Development of Asymmetric Cooperative Gold Catalysis and Beyond

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Cooperative catalysis or catalysis involving metal-ligand cooperation is a highly versatile approach in catalysis that have resulted in a myriad of highly efficient synthetic methods and conferred exceptional value to chemical synthesis of bioactive and/or pharmaceutical compounds. Despite extraordinary advances on this research topic, there are still much need to develop new cooperative systems based on unique ligand designs to enable the development of new and/or much improved synthetic methods for chemical synthesis. In 2014, the PI initiated a program on the development of bifunctional biaryl-2-ylphosphine ligands that are designed to enable cooperative gold(I) catalysis. These ligands feature remote basic groups that can engage bonding interactions with substrates or reagents during catalysis and thereby achieve ligand-metal cooperation. Several preliminary studies, including a ppm-level gold-catalyzed addition of carboxylic acid to alkyne, an asymmetric isomerization of alkyne into allene, and trapping of catalytically generated σ-allenylgold intermediate with aldehyde, have validated the ligand design and the cooperative nature of the catalysis. As the major focus of the PI’s future effort, this proposal seeks to apply this cooperative gold(I) catalysis strategy to the development of asymmetric transformations of exceptional synthetic values. These include expedient construction of chiral butenolids and 2,5-disubstituted pyrrolines and asymmetric propargylation reactions/propargylic C-H functionalizations. The extension of this strategy to much cheaper cooperative Cu(I) and Ag(I) catalysis offers new and distinct opportunities in asymmetric enolate protonation, which would open valuable access to various carbonyl products. The transition to functionalized N,N-bidentate ligands would enable the application of the cooperative ligand design concept to a much broader range of metal catalysis and offer unprecedented opportunities to manipulate carbonyl compounds in asymmetric manners. This proposal, if implemented, would introduce a range of new and versatile chiral bifunctional ligands to metal catalysis and inspire increasing research effort in cooperative catalysis. Moreover, the methods developed would provide efficient access to a variety of chiral structures of high value to chemical synthesis in general and pharmaceutical R&D in particular.