Development of Enantioselective Sm-Catalyzed Transformations

项目摘要 还原SmIII 2介导的转化在生物活性天然产物的合成中普遍存在， 然而，它们需要化学计量量SmIII 2，这妨碍了它们的大规模应用， 对映体选择性变体的设计。原则上，进行还原SmIII 2介导过程的策略 催化量的Sm可以为克服这些限制奠定基础，但人们一直在努力 由于缺乏对机械的理解而受到抑制。在本项目中，这些挑战将通过 不对称还原钐催化反应的机械导向发展。首先，我们将 翻译的条件，我们开发的钐催化还原酮，其中使用镁0作为一个 外源性还原剂，电化学条件。电分析技术将提供深入了解 反应机理，并将提供一个平台反应侦察。这些信息将用于开发 一种用于钐催化还原酮的电催化体系。发现的策略 通过这项工作，将利用开发其他电化学驱动的还原性Sm催化 转化，例如酮与丙烯酸乙酯偶联以产生g-内酯。这种可扩展性 反应将使用连续流动反应器来证明。接下来，我们将介绍一系列不同的手性化合物， 将配体引入酮与丙烯酸乙酯的偶联反应中，以促进对映选择性的形成 的G-内酯。一旦在配体筛选中鉴定出先导命中，将鉴定该配体的类似物家族。 明智地制备具有系统地改变空间，电子和氢键性质。这 将在催化中筛选配体家族，并将所得产物对映体富集 用多元线性回归法与配体的各种物理有机分子描述符进行了关联 分析.这将提供前所未有的洞察力，什么因素是重要的设计不对称 还原钐催化反应，这将用于指导反应优化，并导致在第一个 报道了对映选择性还原钐催化反应。这种转换的实际效用将是 通过（-）-bipinnatin J的简明合成证明了这一点，它是一种生物合成中间体， 几种具有强效细胞毒性的天然产物。总的来说，这项工作将有助于基本的 了解还原钐催化，这将提供一个坚实的基础，为未来的发展 更广泛地说，它促进了新药的发现和制造。

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.