Chemoenzymatic Formal Total Synthesis of ent-Codeine and Other Morphinans via Nitrone Cycloadditions and/or Radical Cyclizations. Comparison of Strategies for Control of C-9/C-14 Stereogenic Centers

Formal total syntheses of ent-codeine and other morphinans were accomplished from 1-phenyl-2-acetoxyethane, which was subjected to enzymatic dihydroxylation by toluene dioxygenase overexpressed in Eschericia coli JM109 (pDTG601A). The resulting cis-dihydroarenediol was coupled with a phenol derived from bromoisovanillin and a subsequent Heck reaction was used to establish the C-13 quaternary center. Two strategies were employed to set the C-14 center: nitrone and nitrile oxide cycloadditions to the C-8/C-14 olefin and a radical cyclization of an aldehyde to C-14. Both strategies yielded tetracyclic products that were converted to known intermediates for the synthesis of ent-codeine, ent-codeinone, and ent-hydrocodone. Experimental and spectral data are provided for all new compounds.