Ethanol-assisted mechanochemical asymmetric cross-dehydrogenative coupling reaction with recoverable chiral amine/NaCl for accessing chiral α-alkyl α-glycine derivatives

Abstract

Chiral α-alkyl α-glycine acids are prevalent structural motifs found in pharmaceuticals and natural products, making them a significant dimension for exploration in modern pharmaceutical and medicinal chemistry. However, the current synthesis methods for these compounds face numerous environmental and practical challenges, highlighting the critical need to establish more sustainable approaches. Herein, we report the first liquid assisted grinding (LAG)-facilitated aerobic asymmetric cross-dehydrogenative coupling reaction involving glycine esters/amides and simple ketones/aldehydes, using a chiral amine catalyst under metal-free and solvent-minimal conditions. A wide variety of α-alkyl α-amino acid derivatives, containing two or three stereocenters, were generated in good yields with remarkable enantioselectivity and diastereoselectivity. Moreover, we propose a new enantioselective control model for mechanical ball milling, suggesting that stoichiometric EtOH may enhance the enantioselectivity by potentially interacting with both the catalyst and the imine ion intermediate. This method, closely aligned with the principles of green chemistry, offers a recoverable catalyst/grinding-aid system, has broad substrate compatibility, and enables the synthesis of multifunctionalized products suitable for diverse transformations, notably including the production of the unnatural amino acid L-cyclohexylglycine (a key intermediate in telaprevir synthesis).