An efficient synthetic method for Z-fluoroalkene dipeptide isosteres: Application to the synthesis of the dipeptide isostere of Sta-Ala

Reaction of γ,γ-difluoro-α,β-enoates having a δ-hydroxyl group with trialkylaluminum (R3Al) was found to be promoted by CuI·2LiCl and to proceed in SN2′ manner giving rise to the α-alkylated (Z)-γ-fluoro-β,γ-enoates, while reductive defluorination of γ,γ-difluoro-α,β-enoates with Me2CuLi followed by reaction with alkyl halides provided the corresponding (Z)-α-alkylated products in high yields. The latter reaction was applied to the preparation of the dipeptide (Z)-fluoroalkene isostere of Sta-Ala, which is the central dipeptide unit in Pepstatin, a natural inhibitor of aspartate proteases.