Development of Enantioselective Sm-Catalyzed Transformations

对映选择性 Sm 催化转化的发展

• 批准号: 10538344
• 负责人: David Charboneau
• 金额: $ 2.48万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-01-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10538344
• 关键词: Acrylates; Address; Catalysis; Collaborations; Complex; Computational Science; Coupling; Data Science; Descriptor; Development; Economics; Electron Transport; Family; Foundations; Future; Goals; Hydrogen Bonding; Ketones; Lactones; Lead; Libraries; Ligands; Linear Regressions; Mediating; Methods; Molecular; Natural Products; Organic Synthesis; Outcome; Oxidation-Reduction; Powder dose form; Preparation; Process; Property; Reaction; Reagent; Reducing Agents; Regression Analysis; Reporting; Route; Samarium; Series; System; Techniques; Testing; Translating; Variant; Work; analog; bioactive natural products; cytotoxicity; design; experience; improved; insight; novel strategies; novel therapeutics; physical model; professor; screening; virtual

Project Summary Reductive SmIII2-mediated transformations are ubiquitous in the synthesis of biologically active natural products, however, they require a stoichiometric quantity of SmIII2, which prohibits their utility on large-scale and impedes the design of enantioselective variants. In principle, strategies to perform reductive SmIII2-mediated processes with catalytic quantities of Sm could lay the foundation to overcome these limitations, but efforts have been inhibited by a paucity of mechanistic understanding. In this project, these challenges will be addressed through the mechanistically-guided development of asymmetric reductive Sm-catalyzed reactions. Initially, we will translate the conditions we developed for the Sm-catalyzed reduction of ketones, which uses Mg0 as an exogenous reductant, to electrochemical conditions. Electroanalytical techniques will provide insight into the mechanism of the reaction and will provide a platform reaction scouting. This information will be used to develop an electrocatalytic system for Sm-catalyzed reduction of ketones on preparative-scale. The strategies discovered through this work will be leveraged to develop other electrochemically-driven reductive Sm-catalyzed transformations, such as the coupling of ketones with ethyl acrylate to produce g-lactones. This scalability of this reaction will be demonstrated using a continuous flow reactor. Next, we will introduce a diverse series of chiral ligands into the coupling reaction between ketones with ethyl acrylate to promote the enantioselective formation of g-lactones. Once a lead hit is identified in ligand screening, a family of analogues of this ligand will be judiciously prepared featuring systematically altered steric, electronic, and hydrogen bonding properties. This family of ligands will be screened in catalysis, and the resulting product enantiomeric enrichment will be correlated to various physical organic molecular descriptors of the ligands using multivariate linear regression analysis. This will provide unprecedented insight into what factors are important for the design of asymmetric reductive Sm-catalyzed reactions, which will be used to guide reaction optimization and result in one of the first reported enantioselective reductive Sm-catalyzed reactions. The practical utility of this transformation will be demonstrated through a concise synthesis of (-)-bipinnatin J, which is a biosynthetic intermediate towards several natural products with potent cytotoxicity properties. Overall, this work will contribute to the fundamental understanding of reductive Sm catalysis, which will provide a robust foundation for the development of future systems and, more broadly, facilitate the discovery and manufacturing of new drugs.

项目摘要 还原SmIII2介导的转化在生物活性天然产物的合成中普遍存在， 然而，它们需要化学计量比的SmIII2，这阻碍了它们的大规模使用，并阻碍了 对映选择性变异体的设计。原则上，执行还原SmIII2介导的过程的策略 使用催化量的Sm可以为克服这些限制奠定基础，但已经做出了努力 被缺乏机械性的理解所抑制。在这个项目中，这些挑战将通过 不对称还原Sm催化反应的力学指导研究进展。最初，我们将 翻译我们为Sm催化酮的还原开发的条件，它使用镁作为一个 外源还原剂，在电化学条件下。电分析技术将提供对 反应机理，将为反应侦察提供平台。这些信息将被用来开发 制备规模的Sm催化酮还原的电催化体系。发现的策略 通过这项工作将利用Sm催化的其他电化学驱动的还原反应来开发 转化，如酮与丙烯酸乙酯的偶联反应，生成g-内酯。这种可扩展性 反应将使用连续流动反应器进行演示。接下来，我们将介绍一系列不同的手性 配体在酮与丙烯酸乙酯偶联反应中促进对映选择性的形成 G-内酯类药物。一旦在配基筛选中确定了铅的命中，该配基的一系列类似物将被 精心制备，具有系统改变的空间、电子和氢键性质。这 配体家族将在催化作用下进行筛选，得到的产物对映体将进行浓缩。 用多元线性回归方法关联配体的各种物理有机分子描述符 分析。这将为非对称设计提供前所未有的洞察力，了解哪些因素是重要的 还原Sm催化的反应，这将用于指导反应优化并导致第一批 报道了Sm催化的对映选择性还原反应。这一转变的实际效用将是 通过简明地合成(-)-bipinnatin J，它是一种生物合成中间体 几种具有强大细胞毒性特性的天然产品。总体而言，这项工作将有助于 对还原Sm催化的认识，为今后的发展奠定坚实的基础 系统，更广泛地说，为新药的发现和制造提供便利。