18,19,20-tet rη- ηοΓ-Ιό-^-οΗΙοτορΗβηοχν-Ι-ΗνόΓοχγτηβΐΗνΙ-δ- cis-13-trans-prostadiene,1-ethylene ketal 1,9-dioxo- 15 i ι x SfeS tt O 1 ρ μ rt 1 0 · O X tt CM X fi a | tt © rt rt rt 1 0 rt 3 feti rCg 2 rt tt ft X · X ft tfl g £ § μ ο μ 0 rt p χ *S tc 1 rt rt a 0 ι, m f tfl rt rt rt 1 A O o tn irt χ tn rt o > 1 P rt >O rt tt 0 ·-< X-X l μ X © μ p tt A O tt fi rt fi β tt l,9-dioxo-15a-hydroxy-18,19,20-tTinor- 17-nhenvl-l-hydroxymethyl-5-cis-13-trans- pros t adi ene,1-ethylene ketal Vinyl Iodide or Vinyl Tin of Example181 182 183 184 180 185 1 186b Cyclopent-2-en-1-one 314 314 fi» ip tn fi- rt tn fi rt tn 314 314 Method of Example 774 774 774 rt X X 774 774 774 Example 1057 CO m © R“l © in © rt © Ό O rt 1061 1062 | 1 1063 322 8207 ι rt ι rt μ X X © rt X Λ ι μ μ © © Ο E fi fix© rt X rt μ ο x μ μ x ι 3 μ © X © CM X I a I rt © rt A rt I © * '“A fi co rt © rt Xrt I C 3 X © rt xx μ 0 CM w μ rt o 3 χ μ XX CM χ μ ι ι © cn a s c in o rt rt μ μ ι Ο μ Ο 3 ι χ f-ι tn ο μ ι-* rt rt I 3 μ cn ι μ ·η © I u * £ ι r9 3 fi rt O rt CM >-ι £- g rt rt X X XUJ c c fi I p © ca rt X fi fi. .

CM rt •η μ μ ρ PI·· I rt 3 3 3 I * X I X « O X © A ο fi tn ox© rt μ μ I © U Ο rt £ Ο Ζ Xrt λ Έ ι rt rt μ I CA rt 0 χ μ X μ rt μ I I XtO X rt O 1 I μ cn 3 rt X O rt χ ι rt ι ιλ μ a * © 3 μ x rt O I fi © O fi X CM © O f rt rt rt X 3 XX ι X μ © μ © A © ί rt £ rt I I ι rt rt μ I CA rt O X μ SS rt rt 3 μ I P © £ rt tn • rt © k rt CA I I rt X O X I- rt o 3 rt μ ( p 3 μ © ΧΟΛ X c ι ( © a cm c 3 ( © rt rt rt I X X OX X X P P o © © rt S I 3 Xrt t X A © o © α μ c rt3 © I rt X S 1 Xrt · CM3 © O •Η I fi Z μ 3 © · μ α μ . ο ι 3 ϋ μ r» 3 ι ο rt Ο I X I fi. © Ο X rt A 3 Ο X · to o xx W x rt μ μ · oo I © © 3 A rt £ £ '—' 3 Bi © CM O £ x rt μ X © ω ζ - 323 4 8 2 0 7 TABLE 44 (continued) © G © ft (fl O b Ph rt X 0 b 0 X »C 1 rri 1 O X o rt 0 1 σι A rft 1 rt 0 A 1 ft X A ί 8 rt P, 1 ( X A X G 0 A b b 0 ft X i £ tn ♦rl rt 0 I , 1 A © rt rt © A f> ^ri a w a in ( ft rt b © 1 0 44 8? ® 0 CM G rtl© 0 rt rt I X X σι £ £ Aft ft rft © © O X rt © X A b o © £ b G ftfO © 1 fc o £ ι ft A ?! © ft rt 1 ι tn X rt X 1 rt 0 A A b rt ft 0 υ © X 1 44 45 «η _ 1 I © a b g in o © rt G rt ι ι X O CM £ X 1 ft 0 rt © rt X ( 0 45 »1 ft * σι g © rt x © 1 Xrt Ο O 0 b b A 45 0 ft ft X A fc<8 © rt p< 1 1 CM rt^ rt £ Xft £ © ft 1 © rft 5, © x e 8® 0 0 X A 45 ft 1 A 78 fc? O A •ss £5 I t © tn rt rt 1 h O A rt X rt A o ©1ft ft 1 © 0 W 44 1 I σι b © * o G rt c © 1,9-dioxo-16-hydroxy-16-methyl-l-hydroxymethvl-2-nor-5-cis-13-trans-prostadiene,- 1-ethylene ketal 1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy- methyl-2-nor-5-cis-l3-trans-17-trans- prostatriene,l-pethylene ketal 1,9-dioxo-lSa-hydroxy-2,17,18,19,20-pent- anor-16-nhenoxy-5-cis-13-trans-prostadi- ene,1-ethylene ketal rt , fc2 ft O © G b 44 © 0 PM X © I rC G © l © CM rt rt cn xjs rt X ft A O © 00 c 1 rt © rt aJ5 * X cu © r-1 rri G - X © CM 45 rt 1 ft 0 X© A X £ ft Ο O A b b 0 0 P b X 3 PU 45 Τ’ 1 1 M-l A art C LH b A rft +4 b 1 i.ft ©S’ x ι »n O © rt • rri rri I 0 1 A ι b rt οι Ο O JS J 1 1 » X fi X G O © b rt 0 0 X A £ ft 1 A rt O ι b X •S J5 > A 1 b © ft rri » ι tn Xrt X I, 0 At b rtl 0 o|rt X I A £ m ft ’ll © © b 44 rri O 1 G © Ο ι C X CM © Ο ι rt rt rt X 0 Xrfi ts Vinyl Iodide or Vinyl Tin of Example 69 74 r- © rft 130 134 186 180 fi σ> rft Cyclopent-2-en-1-one 315 315 315 315 in rri tn 315 315 in rt tn Method of Example 773 tn b- b- 773 i 773 773 774 774 fi b- b. Example 1071 1072 1073 1074 1075 1076 1 1077 00 r- o rt 323a ? fl} a o rt © a s i-t ο ·Η 0 Η ρ ί CO rt rt X X X UJ c e rt rt > > O © rt a 0 o E x « p x © UJ X ι X rt i P rt TO t 0 rt P X 0 0 1 O TO P G δ* S O P rt P υ ι X w U rt , I , Ό TO I I rt tc P rt P ’ .

© To P rt rt ι ©1 rt © ι P CM W © • I X σ> rt ι U rt X ι P X in © Ο ι X P P a o © X C G X I © J CM rt Ό I X rt rt A I X P ox© X P I O © rt rt E * •α x © ι x c © o © •Prt —« tj a rt © rt «;££ ι X p X 0 © X P t 8£1 a x © X ’ δ X rt © I J rt β rt a in X rt rt c p ι © to oxo X 0 P ο ι 0 rt r- | a rt to ό i s • OP rt rt p CM rt px T3 rt s P a X I X Ή ι · rt © I G rt © Xrt £·§ © 0 ι P Ό 0 rt I I TO s?S S3 a f xw X rt rt I ·, rt Ό TO(p rt rt© ι ox o f x w © o t g rt ι—I © a x«-i ι X X cn p a A © P rt E © rf rt tC &® S§ rt TO 1 P rt P § © P &§ p a a rt J 8 I 0 rt I || P P © t I to \0 rt I rt f? w| rt Ρ υ a ι «-j xw « X J p J P © Ό Ο X rt 6 I 1 © o © q X es © Ο I rt rt rt X a xx l X P © P © A © I rt fi rt O I ρ in a , rt Xrt d X X p ι X © Ό Ρ X rt © ι ι © QOS X CM © Ο I rt rt rt X a xx ι X p © p © A© ι rt fi rt S' - 323b 4-8 20 7 TABLE 44 (continued) c a p V) 2 ft rM X X P g fe o μ *51 X 1 © 1 o X 0 •rt © 1 cn t X X 0 μ © £ f ©» 1 © © X * g.§ g·^ μ © ft rt 1 P © rt A-Z © ι μ sO ft © 1 ι rt ο μ μ ρ © ι ΧΜ X © © ι - rt sO ra ρ © © a ι a JrX O k x w a O f fi •rt © a © X? » χ X OS P X * a p fm g a X o a μ fi © a χ Έ ι rt ©. P © w X ? g-i Γ H -t +> A—» | I tc \0 © © *. t rt fe-a 0 ϊ μ ω © ► © X© rt -12 ι X a \O Ρ X © a ι f a o o c xcm a o t I-i •rt r-M X © XX ι X p os p a • a μ © g© Vinyl Iodide or Vinyl Tin of Example 1541 © τ· in © a § t rM I fi a 1 CM I P fi a ft o rM o X CJ T* rM tC 314 Method of Exanple 773 773 Example 1082D 1082E 323c 8207 EXAMPLES 1083-1105 By the methods described hereinabove in Examples 773 and 774, the 1,9-dioxo-l-hydroxymethyl prostene derivatives shown in Table 45 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table 45. It should be understood that the other diastereoisomer is also formed which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the β-chain (the chain containing etc.) to that of the resepctive nat and ent forms of the listed diastereoisomer; both of these diastereoisomers are claimed in this invention as well as their component enantiomers . - 324 48307 TABLE 45 1,9-dioxo-1-hydroxymethylprostene and its diastereomer i 0 rt I 1 • rtrt 0 » 0 rt fc rt I O fc X fi £ x rt p O fc fc fc fc fi 0 8 » Xfc « f i s ait 1 Ol 1 o rt 0 X *rt 0 00 1 rt rt rt w rt 0 *rt fc ( X O|© σι rt ι • 1 0 1-18 18 1 fi rt f8 X 8 fcrt £ rt fi Xfc x © £ 8 £ pep 0 8X8 § SoA 'rt fc fc * fc,P0 8 rt 8 X fi fip£ 8 rt X 0 S rt 0 1 x£< XI 8 O rt fi fc » 8 0 fc rt X 0 0 £ C « 1 rt p 0 fc W rt fc 0 1 1 fc O © fi X CM 1 ο * rt 52 § 1 * fc © CO fc ·» rt 1 rt t 0 1 © rt rt zrt.e ι , rt fc 8 wlfc e rt rt I 8 8 X © £ £ I 0 fc 0 8 fi 8 1 fi rt £ rt 8 ' rt Xrt 1 .te £ X fc fc fc £ rt 8 8 fc filfc 6 8 1 rt 1 1 X © X£ X X fc 0 0 8 rt fc 1 0 0 rt ι X ·» © £ 8 • ι c rt rt 8 I > rt <-»8 0 W fi rt 0 8 fc «-< rt tfl «£2 in p fi rt 8 1 ,B rt 5 fe § 8 fc fc 1 fc 0 0 1 fi rt 0 rt *rt Vrt0 ( , ι rt cnl βί 1 rt 0 xo rt X 1 rt * O 0 « CO fc » fc 0 0 rt 8 rt X fcfi fc 8 rttn 8 fi she© 1 rt 1 1 X O X£ X X fc 0 0 8 •H fc 1 0 0 rt f X * © £ 8 • P fi rt rt 8 ( 1 rt z-x 8 0 0 C rt 0 8 fc rt rt tn • X o Qi £ fc 0 fc fi rt 8 1 . 1 ,B W PM rtl c|fc o| 8 fc 1 1 0 0 0 1 fi rt ω rt * c ^0 rt 1 rt fc OS 1 fc 0 X 1 rt X 0 rt • o <-< m w fc » £ in 0 »-ι 8 rt >> Χ,Χ 1 £ £ fcfi fc 8 SMS 1 rt ι ι X O X£ X X p 0 0 8 •H fc 0 0 rt © £ 8 • 1 fi rt rt 8 1 1 ·Η /rt 8 0 fltf fi rt 0 8 fc rt rt « OS £ fc 0 fc fi rt 8 P. ι , S w p |*rl .)-(1 c fc o 8|p 1 1 0 0 0 1 C rt tfl rt * fi 0 rt I rt fc W 1 fc 0 X 1 Z. X 0 rt • o rt rt 0 fc 1 fc 0 0 rt 8 rt XX* > .£ £ fc 1 fc © rt 0 8 fi cL· g © 1 0 1 rtl * * X 8 0 £ e rt | 8 » rt >fc X 1 0 X fc rt 0 0 fc fc fi rt Ό rt o X fc fc £ fc fi 1 8 > , 0 fc rt rt 1 «Η ι ο o| 0 lrt© fc © ι £ β e rt © © X © rt £ fi 0 Xfc © fi £ 8 rt rt fc s x © X£ I ,E Xfc pH o © rtffc fc ι c fc 0 Vinyl Iodide or Vinyl Tin of Example 246 245 243 243 251 247 Cyclopent-2-en-1-one of Example M· 1—< 0 N rt 0 314 314 N · rM 0 314 Method of Example 773 774 773 773 773 773 Example 1083 1084 1085 1086 Γ- ΟΟ © rt 1088 325 4-8 2 0 7 TABLE 45 (continued) 1 vO A 1 t 1 0 X 1 rt X 1 X X P I rt 0 1 X* X X P 1 1 fr 88 , 0 0 χ μ 1 1 0 rt 1 X μ rt 1 P ra 0 Ό © rt rt 0 X © 0 x © 0 53 0 53 OPP H £ rt t Ό O 1 rt ο 1 rt X 1 rt X 1 rt P A A ι μ ra 53 μ Ή 53 μ rt Ό X rt Ό X rt 53 © © w X O P 1 53 A 1 Ό * 1 1 * » I ..* 1 ' P □ x c ra rh X © Ch X © Ol rt © 01 rt © Ol 1 1 C o ra o X c *X fi « 1 C * A fi © u © μ μ μ rt 1 © rt ) © rt © © rt © © rt rt CM © P Ό P A 1 73 © ra 1 rt rt 1 fi rt 1 fi rt 1 1 A ra μ 0 © X © 1 X ρ ra © S' i g rt* © ’fi OT rt rt ο Φ *5 cfi ι-ι ra <-> © d ra μ 6 1 1 rt X c P X C P Ό XP Ό fe»P Ά ® -Γ H A o © o © rt © ra ιρ © ra rt ra rt χ ra rt rt OQ r-l © rt CM l rt o *P o » Ρ β * Xrt μ χ μ 1 ·© PS X μ es χ μ cd © μ ei a h OT X * © P X rt © rt p X © P P O Ch » χ rt W © X A P 1 © X A rt P » © ε a rt ra ι 2 g δ © ra © ra Q · fi 1 © ra ι .© ra ι . μ ra ι.,Η <4 1.,s 1 rt P ε ra rt oo ra P ε p ε *h P P rt © X *h ό i-η μ ra c rt o CH © fi © o Β Ο Ο fi Ih s rt X 53 1 A 4_l p © 53 ι ©153 i © P 1 © P 1 Ο P g © fi o μ ω σι χ ι Art © © 51 1 © x L l· © Ό X 1 1 © 53 © _ ( © *0 vo | 1- o 53 M3 fi ϋ 53 P fi rt ra fi rt ra fi rt W fi rt ra rr g © © X rt 1 © ( © ra * fi ra * fi 3 * fi rt ra * fi rt ra »X fi rt ,£ e rt e *rt © ra Krt© ra *-/© ¢5 ra ra Krt© cu X X t ή μ ι rt μ ι rt μ P ι rt μ P 1 rt rt X X C rt X os 1 P ω ι p cd ι P © w > P © W J; >, μ P 1 ©I XP X X X 1 X X l © χ l fi © S.L S-S? p H © Q rt X © rt rt X © rt rt x © rt X © 53 1 χ 0 rt ra a 0 rt ra a O rt © a 0 rt © A 0 © Xrt o W μ ι P © μ ι P ot μ ι c ot μ ι CS Μ Β X * ra ε x t- © 53 rt © © 53 rt © © 53 rt © © 53 rt © ©? fi 1 © 53 ra o rt X X fi rt X XX rt X X rt rt x X»H »-« μ rt fi 1 ι ρ μ t X X χ X 1 ,xx X ι. X Λ »*» 1 X o I © Ch P C 53 © P 1 P © pfT p © P 1 P X PIT ρ χ p|T 3 μ rt ra © © c ra© © c rt,© © P rap a p rap r-ι o 53 rt Cl AX © c ή ε © fiH s © fi |rt £ © BM § © - pH *p fi ra μ o © Uh 53 O 53 fi © O rt rt co σι © CM © •e )-h H A ’T © © © © s CM CM CM CM CM CM Vinyl Vinyl Exa © c 0 J, 1 © C rl © A ε -S’ -g- γμ ra rt rH fH rt rt ι x © © © © © © P UJ c , φ Uh A © O o X CJ d of pie © © © © ο ε X X X X X X X rt P X X X X X X X © ω s © A Ch © »-4 CM © ε oo σ» Ch Ch Ch Ol ra o o o o © © X rt rt rt rt rt UJ 326 TABLE 45 (continued) 1,9-dioxo-l-hydroxymethylprostene and its diastereomer 1 1 1 P Ο ·Η 1 tf) χ μ rt p ο ρ μ μ rt 1 P cu 3 »0 © ι , I » μ IA © 1 » rt *© © ui rt rt CM 1 1 1 *3 /-> © © 1 tn e .-ι tn © © a G rt rt 00 Ol * Xr-i μ W X * P 3 P X 1 rt © rt 3 rt 1,6 1 rt P μ rt /-ν ι © g μ Χ'-'Λ © ρ χ x 1 Ο X © 3 © G p G fi rt © © © «β ·Χ £ rt v3 CU X X I rt rt X X G ι XOP © xx μ © r-ι X P 3 Ια O © Xrt OS μ £ X A 3 3 O I © rt χ μ rt G 1 X O i © Pl ι 3 μ<ρ rt3rt 0 3 eJrttw c m 1 O 1 0 1 S5fe 0 Ή 0 rt ι Η ι 3 it 3 rt I ' X A © l X © a© I G rt rt rt © 1 I » rt r-s © μ 3 OS C O rt © © fi μ rt rt cd (A a χ μ o w χ ρ μ 3 μ φ o. rt © μ t l.S 1 (A μ rt © rt fi μ cm © © P A I ι © in 3 © rt 1 fi rt » IA rt · CO fi rt VIA rt W Λ 1 rt * μ μ CO ι b μ « © Xrt 1 Λ rt X 1 3 A O © λ μ χ ι c 3 3 x f-i © rt X O X»H 1 X fi χ X μι © μ X rt 3 χ © μ fi H cm £ © 1 8 1 O I o G X X rt X ο Mi P •kiwi 3 if 3 rt I SH X A © ι X © A© I fi rt AA rt © 1 1 1 rt © μ 3 3 fi o rt © © fi P rt rt rt (A - χ μ o 3 χ ρ μ 3 P © CU rt © Ρ ι , 1 .£ 1 (A μ rt Ο ·Η c μ cm υ ©Ρ α ι 1 © 3 3 © rt 1 fi rt a (A fi a CO fi rt SHtf) rt fi © j rt * μ μ OS t tA. μ © © X^ 1 Λ rt X ι 3 • O /*>rt © Λ μ X ι G 3 3 X «-I © rt x O X—1 t X fi X X pfi © μ X rtln x © p fip cu£ © ( 0 X t > o rt rt rt 1 I 3 3 3 μ ce | k-9 o P © ι c tn a© rt O rt rt μ μ 1 1 P CM /-A © © I , OS C P rt © © 1 rt] rt rt © « * XCM 1 3 x *3 3 P © I rt © r-l tf) I.S A C μ|.Η CO rt rt C μ rt μ rt © μ α μ μ ' ι X I © 3 © rt 3 Λ fi rt 1 rt W 'rs I © '—'3 Xrt fi 1 rt $< x © 3 » OX rt © X fi μ X rt> X © © X a Ο X Ε μ α! μ cm X © 3 3 0 X1rt χ μ o r-i ι χ ο μ ·> μ| k rt 3 © coin χ X fi Cr υχ © 1 O X 1 1 o rt «rt «Η 1 1 3 3 3 μ « ι © μ © ι G ©©’, W CP W © © 1 »rt J rt rt © O| A XCM 1 3 X *3 3 P © 1 rt © rt (A ι ,E * fi μ .rt 3 rt rt G μ rt μ rt © P * P P 1 X 1 © 3 © rt 3 Λ C rt | rt rt a ι © s-/3 Xrt fi 1 rt Κ X © OS I Ο X rt © X G Ρ X rt X © ©X A ο X Β P OS H ft X © 3 3 0 X1 rt X Μ O rt 1 .X Q μ « μΙ 1 rt 3 © rt ιλ Λ S = β H 4> Vinyl Iodide or Vinyl Tin of Example 25S 256 257 258 1 259 Cyclopent-2-en-1-one of Example 314 Tt I-H 3 314 314 314 Method of Example It x X 774 774 774 774 Example 1095 1096 1097 co © © rt 1 1099 327 328 8 2 0 7 EXAMPLES 1106-1189E By the methods described hereinabove in Examples 773 and 774, the 1,9-dioxo-1-hydroxymethylprostene derivatives shown in Table 46 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-1-one.

