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

项目摘要/摘要： 长期以来，高效获取对人类健康至关重要的分子一直推动着创新技术的发展 合成方法。近年来，立体化学的探索越来越受到重视。 在典型的化合物筛选文库中，复杂的分子空间不能很好地代表。在这方面，N- 杂环和胺化碳环是特别吸引人的目标，因为它们普遍存在于药物中， 天然产物、生物分子和配体。统一、模块化的平台，能够快速、灵活地 一组简单前体向氮杂环丁烷、吡咯烷、哌啶和含胺化合物的转化 碳环可以加快复合胺化学空间中的药物发现过程。我们的前提是 开发合成氮杂环丙烷叶立德和2-酰胺基烯丙基阳离子的一般立体选择性路线，与 能够将这些关键中间体的反应性沿多条途径转移，将提供一种通用的方法 到各种、密集官能化的立体化学复杂的N-杂环，包括有用的生物活性 化学空间。 除了开发新的合成方法外，我们还开启了化学空间的生物测试 拟议的工作对其长期意义至关重要。我们的计划以新的氧化联烯胺化为中心 合成稠密官能化和重取代胺基序的方法已产生~500 已提交给礼来公司开放式创新药物发现(OIDD)计划的新胺，如 以及其他学术和产业合作者。令人振奋的结果显示了广泛的生物活性 这个初步的图书馆所覆盖的胺空间。这项建议旨在增加更强大的 从一组模块化、简单的积木中合成复合胺的多种方法。全新的 在这些研究过程中合成的化合物将通过OIDD、UW- 麦迪逊药物化学中心和其他学术和工业项目。

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.