Toward Direct Design of Transfer Hydrogenation Catalysts

转向氢化催化剂的直接设计

基本信息

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
项目类别：
财政年份：
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

项目摘要

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.

总的来说，该项目的目的是扩展一类用于药物合成的新型催化剂，比传统催化剂更安全、更经济，并且还具有根据特定情况直接定制的潜力反应。这些化合物可以通过减少开发时间和生产成本来有利于药物开发。酮对映选择性转移氢化为手性醇是生产手性醇的重要过程。药品。均相催化剂已被开发出来以支持这些反应，使用醇溶剂作为安全和方便的氢源，但这些现有系统依赖于氢化物和质子的往返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合作的分子间相互作用以获得良好的选择性。碱性助催化剂将这些系统限制为碱性耐受底物，并且酒精缔合背后分子间作用力的微妙性通常需要显着的优化催化剂设计以获得良好选择性的开发时间。拟议计划的长期目标是开发一种新型催化剂系列，该系列利用替代的内球氢化物和质子转移通过醇与高度不稳定的金属结合位点的配位解决了这两个问题。这些钌配合物是双功能的，每个都具有氢化物受体位点和位于底物结合位点侧翼的悬垂质子受体。结合本身也高度不稳定，可通过协同反式和顺式效应进行快速反应物/产物交换周围的配体组。醇的直接配位提高了它们的酸度，因此可以使用适度的悬垂碱无需碱助催化剂即可使用。直接配位也更好地定义了结合之间的空间相互作用底物和周围的配体允许对选择性（和对映选择性）进行更仔细的设计控制。这拟议的研究将从一组三个现有的 2,2':6',2"-三联吡啶支持的配合物开始，具体来说： A. 确定所结合的悬垂碱基的几何形状和强度对催化剂选择性和助催化剂依赖性。 B. 评估定制 2,2':6',2"-三联吡啶配体的阴离子和/或给电子取代基对催化氢转移速率。 C.探索用其他紧咬角三齿配体代替三联吡啶的类似催化剂设计更适合设计变化。 D. 将三齿配体的手性版本合并到催化剂中并将配位强化配体底物关联起来相互作用产生的对映选择性。拟议的计划将推动这一有前途的催化剂家族走向制药相关性，并提供为代表性不足的学生参与 MARC ITSTAR 提供质量和相关研究环境，以及化学和生物化学专业。