Radical Chaperones to Harness Remote, Selective C-H Functionalization Mechanisms

激进分子伴侣利用远程选择性 C-H 功能化机制

基本信息

批准号：
10623236
负责人：
David A Nagib
金额：
$ 45.32万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2026-05-31
项目状态：
未结题

项目摘要

Project Summary/Abstract Chiral amines are prevalent motifs in nature and medicine. Conversely, alcohols are among the cheapest and most ubiquitous molecules. This program is dedicated to the development of new, remote C-H functionalization strategies that will streamline the synthesis of biologically relevant amines from abundant alcohol precursors. The key innovation of the proposed approach is the design of catalysts to harness regioselective 1,5-hydrogen atom transfer (HAT) mechanisms via imidate (β) and amidyl (δ) radicals. Through catalyst-controlled generation of nitrogen-centered radicals, as well as newly enabled regulation of their remote (β or δ) terminations, we seek to access new types of reactivity and selectivity. For example, the first asymmetric examples of several radical-mediated transformations are proposed. Additionally, a series of novel, single and double C-H functionalization cascades are described. The elucidation of these divergent mechanisms for intercepting radical intermediates will enable new access to valuable, remote transformations, including the synthesis of several medicinally relevant scaffolds (e.g. α-amino acids, β-amino alcohols, aza- heterocycles) in a rapid, modular, and selective fashion. The significance of these strategies for radical-mediated, remote C-H functionalization is their facilitation of the discovery of otherwise unlikely synthetic reactivity. Specifically, by employing transient imidate radical chaperones, alcohols may be selectively converted to a family of chiral amines. Two metal-catalyzed classes of reactivity (stereoselective HAT and termination, or desymmetrization by HAT) are proposed to facilitate asymmetric β C-H amination and other enantioselective functionalizations. In parallel, new approaches for metal-mediated, amidyl radical generation from amines will facilitate their more rapid and direct access, as well as new avenues for their remote cross-coupling with arenes and other nucleophiles. The newly elucidated mechanisms for harnessing novel δ C-H reactivity (by amidyl radicals) will also enable further developments of chaperone-mediated β C-H functionalizations (by imidate radicals). Together, these studies will further expand our ability to selectively control remote HAT mechanisms and enable novel, useful, and unprecedented C-H editing of alcohols and amines found in medicinally relevant molecules.

项目概要/摘要手性胺是自然界和医学中普遍存在的主题，醇是最便宜的。该计划致力于开发新的远程 C-H。功能化策略将简化从丰富的生物相关胺的合成该方法的关键创新在于利用催化剂的设计。通过亚胺基 (β) 和酰胺基 (δ) 进行区域选择性 1,5-氢原子转移 (HAT) 机制。催化剂控制的以氮为中心的自由基的产生，以及新近启用的远程调控（β 或 δ）终止，我们寻求获得新类型的反应性和选择性，例如第一个。提出了几种自由基介导的转化的不对称例子。描述了单和双 C-H 官能化级联。拦截自由基中间体的机制将使人们能够获得有价值的远程转化的新途径，包括几种医学相关支架的合成（例如α-氨基酸、β-氨基醇、氮杂- 杂环）以快速、模块化和选择性的方式。这些自由基介导的远程 C-H 功能化策略的重要性在于它们促进了具体来说，通过使用瞬态亚胺基团发现了原本不可能的合成反应性。分子伴侣，醇可以选择性地转化为一类手性胺，两种金属催化的类别。提出了反应性（立体选择性 HAT 和终止，或通过 HAT 去对称化）以促进不对称 β C-H 胺化和其他对映选择性功能化同时出现的新方法。金属介导的胺基自由基生成也将促进其更快速和直接的获取作为与芳烃和其他亲核试剂远程交叉偶联的新途径。利用新的 δ C-H 反应性（通过酰胺基）的机制也将有助于进一步发展分子伴侣介导的 β C-H 功能化（通过亚胺基团）一起，这些研究将进一步扩展。我们有能力选择性地控制远程 HAT 机制并实现新颖、有用且前所未有的 C-H 编辑医学相关分子中发现的醇和胺。