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

Key words

α-trifluoromethyl prolines - oxazolidinones -

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.

Comment

The growing interest of fluorinated analogues of proline is based on control of the cis-trans isomerization of prolyl bonds in oligopeptides (R. Golbik et al. Biochemistry 2005, 44, 16026-16034) and for the design and synthesis of enzyme inhibitors (L. Chen et al. J. Org. Chem. 2006, 71, 5468-5473; D. D. Staas et al. Bioorg. Med. Chem. 2006, 14, 6900-6916). Among the available methods for the synthesis of fluoro-substituted prolines (e.g., J. R. Del Valle, M. Goodman Angew. Chem. Int. Ed. 2002, 41, 1600-1602), few are known for the introduction of a fluorinated group in the α-position (M. Eckert et al. Org. Lett. 2005, 7, 3741-3743). The synthesis of racemic ethyl α-difluoromethylproline ester has been recently reported (J. Zhu et al. Tetrahedron Lett. 2005, 46, 2795-2797). The current method appears to be unique for the synthesis of both enantiopure α-trifluoromethyl prolines and may contribute to further studies of these unnatural amino acids.