Carbene-Catalyzed Reactions with Vinyl Sulfones

描述（由申请人提供）：开发新的化学方法是一项重要的努力，可以从天然产物到治疗药物中获得不同的特权和生物活性分子。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法，通常是仿生的方法来合成有机分子而不使用金属。具体来说，N-杂环碳烯（NHCs）由于其仿生、无毒和无金属的特性，作为有机催化剂的使用越来越多。NHC催化是一个不断发展的领域，利用独特的单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是在人体的生物系统中，大自然使用硫胺素（NHC的一种）生成乙酰辅酶a，这是聚酮的重要组成部分。目前NHC催化的模式仅限于1,2加成到羰基上，以及较少常见的1,4加成到1,2不饱和化合物上。为了推动n -杂环碳催化、有机催化和合成有机化学领域的发展，需要探索一种新的、不寻常的化学反应途径。这种新方法采用了迄今为止尚未开发的反应途径，包括NHC添加到非常规亲电试剂乙烯基砜中，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、生物学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将重点研究nhc -乙烯基砜的机理，合成一系列具有抗菌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学和/或合成价值的分子。从Specific Aim 1的机理研究中更好地了解了nhc -乙烯基砜的反应性，Specific Aim 2和3将集中于获取其他生物学上有趣的支架、环丁烷和更复杂的环结构，利用并推进非常规亲电试剂NHCs的合成用途。

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.