Biosynthesis of the Amaryllidaceae alkaloid galanthamine

Application of radioactively as well as C-13-labelled 4'-O-methylnorbelladine to organs of field grown Leucojum aestivum plants resulted in an optimal incorporation into galanthamine (27%), and N-demethylgalanthamine (31%), respectively. In contrast to expectations based on results from the literature, the N-methylated 4'-O-methylnorbelladine was metabolized into a minor extent in L. aestivum and was incorporated into galanthamine as well as into N-demethylgalanthamine to only about 1/3 of the rate of 4'-O-methylnorbelladine. Furthermore, it was shown that N-demethylgalanthamine is N-methylated to galanthamine in the final step of biosynthesis. A revised scheme for the biosynthesis of galanthamine is presented involving the phenol oxidative coupling of 4'-O-methylnorbelladine to a postulated dienone which undergoes spontaneous closure of the ether bridge to yield N-demethylnarwedine which upon stereoselective reduction and N-methylation yields the cholineesterase inhibitor galanthamine. (C) 1998 Elsevier Science Ltd. All right reserved.