In those cases where isomers are obtained at the C^g or C^g positions, only the or C^g-normal isomers are listed in Table 46; it should be understood that the corresponding C^g or C^g-epi isomers are also formed and are part of this invention.

In those cases where the initial conjugate-addition product contains a triphenylmethoxy blocking group, deblocking is conducted in acetic acid-tetrahydrofuran-water 4:2:1 at SO°C for 5 hours. 329 4-8207 © G © Ρ TO Ο Η 0 rt X X Ρ © & X ο Ρ a χ X > rt 0 X 0 •rt a I © l-H 1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,16- trimethy lene-20-nor-13-trans-prostadiene,1-ethylene ketal 1,9-dioxo-15-hydroxy-1-hydroxymethyl-16,- 16-trimethylene-20-methyl-13-trans-prosta- diene,1-ethylene ketal 1,9-dioxo-15-hydroxy-l-hydroxymethyl-16,- 16-trimethylene-20-ethyl-13-trans-prosta- diene,1-ethylene ketal ..... . 1,9-dioxo-16-hydroxy-16-cyclopropyl-20- ethyl-1-hydroxymethy1-13-trans-prostene, 1-ethylene ketal 1,9-dioxo-16-hydroxy-16-vinyl-20-ethyl-1- hydroxymethyl-13-trans-prostene,1-ethy1- ene ketal 1,9-dioxo-16-hydroxy-16-cyclopropyl-1-hy- droxymethyl-13-trans-prostene,1-ethylene ketal 1 « X S5 t © rt I il y ss Έ 9B g ii a ι &§ 1 © in rt X , X Ο P rt x © rt Ο Ε P •rt ·Η © a ρ x t P © 1 © G rt rt © 1 *2 \O rt rt ti 1 © fs h P © a ι >»rt 5« 5 § g 8 ·&?· 5 s s© ro rt p 1 P Ο 1 w tn O rt •H , a rt t X © G a »rt rt > Vinyl Iodide or Vinyl Tin of Example 49 OS rt in |- 193 195 192 tc rt 210a © c 0 1 rt J G © 1 CM 1 P G © 0 O υ X CJ 283 283 tc 00 CM tc 00 CM 283 283 283 283 Method of Example 773 773 773 774 774 774 773 774 © Ϊ ro X ω 1106 1107 1108 1109 1110 1111 1112 1113 330 TABLE 46 (continued) 1,9-dioxo-l-hydroxymethy lprostene •dl-erythro-1,9-dioxo-15-hydroxy-16-methoxy-1-hydroxymethyl-13-trans-prostene,1ethylene ketal d1-erythro-1,9-dioxo-15-hydroxy-16-ethoxy1-hydroxymethyl-13-trans-prostene,1-ethylene ketal dl-erythro-1,9-dioxo-15,16-dihydroxy-1hydroxymethyl-20-nor-13-trans-prostene,1-ethylene ketal 1 1 © P ι tn feg © tn £§ © μ © P 1 1 tc © © * ( ΙΛ © © X i X OP© χ o rt o e p •rt J 4> © © 44 t CS Cl i 0 F © fi © X o ‘XT4 O P X μ a x x ε tt ρ X 4> X X l S2T 1 © fl) © x e © x o dl-erythro-1,9-dioxo-15,16-dihydroxy-1- hydroxymethy1-2 0-ethy1-13-trans-prost- ene,1-ethylene ketal dl-erythro-1,9-dioxo-15,16-dihydroxy-19- methyl-1-hydroxymethy1-13-trans-prost- ene,1-ethylene ketal dl-erythro-1,9-dioxo-15,16-dihydroxy-1- hydroxymethyl-13-trans-17-trans-pTOSta- diene,1-ethylene ketal ι υ x c X a 1 © © X I X X P X V 0 t μ © © * X fi •rt o © P > w o © μ * ft LO 1 © Ul r fi o rt χ μ O P •rl I Ό tC 1 © σι » * © «-» b 1 X O P © ω μ ε +j X rt 1 0 Ρ © μ ο © © 44 Vinyl Iodide or Vinyl Tin of Example 74 77 83 84 in co 98 87 1 69 Cyclopent-2-en-1-one 283 283 283 283 283 283 283 283 Method of Example 773 773 773 773 773 773 773 773 Example 1114 1115 1116 1117 1118 1119 . 1120 1121 331 8207 TABLE 46 (continued) .ρ ο 0 C rt O rt ft rt rt X χ χω s fi rt rt > > ft Ο B X « © tt CM fi I tt X P X w o o μ μ 0 ft X · X «Λ rt fi 0 « μ P I * en ΙΛ rt rt I O X X X o p rt rt tt rt 0 e p ι X tt © x • o rt μ ® 0 e X tt X rt I X rt 45 rt X I X feS S rt 0 A X tt X fi rt tt 0 P ( W © O -ι μ • ft rt χ ί ·$· tt rt B rt X Ρ X tt ο .X μ tt X fi X tt ι ι © P CM VJ I O X μ X I μ ω 0 S £S rt P 0 I I en \0 rt rt I m x rt X rt I P rt O tt P X S tt .a Ο tt ι H fi © 0 tt * X rt rt X X I __ rt P I tt rt I Xrt P tt tt c E tt © tn en Γα Γα - 332 48 207 TABLE 46 (continued) 1,9-dioxo-l-hydroxymethylprostene l,9-dioxo-16-hydroxy-1-hydroxymethy1-18,.19.20-trinor- 13-tTans-prostene, 1-ethylene ketal 1,9-dioxo-16-hydroxy-l-hydroxymethyl-20nor-13-trans-prostene,1-ethylene ketal 1 rt X rt X P o © £ * a x © X c 1 © rt rt 1 X rt X x p X © P 1 © rt 6 * 1 © K rt © I P X w X o O P $ Ϊ x to X s ι rt © P rt p 1 1 0 tn X rt O 1 •rt rt a x , X © p ft © rt g l,9-dioxo-16-hydroxy-20-methyl-l-hydroxymethyl-13-trans-prostene,1-ethylene ketal 1,9-dioxo-16-hydroxy-20-ethyl-l-hydroxymethyl-13-trans-prostene,1-ethylene ketal 1,9-dioxo-16-hydroxy-16-methyl-20-ethy1- 1-hydroxvmethyl-13-trans-prostene,1-ethyl- ene ketal rt ι rt tn p rt © ι X rt X © 5 § XX X P o © P k a rt X * X © 1 G rt © 1 «Η X’S x rt O P P w a o X P X 0 l i , Ό TO] rt «ri I • °1 o < X Ca O rt rt 1 a to 1 G © rt A p rt p ) rt X rt X P o © P X a X © X G 1 © rt rt I X rt X X P X © P 1 © rt © G rt © 1 P X «A 2 S •s ?· X w S © P rt p 1 1 o tn X rt O I tri rt a b , X © p A © rt g 1,9-dioxo-16-hydroxy-17,17,20-trimethyl- 1-hydroxymethyl-13-trans-porstene,1-ethyl- ene ketal 1,9-dioxo-16-hydroxy-16,20-dimethyl-l-hy- droxymethy1-13-trans-prostene,1-ethylene ketal Vinyl Iodide or Vinyl Tin of Example 109 110 rf rt 112 tn rt rt 139a UO rt rt 135 136 137 Cyclopent-2-en-1-one 283 tc co CM tc 00 CM 283 283 283 283 283 283 283 Method of Example 773 773 1 773 I 773 773 773 773 773 tc r- 773 Example © tc rt rt 1131 1132 1133 1134 1135 1136 1137 8EII 1139 333 8 2 0 7 r-l © X I £ X ι o rft b * 0 © X b X £ •rl © 0 ft I A Γ-» O rft b * P b· ι rft A ι G fcS O ft b p 0 tn Xrt x 2 I rt I ft © x ε o x •rl X 0 O ι b CD 0 * X O b· b rt 0 ► X A X C I A © b rft ft I I o tn X rri © O I G •rl rt © 0 Xrt t £ X σι ft £ * © 4-» rri £ © I fc.

O rt b · © X G £ © I rt rri 0 I A rt ft X A X p ft b © P ε ι I A © G CM A 1 b fcV O x b rt 0 I X A ί § © b . rri © I I 44 O tn Xrt© Ο I G •rl rri © 0 X rt I £ X σι ft £ * © ft rt ε © fcS o © I © rt rt I X rt 45 X ft £ © ft I I © © e rt © I ft fco s s.

