Catalytic Methods for Organic Synthesis

PROJECT SUMMARY Transition-metal-catalyzed cross-coupling reactions are among the most important methods for the synthesis of pharmaceuticals and enable facile preparation of molecules essential for synthetic chemistry, medicinal chemistry and pharmaceutical purposes. Further advancement in the field of cross-coupling is closely tied to (1) the development of new broadly applicable cross-coupling precursors, and (2) the design of new highly active catalysts that allow rapid access to important pharmaceutically relevant structural motifs. The goal of our research for the next five years is to develop new, highly active, electron-rich, flexible catalysts and NHC-metal (NHC = N-heterocyclic carbene) complexes to access chemical transformations, mechanisms and concepts of high synthetic value that are not readily available or limited by other methods. Over the past five years, the PI’s laboratory has been focused on (1) the development of a new reaction manifold of carboxylic acids that permits rapid access to metal electrophiles from ubiquitous carboxylic acids, and (2) the development of new classes of well-defined metal catalysts based on NHC ligands. In the past five years, the laboratory has developed several new classes of NHC ligands and NHC- metal complexes. These catalysts include (1) sterically-hindered NHC ligands based on aniline peralkylation, (2) rapidly dissociating [Pd(NHC)(µ-Cl)Cl]2 chloro dimer catalysts, (3) well-defined Pd(II)-NHC catalysts bearing anilines as ancillary ligands, (4) unsymmetrical, adjustable and sterically-flexible NHC ligands, (5) sterically- defined biaryl NHC ligands based on imidazo[1,5-a]pyridine-3-ylidene architecture, (6) amino-decorated imidazo[1,5-a]pyridine-3-ylidenes, (7) sterically-hindered N-alkyl NHC ligands, (8) freely-rotatable NHC ligands, (9) abnormal, sterically-differentiated and strongly s-donating 1,2,3-triazol-5-ylidenes, (10) sterically-hindered CAAC ligands, (11) bifunctional NHC ligands. The ligands and catalysts have been commercialized in collaboration with MilliporeSigma to enable broad access of academic and industrial researchers. In the area of carboxylic acid cross-coupling, the PI has developed a series of decarbonylative transformations with a focus on biaryl, heterobiaryl, alkynyl and heteroatom cross-coupling. A collaboration with Pfizer has established the utility of carboxylic acid building blocks in pharmaceutical research. Our studies will outline the synthesis and generation of catalysts that promote a broad range of important processes by controlling elementary steps of the catalytic cycle and processes that are currently beyond the scope of current methods, including functionalization of p-systems and activation of C–F, C–O, C– S and C–N bonds as well as C–C, C–N and C–X cross-coupling reactions that are routinely employed in the most important pharmaceutical transformations. The new catalytic methods and catalysts targeted by our research program will significantly advance the ability of synthetic chemists to develop structural motifs for the construction of bioactive molecules.