The Application of Metallated Enamines to the Synthesis of Morphine Alkaloids

Author: Mitch, Charles Howard

Year: 1982

Degree: Dissertation (Ph.D.)

Advisor: Grubbs, Robert H.

Committee Members: Evans, David A.; Dervan, Peter B.; Goddard, William A., III; Grubbs, Robert H.

Option: Chemistry

DOI: 10.7907/vf0x-tn08

Abstract

Metallated enamines have been used to prepare a number of morphine-based analgesics, including efficient entry to the 4a-phenylisoquinolines and morphinans. Stereocontrolled formation of both cis and trans-fused perhydroisoquinolines has been accomplished by either kinetic or thermodynamic protonation of the corresponding octahydroisoquinoline. Reaction of 4a-phenyloctahydroisoquinolinium perchlorates with diazomethane afforded the expected aziridinium perchlorate with a component of direct cyclization to the morphinan structure also observed. Kornbloom oxidation to the α-amino-aldehyde was accomplished on treatment of the aziridinium salts with dimethyl-sulfoxide. The aldehydes were cyclized to the morphinan structure on reaction with boron trifluoride etherate, providing ready access to intermediates used by Gates in his pioneering total synthesis of morphine.

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