Catalytic Asymmetric Oxidation: Easy Entry to Highly Functionalized Molecules

现代药物是高度官能化的分子，并且这些分子通常是手性的。在 在医药行业中，单一手性药物占药物市场的一半以上， 前10种药物中有9种是手性药物。手性化合物的生物医学重要性 激发了领先实验室的密集研究工作。最有前途的生产解决方案 这些分子依赖于不对称催化过程，特别是催化不对称氧化， 其可以将多官能团引入分子中。该项目的长期目标是 开发催化不对称氧化过程，可以以最低的成本生产高度功能化的药物。 有用的选择性和可伸缩性级别。开发这些催化剂的目的是提供可靠的 并且容易获得以简单的方式制造以前无法获得的分子。 在此更新建议中，我们概述了开发和使用新型氧化催化剂的计划， 多功能分子的对映选择性合成。与传统的过渡金属基 催化剂，该计划正在开发和研究的催化剂是有机分子或含有 无害金属。这些不含过渡金属的催化剂不仅具有根本意义，而且 具有工业重要性，因为有害的过渡金属在药物中是不希望的。 许多次级项目都得到了有希望的初步成果的支持，而另一些次级项目则是新的 催化剂或方法学开发方向。机械学，晶体学， 计算研究将提供对催化过程的理解， 更有效的催化剂。催化选择性氧化可以引入氧、氮或卤素， 催化地和选择性地对基质进行处理。 我们的主要目标是不对称环氧化。对该反应的研究有望导致 涉及广泛有用的不对称氧化催化方法的开发， 化学合成的方方面面。此外，这项工作将提供出色的合成训练， 方法论的发展，本科生，研究生和博士后学生感兴趣的一个 在制药行业或学术界的研究生涯 修改后的具体目标 催化对映体选择性氧化是医药工业中一个极其重要的过程。这清楚 因为大多数生物活性分子具有高度功能化的结构。简单烯烃和羰基 化合物是合成化学家最有吸引力的起始材料， 数量大，品种多。大自然实现了复杂的高度特异性合成 通过酶催化剂的独特选择性氧化，从这些简单的 化合物.虽然目前有许多广泛有用的催化不对称还原方法， 用于氧化的这些催化不对称技术少得多。值得注意的是，选择性 氧化催化比选择性还原催化代表更艰巨的挑战， 其中最小的是配体在氧化条件下的热力学不稳定性。尽管最近 在这一重要领域取得了进展，但还不够。我们在此提出催化 氧化，其可以化学选择性、区域选择性和对映选择性地将氧和硫引入底物中， 提供了合成高度官能化的复杂分子的简单入口， 知道的因此，我们的贡献，在这里有望提供一套新的和一般的手性氧化 制药实验室和制药工业的催化剂。 下一个供资期的具体目标是不对称环氧化。目标分为两部分： (1)用于环氧化的钒、铪和锆催化剂及其在环氧化中的应用， 环化级联;和（2）用于不对称环氧化和C-H氧化的铁基催化剂， activation.这些催化剂是重要的，因为它们代表着简单，良性的方式来促进 对映选择性环氧化反应。总的来说，拟议的工作不仅将导致一个有效的 选择性氧化的合成路线，但更重要的是，将导致发展 方法学，应证明是具有普遍价值的药物化学。 拟议的项目将包括几个简单的生物活性分子的合成，以证明如何 我们的催化剂起作用了。当然，这些方法的实际效用要广泛得多。还预期 所学到的内容将同样适用于其它体系的新氧化催化剂的开发。 所提出的方法是创新的，因为它们中的每一个都是一个未知的过程， 这是一个全新的催化剂设计概念，由我们的团队利用以前的NIH支持开发。他们还 利用许多其他实验室无法获得的配体库。拟议 这项研究意义重大，因为它有望提供一个很好的催化剂工具箱， 可能提供以前无法实现的复杂分子，需要开发全新的 未来的药理学策略。

Modern drugs are highly functionalized molecules, and often these molecules are chiral. In the pharmaceutical industry, single chiral drugs constitute over half the total drug market, and the key components in 9 of the top 10 drugs are chiral. The biomedical importance of chiral compounds has spurred intense research efforts by leading laboratories. The most promising solution for production of these molecules has relied on asymmetric catalytic processes, especially catalytic asymmetric oxidation, which can introduce multi-functional groups into the molecule. The long term goal of the project 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. In this renewal proposal, we outline plans for the development and use of new oxidation catalysts for enantioselective synthesis of multi-functional molecules. Unlike traditional transition metal-based catalysts, the catalysts being developed and studied in this program are organic molecules or contain non-harmful metals. These transition metal-free catalysts are not only of a fundamental interest, but also of industrial importance, since harmful transition metals are undesirable in pharmaceutical drugs. Many of the subprojects are supported by promising preliminary results, whereas others represent new directions in either catalyst or methodology development. Mechanistic, crystallographic, and computational studies will provide an understanding of the catalytic processes and steer the development of more effective catalysts. Catalytic selective oxidation can introduce oxygen, nitrogen, or a halogen to the substrate catalytically and selectively. Our specific major aim is asymmetric epoxidation. The investigations of this reaction are expected to lead to the development of broadly useful asymmetric oxidation catalysis methodologies that will impact many facets of chemical synthesis. Additionally, the effort will provide excellent training in synthetic methodology development to undergraduate, graduate, and postdoctoral students interested in a research career in the pharmaceutical industry or academia Modified Specific Aim Catalytic enantioselective oxidation is an extremely important process for the drug industry. This is clear because the most bioactive molecules have highly functionalized structures. Simple olefins and carbonyl compounds are the most attractive starting materials available to the synthetic chemist, easily accessible in large quantities and in many varieties. Nature achieves highly specific syntheses of complex substances through the uniquely selective oxidation by enzyme catalysts starting from these simple compounds. While there are currently many broadly useful methods for catalytic asymmetric reduction, there are far fewer of these catalytic asymmetric techniques for oxidation. It should be noted that selective oxidation catalysis represents more formidable challenges than does for selective reduction catalysis, not the least of which is the thermodynamic instability of ligands under oxidative conditions. Although recently there has been progress in this important area, it is not yet sufficient. We propose herein catalytic oxidation which can introduce oxygen and sulfur into substrates chemo-, regio-, and enantioselectively to provide simple entry to the synthesis of highly functionalize complex molecules that have heretofore been known. Thus, our contribution here is expected to provide a set of new and general chiral oxidation catalysts for pharmaceutical laboratories and drug industries. The specific aim of the next funding period is asymmetric epoxidation. The aim is divided into two parts: (1) vanadium, hafnium, and zirconium catalysts for epoxidation and their application to epoxidation- cyclization cascades; and (2) iron-based catalysts for asymmetric epoxidation and C-H oxidation and activation. These catalysts are significant in their representation as simple, benign ways to promote enantioselective epoxidation reactions. Overall, the proposed work will not only lead to an efficient synthetic route for selective oxidations, but, more importantly, will result in the development of methodology that should prove to be of general value to medicinal chemistry. The proposed project will include syntheses of several simple bioactive molecules to demonstrate how our catalysts work. The actual utility of the methods, of course, is much broader. It is also expected that what is learned will be equally applicable to the development of new oxidation catalysts of other systems. The proposed 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 previous 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.