Late Stage Stereochemical Editing to Transform the Synthesis of Bioactive Molecules

项目摘要 手性天然产物和人造药物在癌症的研究和治疗中发挥着关键作用。 人类疾病的各种类型。候选药物中立体定向中心的存在 已被证明与减少靶外毒性，减少对细胞色素P450的抑制有关，以及 作为药物获得监管批准的可能性总体增加。然而，尽管已经建立了 三维结构在生物活性化学结构中的重要性，选择性合成 含有立体中心的复杂有机分子仍然是一个古老的挑战。这个 本提案中描述的研究描述了一种概念上的新方法，以选择 通过立体收敛的C-异构化形成和修正立体发生中心 H键。与绝大多数立体选择转换不同的是，立体选择转换建立了 在一个关键的成键步骤中，立体中心的绝对和相对构型，我们的 方法引入了在绑定后丰富或反转单个立体中心的机会 连通性已经敲定。因此，我们的战略与建立 从建立纽带互联互通战略所需的三维构型 一种复杂的分子。通过瞄准最普遍的官能团-C-H键，该工具具有 广阔的潜力。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揭示了基本的机械发现 进一步预计将对我们理解反应性和 复杂分子环境背景下的选择性模式。 。

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. .