Toward Direct Design of Transfer Hydrogenation Catalysts

转向氢化催化剂的直接设计

• 批准号: 7648138
• 负责人: ERIC P KELSON
• 金额: $ 15.94万
• 依托单位: CALIFORNIA STATE UNIVERSITY NORTHRIDGE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7648138
• 关键词: Acceleration; Acetophenones; Acidity; Alcohol consumption; Alcohols; Alkenes; Attention; Binding; Binding Sites; Biochemistry; Bite; CCL7 gene; Chemistry; Cholesterol; Class; Complex; Computer Simulation; Computer-Aided Design; Condition; Crestor; Dependence; Development; Electrons; Environment; Family; Foundations; Gases; Goals; Guidelines; Hydrogen; Hydrogenation; Hydroxylation; Imidazole; Industry; Investigation; Ketones; Laboratories; Lead; Ligands; Metal Binding Site; Metals; Nature; Oxygen; Pharmacologic Substance; Pliability; Preparation; Process; Production; Property; Protons; Purpose; Range; Rate; Reaction; Research; Ruthenium; Series; Site; Solvents; Source; Specificity; Structure; Students; Substrate Interaction; Surveys; System; Testing; Time; Variant; Water; Work; analog; atorvastatin; base; catalyst; cost; design; desire; drug development; enantiomer; intermolecular interaction; member; novel; oxidation; pinacolone; programs; pyridine; reaction rate; rosuvastatin

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.

一般而言，该项目的目的是扩展一类新的药物合成催化剂 比传统催化剂更安全，更经济，并且有可能直接定制特定的 反应。这些化合物可以通过减少开发时间和生产成本来使药物开发受益。 对映选择性转移酮向手性醇的氢化是生产的重要过程 药品。已经开发了均质催化剂，以使用酒精溶剂作为支持这些反应 安全便捷的氢来源，但是这些现有系统依赖于氢化物和质子转移 弱相关的底物需要基础共同催化剂才能保持足够强的质子受体和 需要合作分子间相互作用才能良好选择性。基本共同催化剂将这些系统限制为基础 耐受的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着 开发时间以优化催化剂设计以良好的选择性。拟议计划的长期目标是 推进一个新的新型催化剂家族，该家族利用了替代的内球氢化物和质子转移 通过酒精协调解决这两个问题，将这两个问题分解为高度衰弱的金属结合位点。这些钌配合物 每个都有氢化物受体位点的双功能和一个侧面底物结合位点的垂直质子受体。 结合本身也高度衰减，以通过合作反式反应剂/产品交换以及从 周围的配体套件。酒精的直接协调提高了它们的酸度，因此可以适度的底座可以是 没有基础共同催化剂。直接协调还更好地定义了界线之间的空间相互作用 底物和周围的配体，可以对选择性（和对映选择性）进行更故意的设计控制。这 拟议的研究将从三个现有的2,2'：6'，2“ - terpyridine支持的复合体开始，并将特别： 答：确定掺入式底座对催化剂选择性的几何形状和强度的影响 共催化剂依赖性。 B.评估自定义2,2'：6'，2“ - terpyridine配体对阴离子和/或电子捐赠取代基的影响 催化氢转移的速率。 C.探索与其他紧缩角角体配体的类似催化剂设计，代替terpyridines 更适合设计变体。 D.将三叉酸配体的手性版本纳入催化剂中，并将强制性配体底物的配位相关联 与最终的对映选择性的相互作用。 拟议的计划将使这个有前途的催化剂家族朝着药物相关性发展，并提供 质量和相关的研究环境，用于参与MARC ITSTAR的代表性不足的学生和 化学和生物化学主要计划。