Total synthesis of (-)- and ent-(+)-vindoline and related alkaloids

J Am Chem Soc. 2006 Aug 16;128(32):10596-612. doi: 10.1021/ja061256t.

Abstract

A concise 11-step total synthesis of (-)- and ent-(+)-vindoline (3) is detailed based on a unique tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which three rings and four C-C bonds are formed central to the characteristic pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. As key elements of the scope and stereochemical features of the reaction were defined, a series of related natural products of increasing complexity were prepared by total synthesis including both enantiomers of minovine (4), 4-desacetoxy-6,7-dihydrovindorosine (5), 4-desacetoxyvindorosine (6), and vindorosine (7) as well as N-methylaspidospermidine (11). Subsequent extensions of the approach provided both enantiomers of 6,7-dihydrovindoline (8), 4-desacetoxyvindoline (9), and 4-desacetoxy-6,7-dihydrovindoline (10).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / chemical synthesis*
  • Alkaloids / chemistry
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Cyclization
  • Molecular Structure
  • Stereoisomerism
  • Vinblastine / analogs & derivatives*
  • Vinblastine / chemical synthesis
  • Vinblastine / chemistry

Substances

  • Alkaloids
  • Antineoplastic Agents
  • minovine
  • vindoline
  • Vinblastine
  • vindorosine