I X A ? s © b rt ft tn X rt Ο ι rt rt Ύ j? r-ι ε A ft © I* X © •v § rt rt ’ b rt 43 Xft 43 © ft I © rt ε * rt © 0 C I © © ft CM A x 8 rt &, H s I rt © I rt rft I X O 43 X ft o © I X σι o * b rft 0 fcj, £ «Γ ί 3 rt β I ft rt A © I ° I d X I 0 X b rt 0 I Is ss Xrt© O t G rt rt © 0 Xrt I 43 X σι ft 45 * © ft rt g © TABLE 46 (continued) •H © 0 G Ο ·Η P H-l Η E A rft rft X X XU1 C G •rri ‘«ft > > σι fi © rft LfJ LO cm tn ld in fi in A CO fi tn eo PM tn oo CM tn CM tn oo CM tn a CM tn co CM tn CM tn oo CM G © P o u X u 4-> X © Ul s β X Ul tn r·. b. tn b. btn r— btn bb* tn bbtn bbtn bbtn bx - 334 4&207 TABLE 46 (continued) 1,9-dioxo-1-hydroxymethyIprost ene 1,9-dioxo-15a-hydroxy-1-hydroxymethyl13-trans-prostadiene,1-ethylene ketal 1 X© x rt O P μ rt © 44 X rt i C © rt 1 © SS 84 1 * © rt es s 1 rt X P X w o o μ μ © ft X I X rt i § ω μ © Ρ 1 1 0 to x © O 1 •rt © © X «AS -8 1,9-dioxo-15a-hydroxy-20-ethyl-1-hydroxymethyl-13-trans-prostene,1-ethylene ketal 1,9-dioxo-15a-hydroxy-16,16-dimethyl-1- hydroxymethyl-13-trans-prostene,1-ethyl- ene ketal 1,9-dioxo-ISa-hydroxy-17,17-dimethyl-1- hydroxymethyl-13-trans-prostene,1-ethyl- ene ketal 1,9-dioxo-15a-hydroxy-16-methy1-1-hydroxy- methyl-13- trans-prostene, 1-ethylene ketal Vinyl Iodide or Vinyl Tin of Exanple 1-iodo-3-triphenylmethoxy- 1-trans- P rt · CU i© b • © OT A0 A—' b co 43 * c ο P · υ o o z 1 - i odo- 3-1 r ipheny 1 methoxy-1-transnonene (U.S. Pat. No. 3,873,607). l-iodo-3-triphenylme thoxy-1-trans- decene (U.S. Pat. No. 3,873,607). l-iodo-3-triphenylmethoxy-4,4-dimethyl-1-transoctene (U.S. Pat. No. 3,873,607). l-iodo-3-triphenylmethoxy-5,5-dimethy1-1-tran soctene (U.S. Pat. No. 3,873,607). l-iodo-3-tripheny1- methoxy-4-methyl- 1-trans-octene (U.S. Pat. No. 3,876,690). Cyclopent-2-en-1-one 283 283 283 283 283 283 Method of Example 773 773 - - 773 773 773 tc b b a © fr rt X CU 01 τ- © © 1150 1151 1152 1153 1 Τ’ in © © 335 8 2 0 7 TABLE 46 (continued) 1,9-dioxo-1-hydroxymethylprostene 1,9-dioxo-15a-hydroxy-16-ethyl-l-hydroxymethyl-13-trans-prostene,1-ethylene ketal 1,9-dioxo-15a-hydroxy-17,2 0-tetranor- 16-cyclopentyl-1-hydroxyme thy1-13-trans- prostene,1-ethylene ketal 1,9-dioxo-15a-hydroxy-16,20 -pentanor-15- cyclohexyl-1-hydroxymethyl-13-trans- p rostene,1-ethylene ketal 1 rt 1 ί s o 3 §? p 0 1 rt O 1 CM rt • X rt 00 £ rt rt P P fc 0 C £5 3 f || tn rt os rt 1 1 I rt rt 0 X * X X 8 0 8 fi rt£ 8 0 α p 1 rt (fl © a o •Xfc rt 8 fi 1 1 00 tfl 7! si .SA 0 rt 1 1 © rt ass O p 8 fc fc fi 0 0« £££ l 1 rt a p 0 I « rt rt I A£1 O § fi rt fi 8 0 O P ι rt tr, ©80 • Xfc rt 8 fi Vinyl Iodide or Vinyl Tin of Example l-iodo-3-triphenylmethoxy-4-ethy11-trans-octene (U.S. Pat. No. 3,876,690) . l-iodo-3-triphenylmethoxy-4-cyclopen tyl-l-transbutene (U.S. Pat. No. 3,884,969). l-iodo-3-triphenylmethoxy- 3-cyclohexyl- 1-transpentene (U.S. Pat. No. 3,884,969). l-iodo-3-tripheny1- methoxy-5-cyclo- hexyl-l-trans- pentene (U.S. Pat. No. 3,884,969). l-iodo-3-tripheny1- methoxy-6-cyclo- pentyl-1- transhexene (U.S..Pat. No. 3,884,969).1 Cyclopent-2-en-l-one 283 283 283 283 283 Method of Example 773 773 773 773 0 Γ* Example 1155 1156 1157 . 1158 1159 336 TABLE 46 (continued) 1,9-dioxo-1-hydroxymethylprostene 1 Xrt X rt 0 P μ » 0 A A tt I fi <-4 tt ί rt rt X XX 53 I A in tt rt fi 1 tt XP X w O 0 μ μ 0 ft X 1 X ω 1 € a rt m μ rt i ι o tn X rt 0 1 •p irt 0 X 1 © p * 2 rt g 1 rt X X P 1 tt rt 1 A CM tt 1 s rt tt X p 5 2 ££ 1 1 tn w rt fi x 2 X P Ο ι μ tn 0 rt X ι X rt 1 8 X rt tn ρ p rt tt tt 1 Ε ,X 0 X X X tt O 0 c rt μ tt 0 0 rt l X X © XX A 1 p rt rt tt 1 fi 1 μ rt P X tt X P p 1 tt rt © £ fi CM XP A X tt © 0 46 ι-ι μ A0 tt 00 X fi rt X tt A J rt Pa rt X rt I X I XP X X tt X ο I p C rt μ tt * 0 X tt X ft fi X O tt ι μ p a o w in 3 O rt rt μ ι «Ρ ft x ij ω •rt © S 0 «-ι μ en L 1 a o tn rt C rt l,9-dioxo-15a-hydroxy-17,18,19,20-tetra- nor-16-phenoxy-1-hydroxymethyl-13-trans- prostene,1-ethylene ketal 1 1 tn fi rt μ ι P rt tt X P X 1 P © tt (Μ E a X rt ©Xrt rt Ο P α μ tt 60 0 x rt x *X tt Γ'* I fi rt rt tt I 1 rt XXX XXX OOP μ β tt 0 tt 1 XX rt < g-o a g fi in O tt rt μ p ι χ w ot.o χ ό4 μ o r ft •rt © I 0 rt tfl © μ j3 rt fi P 1,9-dioxo-15a-hydroxy-17,18,19,20-tetra- nor-16-p-t-butylphenoxy-l-hydroxymethyl- 13-trans-prostene,1-ethylene ketal ι i fi rt μ x P X tt P P tt i £3 CM X P A O tt © μ A rt 0 A X tt 00 X fi rt ι tt * rt rt t- ι X rt XX 1 X P X o o x c μ O tt rt μ x a 0 ft tt X X c X X tt ι Ο P a X tn in ρ o rt tt μ ι E ft ο », ι X fttfl o ‘'S •H © fi 0 rt μ 1 1 P © μ ι * o tn rt fi rt Vinyl Iodide or Vinyl Tin of Example 1-i odo-3-methyl-3trimethylsilyloxy-trans-1-octene (Example 12S). l-iodo-3-methyl-3trimethylsilyloxy-trans- 1-decene (Example 190a) . 159 186 181 I 182 183 Cyclopent-2-en-1-one 283 1 1 1 j 283 283 283 283 283 283 ι- Method of ι Example i_ 773 tn X fA 774 774 774 774 774 Example 1160 rt © rt irt 1162 1163 1164 m © rt •rt 1166 337 B 2 Π 7 TABLE 46 (continued) 1,9-dioxo-1-hydroxymethylprostene 1,9-dioxo-15a-hydroxy-17,18,19,20-tetranor-16-p- chlorophenoxy-1-hy droxyme thy113-trans-prostene,1-ethylene ketal l,9-dioxo-lSa-hydroxy-17,18,19,20-tetra- nor- m-tri f luorophenoxy-1-hydroxyme thy113-trans-prostene,1-ethylene ketal 1,9-dioxo-l5a-hydroxy-l7,18,19,20-tet ra- nor-16-(3,4-dichlorophenoxy)-1-hydroxy- methyl-13-trans-prostene,1-ethylene ketal 1,9-dioxo-15a-hydroxy-18,19,20-trinor-17- phenyl-l-hydroxymethyl-13-trans-prost- ene,1-ethylene ketal 1 1 rt X b rt 4 1 P P © o i .5 ass ι a © © XX CM X a 1 © © rt G rt | © A/—1 rt 60 rt X 5 c?5 - p >, ¢) XX G X P © > © P ω § S O 9 l x rt tn O rt rt A ι β tc G rt P X ό 5 ρ N.gS rt x « O © oo p G rt a © lb? O rt Ρ Ρ , © a t Xrt rt 5 & ® a © e tn x © rt 0P 1 x a oxo X 0 P OX 0 rt Ρ , a © w 1 e s © ι ,rt » oJp rt p 1 CM rt rt S* 8 x 5,5 5? rt rt 1 » X © g§ £S i ?· in to 0 P X P 0 , rt W a «ρ 4 ,» © P A O rt G rt rt P .8 h gl g &· 1 © rt 1 1 rt rt a X © 5 § w to 7 ί Ϊ1 •S P j?tc 1 rt fl ? tn P rt o 1 G O I X CM 0 1 rt rt © P • S rt e Vinyl Iodide or Vinyl Tin of Example 184 180 185 186b I86e P98T j 1 rt £ 1 © (/) X G .5-8 P P P » 1 rt tC t 1 X O X a o o X rt P 1 © rt £ octene (U.S. Pat. No. 3,873,607). S8I Cyclopent-2-en-l-one 283 283 283 283 283 283 310 310 Method of Example 774 774 774 774 . . 774 774 773 773 Example © rt rt 1168 1 1169 1170 1171 1172 tc r* rt rt 1174 338 TABLE 46 (continued) 1,9-dioxo-1-hydroxymethylprostene ( ( © * 1 rt © fi X « X P p tn rt o e μ • X cs rt 1 1 P a © rt ω xx © X 1 P rt o rt fi χ ε rt o x© •iM X X ©ox ι μ p σ> © rt * X J· © x © 1,9-dioxo-15a-hydroxy-16,16-trimethylene1-hydroxymethy1-2-nor-13-trans-prostene, 1-ethylene ketal erythro-1,9-dioxo-15a,16-dihydroxy-1-hydroxvmethy1-2-nor-13-trans-prostene,1ethylene ketal threo-1,9-dioxo-15α,16-dihydroxy-1-hydroxy- methyl-2-nor-13-trans-prostene,1-ethylene ketal fee 0 fi X rt P p rt tn ? 2 ό q © ι ι tn X fi x « ο μ μ ρ © ι Xtc X © a ιΛ Ο © C 1 I Ο CS X 1 © ο © rt •rt ΧΡ © X « 1 +> X oj 2 * e rt © X c ί X rt Ο 0 © μ μ χ feV ΐ rt © © 1 cs © ι rt © Ρ X rt X X Ρ rt rt £S X © O X μ x © P X rt X 1 1 © © A ι rt X c X rt O P μ tn © 0 X H x q t 1 \d tn © S ι rt ο μ X P Ο ι •H «C © © • J cn μ * o © fi © rt p rt X t rt X fi x rt o © μ x © X X p X rt 1 1 rM rM 1 F © rt x c X rt P P rt ra B δ ι μ \o q © 1 ι tn feS ο μ μ Ρ © ι Xtc X © 1 1 μ © 0 > fi O I x cs o t © © Ό X I X Oi P • rt © B 1,9-dioxo-16-hydroxy-16-methyl-1-hydroxy- methy 1-2-nor-13-trans-17-trans-prostadiene,1-ethylene ketal Vinyl Iodide or Vinyl Tin of Example 1-i odo-3-tripheny1methoxy-S,5-dime thy 1-octene (U.S. Pat. No. 3,873,607) . tc rM 76 69 74 107 130 Τ’ · tc © Cyclopent-2-en-1-one 310 310 310 310 310 310 285 285 Method of Example 773 | 773 773 773 773 tc b b 773 773 1 Example 1175 1176 1177 1178 1179 1180 1181 1182 339 8 2 0 7 TABLE 46 (.continued) 1,9-dioxo-1-hydro xyme thylpros tene 1 0 rt 1 1 o rt CM X *£ cn p rt 8 rt • B rt 00 χρ rt X 8 • O £ x fi rt Ό 8 • X β CM £ 8 1 1 rt Xrt X X « £ O X P fi X 8 0 O » X C rt £ 8 · t £ 8 a fi c 0 i 8 rt 0 P 1 rt w O 1 0 X fi fi 0 O fi rt C 1 0 rt W 1 P S © c rt - 8 fi rt CLP 1,9-dioxo-15a-hydroxy-2,17,18,19,20- pentanor-16-m-trifluoromethylphenoxy-l- hydroxymethyl-13-trans-prostene,1-ethylene ketal 1,9-dioxo-16-hydroxy-16-viny1-1-hydroxy- methyl-2-nor-13-trans-prostene,1-ethylene ketal 1,9-dioxo-16-hydroxy-16-cyclopropyl-1-hy- droxymethyl-2-nor-13-trans-prostene,-1- ethylene ketal 8 fi 8 O fi § 3 η fi ρ o< 8 I fi W i § CM fi • fi © 1 rt 0 • rt oo ι rt rt «£ 1 fi O X fi X 0 O x £ 3 £ 0 rt t Xfi a £ © 0 1 £ rt rt 1 1 8 O rt β X X 8 Ο P rt rt 8 X 0 £ £ » fi fi © t 8 • χ ι rt rt rt 1,9-dioxo-15a-hydroxy-2,18,19,20-tetranor- 17-(m-tri fluorophenyl)-l-hydroxymethyl-13- trans-prostene,1-ethylene ketal 1 fi o I e 0 nJ rt fi 1 fi rt vl © 8 N I rt * X rt © Xfi 18.3 00 0 rt X 8 *£ P CM 1 8 i rt rt fcAJs 8£S 0 C 1 sii i S c 0X8 rt O fi 1 £ W O fi p X 8 fi g B fi rt 1 , 1 0 I vrt β © i « *x fi rt rt fi is fi © X* ί s rt 8 Iv fi rt 8 * 1 8 0 β rt 8 1 fi Π j? e 0 fi rt fi 1 1 O 0 X rt O 1 rt rt 0 X 1 £ © P • 8 rt E Vinyl Iodide or Vinyl Tin of Example 180 194 198 1 186b 8 0 O0 rt 0 0 OO rt 2101 Cyclopent-2-en-1-one 2 85 2 85 285 285 285 285 285 283 Method of Example 774 773 774 774 0 x X 0 X x · 774 Example 1183 1184 1185 1186 1187 1188 1189 1189A* 339a TABLE 46 (continued) 1,9-dioxo-1-hydroxymethylprostene I 1,9-dioxo-16-hydroxy-16- ethynyl-1-hydroxymethyl-20 -nor-13- trans-prostene,1-ethylene ketal 1,9-dioxo-16-hydroxy-16- ethynyl - 1 -hydroxymethy 1 - 2 0 - e 1 thy 1 - 1 3- trans-prostene,1-ethylene ketal 1 zrt 1 rft rft X A £§ - §·£ b A CM p ι b rt CM ' I I A © C rt A ι b Xft X 1 Ο H) b rt 0 1 Xrt X ΧΤί 1 X A sss X X © 0 P G .«ft b © 0 0 rt ι X X Ol X X • 1 ft rft rri © 1 zrt rt |§ ss rt rt rt« I rt 1 rt A © Xft rri £ © 1 ft 44 X © X » © Q © G b cm © 0 1 rt Xrt X X XX t X ft © ft © rt © 1 i X X © 0 O G •κ b © 0 0ft t X A σι x p A t b rt 1—1 CU Vinyl Iodide or Vinyl Tin of Example 210P 210Q rt fi tn rt 0 fi in rt Cyclopent-2-en-1-one 283 283 283 283 Method of Example 774 774 tn b b 773 Example 1189B* 1189C* 1189D 1189E - 339b ^.8 2 07 EXAMPLES 1190-1212 By the methods described hereinabove in Examples 773 and 774, the 1,9-dioxo-l-hydroxymethyl prostene derivatives shown in Table 47 are prepared by the indicated method from the indicated vinyl iodide or vinyl tin compound and the indicated cyclopent-2-en-l-one.

