Stable Carbenes: Emerging Ligands for Catalysis

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DESCRIPTION (provided by applicant): Efficient and selective preparation of organic molecules is critical for the synthesis of therapeutics. Many of the most proficient known processes depend on the availability of catalysts. One of the advantages of organometallic catalysis is the ability to tune the activity and selectivity through modification of the ligands around the metal center. Recently, major advances in catalysis, especially in Pd-cross-coupling reactions, have been reported thanks to the use of bulky, electron-rich phosphines and cyclic diaminocarbenes (NHCs). The proposed research program, built on our long standing experience in stable carbene synthesis, has as its objective the synthesis of cyclic carbenes that push upward the electronic and/or steric parameter scales characterizing both phosphine and NHC ligands, with special attention on families of ligands for which it will be possible to precisely tune the stereo-electronic parameters. There is a demanding need for technology to produce therapeutics in a pure enantiomeric form. For the asymmetric versions of the ligands, carbenes with a chirality center in a position alpha to the carbene, and bidentate ligands featuring C2 chirality and two very different donors will be prepared; this should result in high chiral induction effects. We will focus on palladium-catalyzed coupling reactions of aryl chlorides (Suzuki-Miyaura and Negishi processes) and on the alpha-arylation of aldehydes/imines. Thanks to this virtually unknown reaction, and because of the prominent role played by indoles in biological systems, we will develop a novel one-pot synthesis of a variety of indoles from imines and ortho-dihaloarenes. To accelerate the widespread implementation of our ligands, we have already formalized two collaborations and we are looking forward to further partnerships. The ultimate goal of this proposed research effort is to provide the catalytic community with new, readily available ligands, which will allow for the development of practical catalysts that will find applications in both industry and academia for the selective synthesis of biologically important compounds.