Synthesis and Reactivity of α-Haloglycine Esters: Hyperconjugation in Action

A general and efficient synthesis of alpha-haloglycine esters from commercially available feedstock chemicals, in a single step, is reported. The reactivity of these alpha-haloglycine esters with various nucleophiles was studied as surrogates of alpha-iminoesters upon activation with hydrogen-bond donor catalysts. DFT calculations on the alpha-haloglycine structures (X = F, Cl, Br) accompanied by an X-ray characterization of the alpha-bromoglycine ester support the existence of a generalized anomeric effect created by hyperconjugation. This peculiar hyperconjugative effect is proposed to be responsible for the enhanced halogen nucleofugality leading to a facile halogen abstraction by hydrogen-bond donor catalysts. This reactivity was exploited with thiourea catalysts on several catalytic transformations (aza-Friedel-Crafts and Mannich reactions) for the synthesis of several types of non-proteinogenic alpha-amino esters.