In those cases where two diastereoisomers are formed in the conjugate-addition, only one of the diastereoisomers is listed in Table 47. It should be understood that the other diastereoisomer is also formed which in its nat and ent forms has an opposite (mirror image) configuration at the assymmetric carbon atoms on the β-chain (the chain containing etc.) tothat of the respective nat and ent forms of the listed diastereoisomer; both of these diastereoisomers are claimed in this invention as well as their component enantiomers . 340 48207 TABLE 47 1,9-dioxo-l-hydroxymethylprostene and its diastereomer rt ra P © © 1 fi © © rt rt A » X in »-* χ rt I P ι P © X o · X G rt O rt * P P © a p c X © © X P P 1 1 TO © © β rt CM p t * 0 0 © t X rt (Λ Ο · G .ρ oo ra a rt p I * P © x » • rt tC rt I rt ) © l· /rt, C rt P © X G rt X © X P X © a ρ £ fi © X sex ' rt o l ,P P ρ p a ra © x GlP x nat-(and ent)-l,9-dioxo-16-hydroxy-16,17t e t rame thy1ene-18,19,20-1 r inor-1-hydroxymethyl-13-trans-prostene, 1-ethylene ketal rt 1 ι ra 0 XP X X © O O .X •rt P a a © t X G © X © ft 1 rt rt rt >> 1 1 X /-> © P CQ G © © © t rt rt rt A X A 0 X © WPG rt © © i ,6 P Prt TO CP O © P P 1 0 a © » c rt w ra * fi m ra > rt μ Cd 1 P © X > rt x tc « © rt cn Ρ ι mart rt , .X X ρ 1 ι p ram © βί-i g nat-15S,16R-(and ent-15R,16S)-1,9-dioxo15-hydroxy-15,16-1 rime thy1ene-1-hyd roxymethy 1-13-trans-prostene, 1-ethy lene ketal nat-15S,16S-(and ent-15R,16R)-l,9-dioxo- 15-hydroxy-15,16-trimethylene-l-hydroxy- methy1-13-trans-prostene,1-ethylene ketal nat-(and ent)-1,9-dioxo-15-hydroxy-15,16- trimethylene-17,18,19,20-tetranor-l-hydroxy- methyl-13-trans-prostene,1-ethylene ketal nat-(and ent)-l,9-dioxo-15-hydroxy-15,16- pentamethylene-17,18,19,20-tetranor-l- hydroxvmethyl-13-trans-prostene,1-ethylene ketal nat-15S,17R-(and ent-15R,17S)-1,9-dioxo- 15-hydroxy-15,17-dimethylene-1-hydroxy- methyl-13-trans-prostene,1-ethylene ketal Vinyl Iodide or Vinyl Tin of Example 246 245 243 243 251 f*. rr CM 248 249 [ Cyclopent-2-en-l-one | of Example tc cc CM I 283 i 283 i 283 283 283 283 283 Method of Example 773 774 773 tc t*· 773 773 tc r>. t-s. tc t- Example 1190 rt © rt rt 1192 1193 1194 1195 © © rt rt 1197 341 TABLE 47 (continued) 1,9-dioxo-1-hydroxymethylprostene and its diastereomer nat-15S,17S-(and ent-15R,17R)-l,9-dioxo15-hydroxy-15,17-dimethylene-1-hydroxymethyl- 13- trans -prostene, 1-ethylene ketal 1 Xrt I X rt OOP χ μ © O 3 X •rt x 3 42 © 1 1 fi © rt © • I rt rt φ X 1 fi 42 /—S © P 3 rt © © X 1 rt XZ rt α μ a ci © © 3 £ C rt rt © ι, μ μ μ μ ω c © ο © μ Η ι cu 3 © ι fi rt tf) « * C · 3 rt ι ah μ aZ ι μ © X ι rt X 3 * 0 rt 3 μ ι 3 3 rt rt X x 1 ,42 42 μ ι μ rt 3 © e|rt ε nat-15S, 16S-(and ent-15R, 16R)-l,9-dioxo- 15-hydroxy-15,16-tetramethylene-1-hydroxy- me thy 1-1 3- trans -prostene, 1-ethylene ketal nat-15R,16S-(and ent-15S,16R)-l,9-dioxo- ] 15-hydroxy-15,16-trimethylene-16-(3-tri- j fluoromethylphenoxy)-17,18,19,20-tetranor- 1-hydroxymethyl-13-trans-prostene,1-ethylene ketal f iA ό 8 μ μ 3 η ι ο χ η ο a χ ρ X rt 1 © ο <μ η λ id 'Η J 3 μ μ © 1 Ρ ο β © ι G © • 3 rt rt γΗ £ Ζ-'© © Ρ 3 rt ρ © © 1 1 ί rt © Ο rt • β CM * 3 © * © 3 rt © fi . rt Xrt © 1 ,Χ * P μ P CO rt fil © rt P © ε «μ '«H p· 3 μ rt Γ β p 1 2 rt ι β ’*-'© X ra ι rt χ μ BS · O P © 3 G 1 rt rt © 3 • 1 rfj rt OS X CM f 3 X rt rt rt O X X ι ,μ 4= x μ 3 Ρ Ρ ra X© © clx ε ε 1 3 *7 ι ι rt SSfeS Ο Ο ρ Λ SSv « σι ι Js § ι-f>24 >, Λ>ό i $ α μ ο ο \e ι β ι η « a im « δ μ a W © P © 3 rt © fi rt X p © 1 ,42 ι P Ρ P G $ fi © CM O © Β Α μ e-fiS 5 §Y«fS *rt© rt rt ι rt α μ 3 · P © 3 rt I rt rt 1 M • I trtrt es χ x 3 g X rt rt Ο Ο X ι ,μ c x pre © p rt xx © GIX cu£ Vinyl Iodide or Vinyl Tin of Example 250 252 253 254 255 256 Cyclopent-2-en-1-one of Example 283 283 283 283 1 ί 283 283 Method of Example 773 773 773 774 Γ* r* 773 © aH CU ε rt X UJ 1198 1199 1200 1201 1202 1203 342 TABLE 47 (continued) 0 § © fi © ft A O b si Is X .κ © 0 b 0 A X ft 43 .rl 1 rri t 0 X o rt 0 1 Ol rri t o b rri ι O I A 0 3 Xft X rri X © o Mri O At •Η I b 0 fi 0 © , ' X fi oi 1 X © a \Q Irt rt rt rri 1 1 1 X © b ft Vi fi O © ©©fil rri rri TO rri * X b * W X ft © in ft © fi rt © 4J © ι ,B i· ft ftrt © w fi b cm 0 ©|ft a b t Ol CM 0 © rri 1 firt * A A -00 fi w in rt A I rt * b 05 ι ft 5 K S x 1 in 0 x τ* rt xo X I ,x c X ftl ι © ft a m x © Cjrt fi, ε nat-1SR,16S-(and ent-15S,16R)-l,9-dioxo15-hydroxy-15,16-trimethylene-16-(3chlorophenoxy)-17,18,19,20-tetranor-lhvdroxymethyl-13-trans-prostene,1-ethylene ketal © c 1 © o rt X 1 X O rt 45 rt ( I ft 0 tn b © 1 'rt Ο 1 O) 1 fi rt A© A A rt rt b © 1 1 ft fi rri © © © to C ft ft © © 1 A rt rt © O * Xcm b cn x * fi. m ft οι ι rt © rt V) i,6 * fi ft Irt CO A fi b rt b ©ft a 44 ' 1 b J 0 © r-ι tn fi rt » rt A \ I «—'in Xrt 1 rt x x 05 1 o X © X fi ft rt X © © • Ο X E 05 b CM X in 0 o x rt X b p rt ι x O b A ft l rt 0 ft Am x x © C|rri © 43 44 © c 1 © b rri ι 0 X 0 fi X X rt ft o 0 © rt » 1 0 © rt 1 CM * Cl A © A CD fi rt rt © 1 1 ft r-s © A cn c p b rt b rt © fi, A X 1 05 X A in ft c rt © A t ,E b ftrt ft fib i © ft to I rt 0 b ι C rt rt A a X rt' m x 1 rt ft 05 I © b X S rt X X A 0 X cn b p m 0 b rt X0 rt ι ,Χ X a ft | ι X ft Ami© fi rri rt 44 A ft 1 © rt 44 1 b © ι o fi O fi © X rt rt 0 © © 1 CM 1 σι *rt AQ) * rt rt © 1 f fi Zrt © © 05 fi ft b © A rt rt 0 * X b 05 X fi. in ft ι rt © A i,B C ftrt A fib b © ft ft 1 1 0 b tn fi rt rri A A 1 v-'m rt 1 rt X cn ι x b >> ft rt x © A ο E cn b X in 0 X rt X O ι ,X b •Ρ 1 0 Aim X c|rt X rt A ft 1 © © l 44 rt X I X © O 1 c Xrt© 0 1 rt •rl rt X 0 XX 1 X ft O) ft © A Vinyl Iodide or Vinyl Tin of Example 257 25 8 σι ιΛ CM 260 rt © CM 262 Cyclopent-2-en-1-one of Example 283 284 283 283 283 I 283 ‘ Method of Example 773 774 774 773 773 774 1 Example 1204 1205 1206 1207 1208 1209 343 48297 1,9-dioxo-1-hydroxymethylprostene and its diastereomer nat-16R,17R-(and ent-16S,17S)-1,9-dioxo16-hydroxy-16,17-trimethylene-20-methy11-hydroxymethyl-13-trans-prostene,1-ethylene ketal nat- 16R, 17S-(and ent-16S ,17R) -1,9-dioxo- 16-hydroxy-16,17-trimethylene-16-(3-tri- fluoromethylphenoxy)-18,19,20-trinor-1- hydroxymethyl-13-trans-prostene,1-ethyl- ene ketal 1 1 1 0 «rl 1 © χ C © x ο p t x •rl 1 μ P © W 0 rt ι a-* e ι σ> ι © © *\o μ · © © P rt ι ι ι e rt o rt OT fi Ν P b o * w © © OJ 0 * hi OT X * ft \O P 60 i © rt © ra ι, e ι g P © ©A rt C Η χ H « P K P 0 I © b fi w c © rt © 3 *χ ι Α—'Ό ft© Λ © Τ' X ed ι XX b XX p © XP rt © •a o rt s rt ed μ ε xp AO © O X rt © χ μ ο X ι ,χ ο μ P l fi © rt rt Ko © x c c © m x rt Vinyl Iodide or Vinyl Tin of Example 263 264 26S Cyclopent-2-en-1-one of Example 283 283 283 Method of Example 774 774 1 i_ 774 Example 1210 1211 1212 343a - 48207 Example 1213 l,9-Dioxo-lla,16-dihydroxy-16-vinyl-l-acetoxymethyl-5-cis15-trans-prostadiene To a solution of 0.1 g of l,9-dioxo-lla,16-dihydroxy16-vinyl-1-hydroxymethyl-5-cis-13-trans-prostadiene in 0.75 ml of pyridine is added 0.026 g of acetic anhydride. After standing overnight, the pyridine is removed at reduced pressure. The residue is chromatographed on a dry column of silica gel eluting with benzene-ethylacetate 1:1 to give 0.049 g of the product.

In accordance with the above example 1213 the 1hydroxymethyl analogs of Examples 319-772AAA and are treated with acetic anhydride, propionic anhydride, n-butyric anhydride and n-valeric anhydride to give the respective 1-acetoxymethyl 1-propanoyloxy, 1-n-butanoyloxymethyl, and 1-n-pentanoyloxymethyl analogs. - 344 48207 Example 1214 Preparation of l-oxo-98,11a,16-trihydroxy-l-hydroxymethyl16-vinyl 13 trans-prostene and l-oxo-9a,lla,16-trihydroxy-l -hydroxymethyl-16-vinyl 13-trans prostene To a solution of 2.9 g (5.6 mmol) of (E) 4-trimethylsilyloxy-4vinyl-l-tri-n-butylstannylacetene (Fx. 210a) in 4 ml of tetrahydrofuran at 78°C under argon with stirring is added 2.4 ml of 2.4M n-butyllithium in hexane. The solution is stirred at -30° to -20°C for 2 hrs. A solution of .74 g (5.6 mmol) of copper pentyne and 2.3 ml of hexamathylphosphorous10 triamide in 18 ml of ether is added at -78°C. The solution is stirred at -78°C for 1.5 hr. A solution of 2.0 g (5.2 mmol) of l-[6-(4-methoxy-2,2dimethyl-l,3-dioxolan-4-yl)hexenyl]-4-(2-methoxypropyl-2-oxy)cyclopent-2en-1-one in 20 ml of ether is added. The solution is stirred at -30° to -20° for 1.5 hr. To the solution is added 100 ml of saturated ammonium chloride. The mixture is extracted with ether and the ether solution is washed with dilute hydrochloric acid, saturated sodium bicarbonate, and dried over magnesium sulfate. Dry solvent is removed and the residue is dissolved in 30 ml of ethanol and .37 g of sodium borohydride is added.

The mixture is stirred for 8 hrs. The solvent is removed. The residue is dissolved in 90 ml of acetic acid-tetrahydrofuran - water 4:2:1. The solution is stirred at room temperature for 2 hrs. The solvents are moved at reduced pressure. The residue is chromatographed on silica gel to give l-oxo-98,11a,16-trihydroxy-1-hydroxymethyl-16-vinyl-13-trans-prostene and l-oxo-9a,11a,16-trihydroxy-1-hydroxymethyl-16-vinyl-13-transprostene.

By the methods described hereinabove in Example 1214 the vinyl iodides or vinyl tin compounds used in Examples 319-772AAA are exchanged with t-butyi lithium or n-butyllithium respectively to give the vinyl - 345 lithium reagents which on reaction with copper pentyne and hexamethyl phosphorous triamide give the cuprate reagents. Addition of the cyclopent-2-en-l-ones used in Exanples 319-772GG at -78° followed by warming to -20° as described hereinabove in Example 1214 gives the 9-oxo analogs in which the 1-oxo feature is still protected. The reaction of these with sodium borohydride in ethanol followed by deblocking with acetic acid tetrahydrofuran-water 4:2:1 or with dilute hydrochloric acid in tetrahydrofuran gives l-oxo-96-hydroxy and l-oxo-9a-hydroxy analogs corresponding to the 1,9-dioxo analogs of Examples 319-772AAA.

