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: 10176167
• 负责人: Melanie Ann Short Blackburn
• 金额: $ 6.6万
• 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/10176167
• 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.

项目总结/摘要 与健康相关的化合物中含氮官能团的普遍性令人震惊。因此，在本发明的一个方面， 构建新的碳-氮（C-N）键的合成方法仍然处于化学研究的前沿。 创新迄今为止，大多数调查都集中在开发用于安装 C（sp2）-N键。在可推广的和立体选择性的方法方面几乎没有取得进展， 锻造C（sp3）-N键，尽管三维性对化合物的 生物功效因此，许多含C（sp3）-N的官能团被低估， 生物化学探针和治疗剂，纯粹是由于它们的制备困难。的最 未保护的氮部分如伯胺和未保护的氮杂环丙烷的安装具有挑战性。 目前构建这些基序的策略受到多步合成序列的困扰，需要宝贵的 过渡金属催化剂，或需要使用苛刻的反应条件和潜在危险的试剂。 为了克服这些挑战，拟议的研究采用有机催化剂来促进对映选择性 氮原子转移过程。一个共同的和容易获得的激活的补充模式 合成前体将提供一系列具有挑战性的合成目标。研究计划概述了 通过识别适当的氢键实现所需转化的特定策略 （H-键）供体催化剂体系，其将用于通过羟胺衍生物的网络活化羟胺衍生物。 共价和非共价相互作用。虽然H-键供体有机催化已被用作强有力的催化剂， 由于将简单的起始材料转化为高度对映体富集的产物的策略， 不对称氮原子转移反应。因此，对所提出的过程的机械询问将 为氮气装置的催化剂控制提供有价值的见解， 是稀缺的。设想的方法将提供对映体富集的α-氨基羰基和未保护的氮丙啶 架构，这是准备进一步的合成操作或直接生物评估。通过改善 获得这些高价值的功能基序，探索不足的分子支架将在生物学领域进行调查。 背景下，导致发现新的药物线索和改善治疗技术， 最终促进人类健康。