Formal synthesis of optically active ingenol via ring-closing olefin metathesis

J Org Chem. 2004 Nov 12;69(23):7802-8. doi: 10.1021/jo048833l.

Abstract

The construction of strained carbon skeletons by ring-closing olefin metathesis (RCM) was investigated. With well-designed diene 4, RCM was found to be applicable to the formation of a highly strained inside-outside bicyclo[4.4.1]undecane skeleton of ingenol, a bioactive diterpenoid, and formal total synthesis of optically active ingenol (1) was achieved. The key features of this synthesis are construction of an A-ring by spirocyclization of the ketone with an allylic chloride unit, 26, and ring closure of a B-ring by olefin metathesis. Starting from Funk's keto ester 6, the key intermediate aldehyde 9 in Winkler's total synthesis was synthesized in eight steps in 12.5% overall yield. This strategy of direct cyclization of a strained inside-outside skeleton provided the first easy access to optically active ingenol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkenes / chemistry*
  • Cyclization
  • Diterpenes / chemical synthesis*
  • Molecular Conformation
  • Molecular Structure
  • Stereoisomerism

Substances

  • Alkenes
  • Diterpenes
  • ingenol