Enantioselective synthesis of (-)-codeine and (-)-morphine

J Am Chem Soc. 2002 Dec 11;124(49):14542-3. doi: 10.1021/ja0283394.

Abstract

A new synthetic strategy for the synthesis of the opiate and amaryllidaceae alkaloids emerges employing a Pd-catalyzed asymmetric allylic alkylation to set the stereochemistry. The pivotal tricyclic intermediate is available in six steps from 2-bromovanillin and the monoester of methyl 6-hydroxycyclohexene-1-carboxylate, the latter available from glutaraldehyde and the Emmons-Wadsworth-Horner phosphate reagent. This intermediate requires only two steps to convert to (-)-galanthamine. Using a Heck vinylation, we found that the fourth ring of codeine/morphine is 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, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Analgesics, Opioid / chemical synthesis*
  • Codeine / chemical synthesis*
  • Morphine / chemical synthesis*
  • Stereoisomerism

Substances

  • Analgesics, Opioid
  • Morphine
  • Codeine