Example 1215 Preparation of l-oxo-9q,11a,16-trihydroxy-1-hydroxymethyl -16-methyl-13-trans prostene To a solution of 3.4 (0.00675 mol) of (E) 4-trimethylsilyloxy 4-methyl-l-tri-n-butylstannyloctene (Example 210b) in 3.5 ml of tetrahydrofuran at -78° under argon, with stirring is added 2.8 ml (0.00675 mol) of 2.4 M n-butyllithium in hexane. The solution is maintained at -15° to -20° for 2.5 hrs. A solution of 0.89 g (0.00675 mol) of copper pentyne and 2.2 g of hexamethyl phosphorous triamide in 25 ml of ether is added at -78°. After 1 hr, a solution of 2.3 g (0.005 mol) of 1-(820 dimethyl-t-butylsilyloxy-7-oxooctenyl)-4-trimethylsilyloxycyclopent-2-enl-one,7-ethylene ketal in 10 ml of ether is added. The mixture is stirred at -45° for 0.5 hr. and allowed to warm to -20° over 40 min. The solution is reeooled to -30° and 2.5 ml of acetic acid followed by saturated ammonium chloride is added. The mixture is extracted with ether. The ether layer is worked with dilute hydrochloric acid followed by saturated sodium bicarbonate. The solution is dried over magnesium sulfate. The solvent is removed. The residue is dissolved in 10 ml of ether - 346 48207 at -78° under argon with stirring is added 20 ml (0.01 mol) of 0.5 M lithium perhydro-9B-borophenolyhydride in tetrahydrofuran. The solution is allowed to warm to 0° over 35 min. At 0° is added 8 g of sodium carbonate in 60 ml of water followed by 13 ml of 30% hydrogen peroxide. The mixture is stirred for 10 min. and then extracted with ether. The ether solution is washed with water, saturated sodium bisulfite, and saturated sodium bicarbonate. The solution is dried by magnesium sulfate. The residue is dissolved in 60 ml of tetrahydrofuran containing 9.6 ml of water and 1.2 ml of concentrated hydrochloric acid. The solution is stirred at 55°-60° for 4 hrs. 45 min. The mixture is saturated with sodium chloride and extracted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate and dried over magnesium -sulfate. The solvent is removed. The residue is chromatographed on a dry column of silica gel eluting with ethyl acetate containing 4% of methanol to give the title compound.

By the methods described hereinabove in Example 1215 the vinyl iodides or vinyl tin compounds used in Examples 319-772AAA are exchanged with t-butyllithium or n-butyl lithium respectively to give the vinyl lithium reagents which on reaction with copper pentyne and hexamethyl phosphorous triamide give the cuprate reagents. Addition of the cyclopent-2-en-l-ones used in Examples 319-772AAA at -78° followed by warming to -20° as described hereinabove in Example 1214 gives the 9-oxo analogs in which the 1-oxo feature is still protected. The reaction of these with lithium perhydro-9B-boraphenolyhydride at -78° followed by warming to 0°, quenching with sodium carbonate and hydrogen peroxide and deblocking with acetic acid-tetra- 347 » 4 8 3 0 7 hydrofuran-water 4:2:1 or with dilute hydrochloric acid in tetrahydrofuran gives the l-oxo-9n-hydroxy analogs corresponding to the 1,9-dioxo analogs of examples 319-772AAA.

Example 1216 Preparation of l-oxo-9a,lla,16-trihydroxy-hydroxyinethyl16-methyl-13-trans prostene, 1-ethylene ketal and 1-oxo9g,llo,16-trihydroxy-l-hydroxymethyl-16-niethyl-13-trans prostene,1-ethylene ketal.

To a solution of 0.1 g. of l,9-dioxo-llo,16-dihydroxy-l-hydroxymethyl-16-methyl-5-cis,13-trans-prostadiene, 1-ethylene ketal (Example 774) in 25 ml of ethanol is added 0.1 g. of sodium borohydride. After stirring 3 hr. the mixture is poured into water and extracted with ethyl acetate. The ethyl acetate solution is dried over magnesium sulfate. The solvent is removed and the title compounds are separated by silica gel chromatography.

By the method described hereinabove in example 1215 the 1,9-dioxo,1-ethylene ketal analogs of examples 775-1212 are reacted with an excess of sodium borohydride in ethanol to give the corresponding 9^-hydroxy-l-ethylene ketal and 9g-hydroxy-l-ethylene ketal analogs.

Example 1217 Preparation of 1,9-dloxo-16-hydroxy-l-hydroxymethyl-16methyl-10,13-trans-prostadiene.

To a solution of 0.1 g of 1,9-dioxo-lla,16-dihydroxyl-hydroxymethvl-16-methvl-13-trans prostene in 4 ml of tetrahydrofuran is added 2 ml of 1.5N hydrochloric acid. After 2 days the mixture is poured into water and extracted with ether. The ether solution is dried over magnesium sulfate and the ether is removed to give title compound. 348 8 2 0” Example 1218 Preparation of 1,9-dioxo-16-hydroxy-l-hydroxymethyl-16methyl-10,13-trans-prostadiene-l-ethylene ketal To a solution of 0.1 g of 1,9-dioxo-11a,16dihydroxy- 1-hydroxymethyl-16-methyl-13-trans prostene-1ethylene ketal in 4 ml of tetrahydrofuran is added 2 mi of 1.5 N hydrochloric acid. After 2 days the mixture is poured into water and extracted with ether. The ether solution is dried over magnesium sulfate and the ether is removed to give the title compound.

Example 1219 Preparation of l,9-dioxo-16-hydroxy-l-acetoxymethyl-16methyl-10,13-trans-prostadiene.

To a solution of 0.1 g of l,9-dioxo-16-hydroxy1-hydroxymethyl-16-methyl-10,13-trans-prostadiene (Example 1214) in 0.75 ml of pyridine is added 0.026 g of acetic anhydride. After 18 hrs. at room temperature, the solvent is removed at reduced pressure and the residue is chromatographed on silica gel to give the title compound.

By the method described hereinabove in Examples 1218 and 1219 the lla-hydroxy analogs of Examples 319-1213 are treated with 1.5 N hydrochloric acid in tetrahydrofuran for 2 days to give the corresponding Δ10 compounds of this invention. - 349 48207 Example 1220 Preparation of l-oxo-98,lXa,16-trihydroxy-l-hydroxymethyl16-vinyl-5-cis-13-trans-prostadiene and 1-οχο-9α,11α,16-trihydroxy- 1-hydroxymethyl- 16- vinyl-5-cis-15-trans-prostadiene To a solution of 2.9 g (5.6 mmol) of (E) 4-trimethylsilyloxy-4vinyl-l-tri-n-butylstannyloctene (Ex. 210a) in 4 ml of tetrahydrofuran at 78°C under argon with stirring is added 2.4 ml of 2.4 M n-butyllithium in hexane. The solution is stirred at -30° to -20°C for 2 hrs. A solution of .74 g (5.6 mmol) of copper pentyne and 2.3 ml of hexaethylphos10 phoroustriamide in 18 ml of ether is added at -78°C. The solution is stirred at -78°C for 1.5 hrs. A solution of 2.0 g (5.2 mmol) of l-[6(4-*methoxy-2,2-dimethyl-l,3-dioxolan-4-yl(hex-2-enyl]-4-(2-methoxypropyl2-oxy)cyclopent-2-en-1-one in 20 ml of ether is added. The solution is stirred at -30° to -20° for 1.5 hrs. To the solution is added 100 ml of saturated ammonium chloride. The mixture is extracted with ether and the ether solution is washed with dilute hydrochloric acid, saturated sodium bicarbonate, and dried over magnesium sulfate. Dry solvent is removed and the reisdue is dissolved in 30 Ml of ethanol and .37 g of sodium borohydride is added. The mixture is stirred for 8 hrs. The solvent is re20 moved. The residue is dissolved in 90 ml of acetic acid-tetrahydrofuran water 4:2: 1. The solution is stirred at room tenperature for 2 hrs. The solvents are moved at reduced pressure. The residue is chromatographed on silica gel to give l-oxo-98,lla,16-trihydroxy-l-hydroxymethyl 16-vinyl5-cis-3 trans-prostadiene and l-oxo-9a,lla,16-trihydroxy-l-hydroxymethyl16-vinyl-5-cis 13 trans-prostadiene.

By the methods described hereinabove in Example 1220 the vinyl iodides or vinyl tin conpounds used in Examples 319-772AAA are exchanged with t-butyl lithium or n-butyllithium respectively to give the vinyl lithium reagents which on reaction with copper pentyne and hexamethyl phos30 phorous triamide give the cuprate reagents. Addition of the cyclopent-2- 350 4 8 2 0 7 en-l-ones used in Example 319-772AAA at -78° followed by warming to -20° as described hereinabove in Example 1214 gives the 9-oxo analogs in which the 1-oxo feature is still protected. The reaction of these with sodium borohydride in ethanol followed by deblocking with acetic acid tetrahydrofuranwater 4:2:1 or with dilute hydrochloric acid in tetrahydrofuran gives 1oxo-9B-hydroxy and l-oxo-9a-hydroxy analogs corresponding to the 1,9-dioxo analogs of Examples 319-772AAA.

Example 1221 Preparation of l-oxo-9q,11a,16-trihydroxy-1-hydroxymethyl -16-methyl-5-cis-13-trans-prostadiene To a solution of 3.4 (0.00675 mol) of (E) 4-trimethylsilyloxy 4methyl-l-tri-n-butylstannyloctene (Example 210b) in 3.5 ml of tetrahydrofuran at -78° under argon, with stirring is added 2.8 ml (0.00675 mol) of 2.4 M n-butyllithium in hexane. The solution is maintained at -15° to -20° for 2.5 hrs. A solution of 0.89 g (0.00675 mol) of copper pentyne and 2.2 g of hexamethyl phosphorous triamide in 25 ml of ether is added at -78°. After 1 hr., a solution of 2.4 g (0.005 mol) of l-(8-dimethyl-t-butylsilyloxy-7-oxooct-2-enyl)-4-trimethylsilyloxycyclopent-2-en-l-one,7-ethylene ketal in 10 ml of ether is added. The mixture is stirred at -45° for 0.5 hr. and allowed to warm to -20° over 40 min. The solution is recooled to -30° and 2.5 ml of acetic acid followed by saturated ammonium chloride is added. The mixture is extracted with ether. The ether layer is worked with dilute hydrochloric acid followed by saturated sodium bicarbonate.

The solution is dried over magnesium sulfate. The solvent is removed.

The residue is dissolved in 10 ral of ether at -78° under argon with stirring is added 20 ml (0.01 mol) of 0.5 M lithium perhydro-98-borophenolhydride in tetrahydrofuran. The solution is allowed to warm to 0° over - 351 48207 min. At 0° is added 8 g of sodium carbonate in 60 ml of water followed by 13 ml of 30% hydrogen peroxide. The mixture is stirred for 10 min. and then extracted with ether. The ether solution is washed with water, saturated sodium bisulfite, and saturated sodium bicarbonate. The solution is dried of magnesium sulfate. The residue is dissolved in 60 ml of tetrahydrofuran containing 9.6 ml of water and 1.2 ml of concentrated hydrochloric acid. The solution is stirred at 55°-60° for 4 hrs. 45 mins. The mixture is saturated with sodium chloride and extracted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed. The residue is chromatographed on a dry column of silica gel eluting with ethyl acetate containing 4° of methanol to give the title compound.

By the methods described hereinabove in Example 1221 the vinyl iodides or vinyl tin compounds used in Examples 319-772AAA are exchanged with n-butyllithium or n butyl lithium respectively to give the vinyl lithium reagents which on reaction with copper pentyne and hexamethyl phosphorous triamide give the cuprate reagents. Addition of the cyclopent-2-en-lones used in Exaiqdes 319-772AAA -78° followed by warming to -20° as described hereinabove in Example 1214 gives the 9-oxo analogs in which the 1-oxo feature is still protected. The reaction of these with lithium perhydro-98-boraphenolylhydride at -78° followed by warming to 0°, quenching with sodium carbonate and hydrogen peroxide and deblocking with acetic acidtetrahydrofuran-water 4:2:1 or with dilute hydrochloric acid in tetrahydro- 352 48207 furan gives the l-oxo-9 hydroxy analogs corresponding to the 1,9-dioxo analogs of Examples 319-772AAA.

Example 1222 Preparation of l-oxo-9a,lla,16-trihydroxy-l-hydroxyTnethyl16-methyl-5-cis-13-trans-prostadiene, 1-ethylene ketal and 1-oxo-9B,11a,16-trihydroxy-l-hydroxymethyl-5-cis-16-methyl-13-trans-prostadiene,1-ethylene ketal To a solution of 0.1 g of 1,9-dioxo-lla,16-dihydroxy-l-hydroxymethyl-16-methyl-5-cis-13-trans prostadiene, 1-ethylene ketal (Example 774) in 25 ml of ethanol is added 0.1 g of sodium borohydride. After stirring 3 hrs. the mixture is poured into water and extracted with ethyl acetate. The ethyl acetate solution is dried over magnesium sulfate. The solvent is removed and the title compounds are separated by silica gel chromatography.

By the method described hereinabove in Example 1222 the 1,9dioxo, 1-ethylene ketal analogs of Examples 773-1212 are reacted with an excess of sodium borohydride in ethanol to give the corresponding 9a-hydroxy1-ethylene ketal and 96-hydroxy-1-ethylene ketal analogs.

Example 1223 Preparation of 1,9-dioxo-16-hydroxy-1-hydroxymethy1-16 20 methyl-5-cis-10,13-trans-prostatriene To a solution of 0.1 g of 1,9-dioxo-lla,16-dihydroxy-1-hydroxymethyl-lb methyl-5-cis-13-trans prostadiene in 4 ml of tetrahydrofuran is added 2 ml of 1.5 N hydrochloric acid. After 2 days the mixture is poured into water and extracted with ether. The ether solution is dried over magnesium sulfate and the ether is removed to give the title compound.

Example 1224 Preparation of 1,9-dioxo-16-hydroxy-l-hydroxymethyl-16methy 1-5- cis- 10, 13- trans-prostatriene-l-ethylene ketal.

To a solution of 0.1 g of 1,9-dioxo-lla,16-dihydroxy-l-hydroxy353 48307 methyl-16-methyl-5-cis-13-trans prostadiene-l-ethylene ketal in 4 ml of tetrahydrofuran is added 2 ml of 1.5 N hydrochloirc acid. After 2 days the mixture is poured into water and extracted with ether. The ether solution is dried over magnesium sulfate and the ether is removed to give the title compound.

Example 1225 Preparation of l,9-dioxo-16-hydroxy-l-acetoxymethyl-16methyl-5-cis-10,13-trans-prostatriene To a solution of 0.1 g of 1,9-dioxo-16-hydroxy-1hydroxymethyl-16-methyl-5-cis-10,13-trans-prostatriene in 0.75 ml of pyridine is added 0.026 g of acetic anhydride.

After 18 hrs. at room temperature, the solvent is removed at reduced pressure and the residue is chromatographed on silica gel to give the title compound.

By the method described hereinabove in Examples 1223 and 1224 the lla-hydroxy analogs of Examples 319-1213 aTe treated with 1.5 N hydrochloric acid in tetrahydrofuran for 2 days to give the corresponding Δ10 compounds of this invention. - 354 4-8 2 07 EXAMPLE 1226 Preparation of 1,9-dloxo-llX,16-dihydroxy-16methyl-1-hydroxymethy1-13-trans-prostene by hydrogenation of 1,9-dioxo-lL6 lg-dlhydroxy-lg-siethyl1-hydroxymethy1-5-cls, 13-trans-prostadiene A «elution of l,9-dioxo-ll»i,16-dihydroxy-16’· methyl-1-hydroxymethy1-5-cls,13-trans-prostadiene in CH2C12 at 0° is treated with 3.3 equivalents of dihydropyran and a catalytic amount of chloroacetic acid. After 2 hours, solid XHCO3 is added, the solution is filtered, and concentrated in vacuo to provide 1,9-dloxo-ll«Z, 16-bistetrahydropyranyloxy-l-tetrahydropyranyloxymethyl-16-methyl-5-cis, 13-trans-prostadiene.

