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Phenonium ions as control elements for the synthesis of chiral small molecules

铷离子作为手性小分子合成的控制元素

基本信息

批准号：
10219309
负责人：
David A Blank
金额：
$ 37.56万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-03-31
项目状态：
已结题

项目摘要

Project Summary The goal of this proposal is to develop new synthetic methods for the rapid and precise construction of chiral small molecule building blocks. The focal point of the chemistry described is the use of the phenonium ion as a control element to surmount current synthetic limitations associated with stereo- and regiocontrol. Consequently, this reactive intermediate enables the synthesis of benzylic and homobenzylic stereocenters, which are important motifs found in many pharmaceutical agents. Various phases of this proposal concern expanding upon preliminary results from our laboratory for the development of new methods to generate phenonium ions from unconventional starting materials. In each case, new methods for addressing fundamental synthetic limitations will be obtained as well as a deeper fundamental understanding of phenonium ion formation and reactivity. Execution of the chemistry described will enable modular access to small molecule building blocks of relevance to drug discovery programs, e.g., chiral heterocycles. Relevance to public health: The vast majority of pharmaceutical candidates that make it to market are structurally complex, as defined by the presence of sp3 carbons and stereocenters. Many drug molecules contain common architectures such as benzylic and/or homobenzylic stereocenters. New methods that enable streamlined and modular access to these motifs are, therefore, very important. Supporting this program would result in new synthetic approaches to chiral small molecules containing benzylic and/or homobenzylic stereocenters from simple, readily-available starting materials. In so doing, unsolved challenges related to stereo- and regiocontrol will also be addressed.

项目摘要这项提议的目标是开发新的合成方法，以快速和精确地建造手性小分子积木。所述化学的重点是苯离子的使用。作为一种控制元素，以克服目前与立体声和区域控制相关的合成限制。因此，该活性中间体能够合成苄基和高苄基立体中心，它们是在许多药剂中发现的重要基序。这项提案的不同阶段涉及到扩展我们实验室的初步结果开发从非常规原料中产生苯离子的新方法。在每一种情况下，将获得解决基本合成限制的新方法以及更深层次的基本限制理解苯离子的形成和反应性。执行所述的化学物质将使模块化访问与药物发现计划相关的小分子构建块，例如手性杂环化合物。与公共卫生的相关性：按照定义，绝大多数上市的候选药物在结构上都很复杂通过SP3碳和立体中心的存在。许多药物分子包含共同的结构，如苄基和/或高苄基立体中心。新方法可简化、模块化地访问这些因此，主题非常重要。支持这一计划将导致新的手性合成方法含有苄基和/或高苄基立体中心的小分子，从简单、容易获得的开始材料。在这样做的同时，还将解决与立体声和区域控制有关的悬而未决的挑战。