Synthesis of (Z)-Fluoroalkene-type Dipeptide Isosteres Utilizing Organocopper- or SmI₂-medated Reduction

Abstract

(Z)-Fluoroalkene-type dipeptide isosteres have served as potential dipeptide mimetics, where the peptide bond within a parent dipeptide is replaced by fluoroolefin units. Previously, we found that γ-phosphono-γ,γ-difluoro-α,β-enoate was reduced to the corresponding γ-phosphono-γ-fluoro-β,γ-enoate with organocopper reagent. This organocopper-mediated reduction has been successfully applied to the synthesis of the fluoroalkene isosteres. Mechanistic investigation of the organocopper-mediated reduction led us to envision that single electron transfer is responsible for the reduction and SmI₂, a powerful one-electron reducing agent, should be applicable to the synthesis of the isosteres. Reduction with SmI₂ proceeded via formation of the Sm-dienolate which upon kinetically controlled trapping with t-BuOH or a carbonyl compound yielded Xaa-Gly-type or α-substituted isosteres, respectively.