Carboxylation of ammonium ylides with CO2 for the synthesis of α-amino acids: integrating experimental and computational approaches

Abstract α-Amino acids and their derivatives are crucial in bio- and pharmaceutical chemistry. There are numerous synthetic methods for producing α-amino acids. In particular, the utilization of carbon dioxide (CO2) has recently garnered significant attention owing to its abundance, low cost, low toxicity, and renewability. In this CO2-based approach, the generation of α-amino carbanions is a critical step. However, the formation of α-amino carbanions typically requires highly basic organometallic species, which reduce the functional group tolerance of the substrate. Ammonium ylide species have emerged as useful intermediates in amino acid synthesis, addressing the challenges associated with carbanion generation. The position adjacent to the ammonium nitrogen is readily deprotonated owing to the inductive effect of the ammonium cation, forming ammonium ylide. Ylides can also be generated easily from the reaction between a carbene and an amine. This article reports carboxylation reactions of ammonium ylide derivatives to synthesize α-amino acid derivatives, including α,α-difluoroglycine analogues. The latter reaction can be designed using computational reaction path searches with the artificial force induced reaction (AFIR) method, which offers significant advantages in organic synthesis.