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

项目概要/摘要： 长期以来，有效获取对人类健康重要的分子一直推动着创新药物的发展。 合成方法近年来，立体化学的研究越来越受到重视， 复杂的分子空间在典型的化合物筛选文库中没有很好的表现。在这种情况下，N- 杂环和胺化碳环是特别有吸引力的目标，因为它们在药物中普遍存在， 天然产物、生物分子和配体。统一的模块化平台，能够快速、灵活地 将一组简单的前体转化为氮杂环丁烷、吡咯烷、哌啶和含胺的 碳环可以加速复杂胺化学空间中的药物发现过程。我们的前提是， 发展一般的，立体选择性的路线，氮丙啶叶立德和2-酰胺烯丙基阳离子，再加上 将这些关键中间体的反应性沿沿着多个途径转移的能力，将提供一种通用的方法 到包含有用生物活性物质的多种、密集功能化的立体化学复杂N-杂环 化学空间 除了开发新的合成方法，生物测试化学空间解锁我们的 拟议的工作对其长期意义至关重要。我们的计划集中在新的氧化丙二烯胺化 用于合成密集官能化和高度取代的胺基序的方法已经产生了约500 已提交给礼来公司开放创新药物发现（OIDD）计划的新型胺， 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， 这个初步库所覆盖的胺空间。该提案旨在增加更强大的和 从一组模块化的简单结构单元合成复杂胺的通用方法。所有新 在这些研究过程中合成的化合物将提交给OIDD，UW- 麦迪逊药物化学中心和其他学术和工业计划。

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.