Synthesis of 3β-tert-Butyldimethylsiloxy-22-phenylthio-23,24-bisnorchola-5,9(11)-diene and Reductive Nucleophilic Attack on a Branched Aliphatic Aldehyde

Chem Pharm Bull (Tokyo). 2018;66(3):334-338. doi: 10.1248/cpb.c17-00979.

Abstract

3β-tert-Butyldimethylsiloxy-22-phenylthio-23,24-bisnorchola-5,9(11)-diene, which has a double bond between C-9 and C-11 and a phenylsulfenyl group on the terminus of the side chain, is a potential synthetic intermediate for steroids with 9,11-unsaturation or 9,11-seco skeletons. We describe here the synthesis of the title compound from 17-ethylenedioxy-3-acetoxyandrosta-3,5-dien-11-one. The introduction of an ethylene unit to 3β-tert-butyldimethylsiloxyandrosta-5,9(11)-dien-17-one by the action of ethyltriphenylphosphonium bromide under basic conditions resulted in an inseparable mixture of two stereoisomeric products (5 : 1). However, in the subsequent step, only the (Z)-isomer was susceptible to the Lewis acid-catalyzed ene reaction with formaldehyde, giving a stereochemically pure product with the desired configuration. Within three steps, the ene-product was derivatized to the title compound, with a total yield of 53% over seven steps. Reductive terminal anion formation by treatment with lithium di-tert-butylbiphenyl (LiDBB) and subsequent nucleophilic attack on a branched aliphatic aldehyde was demonstrated, with an eye toward the introduction of side chains, especially for steroids with oxygen functionality at C-23.

Keywords: ene reaction; lithium di-tert-butylbiphenyl (LiDBB); phenyl sulfide; pregna-5,9(11),17(20)-triene; reductive nucleophilic attack.

MeSH terms

  • Aldehydes / chemistry*
  • Androstenes / chemical synthesis*
  • Androstenes / chemistry
  • Catalysis
  • Cholic Acids / chemical synthesis
  • Cholic Acids / chemistry*
  • Coordination Complexes / chemistry
  • Lewis Acids / chemistry
  • Lithium / chemistry
  • Oxidation-Reduction
  • Stereoisomerism

Substances

  • Aldehydes
  • Androstenes
  • Cholic Acids
  • Coordination Complexes
  • Lewis Acids
  • norcholic acid
  • Lithium