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奋进。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，提供了一种毒性较小的替代方案，并且通常是仿生的方式来合成有机分子而不使用金属。具体地，N-杂环卡宾（NHC）作为有机催化剂的使用由于其仿生、无毒和无金属的特性而正在增长。NHC催化是一个不断发展的领域，采用独特的孤对轴承杂环，以促进各种有机转化，并用于获得有用的生物活性分子，结构新颖的化合物，和合成的积木。NHC作为催化剂的起源和灵感来自人体的生物系统，其中自然界使用硫胺素（一种NHC）生成乙酰辅酶A，这是聚酮化合物的重要组成部分。目前NHC催化的模式限于羰基上的1，2-加成和较不常见的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、有机催化和有机合成化学领域的发展，需要探索化学反应中新颖的和不寻常的途径。这种新的方法采用了迄今为止尚未探索的反应途径，涉及NHC除了一种非常规的亲电试剂，乙烯基砜，在创建一个化学反应的反应伙伴。我们假设，我们可以使用新的NHC反应性，以获得医学，生物学和合成有用的分子在NHC催化领域的潜在重大进展。 具体目标1将侧重于NHC-乙烯基砜的机理研究，合成一系列具有抗菌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生物和/或合成有价值的分子。通过具体目标1的机理研究更好地了解NHC-乙烯砜反应性，具体目标2和3将集中于访问其他生物学上有趣的支架，环丁烷和更复杂的环状结构，利用和推进NHC与非常规亲电试剂的合成效用。

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.