Synthesis of Nonracemic alpha-Trifluoromethyl alpha-Amino Acids from Sulfinimines of Trifluoropyruvate

We describe a novel and useful method for the synthesis of nonracemic á-trifluoromethyl á-amino acids (á-Tfm-AAs). Key building blocks are the sulfinimines (S)-1a and (S)-1b, prepared by Staudinger reaction from trifluoropyruvate esters and the chiral N-sulfinyl iminophosphorane (S)-8, which were treated with benzyl, allyl, and alkylmagnesium halides. The resulting diastereomeric N-sulfinyl á-Tfm á-amino esters, 12 and 13, were produced with moderate to good stereoselectivity and yields. When alkyl Grignard reagents were used, stereocontrol became progressively higher with in-creasing steric bulk, while reversed, though poor, stereocontrol was achieved with benzyl/allyl Grignard reagents. An explanation for the observed stereochemical outcome is proposed, on the basis of the exclusive E geometry (N-sulfinyl and CF3 trans about the C=N bond) of the chiral sulfinimines 1. This assignment is the product of structural correlation and is supported by ab initio calculations and NOE experiments. Sulfinamides 12 and 13 were transformed into a series of nonracemic á-Tfm-AAs 16-22. The sulfinyl auxiliary can be regenerated and recycled.