Tetrahedron. Vol. 29, PP. 21 to 30. Pcrgamon Press 1973. Printed inGreat Britain zyxwvutsrqponmlkjihgfedcbaZYXWVUTS A NEW STEROID AROMATIZATION REARRANGEMENT INVOLVING INVERSION OF SIDECHAIN CONFIGURATION J. MENEY, YOUNG-HO KIM and R. STEVENSON* Department of Chemistry, Brandeis University, Waltham, Massachusetts 02154 and T. N. MARGULIS Department of Chemistry, University of Massachusetts, Boston, Massachusetts 02 116 (Received in the USA 17 July 1972; Received in the UKforpublication4 September 1972) zyxwvutsrqponmlk Abstmet- The bile acid, cholic acid, has been transformed into 3a_hydroxy- 12-methyl- 18-nor-58, 17crchola-8,11,13-trien-24oic acid. The constitution of this novel type of steroid (benzenoid C-ring with 17wsidechain) has been supported by chemical degradation, and confirmed by crystal structure analysis of the methyl ester iodoacetate derivative. As part of our general studylm4 of routes to ring-C benzenoid steroids from readily available pre- cursors, we recently examined the sodium boro- hydride reduction of conjugated unsaturated 12-ketones derived from cholic acid (l), since it was considered probable that dehydration of the derived epimeric allylic C-12 alcohols may yield molecular rearrangement products capable of aromatization.5 This has now in fact been realized by a simple and novel pathway leading to a 12- methyl- 1&nor-C-benzenoid derivative with inver- sion of configuration of the precursor bile acid sidechaims Methyl cholate (2) is readily converted to methyl 3cr,7cu-diacetoxy-12-oxochol-9( zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 1 zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGF 1)-enate (3) by partial acetylation to the 3,7-diacetate’ followed by consecutive chromic acid and selenium dioxide oxidations.8 Reduction of the conjugated ketone with sodium borohydride in methanol gives a mixture of the epimeric 12~ and 12palcohols (4 and 5) with a slight predominance of the former. Although these could be conveniently separated on a small scale by TLC or the 12~epimer isol- ated by fractional crystallization, we intended to simplify the isolation and yield of 4 by a procedure used successfully in the deoxycholic acid series. Thus Kendall et aLg had shown that each analogue (lacking a C-7 substituent) of epimers 4 and 5 on treatment with methanol and acid catalyst yielded the same allylic 12cy-methyl ether from which the 12cu-alcohol could be readily re-generated. In marked contrast, we find that when hydrogen chloride is passed through a methanolic solution of the epimeric mixture of 4 and 5, there is obtained in 80-90% yield a product which we formulate as methyl3rw-hydroxy-l2-methyl-18-nor-5p,17clf-chol~ 8,11,13-trien-24-oate (6) in which the original 3a- 21 acetoxy group has been hydrolyzed, the 7-acetoxy and 1Zhydroxy group have been eliminated, the tertiary (C-18) methyl group has migrated from C- 13 to C- 12 and the 17psidechain configuration has been inverted. Evidence supporting this struc- ture comes from appropriate sepectroscopic analysis, chemical degradation, and crystal struc- ture analysis of a suitable derivative. Each epimeric allylic alcohol (4 and 5) treated independently yielded the same ring-C benzenoid product (6). An accurate mass measurement indicated an empirical formula C,,H,sO, for this product and the integrated NMR spectrum (Table 2) revealed the presence of a strongly shielded secondary Me group, a tertiary Me group, a benzylic Me group, a methoxycarbonyl group, and one aromatic proton. A signal attributable to an OH proton (exchanged by DzO) and a carbinol proton (shifted downfield by 1.21 ppm on addition of trichloro- acetylisocyanate’0) was characteristic of a secon- dary alcohol function. Difficulties in obtaining 12-methyl- 18-nor-C-benzenoid steroids in crystal- line form have been previously noted;’ from the noncrystalline alcohol (6), however, we have isolated crystalline acetate (7, chloroacetate (8) and iodoacetate (9) ester derivatives by standard techniques, and the crystalline hydroxy acid (10) by base hydrolysis of the acetate methyl ester (7). Esterification of 10 with diazomethane regenerated the noncrystalline alcohol (6), and acetylation of 10 gave a noncrystalline acetoxy acid (11). The UV absorption spectrum of the acetate methyl ester (7) showed typical benzenoid absorp- tion and, in particular, consideration of the B-band fine structure showed a close correspondence to that reported for 22,23-dibromo- 12-methyl-l& norergosta-8,l 1,13-trien-3pyl acetate (12), a ring