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Late Stage Stereochemical Editing to Transform the Synthesis of Bioactive Molecules

后期立体化学编辑改变生物活性分子的合成

基本信息

批准号：
10245416
负责人：
Alison Wendlandt
金额：
$ 125.83万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-23 至 2024-08-31
项目状态：
已结题

项目摘要

Project Summary Chiral natural products and man-made drugs play a pivotal role in the study and treatment of a diverse spectrum of human diseases. The presence of stereogenic centers in drug candidates has been shown to correlate with diminished off-target toxicity, reduced CYP450 inhibition, and an overall enhanced probability of regulatory approval as drugs. However, despite the established importance of three-dimensionality in bioactive chemical structures, the selective synthesis of complex organic molecules containing stereogenic centers remains a venerable challenge. The research described in this proposal describes a conceptually new approach to the selective formation and revision of stereogenic centers through the stereoconvergent epimerization of C– H bonds. In contrast to the vast majority of stereoselective transformations, which establish the absolute and relative configuration of a stereogenic center during a key bond-formation step, our approach introduces the opportunity to enrich or invert individual stereocenters after bond connectivity has been finalized. Our strategy thus decouples the strategies needed to establish bond connectivity from the strategies needed to establish the three-dimensional configuration of a complex molecule. By targeting the most ubiquitous functional group, C–H bonds, this tool has expansive potential. If successful, the research program proposed here is anticipated to transform chemical synthesis, dramatically reducing the time and resources necessary to synthesize complex, bioactive molecules. Fundamental mechanistic findings revealed en route to this goal are further anticipated to contribute significantly to our ability to understand reactivity and selectivity patterns in the context of complex molecular environments. .

项目摘要手性天然产物和人工合成药物在研究和治疗各种各样的人类疾病。候选药物中立体中心的存在已显示与脱靶毒性降低、CYP 450抑制降低和作为药物获得监管批准的可能性整体提高。尽管建立了三维在生物活性化学结构中的重要性，含有立体中心的复杂有机分子仍然是一个古老的挑战。的该提案中描述的研究描述了一种概念上的新方法，通过立体会聚差向异构化的立体中心的形成和修正 H键。与绝大多数立体选择性转化相反，绝对和相对构型的立体中心在一个关键的键形成步骤，我们这种方法引入了在粘合后富集或反转单个立构中心的机会连接已经完成。因此，我们的战略是建立从建立三维构型所需的策略键连接一种复杂的分子通过针对最普遍存在的官能团C-H键，该工具具有扩展潜力如果成功，这里提出的研究计划预计将改变化学合成，大大减少了合成所需的时间和资源复杂的生物活性分子。在实现这一目标的过程中发现了基本的机制性发现进一步预计将大大有助于我们理解反应性的能力，复杂分子环境中的选择性模式。 .