Carbene-Catalyzed Reactions with Vinyl Sulfones

描述(由申请人提供)：新化学方法学的发展是在从天然产品到治疗药物获取不同特权和生物活性分子的能力方面的一项重要努力。特别是，小分子催化在过去十年中经历了强大的复兴，导致了高效和立体选择性的有机合成策略的爆炸性增长，提供了一种毒性较低的替代方法，通常是仿生的方法来合成有机分子，而不使用金属。具体地说，N-杂环卡宾(NHCs)由于其仿生、无毒和不含金属的特性而被用作有机催化剂的情况越来越多。NHC催化是一个正在发展的领域，它利用独特的含孤对杂环来促进各种有机转化，并被用于获得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，在那里，大自然使用硫胺，一种NHC，产生乙酰辅酶A，这是聚酮的重要组成部分。目前NHC的催化模式仅限于在羰基上的1，2-加成，以及不太常见的1，2-不饱和化合物上的1，4-加成。为了促进N-杂环卡宾催化、有机催化和合成有机化学领域的发展，有必要探索一种新的和不寻常的化学反应途径。这一新方法采用了一种迄今未被探索的反应途径，涉及将NHC添加到非传统电泳剂乙烯基砜中，以创建化学反应的反应伙伴。我们假设，我们可以利用新的NHC反应性来获得医学上、生物上和合成上有用的分子，这是NHC催化领域的一个潜在的重大进展。具体目标1将侧重于研究NHC-乙烯基砜的作用机理，合成一系列具有抗菌剂生物活性的异恶唑烷化合物，并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。随着通过对特定目标1的机理研究更好地了解NHC-乙烯基砜的反应活性，特定目标2和3将集中于获得其他具有生物意义的支架、环丁烷和更复杂的环结构，利用并促进非传统电泳剂的NHC的合成应用。 与公共健康相关：我们的研究有能力对公共健康产生广泛和长期的影响，因为它可能用于合成显示出令人鼓舞的生物活性并在治疗学领域有希望的分子。合成有机化学的新发现和新进展使人们能够更有效地获取分子，从而产生新的药物，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.