The tritetrahydropyranyl derivative is dissolved in methanol and hydrogenated at -15 to .-20* under 1 atm of hydrogen with 5% palladium-on-carbon as discribed by Corey, J.A.C.S., 92, 2586 (1970).

The reaction product is isolated and subjected to hydrolysis in acetic acid-water-THP (20:10:5) at 40*C for 4 hours. Reisolation and chromatography on ailica-gel (impregnated with AgN03 if necessary), provides 1,9-dioxo1L<16-dihydroxy-16-methyl-l-hydroxymethyl-13-trans prostene.

Other suitable protecting groups are derived frcm dihydrofuran, ethylvinylether, methoxy-5,6-dihydro-2Hpyran,chloromethylmethylether, chloro-triloweralkyl* silane and the like. 355 EXAMPLE 1227 In accordance with the partial hydrogenation procedure of Example 1226, the corresponding Ej aeries compound may he prepared from the B2 aeries compounds of Examples 319-1213. Also, in accordance with procedure of Example 1226, the F28eries compounds described in Examples 1220-1222, may be partially hydrogenated to provide the corresponding Fj BerieB compound.

EXAMPLE 1228 Preparation of l,9-dioxo-ll«<,16-dlhydroxy16-methyl-l-hydromethyl-13-trans-prostene frcm the corresponding F,< congener.

To a solution of l-oxo-9*<,ll»<,16-trihydroxy-lhydroxymethyl-16-methyl-13-trans-pro»tene (EX. 1215) in dry acetone at -40* is added N-triaethylsilyldiethylamine according to the procedure of Yankee, Lin and Fried, J. Chem. Soc., 1121 (1972).

The reaction mixture is diluted with water and extracted with ether; the ether is dried and concentrated in vacuo to provide i-oxo-13»(-triinethylsilyloxy-9g<,16dlhydroxy-l-trlmethylsllyloxymethyl-13-trans-prostene.

The bissilylated material is oxidized with collens reagent in situ (prepared from CrOj and pyridene in CHjClj) according to the above reference for 5 min. at 25*.followed by desilylation with a mixture of methanol, water and acetic acid (lt 0.1: 0.05) for 1 hour.

The solvent ia removed in vacuo and the product is purified on ailica-gel, to provide 1,9-dioxo-ll^, 16-dihydroxy16-methvl-l-hvdroxvmethvl-13-trana-proiten<. 356 . 48207 EXAMPLE 1229 Preparation of 1,9-dioxo-!!»<, 16-dihydroxy-1hydroxymethyl-13-tranB prostene frcn 1-oxofi,-ll»416-trihydroxy-l-hydroxymethyl-16-methyl13-trans prostene, 1-ethylene ketal.

To solution of l-oxo-9<4 11.416-trihydroxy-l-hydroxymethyl-16-methyl-13-trans-prostene, 1-ethylene ketal, (Ex. 1216) in dry acetone at -40* is added N. trimethylsilyldiethylamine according to the procedure of Yankee, Lin and Fried, J. Chem. Soc., 1121 (1972).

The reaction mixture is diluted with water and extracted into ether; the ether is dryed and concentrated in vacuo to provide l-oxo-9o4l6-trihydroxy-lfi-trlntethylBilvloxv-l-trlmethvlsilvloxvmethyl-16-methyl-13-tran8prostene, 1-ethylene ketal.

This 9k-hydroxy derivative is oxidized by the procedure of the above reference utilizing Collins reagent (prepared in situ from CrO3, and pyridine in CH2C12 ).

After 5 min. at 25*, desilylation is accomplished with a mixture of methanol, water, acetic acid (l* 0.01: 0.05) containing a catalytic amount of HCL, for 1 hour.

The solvents are concentrated in vacuo and the residue is purified by silica-gel chromatography to provide 1,9-dioxo-llei, 16-dihydroxy-16-methyl-l-hydroxymethyl-13-transprostene. 357 48307 EXAMPLE 1230 In accordance with tha procedure of Exanple 1228 the corresponding E^-aeries compound nay be prepared from the Fi-aeriea compound· described in Examples 1214- 1216. s Also in accordance with the procedure of Example 1228, the corresponding E2-series compounds may be prepared from the P2 -series compounds described in Examples 1220-1222.

EXAMPLE 1231 10 In accordance with the procedure of Example 1229, the corresponding Ej-series ethylene ketal or dioxolan compound may be prepared from the P^-aeries ethylene ketal or dioxolan compounds described in Examples 1214-1216.

Also, in accordance with the procedure of Example 1229, the corresponding E2-series ethylene ketal or dioxolan compound may be prepared from the P2-series ethylene ketal or dioxolan compounds described in Examples 1220-1222. ,20 ί 358.

Example 1232 Preparation of 1,9-dioxo-lla. l€-dlhydroxy-16-methyll-hydroxymethyl-proatane from 1,9-dioxo-lla, 15-dlhydroxy16-methyl-l-hydroxvmethyl-5-clB-13-tranB-prosta&ien· A solution of 1,9-dioxo-lla, 16-dihydroxy-16-methyl-lhydroxymethyl-5-eis-13-trans-prostadlene in 50 ml of ethyl acetate may be completely hydrogenated in a Parr apparatus using 500 mg of 52 rhodium-on-carbon. The catalyst is removed by filtration and the filtrate is taken to dryness to furnish the title product.

Example 1233 In accordance with the hydrogenation procedure of Example 1232 the Ej, Ej, Pj or Fj prostaglandin derivatives of Examples 319-1231 herein may be hydrogenated to provide the corresponding Ee and Fo prostaglandin derivative. f 359.

EXAMPLE 1234 PREPARATION OF 1.9-PIOXCh~llB<.16-DIHYnROXY-l-p?_ METHOXYBENZOXXMETHYL-16-METHXL-13-TRANS-PROSTENE To a mixture of 200 mg of l,9-dioxo-ll«<,16-dihydroxyl-hydroxymethyl-16-methyl-13-trans-prostene and 89,2 mg (1 eg) of ^-anisoyl chloride is added 2 ml of dry pyridine. After agitation to complete dissolution, the solution is allowed to stand at ambient temperature for two hours. The solution is applied directly to a silica-gel dry column (31” χ 1”) and developed with ethyl acetate. The column is segmented and the fractions containing the product ester are eluted with ethyl acetate to afford 123 mg of the title compound.

EXAMPLE 1235 PREPARATION OF 1,9-DIOXO-11o<.16-DIHYDROXY-1-e_CHLOROBENZOXYMETHYL-16-METHYL-13-TRANS PROSTENE To a mixture of 303 mg of l,9-dioxo-ll«<,16-dihydroxyl-hydroxvmethyl-16-mathyl-13~trans-proBtene and 139 mg (1 eq) of £-chlorobenzoylchloride is added 2.5 ml of dry pyridine.

After dissolution, the reaction mixture is allowed to stand 18 hours at ambient temperature. The reaction mixture is placed directly onto a silica-gel dry column (50 x 1) containing 225 g of silica-gel and developed with ethyl acetate. The column is segmented and the sections containing the product are eluted with ethyl acetate to provide 121 mg of the title ester as a wax. 360 EXAMPLE 1236 PREPARATION OF 1,9-DIOXO-1K 16-DIHYDROXY 1-CARBETHOXYOXYMETHYL-l6-METHYL-13-TRANS-PROSTENE To a mixture of 200 mg of 1,9-dioxo-ll«<, 16-dihydroxyl-hydroxymethyl-16-methyl-13-trans-prostene and 57 mg (1 eg) of ethyl chloroformate is added 1.5 ml of dry pyridine. After stirring at ambient temperature for 18 hours the mixture is applied directly to a 31 x 1 dry column of silica gel and developed with ethyl acetate. The column is segmented and the portion containing the product is washed with ethyl acetate to afford 105 mg of the product carbonate.

EXAMPLE 1237 PREPARATION OF 1,9-DIOXO-ll°< ,16-DIHYDROXY1-ACETOXYMETHYL-16-METHYL-13-TRANS-PROSTENE To a solution of 218 mg of l,9-dioxo-lle<,16-dihydroxy -l-hydroxvroethvl-16-methvl-13-trans-prostene in 1 ml of dry pyridine at 0° is added, dropwise, a solution of 58 mg (1 eq) of acetic anhydride in 0.6 ml of dry pyridine. After stirring at 0° for 18 hours, the reaction mixture is placed directly onto a silica-gel dry column (150 g silica-gel, 35 x 1, equilibrated with 15 ml ETOAC) and developed with ethyl acetate. The column is segmented and the portions containing the product are eluted with ethyl acetate to afford 88 mg of the 1-oxo1-acetoxymethyl prostanoid. 361 EXAMPLE 1238 Treatment of 1,9-dioxo-114,16-dihydroxy-l-hydroxymethyl-16-methyl-13-trans-prostene or the individual optical isomers thereof with 1.1 eg of the following acid halides by the procedure of Examples 1234-1236 or a carboxylic acid anhydride by the procedure of Example 1237 provides the corresponding 1-substituted earboxymethyl prostanoic derivative; CARBOXYLIC HALIDES Acetyl bromide Acetyl chloride O-Acpt. ylmandelic acid chloride O-Acetylisalicyloyl chloride Acryloyl chloride 1- Adamantanecarboxylic acid chloride p-Anisoyl chloride Benzoyl bromide Benzoyl chloride 4-Biphenylcarbonyl chloride Bromoacetyl bromide 2- Bromobenzoyl chloride 4-Bromobenzoyl chloride 2-Bxomo-2,2-diphenylacetyl bromide 2- Bromopropionyl chloride 3- Bromopropionyl chloride p-tert,Butylacetyl chloride tert-Butylacetyl chloride Butyryl chloride 3-Carbomethoxypropionyl chloride Chloroacetyl chloride o-Chlorobenzoyl chloride 362 4820^ CARBOXYLIC HALIDES (eont'd) m-Chlorobenzoyl chloride p-Chlorobenzoyl chloride 4- Chlorobutyryl chloride χ-Chloro- XA-diphenylacetyl chloride p-(Chloroformyl)-phenyl methyl carbonate =<-Chlorophenylacetyl chloride 2- Chloropropionyl chloride 3- Chloropropionyl chloride - Chlorovaleryl chloride Cinnamoyl chloride Crotonyl chloride 4- Cyanobenzoyl chloride Cyclobutanecarboxylic acid chloride Cyclohexanecarboxylic acid chloride Cyolopropanecarboxylic acid chloride Decanoyl chloride Dichloroacetyl chloride 2.4- Dichlorobenzoyl chloride 2,6-Dichlorobenzoyl chloride 3.4- Dichlorobenzoyl chloride Diethylcarbamyl chloride 3.5- Dimethoxybenzoyl chloride 3,3-Dimethylacryloyl chloride 3.5- Dinitrobenzoyl chloride Diphenylcarbamyl chloride trans-3,6-Endomethylene-l,2,3,6-tetrahydrophthaloyl chloride 2-Ethylhexanoyl chloride Ethyl malonyl chloride 363 CARBOXYLIC HALIDES (cont'd) Ethyl oxalyl chloride Ethyl succinyl chloride o-Fluorobenzoyl chloride m-Fluorobenzoyl ehloride p-Fluorobenzoyl chloride 2-Furoyl chloride Hexanoyl chloride Isobutyryl chloride Isophthaloyl dichloride Isovaleryl chloride Itaconyl chloride Lauroyl chloride Methacryloyl chloride Methoxyacetyl ehloride Methyl 4-(chloroformyl)-butyrate Methyl oxalyl chloride Myristoyl chloride m-Nitrobenzoyl chloride p-Nitrobenzoyl chloride Nonanoyl chloride -Norbomene-2-carbonyl chloride Octanoyl chloride Palmitoyl chloride Pentafluorobenzoyl chloride Phenoxyacetyl chloride Phenylacetyl chloride trans-2-Phenylcyclopropane-l-carboxylic acid chloride Propionyl chloride 364 CARBOXYLIC HALIDES (cont'd) 2- Quinoxaloyl chloride Terephthaloyl chloride o-Toluoyl chloride m-Toluoyl chloride ρ-Toluoyl chloride 3,4,5-Trimethoxybenzoyl chloride Trimethylacetyl chloride 10-Undecenoyl chloride Valeryl chloride CARBOXYLIC ACID ANHYDRIDES Acetic anhydride n-Butyric anhydride 2.2- dimethylglutaric anhydride 3.3- dimethylglutaric anhydride 2.3- dimethyl glutaric anhydride Heptafluorobutyric anhydride Homophthalic anhydride Maleic anhydride 3- methylglutaric anhydride Methylsuccinic anhydride Propionic anhydride Succinic anhydride 3.3- tetramethylene glutaric anhydride benzoic anhydride Phthalic anhydride 3-nitrophthalic anhydride Tetrabromophthalic anhydride Tetrachlorophthalic anhydride dl-Camphoric anhydride 365 4820 CARBOXYLIC ACID ANHYDRIDES (cont'd) cis-l,2-Cyclobutanedicarboxylic anhydride cis-l,2-Cyclohexanediearboxylic anhydride Hexahydro-4-methylphthalic anhydride cis-l,2,3,6-Tetrahydrophthalic anhydride 3,4,5,6-Tetrahydrophthalic anhydride EXAMPLE 1239 Treatment of 1,9-dioxo-lJK ,16-dihydroxy-l-hydroxymethyl-16-methyl-5-cis,13-trans-prostadiene, or the individual isomers thereof, with 1.1 eq of the acid halides or anhydrides listed in Example 1238 by the procedures of Examples 1234-1237 is productive of the corresponding 1-substituted carboxymethyl prostanoic derivative.

EXAMPLE 1240 Treatment of the l-oxo-hydroxymethyl E,F and A prosta noids described herein with the acid halides and anhydrides described in Example 1238 by the procedures of Examples 12341237 is productive of the corresponding 1-oxo-l-substituted carboxymethyl prostanoic derivatives. 366 4-8 207 In its broad aspect, this invention encompasses prostaglandin type compounds characterized by an α-chain having a terminal hydroxy methyl ketone group or the acyl or protected precursor derivatives thereof. The tern achain as employed herein is intended to connote the prostaglandin side-chain which, in natural mammalian or racemic prostaglandins carries the carboxylic acid function. Prostaglandins, as pointed out earlier in the specification, are named as derivatives of the basic prostanoic acid molecule. See, also, Journal of Medicinal Chemistry 1974, Vol, 17, No. 9, pp. 911-918 and Chemistry and Industry, April 17, 1976, pp. 334-338. As shown throughout this specification, the prostaglandin type compound to which this invention is applicable vary widely. Over the past several years, numerous prostaglandins have been made and the present invention is applicable to the many diverse derivatives of the basic prostaglandin structure. In its broadest aspect, this invention encompasses all prostaglandins, i.e. the functionalized derivatives of prostanoic acid, in its conventionally accepted meaning, which are characterized by having on the terminal methylene carbon of the alpha chain a substituent selected from the group consisting of: 0, IH IH or OR prostaglandins of type E, F and A having a terminal alpha chain substituent as defined in the preceding paragraph. wherein R and R^ are as previously defined.

