Asymmetric Synthesis of (S)‐5,5,5,5′,5′,5′,5′‐Hexafluoroleucine

Abstract (S)‐5,5,5,5′,5′,5′‐Hexafluoroleucine ((S)‐13) of 81 % ee is prepared from hexafluoroacetone (l) 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 α‐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)‐ l‐phenylethyl]‐5,5,5,5′,5′,5′‐hexafluoroleucine ethyl ester.