Reflexive Chirality Transfer (RCT): Asymmetric 1,3-Dipolar Cycloaddition of α-Amino Acid Schiff Base with Nonchiral...

Although optically pure α-amino acids are ubiquitous, their chirality is usually lost during the α-C-H deprotonation. Consequently, precious chiral catalysis has been necessary to synthesize optically active α-tetrasubstituted unnatural α-amino acid derivatives, even when starting with optically pure α-amino acids. However, here, we report a catalytic asymmetric 1,3-dipolar cycloaddition that preserves the α-carbon chirality of α-amino acid derivatives. This process directly converts readily available optically active α-amino acid Schiff bases into optically active α-tetrasubstituted pyrrolidine derivatives without external chiral additives, despite the temporary loss of α-carbon chirality through the formation of planar 1,3-dipole intermediates. Mechanistic studies revealed that the α-carbon chirality of the α-amino acid Schiff base is transiently transferred to metal-centered chirality in enolates and subsequently restored as the carbon-centered chirality of the products. This conceptually novel "reflexive chirality transfer (RCT)" strategy offers a simple and cost-effective approach to optically active unnatural α-amino acid derivatives, addressing the current limitations of chiral pool synthesis.