Chiral Lithium Amides: Advancements in Methodology and Applications in Complex Molecule Synthesis

Chiral lithium amides (CLAs) have evolved from specialized reagents for enantioselective deprotonation into versatile platforms enabling diverse asymmetric transformations of ketones, carboxylic acids, and heterocycles. Building on Koga's foundational work, recent advances have dramatically expanded this area of research to include asymmetric alkylation, conjugate additions, construction of tetrasubstituted carbon centers, sigmatropic rearrangements and functionalization of complex substrates including an array of carboxylic acids and heterocycles. The synthetic utility of these methods is validated through applications in total synthesis of structurally complex natural products such as pinnatoxin A, hyperforin, dragmacidin D, as well as the synthesis of pharmaceutical agents and successful implementation in process chemistry. This review emphasizes recent methodological innovations, mechanistic foundations, strategic applications in complex molecule synthesis, and opportunities for future development.