New Metal-Catalyzed Reactions for the Synthesis of Bioactive Agents

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The increasing cost of drug discovery because to the low success rate of clinical candidates progressing through the various phases of drug development (0.2%), has prompted serious analysis of the factors that contribute to the failure rate. For example, the average cost to market a new drug is in excess of $1 billion, in which only one out of ten drugs generate enough revenue to cover the research and development costs. Additionally, despite the advent of new technologies, pharmaceutical productivity levels have not dramatically increased over the last decade. A recent study illustrated that the number of saturated-carbon atoms, particularly ones that are stereogenic, and the reduction in the number of aromatic rings correlates with an agent's successful transition from drug discovery to a marketable entity. Hence, the escalating costs of drug-discovery coupled with the drive to prepare drugs in a more cost effective manner, provides a compelling mandate to develop new and more powerful methods for preparing architecturally challenging pharmacologically active agents in a predictable and expeditious manner. In this proposal, we outline the development of new transition metal-catalyzed reactions that facilitate the construction of structural motifs that are generally not accessible via conventional methods. The proposal also addresses the critical and ongoing challenge with synthetic methods development, in that relatively simple changes in a substrate can present unforeseen challenges that limit the scope of the chemistry. Hence, these obstacles often require time consuming and costly studies to optimize a specific chemical process, because of the lack of insight into the way it works. We have a longstanding program in the development of new catalytic reactions using theoretical and mechanistic insight to provide unique solutions to challenging problems that address these types of knowledge gaps. Hence, in contrast to enzymes, which evolve through multiple iterations, i.e. evolutionary development, our approach provides unique insight into new chemical reactivity and thereby leads to the development of more robust and general methods. We anticipate that our program will continue to make significant contributions in the development and understanding of methods that facilitate the construction of complex molecules in an efficient, selective and atom-economical manner. Hence, this proposal will significantly expand the current "tool-kit" of chemical reactions through the development of innovative and cutting-edge synthetic methods, which provides world-class environment for HQP training. In addition, the budget reflects the commitment to training HQP (>70% of the total costs), which will enhance the reputation of synthetic organic chemistry in Canada with high-profile publications and seminars that are widely disseminated, which address the aforementioned problems.