New Metal-Catalyzed Reactions for the Synthesis of Bioactive Agents

由于临床候选人在药物开发的不同阶段进展的成功率较低(0.2%)，药物发现的成本不断增加，这促使人们认真分析导致失败率的因素。例如，销售一种新药的平均成本超过10亿美元，其中只有十分之一的药物产生的收入足以支付研发成本。此外，尽管出现了新技术，但制药生产率水平在过去十年中并没有显著提高。最近的一项研究表明，饱和碳原子的数量，特别是那些立体生成的原子，以及芳香环数量的减少与药物从药物发现到市场实体的成功过渡相关。因此，药物发现成本的不断上升，加上以更具成本效益的方式制备药物的努力，提供了一种迫切的任务，需要开发新的和更强大的方法，以可预测和快速的方式制备具有结构挑战性的药理活性物质。*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传统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的挑战，因为底物中相对简单的变化可能会带来无法预见的挑战，限制了化学的范围。因此，这些障碍往往需要耗时和昂贵的研究来优化特定的化学过程，因为缺乏对其工作原理的了解。我们在开发新的催化反应方面有一个长期的计划，利用理论和机理上的见解，为解决这些类型的知识差距的挑战性问题提供独特的解决方案。因此，与酶通过多次迭代进化，即进化发展不同，我们的方法为新的化学反应提供了独特的见解，从而导致了更强大和通用方法的发展。我们预计，我们的计划将继续为以高效、选择性和原子经济的方式构建复杂分子的方法的开发和理解做出重大贡献。因此，该建议将通过开发创新和尖端的合成方法来显著扩展当前的化学反应“工具包”，为HQP培训提供世界级的环境。此外，预算反映了对HQP培训的承诺(占总成本的70%)，这将通过广泛传播的高知名度出版物和研讨会来提高合成有机化学在加拿大的声誉，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.