New Frontiers in Chemical Reactivity Via Catalytic Hydrogen Atom Transfer

通过催化氢原子转移实现化学反应的新领域

• 批准号: 10440504
• 负责人: Julian G West
• 金额: $ 37.75万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440504
• 关键词: Alcohols; Alkenes; Amines; Architecture; Area; Aziridines; Chemicals; Complex; Cues; Data; Development; Electrons; Elements; Enzymes; Epoxy Compounds; Goals; Health; Human; Hydrogen; Hydrogenation; Isotopes; Mentors; Methodology; Methods; Molecular; Movement; Mutase; Nature; Process; Protons; Reaction; Reagent; Research; Source; System; Translating; Vitamin B 12; Work; career; catalyst; dehydrogenation; desaturase; design; frontier; functional group; methyl group; salen; unsaturated bonds

PROJECT SUMMARY Hydrogen atom transfer (HAT), or the movement of one proton and one electron simultaneously, is an increasingly important element in synthetic methodology. While nature has made extensive use of HAT steps in processes such as those performed by desaturase and mutase enzymes, synthetic chemists are just beginning to realize the potential of this powerful, radical transformation. This MIRA proposal describes two important new areas enabled by HAT that the PI will explore over the next 5 years: modular radical hydrogenation and transpositional functionalization. The PI is prepared to make an impact in this important field from his mentored career, where he designed catalytic dehydrogenation and dehydroformylation systems functioning via HAT. The first area of research concerns development of a modular, stereoselective hydrogenation system able to completely control the configuration and isotopic composition at each reduced center (Project 1). Preliminary work by the PI has demonstrated radical hydrogenation can be achieved using cooperative hydrogen atom transfer (cHAT), a mechanism where each hydrogen atom arrives from a separate catalyst, allowing for each catalyst to be modified independently. One goal of this project is independent stereocontrol of each new stereocenter though use of two asymmetric catalysts (Project 1a). This design will allow for enantioselective anti- reduction, a currently impossible transformation. A simultaneous, independent goal builds on preliminary data showing each catalyst receives its hydrogen atom from an orthogonal source, permitting different isotopes to be predictably delivered in the same reaction (Project 1b). Together, this project area will provide a method to install H, D, or T in any configuration starting from an unsaturated bond, selecting between all possible isotopologues and stereoisotopomers via catalyst and reagent control. The second research area focuses on the development of new mustase-like reactions, where functionality is regioselectively transposed in a 1,2-fashion to remodel molecular architectures (Project 2). However, unlike mutase enzymes, these methods will exchange the functional group during the transposition, allowing rapid diversification of complex molecules. Preliminary data from the PI demonstrates this principle using vitamin B12 and Co(Salen) cocatalysts to achieve “remote elimination”, where primary alkyl electrophiles are translated into a 2-alkenes with terminal methyl group. We anticipate this approach will be general, allowing for transpositional C–X, C–N, C–O, and C–C bond-forming reactions (Project 2a). In parallel, the ability of vitamin B12 to enantioselectively convert meso-epoxides and aziridines to allylic alcohols and amines will be used to achieve enantioselective C–H functionalization of the epoxides and aziridines (Project 2b). Together, the proposed research will leverage the unique reactivity of HAT to deliver a suite of new catalytic reactions both making -and using- olefins to streamline the synthesis of molecules important to human health.

项目摘要 氢原子转移（HAT）或一个质子和一个电子的移动是一个 综合方法中日益重要的要素。而大自然已经广泛使用了帽子的步骤 诸如去饱和酶和突变酶进行的过程，合成化学家才刚刚开始 实现这种强大的，激进的转变的潜力。这个Mira提议描述了两个重要的新 PI在接下来的5年中将通过HAT启用的区域：模块化自由基氢化和 转位功能化。 PI准备从他的思想中对这个重要领域产生影响 职业，他设计了通过HAT运行的催化脱氢和脱氢甲基化系统。 研究的第一个领域涉及一个模块化，立体选择性氢化系统的发展 在每个还原中心（项目1）中完全控制配置和同位素组成。初步的 PI的工作表明可以使用合作氢原子来实现自由基氢化 转移（CHAT），每个氢原子从单独的催化剂到达的机制，允许每个催化剂 催化剂要独立修改。该项目的一个目标是每个新的独立立体控制 虽然使用两个不对称催化剂（项目1A），但立体中心。这种设计将允许对映选择性抗 减少，目前不可能的转变。一个简单的独立目标以初步数据为基础 显示每个催化剂从正交来源接收其氢原子，允许不同的同位素为 可以预见的是在同一反应中传递（项目1b）。该项目区域将提供一种安装方法 从不饱和键开始的任何配置中的h，d或t，在所有可能的同位素学之间选择 通过催化剂和试剂对照来进行立体异位体。第二个研究领域的重点是发展 新的必须类似反应，其中功能在1,2时进行了调节以重塑 分子体系结构（项目2）。但是，与突变酶不同，这些方法将交换 换位期间的功能组，允许复杂分子的快速多样化。初步数据 从PI使用维生素B12和CO（Salen）Cocatalysts来证明这一原理以实现“遥远” 消除”，其中一级烷基电物质被翻译成具有末端甲基的2-烯烃。 预期这种方法将是一般的，允许转置C – X，C – N，C – O和C-C键形成 反应（项目2a）。同时，维生素B12的能力对立性转化中环氧化物和 赤紫醇和胺的氮杂氨酸将用于实现对映选择性的C – H功能化 环氧化物和氮杂氨酸（项目2b）。拟议的研究一起将利用帽子的独特反应性 提供一套新的催化反应，既可以制造 - 使用 - 烯烃来简化合成 分子对人类健康很重要。