Asymmetric synthesis of (S)-5,5,5,5′,5′,5′-hexafluoroleucine

(S)-5,5,5,5',5',5'-Hexafluoroleucine ((S)-13) of 81% ee is prepared from hexafluoroacetone (1) and ethyl bromopyruvate (= ethyl 2-oxopropanoate) in 7 steps with an overall yield of 18% (Schemes 1 and 2). Key step in this sequence is the highly enantioselective reduction of the carbonyl group in alpha-keto ester 4 either by bakers' yeast (91% ee) or by 'catecholborane' 6 utilizing an oxazaborolidine catalyst, yielding hydroxy ester (R)-5 with 99% ee. The absolute configuration was determined by X-ray analysis of the HCl adduct (S,R)-9b of (2S)-N-[(R)-1-phenylethyl]-5,5,5,5',5',5'-hexafluoroleucine ethyl ester.