Chiral Pyridoxals Enabled Efficient Enantioselective Synthesis of α-Substituted Tryptophan Derivatives

Tryptophan derivatives represent privileged molecular architectures in chemical biology and medicinal chemistry. Although extensive efforts have been devoted to their diversification, tryptophan analogues bearing an α-quaternary stereogenic center are highly bioactive yet synthetically challenging subclass. The direct and modular union of an indole-based electrophilic template with an N-unprotected amino acid nucleophile would provide an exceptionally efficient approach to such α-quaternary tryptophan derivatives. Here we report an axially chiral pyridoxal-catalyzed, enantioselective conjugate addition that forges the key C-C bond between indolenyl vinylogous imino electrophiles and N-unprotected α-substituted glycine esters. Under mild conditions, this organocatalytic protocol delivers structurally diverse α-quaternary tryptophan derivatives in up to 94% yield and 99% ee, and exhibits broad tolerance toward indole ring substitution as well as α-alkyl substituted glycinates. This carbonyl catalysis strategy establishes a modular and efficient platform for accessing α-quaternary tryptophan derivatives, underscoring the unique capability of carbonyl catalysis in the synthesis of structurally complex chiral amine compounds.