New Metal-Catalyzed Reactions for the Synthesis of Bioactive Agents

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Alchemy represents the origin of synthetic chemistry, which envisioned producing valuable and functional products from readily available and inexpensive starting materials. Consequently, the ongoing desire to prepare value-added compounds with unique functionality aided by the development of new spectroscopic techniques to characterize and confirm their identity led to the evolution of the modern chemical and pharmaceutical industries. Nevertheless, despite these enormous advances, the ability to manufacture metric tons of critical materials in a robust and efficient manner remains an ongoing challenge, with an ever-increasing emphasis on the environmental impact of the processes. For example, the challenges associated with developing and manufacturing drugs highlight synthetic chemistry's current strengths and weaknesses. A recent study revealed that the increasing cost of drug discovery, which is ascribed to the low success rate of clinical candidates progressing through the various phases of drug development (0.2%), is attributed to the relatively simple nature of the drugs. The outcome of this inefficient process is that the average cost to market a new drug now exceeds $1.3 billion (CAD) and that only one out of ten drugs generate enough revenue to cover the research and development costs. The study also concludes that more complex structures improve the successful transition from a lead to a commercial entity. Nevertheless, the increased complexity mandates the development of new, more sophisticated synthetic processes to expand the repertoire of methods that can be deployed for their preparation. GOAL: We plan to develop new chemical reactions that facilitate the construction of challenging structural motifs that are not easily accessible by more conventional methods. The proposal will also address the critical and ongoing challenges that limit the scope of the chemistry, which can be ascribed to the lack of insight into the fundamental problem. We have a longstanding program in developing new catalytic reactions using theoretical and mechanistic understanding to provide unique solutions to challenging problems and address important knowledge gaps. We anticipate that this proposal will make significant strides in developing and understanding new methods that facilitate the construction of complex molecules in an efficient, selective and atom-economical manner. IMPACT: The proposal is expected to expand the current "toolkit" of chemical reactions by developing innovative and cutting-edge synthetic methods, thereby providing the HQP with a world-class training environment. The proposed work is highly collaborative, giving the HQP opportunities to work at the interface of chemistry and biology. This unique training environment is expected to enhance Canada's reputation in synthetic organic chemistry by disseminating the work in the form of high-profile publications, news articles and seminars by the HQP.