New Metal-Catalyzed Allylic Substitution and Higher-Order Carbocyclization Reactions

以可预测和快速的方式构建具有建筑挑战性的结构母题仍然是合成有机化学的重大挑战。这一限制严重限制了在一系列生物学上有趣的分子中促进结构-活性关系研究的能力，这限制了许多有趣的和潜在有用的先导化合物的开发。天然产物历来被证明是药物发现的可靠先导化合物。例如，在过去的30年里，这些药物激发了超过60%的抗癌药物和70%的抗生素进入临床试验。然而，许多公司已经放弃了天然产品，因为在为详细的结构-活性关系研究准备天然产品类似物库时存在一些问题。过渡金属催化反应有助于构建通常无法通过传统方法获得的结构基序，使这些反应成为靶向合成的极其强大的工具。然而，该领域的许多发展涉及繁琐的催化剂调整和反应条件的优化。我们相信，理论/实验相结合的方法将通过描述选择性的起源来加速这一过程，从而以一种通过实证研究更具挑战性的方式为长期存在的问题提供解决方案。因此，与酶通过多次迭代进化（即进化发展）相比，这种方法应该通过提供对新化学反应性的洞察来加快催化剂的识别和开发。我们预计，这一计划将导致发展最先进的转化，促进复杂分子的高效，选择性和原子经济的方式建设。因此，这项工作将扩大目前化学反应的“工具箱”，这将有助于更快速地构建生物学上重要的结构，并提供尖端的HQP培训。

The construction of architecturally challenging structural motifs in a predictable and expeditious manner remains a Grand Challenge for synthetic organic chemistry. This limitation has severely limited the ability to facilitate Structure-Activity Relationship Studies in a range of biologically interesting molecules, which has limited the exploitation of many interesting and potentially useful lead compounds. Natural products have historically proven reliable lead compounds for drug discovery. For example, these agents have inspired over 60% of the anticancer agents and 70% of the antibiotics entering clinical trials in the last 30 years. Nevertheless, many companies have abandoned natural products due to the perceived problems associated with the preparation of libraries of natural product analogues for detailed Structure Activity Relationship Studies. Transition metal-catalyzed reactions facilitate the construction of structural motifs that are generally not accessible via conventional methods making these reactions an extremely powerful tool for target directed synthesis. Nevertheless, many of the developments in this area involve tedious catalyst tuning and optimization of reaction conditions. We believe that a combined theoretical/experimental approach will expedite this process by delineating the origin of selectivity and thereby provide solutions to longstanding problems in a manner that would be infinitely more challenging through empirical studies. Hence, in contrast to enzymes, which evolve through multiple iterations, i.e. evolutionary development, this approach should expedite catalyst identification and development by providing insight into new chemical reactivity. We anticipate that this program will result in the development of state-of-the-art transformations that facilitate the construction of complex molecules in an efficient, selective and atom-economical manner. Hence, this work will expand the current "tool-kit" of chemical reactions, which will facilitate the construction of biologically important structures in a more expeditious manner and provide cutting-edge HQP training.