Toward Direct Design of Transfer Hydrogenation Catalysts

总的来说，该项目的目的是扩大一类新的用于药物合成的催化剂， 比传统催化剂更安全、更经济，并且还具有直接定制特定催化剂的潜力。 反应.这些化合物可以通过减少开发时间和生产成本而有利于药物开发。 酮的不对称转移氢化是制备手性醇的重要方法， 大药厂已经开发了均相催化剂来支持这些反应，使用醇溶剂作为 安全和方便的氢源，但这些现有的系统依赖于氢化物和质子转移， 弱缔合的基质，其需要碱助催化剂来维持足够强的质子受体， 需要协同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在碱性 耐受的底物，和微妙的分子间的力量背后的酒精协会往往需要显着 开发时间，以优化催化剂设计，获得良好的选择性。该计划的长期目标是 提出了一种新的和新颖的催化剂族，其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。这些钌络合物 是双官能的，每个具有氢化物受体位点和侧接在底物结合位点两侧的侧质子受体。 结合本身也是高度不稳定的，用于快速反应物/产物交换，这是通过以下的协同反式和顺式效应实现的： 周围的配体集合醇的直接配位提高了它们的酸性，因此适度的侧基可以 在没有碱助催化剂的情况下使用。直接配位也更好地定义了键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）进行更谨慎的设计控制。的 所提出的研究将从一组三种现有的2，2 '：6'，2”-三联吡啶负载的络合物开始开始，并且将具体地： A.测定结合的侧基的几何形状和强度对催化剂选择性的影响， 助催化剂依赖性。 B。评估定制的2，2 '：6'，2”-三联吡啶配体的阴离子和/或供电子取代基对 催化氢转移的速率。 C.探索类似的催化剂设计与其他紧咬角的三齿配体代替三联吡啶， 更容易适应设计变化。 D.将手性三齿配体引入催化剂并关联配位强制配体-底物 相互作用产生的对映体选择性。 拟议的计划将推动这一有前途的催化剂家族走向药物相关性，并提供一个新的催化剂。 质量和相关的研究环境，代表性不足的学生在MARC ITSTAR的参与， 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.