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主题仍然是合成有机化学的一个巨大挑战。这一局限性严重限制了对一系列生物分子进行构效关系研究的能力，从而限制了许多有趣的和潜在有用的先导化合物的开发。历史上，天然产品已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，这些药物激励了超过60%的抗癌药物和70%的抗生素进入临床试验。尽管如此，许多公司已经放弃了天然产品，因为人们意识到与为进行详细的结构活性关系研究而准备天然产品类似物库有关的问题。过渡金属催化的反应有助于构建通常无法通过传统方法获得的结构基序，使这些反应成为目标定向合成的一个极其强大的工具。然而，这一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。我们认为，理论/实验相结合的方法将通过描绘选择性的来源来加速这一进程，从而为长期存在的问题提供解决办法，而通过经验研究将具有无限的挑战性。因此，与酶通过多次迭代(即进化开发)进化不同，这种方法应该通过提供对新的化学反应的洞察来加速催化剂的识别和开发。我们预计，这一计划将导致最先进的转化的发展，以高效、选择性和原子经济的方式促进复杂分子的构建。因此，这项工作将扩大目前的化学反应工具包，将促进以更快的方式建造具有生物重要性的结构，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.