In certain preferred forms, this invention is directed to 367 A 15-deoxy-16-hydroxy substituted prostaglandin consists of two dl racemates (16a-hydroxyl and 16β-hydroxyl), and similarily a 15-hydroxy-15-substituted compound consists of two dl-racemates (15α-hydroxyl and 150-hydroxyl) unless specified otherwise, which respectively are separable into the 16a and 163 epimers, and 15a and 153 epimers. A species claim wherein the stereochemistry of the C., or C,. carbon is not specified 15 16 encompasses the nat.-15a and 15β, and nat. -16><- and 16& forms of the compound and the racemic mixtures thereof.' This invention has been described in terms of specific embodiments set forth in detail herein, but, it should be understood that these are by way of illustration only and that the invention is not necessarily limited thereto. Modifications and variations will be apparent from this disclosure and may be resorted to without departing from the spirit of this invention, as those skilled in the art will understand. Accordingly, such variations and modifications of the disclosed invention are considered to be within the purview and scope of this invention and the following claims.

Claims (1)

1. Claims *· 1. An optically active compound of the formula: >)-Rl 13 _C 14 R 2 wherein Q is -(CH.)-, or -CH.-CH=CH-(CH.) -, wherein f is an 2 f 2 cis 2 5 integer from 5 to 7 inclusive, and g is an integer from 2 to 4, inclusive; C 13 -C 14 is ethylene or trans-vinylene; W is selected from the group consisting of: wherein X is: and is hydrogen or hydroxyl; R^ is selected from the group consisting of: consisting of C^-C^ alkyl, di-CC^-C^J-alkylamino, and phenyl or phenyl substituted with one or more substituents selected from the group consisting of Cj-C4 alkyl, -OR,-SR, F or Cl wherein R is as previously defined; and R£ is selected from the group consisting of: ΐ 8 OH II ) ;7 c - (ck *’p’ ch \ / Oh /CKs-CHj •V Oil ^C—tCK,) -CH^ * P V en II ,ch 2 —cu .(CPq 'll ) 370 (S) ” Ci,A 7' c \~’ ,Al ? OH ti <*) il. -CH 2 --C- Ru , , ti OH 011 II H “ C,1 2 s\ *11 ? CHj OH -CH,—C-R B 3 C—cJSoH Ί CH, OH ti _CH 2-^- R 9 » CH 3 CJ52 oh X 1 ·: y\ M Oil M ‘OH -JZ*11 * C 2 / C “i ,C ~ R « . 7 - K! 2 /f 9 > CII, OH U HOC OH CH OH 3 -ch?—c—>c. -CH—- C — ft /\ \ 5 A i 5 OH « CH^’CH OH 0 „ c„—c„ 2 , * ai riZ c \ riZx * n ) > oil -«H 011 II 5 C.-ti, /\ 11 . —,c--JC-Rl H OH OH ti ' 7 C \/\ 11 ’ of Έ f Ol! Z~\ a,· ftf .ΛΒ *U 2 Oil H Otig Ή 371 -χ—ch 2 -z OH Ή and y ^‘ CH 2>m-X x <- (Cii 2> n _> wherein R^ is hydrogen or methyl; Rg is selected from the group consisting of C 4 -C 7 alkyl; *6 is selected from the group consisting of C 3‘ C 6 alkyl; R 7 is selected from the group consisting of C 2“ C 4 alkyl; *8 is selected from the • group consisting of C 1 C 2 alkyl; r 9 is selected from the group consisting of C 3 -C g alkyl; R 1Q is selected from the group consisting of C^-C 4 alkyl; Rjj is selected from the group consisting of C^-C? alkyl; R 12 is selected from the group consisting of C^-C^ alkyl; p is an integer from 0 to 3; g is 1 or 2; X is a divalent radical selected from the group consisting of: wherein is selected from the group consisting of Cj“ C 7 alkyl, hydrogen, and a phenoxy group optionally substituted with a substituent selected from the group consisting of halogen, trifluoromethyl and Cj-C^ alkyloxy; Y is a divalent radical selected from the group consisting of: 372 Z is a divalent radical selected from the group consisting of -0- and -ch 2 -; m is aero or an integer from 1 to 4 inclusive; n is zero or an integer from 1 to 4, inclusive; with the proviso that the sum of m and n has the value of 1 to 4; β is 5 zero or the integer 1;: and t is selected from the group consisting of hydrogen, chloro, fluoro, dichloro, trifluoromethyl, methoxy; the racemic mixture thereof; and the mirror image thereof. 373 (2) A Method for preparing the compounds of Claim 1 comprising: (A) reacting a racemic or optically active cyclopentenone of the formula: I wherein 0 is as previously defined, R3 is hydrogen or a blocked oxygen group such as 2-methoxy-propyl-2-oxy or tri-(C^-C 4 )- alkylsilyloxy and Rj is selected from the group consisting of: P or -C-CH.,-P, wherein P is a blocked οχνσβη group such as trialkyl silyloxy, or 2-methoxy-propyl-2-oxy, and R is Cj-C4alkyl,' witn a lithiocuprate selected from the group consisting of: 374 wherein R^ is a moiety selected from the hydroxyl substituted moieties of the group R 2 wherein the hydroxyl group is blocked with a protecting group such as tri-(C1-C4)alkyl silyl? to provide a racemic or optically active compound of the formula; 48307 1 , 1 wherein Q, R^, R 3 and R 2 are as previously defined; followed by the (B) removal of the protecting groups to provide compound of the formula: wherein Q, R 2 , R, are as previously defined and R^ is; OH or wherein R is (C) steps (A) or as previously defined, and if desired, followed by the complete hydrogenation of the products of (B) to provide a compound of the formula: z(cH 2 )r\ ch 2 -ch2-R2 375 wherein f, R 2 , R 2 and R i are as previously defined, or (D) the partial hydrogenation of the compounds of steps (A) or (B) of the formula: wherein R 3 , f, Rj and R 2 are as previously defined; and if desired followed by (E) the treatment of the products of steps (A), (Β), I (C) or (D) wherein R^ or R^ includes a cyclic moiety, with a stereo-selective carbonyl reducing agent such as lithium perhydro-9b-boraphenalylhydride to provide the 9a-hydroxy derivative of the compounds of steps (A)-(D), or if desired, (F) the treatment of the products of steps (A), (Β), (C) or (D) wherein R^ or Rj includes a cyclic moiety, with a carbonyl reducing agent such as sodium borohydride to provide a separable mixture of the 9a- and 96-hydroxy derivatives of steps (A)-(D) and if desired, followed by (G) the partial hydrogenation of the products of steps (E) or (F) wherein Q is cis-vinylene and is trans-vinylene to provide from the 9a-hydroxy compounds of step (S) the compound of the formula: 376 or to provide from the 9a/B compound of step (F) the separable mixture of the compounds of the formula: wherein R^, R 2 , and R 3 are as previously defined, or if desired followed by (H) the complete hydrogenation of the products of steps (E) or (F) to provide from the 9a-hydroxy product of steps (E) or (F) the compound of the formula: and from 9α/β -hydroxy products of step (F) the separable mixture of compounds of the formula: 377 wherein ΐ, and R^ are as previously defined, and if desired followed by (I) the dehydration of the products of steps (A), (Β), (C) or (D) to provide the compound of the formula: wherein Q, C 13 -C 14 , and R 2 are as previously defined, and if desired (J) the products of steps (A), (F), (G), (H) or (1) wherein R x is (B), (C), (D), (E), OR tiay be treated with acid to provide β Λ of said step wherein R^ is the corresponding product and if desired (K) the products of steps (A)-(J) wherein R^ is -C-CH 2 OH may be treated with an anhydride of the formula: (R,-CO )0 or Q 15 X an acid chloride of the formula: R-irC-Cl wherein R is J 15 as previously defined to provide the compound of the formula: -CHjfXcH^O-jj-R^ 13“ C 14” Il l wherein S 15 -Q, W, C 13 -C 14 - and R 2 are as previously defined, and if desired, followed by (L) the resolution of the racemic products of steps (A)-(K), 378 3. An optically aetive or racemic compound of the formula: wherein R3 is hydrogen, hydroxy or a blocked oxygen group such as 2-methoxy-propyl-2-oxy or tri(Cj-C^)lower alkylsilyloxy cis Q is -(CH 2 )f- or -CH 2 -CH=CH-(CH 2 ) g - wherein f is an integer from 5 to 7, inclusive, and g is an integer from 2 to 4, 10. inclusive, and R^ is selected from the group consisting of: wherein R is selected from the group consisting of C^-C^ alkyl and P is hydroxy or a blocked oxygen group such as 2-methoxy20 propyl-2-ojy , dimethyl-trbutylsilyloxy or tri(Ci-C4) lower alkylsilyloxy» 379 48307 4. A method for the preparation of the optically active or. racemic compound of the formula: wherein Q is or -CHj-CH’CH-(CH 2 )g- wherein f is an integer from 5 to 7, and g is an integer from 2 to 4; is hydrogen, hydroxy, or a blocked oxygen group such as tri-iCj-C^) lower alkylsilyloxy , dimethyl-t-butylsilyloxy, or and R^ is wherein R is CpC^ alkyl, ana P is hydrogen or a protecting group such as tri-(C1-C4)lower alkylsilyl or dimethyl-t-butyIsilyl; comprising (A) converting the compound of the formula: q-co 2 h wherein Q is as previously defined, to the acid halide, of the formula: 38q β-CO-L wherein fi is as previously defined and L is chloro or bromo, or (B) treatment of the compound of the formula: Q-CO 2 H HO with a blocking reagent such as dimethyl-i-butyl-silylchloride to provide the compound of the formula: wherein P’ is a blocking group such as dimethyl-t-butylsilyl, 20 follwed by (C) the selective removal of the carboxylate protecting group to provide a compound of the formula: J 2 h PO wherein Ϋ is as previously defined, followed by (S) the conversion of the product of step (C) to the acid halide of the formula: 'Q-CO-L 381 wherein L is chloro or bromo, and / is previously defined, or (E) treatment of the product of step (B) with the compound of the formula: L-COCO-L wherein L is chloro or bromo to provide the compound of the formula: / Q-CO L /, P( wherein L, Q and P are as previously defined, followed by (F) the treatment of the product of steps (A), (D) or (E) with diazomethane to provide the compound of the formula: CH-N, ✓ P* wherein Q is as previously defined and P is hydrogen or a blocked oxygen group such as diroethyl-t-butylsilyloxy, or (G) the treatment of the product of steps (A), (D) or (E) with a-1,1,2—tris-trialkyl (C^-C^silyloxyethylene such as 1,1,2-ttiss-trimethylsilylox^atlgilene to provide a compounc of the formula: OTMS wherein P*and Q are ae previously defined and TMS is trialkylailyl, followed by, 382 8307 (H) the hydrolysis of the products of steps (F) or (G) to provide the compound of the formula: AX CH 2 0H; wherein R defined, 3 is hydrogen or hydroxy and Q is as previously and if desired followed by (I) treatment with the compounds of the formula: RO OR z\ wherein R is as previously defined, to provide the compound of the formula: wherein P 1 is hydrogen, hydroxy or -0 R RO R wherein R is as previously defined, or (J) treatment with the compound of the formula: OR wherein R is as previously defined to provide the compound of the formula: z Q-C-CH 2 -(k/R RCT^R 383 wherein Ρ ie hydrogen or wherein R is as previously defined, or (K) treatment with an alkylene diol such as ethylene glycol wherein Rjis hydrogen or hydroxy, and if desired (L) the products of steps (Η), (I) or (X) wherein R 3 is hydrogen or hydroxyl nay be treated with a blocking reagent to provide the compound of the formula: wherein R^ is hydrogen or a blocked oxygen aroup such as dimethvl-tbutylsilyloxy or tri-(Cj-Cj)-lower alkylsilyloxy and Rj is Λ. wherein P is a blocking group such as dimethyl-t-butylsilyl or tri-(C 1 -C 4 )-loweralkylsilyl. 384 5. A method for the preparation of the cctically active or racemic -compound of Claim 1 of the formula: «A. R 3 ^ c 13” c 14 r 2 wherein Rj, R 2 , R^, Q and C 13 ~Cj4 are as previously defined, and R 14 is -CHjOH, comprising; (A) protecting the compound of the formula wherein R , R 2 , R 3 , Q and C 13 -C 3 4 are as previously defined, followed by (B) treatment with an oxidizing agent such as Collens reagent and removal of che protecting groups. 385 48307 6. A method for the preparation of the ‘optically active or racemic compound of the formula: cis H 2 -CH-CH-(CH 2 )g-Ri P<< wherein g is an integer from 2 to 4, inclusive, and R^ is selected from the group consisting of: wherein P is hydrogen or a protecting group such as dimethyl-ir butyl-silyl, or tri-(C^-C^)lower alkyl silyl> pomprising (A) Treating the compound of the formula: Br+ wherein P is a protecting group such as dimethyl-i-butylsilyl and g is as previously defined, with sodium methylsulfinylmethide, followed by (B) the reaction of the product of step A with the compound of the formula: CHO 386 to provide the compound of the formula: CH 3 0 OCH CH 2 J q CH 2 OP wherein P and g are as previously defined, followed by (C) refluxing a buffered solution of the product of step (B) to provide the compound of the formula: wherein g and P are as previously defined, followed by (D) treatment with chloral and triethylamine and then hydrolysis to provide the compound of the formula: z z HO wherein g is as previously defined, or if desired, (E) the product of step (C) may be treated with chloral and triethylamine to provide the compound of the formula: 387 wherein g and P are as previously defined and P* is hydroxyl, and if desired, followed by (F) the blocking of the 4-hydroxy group of the product of step (E) to provide the product of step (E) wherein P‘ is a protecting group such as tri-fC^-C^) lower alkyl silyl or dimethyl-t-butyl-silyl. 