Catalytic Asymmetric Synthesis of Unprotected β2-Amino Acids

We report here a scalable, catalytic one-pot approach to enantiopure and unmodified beta(2)-amino acids. A newly developed confined imidodiphosphorimidate (IDPi) catalyzes a broadly applicable reaction of diverse bis-silyl ketene acetals with a silylated aminomethyl ether, followed by hydrolytic workup, to give free beta(2)-amino acids in high yields, purity, and enantioselectivity. Importantly, both aromatic and aliphatic beta(2)-amino acids can be obtained using this method. Mechanistic studies are consistent with the aminomethylation to proceed via silylium-based asymmetric counteranion-directed catalysis (Si-ACDC) and a transition state to explain the enantioselectivity is suggested on the basis of density functional theory calculation.

Automated summary

A scalable catalytic approach for enantiopure and unmodified beta(2)-amino acids was developed, utilizing a confined imidodiphosphorimidate (IDPi) catalyst and a silylated aminomethyl ether. Both aromatic and aliphatic beta(2)-amino acids can be obtained in high yields, purity, and enantioselectivity. Mechanistic studies suggest the reaction proceeds via silylium-based asymmetric counteranion-directed catalysis (Si-ACDC) with a proposed transition state for explaining enantioselectivity based on density functional theory calculations.