Formal synthesis of (−)-morphine from d-glucal based on the cascade Claisen rearrangement

Abstract

The formal synthesis of (−)-morphine is described. The C-ring in morphine was prepared in an optically pure form from d-glucal using Ferrier’s carbocyclization reaction, and the vicinal tertiary and quaternary stereocenters in the C-ring were stereoselectively generated in a one-step reaction based on the cascade sequential Claisen rearrangement of an allylic vicinal diol derivative. After the one-step formation of the dibenzofuran structure, the intramolecular Friedel–Crafts type reaction effectively constructed the ABCE-phenanthrofuran skeleton. Introduction of a tosylamide function, followed by reductive cyclization furnished (−)-dihydroisocodeine, the known synthetic intermediate for (−)-morphine.