Chemoenzymatic enantiodivergent total syntheses of (+)- and (−)-codeine

Whole-cell fermentation of β-bromoethylbenzene with the recombinant strain Escherichia coli JM109 (pDTG601) that over-expresses toluene dioxygenase provided the corresponding cis-dihydrodiol 19, which served as a starting material for both enantiomers of codeine. The key intermediate for the synthesis of (+)-codeine was diol 25b, whose Mitsunobu coupling with bromoisovanillin was followed by an intramolecular Heck cyclization to aldehyde 35b. Elaboration of this material to vinyl bromide 27b allowed for the second Heck cyclization 36b. Adjustment of the C-6 stereogenic center and hydroamination completed the synthesis of ent-codeine in 14 steps from β-bromoethylbenzene. Diol 33b was converted via Mitsunobu reaction to epoxide 29, whose allylic opening with bromoisovanillin provided ether 54, the enantiomer of 35b. The synthesis of (−)-codeine was completed via two Heck cyclizations and a hydroamination protocol, in an analogous manner as that of ent-codeine. In addition, both enantiomers of epoxide 29, convenient precursors for the coupling with bromoisovanillin, were prepared from diol 33b by Mitsunobu reactions and cyclizations of the trans-diol moiety. Spectral and experimental data are provided for all compounds.