Induced-Fit Chiral N-Heterocyclic Carbene Ligands for Asymmetric Catalysis

ConspectusAsymmetric transition-metal catalysis stands as a cornerstone in the construction of molecules with stereogenic centers, profoundly impacting modern organic synthesis. Over the past decades, catalytic asymmetric synthesis has witnessed remarkable advancements, largely driven by the development of sophisticated chiral ligands. While chiral phosphorus ligands have experienced rapid growth and widespread application, chiral N-heterocyclic carbene (NHC) ligands remain underexplored, primarily due to the inherent challenges in designing and synthesizing suitable chiral frameworks. Given the unique topology and modular steric environment of NHCs, the development of novel NHC ligands holds significant promise.In our pursuit of broadly applicable and privileged catalysts with innovative structural motifs, we have developed a family of induced-fit chiral NHC ligands based on the privileged chiral fragment strategy using a C₂-symmetric chiral aniline. These ligands are characterized by their ease of structural modification, bulky yet flexible nature, and versatile utility in asymmetric metal catalysis. Notably, they can be synthesized on a large scale from inexpensive starting materials without the need for column chromatography, offering a modular and straightforward preparation method that facilitates further exploration of their applications in asymmetric reactions. In this Account, we summarize recent progress in our group regarding the diverse and unique applications of these induced-fit NHC ligands in Pd-, Ni-, and Cu-catalyzed asymmetric reactions, encompassing reaction types, substrate scope, stereocontrol steps, and mechanistic insights. Our work is categorized into five sections based on reaction types: asymmetric cross-coupling reactions, asymmetric functionalization of alkenes, asymmetric hydrogen transfer reactions, asymmetric C-H functionalization reactions, and asymmetric nucleophilic addition reactions. These studies demonstrate the broad utility of the ligands in asymmetric catalysis, with their bulky yet flexible nature enabling adaptive stereocontrol across diverse elementary steps and challenging transformations.We anticipate that this Account will not only broaden the application of this class of chiral ligands but also inspire the design of new chiral NHC ligands for transition-metal-catalyzed asymmetric reactions. We believe that continued efforts focused on bulky yet flexible NHC ligands will offer practical solutions to critical challenges in chemical synthesis, further advancing the field of asymmetric catalysis.