Carbene-Catalyzed Reactions with Vinyl Sulfones

描述（由申请人提供）：新化学方法的开发是获得从天然产物到治疗药物的不同特权和生物活性分子的能力的重要努力。特别是，小分子催化在过去十年中经历了强大的复兴，导致有机合成的高效和立体选择性策略的爆炸式增长，提供了一种毒性较小的替代方案，并且通常是仿生的方法来合成有机分子而不使用金属。具体而言，N-杂环卡宾（NHC）由于其仿生、无毒和不含金属的特性，作为有机催化剂的使用正在增长。 NHC 催化是一个不断发展的领域，利用独特的孤对杂环来促进各种有机转化，并用于获取有用的生物活性分子、结构新颖的化合物和合成构件。 NHC 作为催化剂的起源和灵感来自于人体的生物系统，大自然利用硫胺素（一种 NHC）来生成乙酰辅酶 A，这是聚酮化合物的重要组成部分。目前 NHC 催化模式仅限于羰基上的 1,2-加成反应，以及 1, 2-不饱和化合物上的 1,4-加成反应（不太常见）。为了推进N-杂环卡宾催化、有机催化和有机合成化学领域的发展，需要探索一种新颖且不寻常的化学反应途径。这种新方法采用了迄今为止尚未探索的反应途径，涉及 NHC 加成到非常规亲电子试剂乙烯基砜上，以创建化学反应的反应伙伴。我们假设我们可以利用新颖的 NHC 反应性来获取医学、生物学和合成上有用的分子，这可能是 NHC 催化领域的重大进步。 具体目标1将重点研究NHC-乙烯基砜的机理，合成一系列具有抗菌活性的异恶唑烷化合物，以及将这些生物活性产物转化为其他具有生物和/或合成价值的分子。通过特定目标 1 的机理研究更好地了解 NHC-乙烯基砜反应性，特定目标 2 和 3 将集中于获取其他生物学上感兴趣的支架、环丁烷和更复杂的环状结构，利用和推进 NHC 与非常规亲电子试剂的合成效用。 公共健康相关性：我们的研究有能力对公共健康产生广泛而深远的影响，因为它可能用于合成具有令人鼓舞的生物活性并在治疗领域有希望的分子。合成有机化学的新发现和进步允许更有效地获取分子，从而产生新药、更好地了解疾病和生物过程以及更安全的疫苗。

DESCRIPTION (provided by applicant): The development of new chemical methodology is an important endeavor in the ability to access different privileged and bioactive molecules from natural products to therapeutic drugs. In particular, small molecule catalysis has undergone a powerful renaissance over the last decade leading to an explosion of efficient and stereoselective strategies for organic synthesis, providing a less toxic alternative and often biomimetic way to synthesize organic molecules without the use of metals. Specifically, the use of N- heterocyclic carbenes (NHCs) as organocatalysts is growing due to its biomimetic, nontoxic, and metal-free characteristics. NHC catalysis is a growing field, employing unique lone pair-bearing heterocycles to facilitate a variety of organic transformations, and is used to access useful biologically active molecules, structurally novel compounds, and synthetic building blocks. The origin and inspiration of an NHC as a catalyst is in the human body's biological systems, where Nature uses thiamine, an NHC, to generate acetyl CoA, an important building block for polyketides. The current modes of NHC catalysis are limited to the 1,2-addition onto carbonyl and less common, 1,4-addition onto an 1, 2-unsaturated compound. In order to advance the field of N-heterocyclic carbene catalysis, organocatalysis, and synthetic organic chemistry, there is a need to explore a novel and unusual pathways in chemical reactivity. This new methodology employs a heretofore unexplored avenue of reactions involving the NHC addition to an unconventional electrophile, vinyl sulfone, in creating a reactive partner for chemical reactions. We hypothesize that we can use the novel NHC reactivity to access medicinally, biologically, and synthetically useful molecules in a potentially major advancement in the NHC catalysis field. Specific Aim 1 will focus on the investigation into the mechanism of the NHC-vinyl sulfone, the synthesis of a collection of isoxazolidine compounds, which has exhibited bioactivity as antibacterial agents, and the transformation of these bioactive products into other biologically and/or synthetically valuable molecules. With a better understanding of the NHC-vinyl sulfone reactivity from the mechanistic investigations of Specific Aim 1, Specific Aims 2 and 3 will concentrate on accessing other biologically interesting scaffolds, cyclobutane and more complex cyclic structures, capitalizing on and advancing the synthetic utility of NHCs with an unconventional electrophile. PUBLIC HEALTH RELEVANCE: Our research has the capacity to have a widespread and long-reaching impact on public health because of its potential use in the synthesis of molecules that exhibit encouraging bioactivity and have promise in field of therapeutics. New discoveries and advancements in synthetic organic chemistry allow for more efficient routes to access molecules that can lead to new drugs, better insight into diseases and biological processes, and safer vaccines.