Enantioselective Synthesis of (S)-γ-Fluoroleucine Ethyl Ester

Significance

A concise synthesis of (S)-γ-fluoroleucine ethyl ester is reported. An enantioselective Ti-catalyzed ene reaction of ethyl glyoxylate with isobutene afforded the desired α-hydroxy ester in excellent enantioselectivity. Addition of HF to the terminal double bond gave the fluorinated intermediate, which was subsequently converted into the final product by triflation, S_N2 substitution by BnNH₂ and benzyl group deprotection using Pearlman’s catalyst. The final product was obtained in 95% ee and 25% overall yield in five steps.