Enantioselective Total Synthesis of (+)-and (-)-Asenapine.

Asenapine is a pharmacological agent used in the treatment of schizophrenia and bipolar disorders. Both (+)- and (-)-asenapine exhibit favorable plasma concentrations in rats and mice; however, the (+)-isomer demonstrates superior efficacy. We report herein a successful enantioselective total synthesis of both enantiomers of asenapine. The key sequence involved Evans' chiral auxiliary-assisted Michael addition of a vinyl Grignard reagent, followed by a sodium borohydride-mediated one-pot removal of the auxiliary and lactone formation. The asymmetric 1,4-addition of vinyl Grignard provided the diastereomers in excellent yield with a 5.9:1 dr and 98% ee. The opposite isomer, (-)-asenapine, was accessed using the enantiomeric Evans auxiliary under identical conditions.