Potential Antifertility Agents. 6. Synthesis and Biological Activities of Optical Isomers of 4P-(p-Methoxyphenyl)-2P-methylcyclohexane-cu-carboxylic Acid and Related Compounds1 R. R. Crenshaw,* T h o m a s A. Jenks, George M . Luke, and Gabriel Bialy Research Dioision, Brktol Laboratories, Division of Aristoi-A4yer.s Cornpan\, S> ~ ( I C U S C ,.Veu
)'ark 13201. liecpiced Jui?, 1 I , 1974
Syntheses and biological activities are reported for ( + ) and ( - ) isomers of 4 ~ - ~ p - m e t h o x y p h e n y l i - Z ~ - m e t h y l ~ y c l o hexane-tu-carboxylic acid and related cyclohexene acids. The approximately equal uterotropic activity seen with the optical isomers of the title compound is interpreted in terms of an estrogenic receptor model in which there is proposed a new spatial area which may be involved in the elicitation ofa uterotropic response. Recently, we reported a series of compounds which had fractionation of asymmetric amine salts were unsuccessa large separation between uterotropic and hypocholesterful. Although several asymmetric amines gave salts with olemic activities.2 T h e compound chosen for more exten( & ) - I which were recrystallized to constant melting point sive studies was racemic 4,!l-(p-methoxyphenyl)-2,!l-meth-and rotation, the free acids obtained after liberation from ylcyclohexane-a-carboxylicacid [( * ) - l ] for which evidence salts were not optically pure. As a n alternative approach was presented t h a t the biological activity seen with the to resolution, we investigated various esters of ( & ) - I with compound was resultant from its stereochemical relationasymmetric alcohols such as (-)-menthol, methyl ( - ) ship with steroidal estrogens. It has been reported that mandelate, ( - )-2-octanol, testosterone, and methyl ( - I the unnatural ( - ) enantiomer of estradiol retains 90% of (\-hydroxy-a-trifluoromethylphenylacetate. This approach the hypocholesterelemic activity of (+)-estrone having the provided not only a potential method of resolution hut natural configuration, yet possesses only 0.06% of the u t also a quantitative method of assay for optical purity of a erotropic activity of (+)-estrone.3 We therefore predicted sample thought t,o have been resolved by another method that a n analogous relationship should exist between the if the two diastereoisomeric esters formed could be distinlm,2/3,4/3 and l/3,2a,4a optical isomers of 1 which correguished by glpc or nmr. T h e pure ( - ) - I isomer was obspond in configuration to (+)- and (-)-estradiol, respectained from this approach by fractionation of the esters tively. Thus, we expected the 1@,2tu,4cu isomer to show an formed from ( * ) - I and testosterone. Although successful. even greater separation between uterotropic and hypochothis method was impractical for providing quantities of lesterolemic activities t h a n seen with (*)-I. We now reantipodes of 1 desired for biological evaluation. A very port the preparation and biological activities of the optical feasible approach appeared to be synthesis of the enanantipodes (+)- and ( - ) - I and discuss implications of their tiomers of 1 starting with the optical antipodes of the keto biological activity in terms of structural requirements a t acid 2 and elaboration uia the stereospecific synthesis2 ahthe receptor level. I t should be noted t h a t use of the cy and breviated in Scheme I. This approach would not only proB designations herein refers to depiction of the structures vide enantiomeric forms of I but also chiral forms of 3, as shown in Scheme I so t h a t carbons 1, 2, and 4 of the the racemate of which has biological activity similar t,o cyclohexane ring correspond to carbons 13, 14, and 9, rethatof(+)-l.' spectively, of the steroidal skeleton. Attempts to form crystalline salts between ( & ) - 2 and Chemistry. A number of attempts to resolve ( & ) - I L>ia dehydroabietylamine or ( - )-(t-(1-naphthy1)ethylamine failed. Surprisingly. diastereoisomeric esters from (i)-2 and the optically active alcohols mentioned above were Scheme I indistinguishable in several glpc and tlc systems tried. COLH .4ddit~ionally, ester formation and/or attempted fractionation in some instances led to epimerizition to the trans isomer of 2. Because of these difficulties, use was made of 0 commercial facilities? for resolution of 2. Samples of ( + I (-1-2. [ t k l l l -12.8" 3a,[a30 +6.H" and (-1-2 provided to us were shown to be optically pure b, [a111+47.8" by nmr analysis of diastereoisomeric esters formed with methyl (-)-mandelate (cf. Experimental Section). T h e two optical antipodes of 2 were elaborated as indicated in Scheme I to optically active forms of 3, 1, and 1 . Two forms of 3 (3a and 3b) from ( - ) - 2 were isolated. The only chemical difference between Ja and 3b is the ratio of 1 4 : 1 3 isomers (approximately 2.5 and 1.4 for 3a and 3b. respectively). Samples of :la and 3b each were hydrogenated separately t o give samples of ( - ) - 4 of essentially the sanie specific rotation. Therefore, the pure A 4 and l3 isomers of 3 m u s t differ greatly in their rotations a t the I) wavelength. Specific rotations of ( - ) - I obtained by synthesis according to Scheme I agreed with those obtained from resolution of ( & ) - I i3ia the testosteronyl ester. Optical purity of I was confirmed by n m r studies employing methyl i- )-mandelate (cf. Experimental Section). (+I-4,
+W
AT = p-CHJOC,,H,
(-)-&
[a]D -17.5"
i U o r s e Lah
