Improving Efficiency in Organic Synthesis via Metal and Multimetal Catalysis

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Our objectives are to improve synthetic efficiency when making medicinally interesting scaffolds of bioactive products. Our research directly impacts diverse fields including pharmaceuticals, agrochemicals and materials chemistry. Graduates of the group are highly sought by these industries. Machine learning and design of experiments algorithms are making an increasing and valuable impact on organic synthesis. So too is automation, using rapid screening to reach the optimal set of conditions in a multivariable setting. Yet the invention of new reactions remains one of the essential steps where human ingenuity continues to play a central role.  Doing so can allow exploration of previously unknown chemical space. The drugs of tomorrow will need novel molecular architectures and new methods are needed to access these structures. Our research program aims to invent new metal and multi-metal catalyzed reactions. Our projects to address the challenges of higher efficiency include: Multicatalysis: Chemists have been inventing metal catalysts that are broadly substrate-selective yet still reaction-specific. We have coined our approach multicomponent-multicatalyst reactions, (MC)2R, as a strategy to build up complex products from simple building blocks through "time-resolved" synthetic sequences each promoted by a different metal complex. We observe selectivity due to i) preferential binding between ligand and metal or ii) preferential rate increases of one metal-ligand complex over other possible complexes. Our prior work focused on expensive metals such as rhodium and palladium but our next generation (MC)2R will use base metals such as nickel, copper and cobalt. Furthermore, we will be building ligand scaffolds that can simultaneously bind more than one metal to create an "assembly line" ligand that could show rate acceleration. The ultimate goal is to use (MC)2R to find new reactions. Isomerization Reactions: The invention of reactions wherein all the atoms of the starting material(s) appear in the product are needed. We seek reactions that increase complexity but minimize waste. "Atom efficiency" is an important objective, particularly catalytic reactions that use less solvent. We recently found base metals including nickel catalyzes novel C-C & C-X bond-forming reactions and this is a key area outlined in the proposal. Domino Reactions: We will be developing enantioselective routes to useful carbo- and heterocyclic compounds based on domino reactions. We have recently reported copper catalyzed domino "click"-cyclization reactions and will be building on this emerging area. We have also found asymmetric borylcupration domino reactions and will explore the synthetic potential of this reaction in making heterocyclic scaffolds. Cobalt is an attractive metal for catalysis and we identified a domino process involving cyclization and C-H activation as key steps. The proposal outlines how we will explore the synthetic potential of this methodology.