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: 10275111
• 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/10275111
• 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.

项目概要 氢原子转移 (HAT)，或一个质子和一个电子同时移动，是一种 合成方法中越来越重要的元素，而自然界已广泛使用 HAT 步骤。 诸如去饱和酶和变位酶等过程，合成化学家才刚刚开始 为了实现这一强大而彻底的变革的潜力，MIRA 提案描述了两个重要的新内容。 PI 将在未来 5 年内探索 HAT 所支持的领域：模块化自由基氢化和 PI 准备在他的指导下在这个重要领域产生影响。 在他的职业生涯中，他设计了通过 HAT 运行的催化脱氢和脱氢甲酰化系统。 第一个研究领域涉及模块化立体选择性氢化系统的开发，该系统能够 完全控制每个还原中心的构型和同位素组成（项目1）。 PI 的工作证明可以使用合作氢原子实现自由基氢化 转移（cHAT），一种机制，其中每个氢原子从单独的催化剂到达，允许每个 该项目的一个目标是对每个新的催化剂进行独立的立体控制。 通过使用两种不对称催化剂（项目 1a）实现立体中心。该设计将允许对映选择性反-。 减少，这是目前不可能的转变，同时的、独立的目标建立在初步数据的基础上。 显示每种催化剂从正交源接收氢原子，从而允许不同的同位素 预计在同一反应中交付（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构型的 H、D 或 T，在所有可能的同位素体之间进行选择 第二个研究领域侧重于通过催化剂和试剂控制的立体同位素异构体的开发。 新的类似 Mustase 的反应，其中功能以 1,2-方式区域选择性地转置以进行重塑 分子结构（项目 2） 然而，与变位酶不同，这些方法将交换 转座期间的官能团，允许复杂分子的快速多样化。 PI 演示了这一原理，使用维生素 B12 和 Co(Salen) 助催化剂实现“远程控制”。 消除”，其中伯烷基亲电子试剂被转化为带有末端甲基的2-烯烃。 预计这种方法将是通用的，允许转位 C-X、C-N、C-O 和 C-C 键形成 反应（项目 2a）同时，维生素 B12 能够对映选择性地转化内消旋环氧化物和 氮丙啶到烯丙醇和胺将用于实现对映选择性 C-H 官能化 环氧化物和氮丙啶（项目 2b）一起，拟议的研究将利用 HAT 的独特反应性。 提供一系列新的催化反应来制造和使用烯烃，以简化合成 对人类健康重要的分子。