Asymmetric Synthesis of Nitrogen Heterocycles

项目摘要/摘要 氮是药物和生物活性分子中的第四大常见元素，仅次于 只有C、H和O，其发生率大大超过其他重要元素，如S和F。 将含氮部分引入常见的起始材料中将为从业者提供快速 进入更复杂的结构。长期以来，我们一直对组装含氮杂环感兴趣 由于它们的普遍存在和重要性。我们的工作始于构建双环结构的方法 使用环加成化学。随着时间的推移，它演变成使用C-H激活和生成单环 结构。着眼于提高实用性和影响力，我们继续发展我们的方法，以 使用日益丰富的烯烃伙伴和广泛用途的胺衍生物继续 含氮杂环及非环支架的合成。因此，这种竞争性更新是关注的焦点 几个互补的场馆： 目的1：立体专一性催化烯烃双官能化反应。烯烃是最普遍存在的 可用的起始材料。通过立体化学定义的烯烃传递两个官能团 如果反应是立体专一性的，则允许获得互补的非对映异构体。我们将开发一套 双官能化反应包括碳胺化、碳化及相关转化。哪里 我们可能会以这样一种方式使用未功能化的前体，以增加实用性和执行的简便性。 目的2：烯烃和氮亲电体的化学选择性偶联。我们将延长烯烃官能化 将简单的-烯烃直接转化为吡咯烷、哌啶和烯丙基胺衍生物的化学方法， 不仅使烯烃本身官能化，而且使烯丙基、高烯丙基和双高烯丙基位置官能化。 目的3：设计人工金属酶以增强反应活性和不对称催化。其中许多 反应产生手性产物。我们将用小说来控制转型的绝对立体化学 金属酶来源于连接在单体链霉亲和素蛋白支架中的过渡金属催化剂。

Project Summary/Abstract Nitrogen is the fourth most common element in pharmaceuticals and biologically active molecules, after only C, H and O. Its incidence greatly eclipses that of other important elements such as S and F. Methods to introduce nitrogen moieties into commonly available starting materials would provide practitioners with rapid access to more complex structures. We have had a long-standing interest in assembling nitrogen heterocycles due to their prevalence and importance. Our work began with approaches to construction of bicyclic structures using cycloaddition chemistry. Over time, it evolved to using C–H activation and generating monocyclic structures. With an eye towards increased utility and impact, we have continued to evolve our approach to using increasingly abundant alkene partners with broadly versatile amine derivatives for the continued synthesis of nitrogen heterocycles as well as acyclic scaffolds. Thus, this competitive renewal is focused on several complementary venues: Aim 1: Stereospecific Catalytic Alkene Difunctionalization Reactions. Alkenes are among the most ubiquitous starting materials available. The delivery of two functionalities across the stereochemically defined alkene allows access to complementary diastereomers if the reaction is stereospecific. We will develop a suite of difunctionalization reactions including carboamination, carbocarbation and related transformations. Where possible we will use unfunctionalized precursors in such a way to increase utility and ease of execution. Aim 2: Chemoselective Coupling of Alkenes and Nitrogen Electrophiles. We will extend alkene functionalization chemistry to convert simple -olefins directly into pyrrolidines, piperidines and allylic amine derivatives, functionalizing not just the alkene itself but also the allylic, homoallylic and bis-homoallylic positions. Aim 3: Design of Artificial Metalloenzymes for Enhanced Reactivity and Asymmetric Catalysis. Many of these reactions create chiral products. We will control the absolute stereochemistry of the transformations with novel metalloenzymes derived from transition metal catalysts docked within monomeric streptavidin protein scaffolds.