Divergent enantioselective synthesis of (-)-galanthamine and (-)-morphine

J Am Chem Soc. 2005 Oct 26;127(42):14785-803. doi: 10.1021/ja054449+.

Abstract

An efficient divergent synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges by employing a Pd-catalyzed asymmetric allylic alkylation (AAA) to set the stereochemistry. Three generations of syntheses of galanthamine are discussed in detail with particular focus on the scope of the palladium-catalyzed AAA reactions and intramolecular Heck reactions. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate. This intermediate requires only two steps to convert to (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine could be formed. The final ring formation involves a novel visible light-promoted hydroamination. Thus, six steps are required to convert the pivotal tricyclic intermediate into codeine, which has been demethylated in high yield to morphine.

Publication types

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

MeSH terms

  • Galantamine / chemical synthesis*
  • Galantamine / chemistry
  • Molecular Structure
  • Morphine / chemical synthesis*
  • Morphine / chemistry
  • Stereoisomerism

Substances

  • Galantamine
  • Morphine