388 7. A method fox preparing the compound of Claim 1 wherein Κ η is β comprising OH S 1 is jj /V S (A) converting the compound of the formula: J3-C00H C 13 -C 14 R 2 .wherein w, R 2 , Q and are as previously defined, to the compound of the formula: jQ-CO L SL 13 _C 14“ R 2 wherein W is selected from the group consisting of: 20 B Λ PO or PO 389 wherein P is a protecting group such as tri-(C^-C^)lower alkylsilyl, or dimethy1-t-butylsilyl and B is hydrogen or. a blocked oxygen such as tri-(C^-C^)lower alkylsilyloxy or dimethyl-t-butylsilyloxy; R 2 a noiety selected from the group R 2 having a protected hydroxyl group; L is chloro or bromo; and Q and C^-Cj^ are as previously defined, followed by (B) treatment with diazomethane and then hydrolysis. 8. The compound according to Claim 1, 1,9-dioxollo(,16-dihvdroxv-l-hvdroxymethyl-16-methyi-5-cis-13-transprostadiene. 9. The compound according to Claim 1, 1,9-dioxo11<,16-dihvdroxv-16-vinvl-l-hydroxymethyl-5-cis-13-transprostadiene. 10. The compound according to Claim 1, 1,9-dioxolltf,15-dihydroxy-16,16-trimethylene-l-hydroxyroethyl-5-els13-trans-prostadiene. 11. The compound according to Claim 1, 3,9-dioxo15-hvdroxv-15-methvl-l-hvdroxvroethyl-13-trans-pro8tene. 12. The compound according to Claim 1, l,9,dioxo-15hydroxy- 1-hy droxymethyl-prosto-ne. 13. The compound according to Claim 1, 1,9-dioxo1W,16-dihvdroxv-16-vlnvl-l-acetoxymethyl-5-cls-13-transprostadiene. 14. The compound according to Claim 1, 1,9-dioxollcM6-dihvdroxv-16-ethyl-l-hydroxyroethyl-5-elg-13-transprostadiene. 390 15. The compound according to Claim 1, 1,9-dioxo114, 16-dihvdroxv-16-methyl-l-hydroxymethyl-13-trans-pro8tene,. 16. The compound according to Claim 1, 1,9-dioxo11ξ,16-dihvdroxv-16-vinvl-l-hvdroxvmethvl-13-trans-prostene. 5 17. The compound according to Claim 1, l;9-dioxo1Μ,15 -dihydroxy-16,16-trimethylene-l-hydroxymethyl-13trans-prostene. 18. The compound according to Claim 1, 1,9-dioxo114,15 -dihydroxy-l-hydroxymethyl-13-trans-prostene. 10 19. The compound according to Claim 1, 1,9-dioxo114.16- dihydroxy-16,20-dimethyl-l-hydroxymethyl-13-transprostene. 20. The compound according to Claim 1, 1,9-dioxo-15hydroxy-l-hydroxymethyl-13-trans-prostene. 15 21. The compound.according to Claim 1, 1,9-dioxo114,15 -dihydroxy-16,16-trimethylene-5-cis-13-transprostadiene. 22. The compound according to Claim 1, 1,9-dioxo114.16- dihydroxy-16,20-dimethyl-l-hydroxymethyl-5-cis-13-trans 2. O prostadiene. 23. The compound according to Claim 1, 1,9-dioxollc(.16-dihvdroxv-16-methvl-l-hydroxymethyl-5-cis-13-transprostadiene,1-ethylene ketal. 391 24. The compound according to Claim 1, nat.-1,9dioxo-lla,16 (S) -dihydroxy-l-hydroxyroethyl-ie-methyl-s-cis^S-transprostadiene. 25. The compound according to Claim 1, nat.-1,9dioxo-lla,16(R)-dihvdroxy-l-hydroxymethy1-16-methy1-5-cis,13trans-prostadiene. 26. The compound according to Claim 1, nat.-1,9dioxo-lla,16(S)-dihvdroxv-l-hydroxymethyl-16-methyl-13-transprostene. 27. The compound according to Claim 1, nat.-1,9dioxo-lla,16(R)-dihydroxy-l-hydroxymethyl-16-methyl-13-transprostene, 28. The compound according to Claim 1, 1,9-dioxolla, 16 (S)-dihvdroxy-l-hydroxymethyl-16-methyl-5-cis,13-transprostadiene. 29. The compound according to Claim 1, 1,9-dioxolla, 16 (R)-dihydroxy-l-hydroxymethyl-16-methyl-5-cis,13-transprostadiene. 30. The compound according to Claim 1, 1,9-dioxo-lla, 16(S)-dihydroxy-l-hydroxymethyl-16-methy1-13-trans-prostene. 31. The compound according to Claim 1, 1,9-dioxolla, 16(R)-dihydroxy-l-hydroxymethy1-16-methy1-13-trans-prostene. 32. The compound according to Claim 1, nat.-1,9dioxo-lla,16(R/S)-dihydroxy-l-hydroxyraethyl-16-methyl-5-cis, 13-trans-prostadiene. 33. The compound according to Claim 1, nat.-1,9dioxo-lla,16(R/S)-dihydroxy-l-hydroxymethyl-16-methyl-13trans-prostene. 392 34. The compound according to Claim 1, nat.-l,9-dioxo11a,16(R)-dihydroxy-l-hydroxymethyl-16-viny1-13-trans-prostene 35. The compound according to Claim 1, nat.1.9- dioxo-lla,16(S)-dihydroxy-l-hydroxymethyl-16-vinyl-135 trans-prostene. 36. The compound according to Claim 1, nat.1.9- dioxo-lla,16(R)-dihydroxy-l-hydroxymethyl-16-vinyl-5cis,13-trans-prostadiene. 10 37. The compound according to Claim 1, nat.1.9- dioxo-lla,16(S)-dihydroxy-1-hydroxymethyl-16-vinyl-5cis,13-trans-prostadiene 38. The compound according to Claim 1, 1,915 dioxo-lla,16(R)-dihydroxy-1-hydroxymethyl-16-viny1-13-transprostene. 39. The compound according to Claim 1, 1,9dioxo-lla, 16 (S)-dihydroxy-1-hydroxymethyl-16-vinyl-13-trans20 prostene. 40. The compound according to Claim 1, '1,9dioxo-lla, 16 (R)-dihydroxy-1-hydroxymethyi-l6-vinyl-5-cis, 13-trans-prostadiene 25 The compound according to Claim 1, -1,9dioxo-lla,16(S)-dihydroxy-l-hydroxymethyl-16-vinyl-5-cis r 13-trans-prostadiene. 393 42. The compound according to Claim 1, nat.-1,9dioxo-lla,16(R)-dihydroxy-16-ethynyl-l-hydroxyraethyl-20-nor5-cis,13-trans-prostadiene. 43. The compound according to Claim 1, nat.-1,9dioxo-lla,16(R)-dihydroxy-16-ethynyl-l-hydroxymethyl-20-ethyl5-cis,13-trans-prostadiene. 44. The compound according to Claim 1, nat.-1,9dioxo-ll a ,16(R)-dihvdroxv-16-ethynvl-l-hydroxymethyl-5-cis, 13-trans-prostadiene. 45. The compound according to Claim 1, nat.-1,9dioxo-lla,16(R)-dihydroxy-16-ethynyl~l~hydroxymethyl-20-nor13-trans-prostene. 46. The compound according to Claim 1, nat.-1,9dioxo-lla,16(R)-dihydroxy-16-ethynyl-l-hydroxymethyl-20-ethyl13-trans-prostene. 47. The conpound according to Claim 1, nat.-1,9dioxo-lla,16(R)-dihvdroxv-16-ethvnyl~x-hydroxymethyl-13-transprostene. 48. The compound according to Claim 1, nat.-1,9dioxo-lla,16(R)-dihydroxy-l-hydroxymethyl-16-(1-propynyl)-5cis,13-trans-prostadiene. 49. The conpound according to Claim 1, nat.-1,9dioxo-ΙΙα»16(R)-dihydroxy-16-(1-propynyl)-1-hydroxymethyl-20ethy 1-5-cis,13-trans-prostadiene. 50. The conpound according to Claim 1, nat.-1,9dioxo-llar16(R)-dihydroxy-16-(1-propynyl)-l-hydroxymethyl-13trans-prostene. 394 51. The compound according to Claim 1, nab.-1,9dioxo-lla,16(R)-dihydroxy-16-(1-propynyl)-l J hydroxymethyl-20ethyl-13-trans-prostene. 52. The compound according to Claim 1, 1,9-dioxo5 11a,16(R)-dihydroxy-16-ethynvl-l-hvdroxvmethvl-20-nor-5-cls, 13—trans-prostadiene. 53. The compound according to Claim 1, 1,9-dioxolla, 16 (R)-dihydroxy-16-ethynyl-l-hydroxymethyl-20-ethyl-5cis,13-trans-prostadiene. 10 54. The compound according to Claim 1, 1,9-dioxo11a,16(R)-dihydroxy-16-ethynyl-l-hydroxymethy1-5-cis,13-transprostadiene. 55. The compound according to Claim 1, 1,9-dioxolla, 16(R)-dihydroxy-16-ethynyl-l-hyaroxvmethyl-20-nor-1315 trans-prostene. 56. The compound according to Claim 1, 1,9-dioxolla, 16 (R)-dihydroxy-16-ethynyl-l-hydroxymethyl-20-ethyl-13trans-prostene. 57. The compound according to Claim 1, 1,9-dioxo20 Ila,16(R)-dihydroxy- -1-ethyny1-1-hydroxymethyl-13-trans-prostene 58. The compound according to Claim 1, 1,9-dioxolla, 16 (R)-dihydroxy-1-hydroxymethy1-16-(1-propynyl)-5-cis,13trans-prostadiene . 59. The compound according to Claim 1, 1,9-dioxo25 11a,16(R)-dihydroxy-16-(1-propynyl)-1-hydroxymethy1-20-ethyl5-cis,13-trans-prostadiene. 395 60. The compound according to Claim l f nat.-1,9dioxo-lla,16(S)-dihydroxy-16-ethynyl-l-hydroxymethyl-20-nor 3. 5-cis,13-trans-prostadiene. 61. The compound according to Claim 1, nat.-1,9dioxo-lla,16(S)-dihydroxy-16-ethynyl-l-hydroxymethyl-20-ethyl5-cis,13-trans-prostadiene. 62. The compound according to Claim 1, nat.-1,9dioxo-lla,16(S)-dihydroxy-16-ethynyl-l-hydroxymethyl-5-cis, 13-trans-prostadiene. 63. The compound according to Claim 1, nat.-1,9dioxo-lla,16(S)-dihydroxy-16-ethynyl-l-hydroxymethyl-20-nor13-trans-prostene. 64. The compound according to Claim 1, nat.-1,9dioxo-lla,16(S)-dihydroxy-16-ethynyl-l-hydroxymethyl-20-ethyl13-trans-prostene. 65. The compound according to Claim 1, nat.-1,9dioxo-lla,16(S)-dihydroxy-16-ethynyl-l-hydroxymethyl-13-trans~ prostene. 66. The compound according to Claim 1, nat.-1,9dioxo-lla,16(S)-dihydroxy-l-hydroxymethyl-16-(1-propynyl)-5cis,13-trans-prostadiene. 67. The compound according to Claim 1, nat.-1,9dioxo-lla,16(S)-dihydroxy-16-(1-propynyl)-l-hydroxymethyl-20ethyl-5-cis,13-trans-prostadiene. 68. The compound according to Claim 1, nat.-1,9dioxo-lla,16(S)-dihydroxy-16-(1-propynyl)-l-hydroxymethyl-13trans-prostene. 396 69. The conpound according to Claim 1, nat.-1,9dioxo-lla,16(s)-dihydroxy-16-(1-propynyl)-l-hydroxymethyl-20ethyl-13-trans-prostene. 70. The compound according to Claim 1, 1,9-dioxo5 11a, 16 (S)-aihydroxy-16-ethynylri-hydroxymethyl-20-nor-5-cis,13trans-prostadiene . 71. The compound according to Claim 1, 1,9-dioxolla, 16 (s)-dihydroxy-16-ethynyl-l-hydroxymethyl-20-ethyl-5cis,13-trans-prostadiene. 4. 10 72. The compound according to Claim Ί, 1,9-dioxolla,16 (S)-dihvdroxv-16-ethynyl-l-hydroxymethyl-5-cis,13-transprostadiene. 73. The compound according to Claim 1, 1,9-dioxolla,16 (S)-dihydroxy-16-ethynyl-l-hydroxymethyl-20-nor-1315 trans-prostene. 74. The compound according to Claim 1, 1,9-dioxolla, 16 (S) -dihydroxy-16-ethynyl-l-hydroxymethyl-20-ethyl-13trans-prostene. 75. The compound according to Claim 1, 1,9-dioxo20 11α, 16 (S) -dihydroxy-lfr-ethvnyl-l-hydroxymethyl-13-trans-prostene 76. The compound according to Claim 1, 1,9-dioxolla, 16 (S)-dihydroxy-l-hydroxymethyl-16-(1-propynyl)-5-cis,13trans-prostadiene . 77. The compound according to Claim 1, 1,9-dioxo25 11a,16 (S)-dihydroxy-16-(1-propynyl)-l-hydroxymethyl-20-ethy 15-cis,13-trans-prostadiene. 397 78. The compound according to Claim 1, 1,9-dioxolla, 16 (R)-dihydroxy-16-(1-propynyl)-l-hydroxymethyl-13-transprostene. 79. The compound according to Claim 1, 1,9-dioxo5 11a,16(R)-dihydroxy-16-(l-propynyl)-l-hydroxymethyl-20-ethyl13-trans-prostene. 80. The oonpound according to Claim 1, 1,9-dioxolla, 16(S)-dihydroxy-16-(1-propynyl)-l-hydroxymethyl-13-transprostene. 81. The compound according to Claim 1, 1,9-dioxo11a,16(S)-dihydroxy-16-(1-propynyl)-l-hydroxymethyl-20-ethyl13-trans-prostene. 82. The compound according to Claim 1, wherein F is 6, g is 3, and Cj^-C^ is trans-vinylene. 83. The compound according to Claim 8, wherein R 2 is selected from the moieties of the group having an ethynyl, propynyl, vinyl or methyl substituent. 84. The compound according to Claim 83, wherein W is HO W is 85. The compound according to Claim 83, wherein H<\ £ 398 4821)7 88. A method for the preparation of the compound of claim 1 of the formula: Q-R: HO C 13“ C 14 R 2 wherein Q, Ci3~C 14 , R 2 and R 2 are as previously defined 5 comprising; (A) treating the compound >5- R l 5. 15 is C 13~ c 14 r 2 with alkaline hydrogen peroxide followed by (B) treatment with chromous acetate or aluminum 10 amalgum, to provide a separable mixture of the 11a and 11β derivatives of the product compound, and if desired followed by the treatment of the product of step B wherein to provide the product of step (B) wherein Rj , wherein R3.5 is C1-C4 alyl, di-(Ci -C 4 ) -alkylamino, or phenyl or phenyl substituted with one or more substitutents selected from group consisting of (Ci~C 4 ) alkyl, OR, SR, F or Cl wherein R is selected from the group consisting of C1-C4 alkyl. (C) iH i is is 399 87. A method for the preparation of the compound of claim 1 of the formula: , < cfi 2y. x H -> c= < R 3 ' H >> wherein R 3 , R 2 , F and Κχ are as previously defined comprising: A. treating the compound of the formula: JC- CIi 2 / > / c=l «3 H «2 wherein R3 is hydrogen or a blocked oxygen group such as 2methoxy-propyl-2-oxy or tri-(C^-C 4 )-alkysilyloxy, and R 2 is a substituent selected from the group R 2 having a protected hydroxyl group; with the compound of the formula Mg(CH2)^ Rl in the presence of a catalytic amount of Bu P.Cul, wherein. R| is: X A? or wherein P is a blocked oxygen group suoh as tri-(Cj-C4)15 alkylsilyoxy or 2-methoxy-propyl-2-oxy, and R is C1-C4 alkyl, followed by deblocking. 400 88. The compound according to Claim 83, wnerein W is 89. Λ prostaglandin compound having on the terminal methylene carbcn of tne α-chain a substituent selected from the group consisting 5 of R R wherein R is C-j-C^ alkyl and R^ is selected from the group consisting of c i' C 4 alkyl, di-(Cj-C 4 )-alkylamino, and phenyl or phenyl substituted with one or more substituents selected from the group consisting of C^-C^ alkyl, OR, SR, F, or Cl, wherein R is as previously defined. 90. Each and every novel compound described herein. 91. A method of preparing a compound according to Claim 1 or 90, substantially as described herein in any of the Examples. 92. A compound prepared by a method according to any of Claims 2, 4, 5,, 6, 7, 86, 87 or 91. 93. A pharmaceutical composition containing a compound according to any of Claims 1, 3, 8-85, 88 or 89. 94. 1,1,2-tris -trimethylsilyloxy ethylene.