Toward Direct Design of Transfer Hydrogenation Catalysts

总而言之，这个项目的目的是扩大一类新的药物合成催化剂，这些催化剂是 比传统催化剂更安全、更经济，还有可能直接定制特定的 反应。这些化合物可以缩短开发时间，降低生产成本，有利于药物开发。 摘要酮对映体选择性转移氢化制手性醇是合成手性醇的重要步骤。 制药公司。已经开发出均相催化剂来支持这些反应，使用乙醇溶剂作为 安全和方便的氢源，但这些现有的系统依赖于氢化物和质子的来回转移 弱缔合底物，需要碱性助催化剂来维持足够强的质子受体和 需要分子间的相互作用才能获得良好的选择性。碱性助催化剂将这些体系限制在碱性 耐受性底物，以及酒精关联背后的分子间力的微妙之处通常需要显著的 开发时间，以优化催化剂设计，获得良好的选择性。拟议计划的长期目标是 提出了一种新的新型催化剂家族，它利用了替代的内球氢化物和质子转移， 通过酒精配位到高度不稳定的金属结合部位来解决这两个问题。这些Ru络合物 都是双功能的，每个都有一个氢化物受体位置和一个悬挂的质子受体，位于底物结合位置的两侧。 结合本身也被高度标记，以便通过合作的反式和顺式效应快速交换反应物/产物 周围的配基设置好了。醇的直接配位增加了它们的酸性，所以适度的侧碱可以 使用时没有碱性助催化剂。直接配位也更好地定义了束缚之间的空间相互作用 底物和周围的配体允许对选择性(和对映体选择性)进行更仔细的设计控制。这个 拟议的研究将从一套现有的三个2，2‘：6’，2“-三联吡啶支撑的络合物开始，具体如下： A.确定所结合的侧基的几何形状和强度对催化剂选择性的影响 对助催化剂的依赖。 B.评估定制的2，2‘：6’，2“-联吡啶配体的阴离子和/或电子给体取代基对 催化氢转移的速率。 C.探索类似的催化剂设计，用其他紧密咬合角的三齿配体取代联吡啶 更容易接受设计的变化。 D.将三齿配体的手性形式引入催化剂，并将配位增强的配体底物关联起来 相互作用导致的对映体选择性。 拟议的计划将推动这一前景看好的催化剂家族朝着与制药相关的方向发展，并提供 代表不足的学生参加MARC ITSTAR的质量和相关研究环境 化学和生物化学专业。

In general terms, the purpose of this project is to expand a new class of catalysts for pharmaceutical synthesis that are more safe and economical than traditional catalysts and also have potential for direct customization to specific reactions. These compounds could benefit drug development by reducing development time and production cost. Enantioselective transfer hydrogenation of ketones to chiral alcohols is an important process in the production of Pharmaceuticals. Homogeneous catalysts have been developed to support these reactions using alcohol solvents as safe and convenient hydrogen sources, but these existing systems rely on hydride and proton-transfer to and from weakly associated substrates that necessitates base co-catalysts to maintain sufficiently strong proton acceptors and requires cooperative intermolecular interactions for good selectivity. Basic co-catalysts limit these systems to base tolerant substrates, and the subtleties of the intermolecular forces behind alcohol association often requires significant development time to optimize catalyst design for good selectivity. The long-term goal of the proposed program is to advance a new and novel catalyst family that utilizes an alternative inner-sphere hydride and proton transfer that resolves both issues through alcohol coordination to a highly labilized metal binding site. These ruthenium complexes are bifunctional each with a hydride acceptor site and a pendent proton acceptor that flank the substrate binding site. The binding itself is also highly labilized for rapid reactant/product exchange by cooperative trans and cis-effects from the surrounding ligand set. The direct coordination of alcohols boosts their acidity so modest pendent bases can be employed without base co-catalysts. Direct coordination also better defines the steric interactions between bound substrate and surrounding ligands allowing more deliberate design control over selectivity (and enantioselectivity). The proposed research will begin from a set of three existing 2,2':6',2"-terpyridine supported complexes and will specifically: A. Determine the impact of the geometry and strength of incorporated pendent bases on catalyst selectivity and co-catalyst dependence. B. Assess the influence of anionic and/or electron donating substituents of customized 2,2':6',2"-terpyridine ligands on the rate of catalytic hydrogen transfer. C. Explore analogous catalyst designs with other tight-bite-angle tridentate ligands in place of terpyridines that are more amenable to design variations. D. Incorporate chiral versions of tridentate ligands into catalysts and correlate the coordination enforced ligandsubstrate interactions to the resulting enantioselectivity. The proposed program will advance this promising catalyst family toward pharmaceutical relevance and provide a quality and relevant research environment for the participation of underrepresented students in the MARC ITSTAR and chemistry and biochemistry major programs.