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

Abstract

We describe a novel and useful method for the synthesis of nonracemic α-trifluoromethyl α-amino acids (α-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 α-Tfm α-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 increasing 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 α-Tfm-AAs 16−22. The sulfinyl auxiliary can be regenerated and recycled.