A Formal Synthesis of (±)-Morphine

Key words

morphine - opioids - kinetic protonation - iminium aziridination - Kornblum oxidation - Lemieux–Johnson reaction

Significance

In 1982, Evans and Mitch disclosed an elegant route to access the core of morphine alkaloids. Their synthetic route provides access to an intermediate from Gates’ seminal morphine synthesis (J. Am. Chem. Soc. 1956, 78, 1380). ­Evans’ formal synthesis, which features an unusual Kornblum oxidation as its centerpiece, accesses known tetracycle J, which can be transformed into the natural product in nine additional steps.

Comment

Metalation and double alkylation of C affords enamine E which is, under kinetic conditions, transformed into the cis-configured iminium F. A subsequent aziridination and Kornblum oxidation sequence gives rise to α-amino aldehyde H. A Friedel–Crafts-type reaction of H affords tetra­cycle I, which is then elaborated into known intermediate J, thereby completing the formal synthesis of (±)-morphine.

Publication History

Article published online:
13 September 2024