Total Synthesis of Dihydrocodeine and Hydrocodone via a Double Claisen Rearrangement and C-10/C-11 Closure Strategy

Abstract

Dihydrocodeine and hydrocodone were synthesized from bromobenzene in 16 and 17 transformations, respectively. The key steps involved the toluene dioxygenase-mediated dihydroxy­lation of bromobenzene by whole-cell fermentation with E. coli JM109(pDTG601A), Kazmaier–Claisen rearrangement of glycinate ester, Claisen rearrangement to set the C-13 quaternary center, and C-10–C-11 closure. Experimental procedures are provided for the key steps.

Key words

enzymatic dihydroxylation of arenes - whole-cell ­fermentation - Kazmaier–Claisen rearrangement - hydrocodone - ­dihydrocodeine - morphine alkaloids

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