Catalytic Asymmetric Oxidation: Easy Entry to Highly Functionalized Molecules

描述(申请人提供)：项目总结：现代药物是高度官能化的分子，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，特别是催化不对称氧化，它可以在分子中引入多个官能团。长期目标是开发催化不对称氧化过程，这种过程可以在有用的选择性和可扩展性水平上产生高度官能化的药物。开发这些催化剂的目的是提供可靠和容易的途径，使以前无法以简单方式获得的分子。氧化催化剂的分子设计是成功的关键。催化选择氧化可以催化选择性地将氧、氮、卤素引入到底物中。在强大的初步数据的指导下，这一假说将通过追求四个具体目标来验证：1)利用亚硝基化学不对称构建季碳；2)催化不对称亚硝基杂-Diels-Alder反应和相关的不对称环加成反应；3)不对称环氧化反应及其动力学拆分；以及4)不对称卤化反应。所有四种方法都是创新的，因为每一种方法都是一个未知的过程，它利用了我们团队利用早期NIH支持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没有的配位体库。这项拟议的研究意义重大，因为它有望提供一个很好的催化剂工具箱，这将使未来开发全新药理学策略所需的以前无法获得的复杂分子的提供成为可能。与公共健康相关：这是有机合成的一个重要领域，具有有效加强药物的潜在适用性，最终包括用于人类的药物。最后，这里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，这些经验将为他们的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.