Complementary Activation of Hydroxylamine Derivatives by Hydrogen-Bond Donor Catalysts to Enable Enantioselective Nitrogen-Atom Transfer Processes

通过氢键供体催化剂互补活化羟胺衍生物以实现对映选择性氮原子转移过程

• 批准号: 10404949
• 负责人: Melanie Ann Short Blackburn
• 金额: $ 6.76万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404949
• 关键词: 3-Dimensional; Address; Adopted; Alkenes; Amines; Architecture; Aziridines; Biochemical; Biological; Carbon; Catalysis; Chemicals; Complex; Data; Development; Electrons; Evaluation; Goals; Health; Human; Hydrogen Bonding; Hydroxylamine; Improve Access; Investigation; Link; Methodology; Methods; Molecular; National Institute of General Medical Sciences; Natural Products; Nitrogen; Oxygen; Pharmaceutical Chemistry; Pharmacologic Substance; Preparation; Prevalence; Procedures; Process; Reaction; Reagent; Research; Stereoisomer; Surveys; System; Technology; Therapeutic; Therapeutic Agents; Transition Elements; carbonyl compound; catalyst; forging; functional group; innovation; insight; new technology; novel; oxidation; protocol development; scaffold; success; tertiary amine; therapeutic target

Project Summary / Abstract The prevalence of nitrogen-containing functionalities within health-relevant compounds is staggering. As such, synthetic methodologies to construct new carbon–nitrogen (C–N) bonds remain at the forefront of chemical innovation. The majority of investigations to date have been focused on the development of protocols to install C(sp2)–N linkages. Few advances have been made toward generalizable and stereoselective approaches to forging C(sp3)–N bonds, despite the recognized importance that three-dimensionality has on a compound’s biological efficacy. As a result, many C(sp3)–N-containing functional groups have been underevaluated as biochemical probes and therapeutic agents purely due to the difficulty of their preparation. Among the most challenging to install are unprotected nitrogen moieties, such as primary amines and unprotected aziridines. Current strategies to construct these motifs are plagued by multistep synthetic sequences, require precious transition-metal catalysts, or necessitate the use harsh reaction conditions and potentially hazardous reagents. To overcome these challenges, the proposed research engages organocatalysts to promote enantioselective nitrogen-atom transfer processes. Complementary modes of activation of a common and readily accessible synthetic precursor will deliver a diverse array of challenging synthetic targets. The research plan outlines specific tactics that will enable the desired transformations through identification of appropriate hydrogen-bond (H-bond) donor catalyst systems, which will serve to activate hydroxylamine derivatives through networks of covalent and non-covalent interactions. While H-bond donor organocatalysis has been adopted as a powerful strategy to convert simple starting materials into highly enantioenriched products, it has seen very limited use in asymmetric nitrogen-atom transfer reactions. Thus, mechanistic interrogation of the proposed processes will provide valuable insight into catalyst control over nitrogen installation, where current data for such technologies is scarce. The envisioned methodologies will deliver enantioenriched a-amino carbonyl and unprotected aziridine architectures, which are poised for further synthetic manipulation or direct biological evaluation. By improving access to these high-value functional motifs, underexplored molecular scaffolds will be surveyed in biological contexts, leading to discovery of new pharmaceutical leads and improvements in therapeutic technologies, ultimately advancing human health.

项目摘要/摘要 与健康相关的化合物中含氮官能团的普遍程度令人震惊。因此， 构建新碳-氮(C-N)键的合成方法仍处于化学研究的前沿 创新。到目前为止，大多数调查都集中在开发要安装的协议上 C(Sp2)-N键。在可推广和立体选择性的方法方面取得的进展很少 锻造C(SP3)-N键，尽管三维结构对化合物的 生物功效。因此，许多含C(SP3)-N的官能团被低估为 生物化学探针和治疗剂纯粹是因为它们的制备困难。其中最多的 安装具有挑战性的是无保护的氮部分，如伯胺和无保护的氮杂环丙烷。 目前构建这些基序的策略受到多步骤合成序列的困扰，需要宝贵的 过渡金属催化剂，或必须使用苛刻的反应条件和潜在的危险试剂。 为了克服这些挑战，拟议的研究聘请了有机催化剂来促进对映体选择性 氮原子转移过程。共同的和易于访问的激活的补充模式 合成前体将提供一系列具有挑战性的合成靶标。这项研究计划概述了 通过识别适当的氢键实现所需转变的具体策略 (氢键)给体催化剂系统，这将有助于通过网络激活羟胺衍生物 共价和非共价相互作用。而氢键供体有机催化已被认为是一种强有力的 将简单的起始原料转化为高对映体浓缩物的战略，它在 不对称氮原子转移反应。因此，对拟议进程的机械性审问将 对氮气装置的催化剂控制提供有价值的见解，其中此类技术的当前数据 是稀有的。设想的方法将提供富含对映体的a-氨基羰基和无保护的氮杂环丙烷。 架构，为进一步的合成操作或直接的生物学评估做好准备。通过改进 获得这些高价值的功能基序，未被开发的分子支架将在生物学中进行调查 背景，导致发现新的药物先导和治疗技术的改进， 最终促进人类健康。