Catalytic Asymmetric Oxidation: Easy Entry to Highly Functionalized Molecules

描述（由申请人提供）： 项目摘要：现代药物是高度功能化的分子，并且通常这些分子是手性的。生产这些分子最有前途的解决方案依赖于不对称催化过程，尤其是催化不对称氧化，它可以将多个官能团引入分子中。长期目标是开发催化不对称氧化工艺，能够以有效的选择性和可扩展性水平生产高度功能化的药物。开发这些催化剂的目的是提供可靠且容易的途径，以简单的方式制造以前无法获得的分子。成功的关键是氧化催化剂的正确分子设计。催化选择性氧化可以催化选择性地将氧、氮和卤素引入基材。在强有力的初步数据的指导下，该假设将通过四个具体目标进行检验：1）使用亚硝基化学不对称构建季碳，2）开发催化不对称亚硝基杂狄尔斯-阿尔德和相关的不对称环加成，3）不对称环氧化及其动力学拆分，以及4）不对称卤化。所有四种方法都是创新的，因为它们都是一个未知的过程，利用了我们小组在早期 NIH 支持下开发的全新催化剂设计概念。他们还利用了许多其他实验室无法提供的配体库。拟议的研究意义重大，因为它有望提供一个良好的催化剂工具箱，这将使提供以前无法实现的复杂分子成为可能，而这些分子是未来开发全新药理学策略所需的。与公共卫生的相关性：这是有机合成的一个重要领域，具有有效增强药物的潜在适用性，最终包括用于人类的药物。最后，本文描述的项目将为研究生和博士后提供催化方面的优秀培训，这些经验将为他们为独立研究生涯做好准备，为公共卫生做出贡献。

DESCRIPTION (provided by applicant): Project summary: Modern drugs are highly functionalized molecules, and often these molecules are chiral. The most promising solution for production of these molecules has relied on an asymmetric catalytic process, especially catalytic asymmetric oxidation, which can introduce multi functional groups into the molecule. The long-term goal is to develop catalytic asymmetric oxidation processes which can create highly functionalized drugs at a useful level of selectivity and scalability. The objective of developing these catalysts is to provide reliable and easy access to make molecules previously unattainable in a simple manner. The key to success is proper molecular design of an oxidation catalyst. Catalytic selective oxidation can introduce oxygen, nitrogen, and halogen to the substrate catalytically and selectively. Guided by strong preliminary data, this hypothesis will be tested by pursuing four specific aims: 1) asymmetric construction of quaternary carbon using nitroso chemistry, 2) development of catalytic asymmetric nitroso hetero-Diels-Alder and related asymmetric cycloadditions, 3) asymmetric epoxidation and its kinetic resolution, and 4) asymmetric halogenation. All four approaches are innovative, because each of them is an unknown process which capitalizes on a totally new concept of catalyst design developed by our group using earlier NIH support. They also take advantage of a number of ligand libraries which are available in no other laboratory. The proposed research is significant, because it is expected to provide a fine toolbox of catalysts, which will make possible the provision of previously unattainable complex molecules needed to develop entirely new pharmacologic strategies in the future. Relevance to Public Health: This is an important area of organic synthesis that has potential applicability to efficiently strengthen drugs, ultimately including those for human beings. Finally, the projects described herein will provide excellent training for graduate students and postdoctoral associates in catalysis, experience that will prepare them well for independent research careers to contribute for public health.