A Chemoenzymatic Dynamic Kinetic Resolution Approach to Enantiomerically Pure (R)- and (S)-Duloxetine

The synthesis of (R)-duloxetine is described. Dynamic kinetic resolution of beta-hydroxynitrile rac-1 using Candida antarctica lipase B (CALB, N435) and ruthenium catalyst 6 afforded beta-cyano acetate (R)-2 in high yield and in excellent enantioselectivity (98% ee). The subsequent synthetic steps were straightforward and (R)-duloxetine was isolated in 37% overall yield over 6 steps. The synthetic route also constitute a formal total synthesis of (S)-duloxetine.