Enantioselective synthesis of (-)-codeine and (-)-morphine.
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.
Trost
Barry M
BM
Department of Chemistry, Stanford University, Stanford, California 94305-5080, USA. bmtrost@stanford.edu
Tang
Weiping
W
D000701:Analgesics, Opioid / Q000138:chemical synthesis*; D003061:Codeine / Q000138:chemical synthesis*; D009020:Morphine / Q000138:chemical synthesis*; D013237:Stereoisomerism
D000701:Analgesics, Opioid; D009020:Morphine; D003061:Codeine