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

Abstract 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.