New Metal-Catalyzed Reactions for the Synthesis of Bioactive Agents

由于临床候选药物在药物开发的各个阶段的成功率较低（0.2%），药物发现的成本不断增加，促使人们认真分析导致失败率的因素。 例如，一种新药的平均销售成本超过10亿美元，而每10种药物中只有一种产生足够的收入来支付研发成本。 此外，尽管出现了新技术，但制药生产力水平在过去十年中并没有大幅提高。 最近的一项研究表明，饱和碳原子的数量，特别是立体异构的碳原子的数量，以及芳香环数量的减少与药物从药物发现到可销售实体的成功过渡相关。 因此，药物发现的不断上升的成本加上以更经济有效的方式制备药物的驱动力，提供了开发新的和更强大的方法以可预测和快速的方式制备结构上具有挑战性的药物活性剂的迫切要求。** 在本提案中，我们概述了新的过渡金属催化反应的发展，这些反应有助于构建通常无法通过常规方法获得的结构基序。 该提案还解决了合成方法开发方面的关键和持续挑战，因为底物中相对简单的变化可能会带来限制化学范围的不可预见的挑战。 因此，这些障碍通常需要耗时和昂贵的研究来优化特定的化学过程，因为缺乏对其工作方式的洞察。 我们有一个长期的计划，在新的催化反应的发展，利用理论和机理的见解，提供独特的解决方案，以解决这些类型的知识差距的挑战性问题。 因此，与通过多次迭代（即进化发展）进化的酶相反，我们的方法提供了对新化学反应性的独特见解，从而导致更稳健和通用方法的发展。 我们预计，我们的计划将继续在开发和理解促进以有效，选择性和原子经济方式构建复杂分子的方法方面做出重大贡献。因此，这项建议将通过开发创新和尖端的合成方法，大大扩展目前化学反应的“工具包”，为HQP培训提供世界一流的环境。此外，预算反映了对培训HQP的承诺（超过总成本的70%），这将通过广泛传播的高知名度出版物和研讨会来提高加拿大合成有机化学的声誉，这些出版物和研讨会解决了上述问题。

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.