Unnatural α-amino acids with sterically congested centers are valuable in pharmaceuticals and materials science, yet their synthesis mechanism remains unclear. This study uses DFT calculations to clarify the mechanism of Cu-catalyzed C(sp3)-H alkylation of amino acid Schiff bases with tertiary alkyl bromides for constructing such compounds. Key findings include the following: the reaction proceeds via a Cu(II)-Cu(I)-Cu(II) redox cycle without Cu(III) intermediates; Cu(II)-acetate promotes aza-allyl radical (R1·) formation through single-electron transfer (SET); the tertiary alkyl radical (R2·) is generated via halogen-atom transfer (XAT) by the Cu(I)-deprotonated Schiff base complex rather than the previously proposed Cu(I)-acetate complex; and R1· preferentially undergoes heterocoupling with R2· over homocoupling to form the desired product. These findings clarify experimentally ambiguous mechanistic issues, explain why the expected heterocoupled product rather than self-coupled byproducts is obtained, and provide important theoretical insights for developing efficient synthetic methods for unnatural α-amino acids.
Peng et al. (Tue,) studied this question.