SIDE-CHAIN REDUCTION OF DEOXYCHOLIC AND CHOLENIC ACIDS
June 5 , 1959 [CONTRIBUTION FROM
THE
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DIVISIONOF CHEMISTRY, AND THE DIVISIONOF PATHOLOGY AND MICROBIOLOGY, MEDICAL UNITS UNIVERSITY OF TENNESSEE]
Seroflocculating Steroids. V1II.l Side Chain Reduction of Deoxycholic, 12aHydroxy-3-cholenic and 3 a-Hydroxy-1 1-cholenic Acids2 BY ROBERT T. BLICKENSTAFF~" AND FREDERIC c. CHANG3* RECEIVEDNOVEMBER 17, 1958 Methyl deoxycholate, methyl 12~~-hydroxy-3-cholenate and methyl 3a-hydroxy-l l-cholenate were reduced to the corresponding C-24 hydroxy compounds. The latter were selectively deoxylated at (2-24 to give 3cu,l2a-cholanediol, 3-cholenSome ester and chloro derivatives are active seroflocculants. 12a-01 and ll-cholen-3cu-ol, respectively.
Certain derivatives of bile acid esters (;.e., containing unsaturation or chloro or acetoxy substituents) are seroflocculating agents4 The reduction of the bile acid side chain to a hydrocarbon moiety comprises one of the structural variations under study. The reduction of a model compound, 3a,24-cholanediol, derivable from the simplest of the bile acids (lithocholic acid), was reported re~ e n t l y ; the ~ diol was converted into 3a-cholanol by selective tosylation, and reduction of the 24monotosylate. The most sensitive seroflocculants in the bile acid ester group contain two functional groups on the nucleus. I n order to prepare reduced side chain analogs of these more sensitive seroflocculants, the reduction sequence has now been applied to methyl deoxycholate, methyl 12a-hydroxy-3cholenatee and methyl Sa-hydroxy-1 1-cholenate.? Lithium aluminum hydride reduction of these esters gave 3a,12a,24-cholanetriol (l), 3-cholen12a,24-diol (9) and ll-cholen-3a,24-dio1 (15), respectively. Under selective tosylation conditions similar to those proved successful on 3a,24-cholanediol, 11cholen-3a,2-l-diol (15) gave a low yield8 of 24tosyloxy-11-cholen-3a-01 (17), which was easily reduced to 11-cholen-3a-01 (18) with lithium aluminum hydride. Hydrogenation of 18 to 3a-cholano16 (rather than 24cholanol) proved that the tosylation had occurred a t C-24. 3a, 12a724-Cholanetriol (1) and 3-cholen-12a,24-diol (9), on the other hand, failed to yield crystalline monotosylates; consequently the crude tosylation products were reduced to give 3a,l2a-cholanediol (4) and 3-cholen-12a-01 (1I), respectively. The tosylations of 15 and 1 were not entirely selective, as evidenced by products isolated ultimately in minor amounts from each of these tosylation reactions. Thus, 11-cholene (21) was (1) Paper VI of this series, Chemistry ti I n d u s f r y , 590 (1958); paper VII, THIS J O U R N A L , 80, 2906 (1958). (2) This investigation was supported in part by grants ('2-2249 and C-3407) from the National Cancer Institute, of the Piational Institutes of Health, Public Health Service. (3) (a) Veterans Administration Hospital, Indianapolis, Ind. (b) T o whom correspondence concerning this paper should be addressed. (4) F. C . Chang. R . T. Blickenstaff, A. Feldstein, J. R. Gray, G. S. McCaleb and D. H. Sprunt, THISJOURNAL, 70, 2161 (1957). ( 5 ) R. T. Blickenstaff and F. C. Chang, ibid., 80, 2726 (1968). (5) F. C. Chang. A. Feldstein, J. R. Gray, G. S. McCaleb and D. H. Sprunt, ibid., 79, 2167 (1957). (7) J. Press and T. Reichstein, Helo. Chim. Acta, 26, 878 (1842): 1,. L. Engle, V. R. Mattox, B. F. McKenzie, W. F. McGuckin and E. C. Rendall, J. B i d . Chem.. 162, 565 (1946). (8) However, the yield based on 15 actually consumed is 87.5%. The starting diol has a low solubility in pyridine and much of i t is recovered unchanged.
obtained by chromatography of the lithium reduction products of the crude tosylate fraction from 15. Similarly, 12a-cholanol (3) was obtained from 1. I n addition, 3-cholen-l2a,24diol was formed when the tosylate fraction from 1, chromatographically separated on alumina, was dehydrotosylated in l ~ t i d i n e . These ~ products show the presence of 3,24-ditosylates in the tosylate fractions. However, no indication of ditosylation was observed in the tosylation of 9, as might be predicted from the known marked difference in esterification activity between the 3a- and 12a-hydroxy groups in the bile acids. Under conditions identical to those used in the lithocholate series,6 3,ll-choladiene (22) was prepared from 11-cholen-3a-yl tosylate (20) ; 24-chloro3-cholen-12a-01 (13) and 24-chloro-11-cholen-3a-01 (24) were prepared from crude 24-tosyloxy-3cholen-12a-01 and 24-tosyloxy-11-cholen-3a-01 (17), respectively, a t room temperature; and 3p-chloro12a-cholanol(7) and 3j3-chloro-11-cholene(23) were prepared from the corresponding tosylates a t 78". An inspection of the compounds prepared in this work reveals that most of the products that have resisted crystallization efforts are esters (tosylates and acetates) of 12a,24-diols. This behavior probably is related to the erratic melting behavior of the successfully crystallized diols and esters of this group (e.g., compounds 1, 8 and 9 have broad melting ranges and/or variable melting points ; 4 and 5 appear to be polymorphic). The property is exhibited to a certain extent by the 12a-hydroxycholanic acid esters.I0 Infrared spectra of the alcohols reported here (plus those in paper V6) contain maxima which are characteristic of the position of the hydroxyl group. Both the 3a- and the 24-hydroxyl groups give rise to a strong band near 3 p ; the 3a-hydroxyl in addition causes a strong band t o appear a t 9.58-9.68 p , whereas, with the 24-hydroxyl group this band is shifted to 9.42-9.49 p. The 12a-hydroxyl group gives rise to a very weak band a t 2.77-2.79 p and a strong band a t 9.66-9.68 p. (9) 3-Cholen-12a,24-dioI results from the lutidine dehydrotosylation of the triol 3-monotosylate, which most likely was formed from 3a,24-ditosylate by partial hydrolysis (see ref. 5 and paper V I , ref. 1) in the initial alumina separation of the tosylation mixture. The alternative explanation t h a t the 3-monotosylate was directly formed by selective tosylation of the triol appears improbable. (10) Some examples from the literature are ethyl 3a,12a-diacetoxycholanate (F. C. Chang, el al., THIS J O U R N A L , 79, 2164 (1957)), methyl 12a-benzoyldeoxycholate (B. F. McKenzie, W.F. McGuckin and E. C. Rendall, J . B i d . Ckcm., 162, 555 (1946). A. Lardon, P. Grandjean, J. Press, H. Reich and T . Reichstein, Helo. Chim. A d o , 26, 1444 (1942)), methyl lea-benzoxycholanate ( ; b i d . ) , and methyl 3a-acetoxy-12a-tosyloxycholanate(J. von Euw and T. Reichstein, i b i d . , 29, 654 (1946)).
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ROBERT T. BLICKENSTAFF AND FREDERIC C . CHANG
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