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 还原性SMIII2介导的转化在合成生物活性天然产物中无处不在， 但是，它们需要化学计量量的SMIII2，这禁止其在大规模和阻碍上的效用 对映选择性变体的设计。原则上，执行还原性SMIII2介导的过程的策略 使用催化量的SM可以为克服这些局限性奠定基础，但努力一直是 由于缺乏机械理解而抑制。在这个项目中，这些挑战将通过 不对称还原Sm催化反应的机械引导的发展。最初，我们会的 翻译我们为SM催化酮的减少酮所开发的条件，该酮使用MG0作为一个 外源还原剂，对电化学条件。电分析技术将为您提供深入的了解 反应的机制，并将提供平台反应侦察。此信息将用于开发 用于在制备尺度上降低酮的SM催化降低的电催化系统。发现的策略 通过这项工作将被利用以开发其他电化学驱动的还原性SM催化 转化，例如酮与丙烯酸乙烯酸乙酯的偶联以产生G-lactones。这种可扩展性 将使用连续的流动反应器证明反应。接下来，我们将介绍各种各样的手性 酮与丙烯酸乙烯酯之间的偶联反应，以促进对映选择性形成 G-lactones。一旦在配体筛选中确定了铅命中率，该配体的类似物将是 明智地制备具有系统改变的空间，电子和氢键特性。这 配体系列将在催化中筛选，由此产生的产品对映体富集将是 使用多元线性回归与配体的各种物理有机分子描述相关 分析。这将提供前所未有的见解，即哪些因素对于不对称的设计很重要 还原性SM催化反应，该反应将用于指导反应优化并导致第一个 报道了对映选择性还原性SM催化反应。这种转变的实际实用性将是 通过（ - ） - 双生素J的简明合成来证明，这是一种生物合成中间体 几种具有有效细胞毒性特性的天然产物。总体而言，这项工作将有助于基本 了解还原性SM催化，这将为未来的发展提供强大的基础 系统，更广泛地促进了新药的发现和制造。