Guanidine-Amide-Based Chiral Organocatalysts and Ligands for Asymmetric Catalysis

Conspectus Guanidine exhibits both similarities and differences compared to amines, endowing it with unique catalytic properties. The synthesis of chiral guanidine organocatalysts has garnered significant interest, focusing on three primary guanidine backbones: bicyclic, monocyclic, and open-chain structures. Acyclic guanidines, while more synthetically accessible than their cyclic counterparts, present challenges due to their flexible conformations and multiple substitution patterns. Moreover, the potential of chiral guanidine ligands in metal complex catalysis remains largely underexplored. Our research group has been actively exploring chiral guanidine-amide-based asymmetric catalysis since 2009. The design strategy for these catalysts is rooted in the bifunctional capabilities of amino acids, which are easily functionalized into acyclic guanidine amides. These compounds incorporate new Brønsted base units and hydrogen bond donors. The readily tunable structure of guanidine amides allows five forms, including monoguanidine amide ( GA ), bisguanidine and its hemisalt ( GB ), guanidine sulfonamide ( GC ), hybrid guanidine amide–pyridine ( GD ), and quaternary guanidinium salt ( QG ). The applications of these compounds in asymmetric catalysis can be driven into four modes based on the role of guanidines: organocatalysis, organo-metal synergistic catalysis, guanidine/transition metal complex catalysis, and phase-transfer catalysis. First, as bifunctional organocatalysts through base/H-bond activation, guanidine derivatives have demonstrated exceptional diastereo- and enantioselectivity in a wide range of reactions including polar addition and cascades, cyclization, substitution, and insertion, etc. In these cases, abundant and labile H-bond interactions from both guanidine and amides account for the high diastereo- and enantioselectivity. Second, the combination of chiral guanidines with achiral dirhodium salts enabled synergistic catalysis to activate the reaction partners simultaneously, where the guanidine unit is disclosed as a proton shuttle or a chalcogen bond acceptor. Third, the copper complexes of guanidine amides and hybrid guanidines could promote both polar and radical reactions. The unique performance of these new catalysts lies in either bifunctional catalysis via a combination of metal coordination and H-bond assistance or rich electronic and coordination properties to leverage the redox ability of the catalytic species. In addition, the quaternary guanidinium salt has emerged as an effective bifunctional phase-transfer catalyst for tackling the challenging enantioselectivity issue in asymmetric α-aromatization of arynes. In this Account, we recount the development of a series of chiral guanidine-amide-based organocatalysts and ligands derived from amino acids. Their applications are meticulously selected from a diverse array of asymmetric reactions, highlighting the evolution of their structures, functionalities, and mechanistic features. Special emphasis is placed on the key factors that contribute to high stereoselectivity in representative catalytic processes.