Versatile complex amine synthesis via aziridinium ylides and 2-amidoallyl cations

通过氮丙啶叶立德和 2-酰胺基烯丙基阳离子合成多功能复合胺

• 批准号: 10391455
• 负责人: Jennifer Marie Schomaker
• 金额: $ 29.24万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391455
• 关键词: Amination; Amines; Aziridines; Behavior; Biological Testing; Carbon; Cations; Chemicals; Chemistry; Complex; Coupled; Coupling; Cycloheptanes; Cyclopentane; Development; Geometry; Health; Human; Industrialization; Libraries; Ligands; Metals; Methods; Molecular; Natural Products; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Process; Pyrazines; Pyrrolidines; Reaction; Research; Route; Sampling; Speed; Work; azetidine; carbene; cycloaddition; drug discovery; flexibility; innovation; morpholine; nitrene; novel; open innovation; piperidine; programs; propadiene; screening; ylide

Project Summary/Abstract: Efficient access to molecules of importance to human health has long driven the development of innovative synthetic methods. In recent years, greater emphasis has been placed on explorations of stereochemically complex molecular space not well-represented in typical compound screening libraries. In this context, N- heterocycles and aminated carbocycles are particularly attractive targets, as they are prevalent in drugs, natural products, biomolecules, and ligands. A unified and modular platform capable of rapid, flexible transformations of a simple set of precursors into azetidines, pyrrolidines, piperidines and amine-bearing carbocycles could speed drug discovery processes in complex amine chemical space. Our premise is that developing general, stereoselective routes to aziridinium ylides and 2-amidoallyl cations, coupled with the ability to divert reactivity of these key intermediates along multiple pathways, will provide a versatile approach to diverse, densely functionalized stereochemically complex N-heterocycles comprising useful bioactive chemical space. In addition to the development of new synthetic methods, biological testing of chemical space unlocked by our proposed work is critical to its long-term significance. Our program centered on new oxidative allene amination methods for the synthesis of densely functionalized and heavily substituted amine motifs has yielded ~500 novel amines that have been submitted to the Eli Lilly Open Innovation Drug Discovery (OIDD) program, as well as other academic and industrial collaborators. Promising results showing a broad range of bioactivities in the amine space covered by this preliminary library. This proposal aims to add even more powerful and versatile methods for the syntheses of complex amines from a set of modular, simple building blocks. All new compounds synthesized in the course of these studies will be submitted for screening through OIDD, the UW- Madison Medicinal Chemistry Center and other academic and industrial programs.

项目摘要/摘要： 有效获取对人类健康的重要性分子，长期以来一直促进了创新的发展 合成方法。近年来，更加重视立体化学的探索 复杂的分子空间在典型的化合物筛选文库中没有很好地代表。在这种情况下，n- 杂环和杏仁核苷是特别有吸引力的靶标，因为它们在药物中很普遍， 天然产物，生物分子和配体。一个统一的模块化平台，能够快速，灵活 一组简单的前体转化为硫苷，吡咯烷，哌啶和胺胺的转化 碳循环可以加快复杂胺化学空间中的药物发现过程。我们的前提是 开发一般的立体选择路线，向氮杂丁岛和2-氨基甲基阳离子开发，并与 能够沿多个途径转移这些关键中间体的反应性，将提供一种多功能方法 具有有用的生物活性 化学空间。 除了开发新的合成方法，我们解锁的化学空间的生物学测试 拟议的工作对于其长期意义至关重要。我们的计划集中于新的氧化艾琳胺化 合成密集官能化和重大取代胺序的方法已产生〜500 已提交给Eli Lilly开放创新药物发现（OIDD）计划的新颖胺， 以及其他学术和工业合作者。有希望的结果显示了广泛的生物活性 该初步库涵盖的胺空间。该建议旨在增加更强大的功能和 从一组模块化，简单的构建块中的复杂胺合成的多功能方法。全新 在这些研究过程中合成的化合物将通过UW-的OIDD提交进行筛查 麦迪逊药物化学中心以及其他学术和工业计划。