Synthesis of Enantiopure (S)- and (R)-α-Trifluoromethyl Proline

Significance

A convenient route to enantiopure α-trifluoromethyl proline is reported. Lewis acid catalyzed allylation of an easily accessible oxazolidinone derived from (R)-phenylglycinol generates a morpholin-2-one derivative in 86-92% yields as a diastereomeric mixture (dr = 69:31 to 75:25), independent of the diastereomeric ratio of the educt. Following PTSA-catalyzed lactonization, hydroboration, and mesylation, the pyrrolidine ­lactone is obtained as a diastereomeric mixture which may be separated by column chromatography. Standard hydrogenolysis affords both enan­tiomers of trifluoro­methyl proline in five steps and up to 36% overall yield.