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

项目摘要 该提案的目标是开发新的合成方法，用于快速和精确地构建 手性小分子结构单元。所描述的化学的焦点是使用苯鎓离子 作为控制元件，以克服与立体声和区域控制相关联的当前合成限制。 因此，该反应性中间体能够合成苄基和均苄基立构中心， 其是在许多药剂中发现的重要基序。 该建议的各个阶段涉及扩展我们实验室的初步结果， 开发从非常规起始材料产生苯鎓离子的新方法。在每种情况下， 将获得解决基本合成限制的新方法，以及更深层次的基本 了解苯鎓离子的形成和反应性。执行所述化学过程将使 模块化访问与药物发现计划相关的小分子构建模块，例如，手性 杂环 与公共卫生的相关性： 绝大多数进入市场的候选药物都是结构复杂的， 通过sp3碳和立构中心的存在。许多药物分子含有共同的结构，例如 苄基和/或同苄基立构中心。新的方法，使这些简化和模块化的访问， 因此，主题非常重要。支持这一计划将导致新的合成方法，手性 含有苄基和/或同苄基立构中心的小分子， 材料.在这样做时，还将解决与立体声和区域控制有关的未解决的挑战。

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.