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.

项目摘要 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。虽然大自然已经广泛使用了HAT步骤， 合成化学家们才刚刚开始研究去饱和酶和脱氢酶等合成过程， 来实现这种强大的、彻底的转变。这MIRA提案描述了两个重要的新 PI将在未来5年内探索的HAT领域：模块化自由基氢化和 换位功能化PI准备通过他的指导在这个重要领域产生影响 他设计了通过HAT运行的催化脱氢和脱氢系统。的 第一个研究领域涉及开发一种模块化的立体选择性氢化系统， 完全控制每个还原中心的构型和同位素组成（项目1）。初步 PI的工作表明，使用协同氢原子可以实现自由基氢化 转移（cHAT），一种机制，其中每个氢原子从单独的催化剂到达，允许每个氢原子从催化剂转移到催化剂。 催化剂可独立改性。这个项目的一个目标是独立的立体控制每个新的 通过使用两种不对称催化剂（项目1a），这种设计将允许对映选择性抗- 减少，目前不可能的转型。一个同步的、独立的目标建立在初步数据的基础上 显示每个催化剂从正交源接收其氢原子，允许不同的同位素 在相同的反应中可预测地递送（项目1b）。此项目区域将提供一种方法， 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选择 和立体同位素异构体。第二个研究领域侧重于发展 新的mustase样反应，其中功能是区域选择性转置在1，2-时尚，以重塑 分子结构（项目2）。然而，与生物酶不同的是，这些方法将交换 在转座过程中的功能基团，允许复杂分子的快速多样化。初步数据 来自PI的研究证明了使用维生素B12和Co（Salen）助催化剂实现"远程"的原理。 消除"，其中伯烷基亲电体被转化为具有末端甲基的α 2-烯烃。我们 预计这种方法将是通用的，允许易位C-X，C-N，C-O和C-C键的形成 反应（项目2a）。同时，维生素B12对映选择性转化内消旋环氧化物和 将使用氮丙啶到烯丙醇和胺的反应来实现对映选择性的C-H官能化。 环氧化物和氮丙啶（项目2b）。总之，拟议的研究将利用HAT独特的反应性， 提供一套新的催化反应，既制造-和使用-烯烃，以简化合成 对人类健康很重要的分子。