PAd-dalPhos: a new ligand class for nickel-catalyzed cross-coupling

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Transition metal catalysts have proven to be effective in enabling the transformation of simple molecules into more complex, value-added products under mild conditions. Modern pharmaceutical synthesis relies heavily on the application of molecular palladium catalyst complexes to enable cross-coupling reactions that are utilized in the construction of C-C, C-N, C-O and other bonds found within sought-after drug molecules. Such catalyst complexes are comprised of a palladium-based fragment that is bound to an electron-donating ancillary ligand molecule ("ligand"). The judicious choice of ligand is crucial in terms of enabling the successful outcome of a given palladium-catalyzed reaction of interest. In this regard, a number of proprietary ligand classes have been developed and commercialized for use in the pharmaceutical industry, as well as in academic research. However, palladium is both expensive and relatively low in abundance, and ligands used with palladium are often more expensive (per-mole) than palladium itself. This provides motivation for the development entirely new classes of inexpensive ligands that enable nickel (ca. 1000X cheaper than palladium) to do the work of palladium. The requested funds are sought to accelerate the development and optimization of our novel "PAd-DalPhos" ancillary ligands (Fig. 1, PhosphaADamantane-DALhousie PHOSphine), and derived nickel pre-catalysts, for use in sought-after nickel-catalyzed cross-coupling reactions that are of relevance to the pharmaceutical industry, in particular amination. Having secured provisional patent protection, and in an effort to accelerate the development of this promising technology in order to promote commercialization, this proposal seeks to carry out key R&D work that will allow us to: (a) optimize our lead ligand prototype, so as to broaden our patent claims regarding composition of matter; (b) assess the utility of PAd-DalPhos ligand variants and their derived nickel pre-catalysts in enabling pharmaceutically relevant nickel-catalyzed reactions for which expensive palladium catalysts are normally employed; and (c) evaluate the shelf-life of optimized PAd-DalPhos ligand variants and their derived nickel pre-catalysts under user-friendly benchtop conditions.