Steroids and Steroidases. XIII. Illustrations of the Potential of Lithiodithiane–Epoxide Reactions for the Stereospecific Introduction of Substituents into the Steroid Nucleus

Abstract

The reactions of 2-lithio-1,3-dithiane with both 2c(,3c(-and 2/l,3/l-oxiranyl-5cc-cholestane have been used to prepare both epimers of 2-methyl-3-0x0-and 3-methyl-2-0x0-5a-cholestane. The results obtained illustrate the potential of the dithiane-epoxide route as an attractive and versatile general procedure for the stereospecific introduction of substituents into alicyclic compounds. Furthermore, since for six-membered ring compounds the epoxide ring is opened in a trans-diaxial manner, the substituent is introduced into the thermodynamically less stable orientation. Subsequent isomerization to the preferred equatorial isomer is thus possible and accordingly, both epimers are obtainable from the same synthetic sequence.On a utilisi' les reactions du 2-lithio-l,3-dithiane avec le 2a,3a-et le 2/l,3~-oxyranyl-5a-cholestane pour preparer les epimeres du 2-methyl-3-0x0-et du 3-methyl-2-0x0-5a-cholestane. Les resultats obtenus illustrent le potentiel du dithiane-epoxyde comme ttant une procedure generale attractive et versatile pour I'introduction sttreosptcifique de substituants dans les composes alicycliques. De plus, puisque le noyau epoxyde, de f a~o n trans-diaxiale pour les composts possedant un cycle a six, le substituant est introduit dans I'orientation la moins stable au point de vue thermodynamique. L'isomtrisation subsequente en isomere equatorial plus stable est alors possible e t a partir de cela, les deux epimeres peuvent itre obtenus a partir de la m&me sequence de synthtse.Canadian Journal of Chemistry, 50, 810 (1972) As a result of our interest in the mechanism of action of the A5+A4-3-ketoisomerase of P. testosteroni (la. b) we became interested in , , , developing convenient and versatile routes to stereospecifically substituted steroids suitable for "mapping" the active site of the enzyme. Of the general routes surveyed those based on a lithiodithiane-epoxide reaction appeared the most attractive and examples of the feasibility and advantages of this approach have been reported in communication form (lc). This note records the experimental and other details omitted from the preliminary communication since it is now apparent that the human resources required to continue the project as originally planned are unlikely to become available in the foreseeable future.The possibilities of achieving a satisfactory general method for introducing substituents into the steroid nucleus by exploiting the properties of epoxides was drawn to our attention by the previous application of the reactions of As-epoxides with Grignard reagents (2-5). Disappointingly, this approach to the stereospecific introduction of alkyl groups did not 'For part XI1 see ref. la. prove to be universally applicable since when the epoxide was not located at a ring junction, ring contraction predominated with both steroidal (6) and cyclohexene oxide (7) reactiom2 However, the fact that the latter compound underwent the expected ring opening with 2-lithio-1,3-dithiane (9a, b) indicated that similar reactions could be expected in the ...