Highly Selective Catalytic Reactions of Alkenes and Alkynes Relevant to Medicinal and Process Chemistry

与医药和工艺化学相关的烯烃和炔烃的高选择性催化反应

• 批准号: 10581995
• 负责人: T V RAJANBABU
• 金额: $ 7.97万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581995
• 关键词: 20 year old; Acrylates; Aging; Alkenes; Alkynes; Amino Acids; Antifungal Agents; Benign; Biological; Carbon; Catalysis; Cations; Chemistry; Cobalt; Complex; Custom; Cyclization; Cyclobutanes; Diels Alder reaction; Economics; Ethylenes; Frequencies; Funding; Goals; Heterodimerization; High Pressure Liquid Chromatography; Hydroxy Acids; Keto Acids; Ligands; Manufacturer Name; Mediating; Metalloproteases; Metals; Methods; Outcome; Pharmacologic Substance; Phase; Planet Earth; Process; Reaction; Reporting; Research; Route; Running; Services; Time; Work; analog; antimicrobial; catalyst; cycloaddition; design; diene; drug candidate; flexibility; gamma-Aminobutyric Acid; inhibitor; insight; instrument; pharmacophore; rapid test; success; time use; tool; tumor

Project Summary/Abstract Discovery of fundamentally new catalytic reactions, especially enantioselective ones, showing high turnover frequencies (i.e., substrate/ catalyst/unit time), that use readily available precursors, will have a significant impact on medicinal and process chemistry. Through an approach that relies heavily on mechanistic insights and attendant ligand designs, we aim to discover new enantioselective reactions of alkenes and alkynes. For example, use of low-valent chiral (L*)cobalt complexes has enabled heterodimerization between a broad range of 1,3-dienes, and, ethylene and alkyl acrylates, which are feedstock materials. The products of these reactions are synthetically valuable chiral 1,4-skipped dienes (produced in >90% yield and ee) which can be turned into pharmaceutically relevant classes of compounds. Examples cited include anti-microbial and anti- tumor and antifungal agents, GABA analogs, and metalloproteinase inhibitors. On-going mechanistic studies strongly suggest the intermediacy of a cationic [(P~P)Co(L)]+X– species in these exceptionally selective C-C bond-forming reactions that proceed under ambient conditions. Most remarkably, we recently (2020/2021) found that the chiral cationic Co(I) complexes with custom- designed ligands catalyze enantioselective [2+2]-additions of alkynes and vinyl-X derivatives, opening, arguably, the best route to enantiopure 3-substituted cyclobutenes, potential precursors of many other valuable compounds. In sharp contrast to 1,3-dienes, 1,3-enynes form, initially, vinylcyclobutenes and then, in a tandem fashion, highly functionalized cyclobutanes with an all- carbon quaternary centers. Such reactions are highly efficient and uncommon. Preliminary results also indicate that chiral cationic Co(I)-complexes catalyze at least 4 other types of enantioselective reactions (hydroboration, hydroacylation and hydrosilylation of prochiral 1,3-dienes, and, cyclizaion/hydrovinylation of 1,6-enynes). We plan to explore how some of the combinations of reactions can be run in tandem, in attempts to exploit the full potential of the new cobalt chemistry in organic syntheis. Historically some of the reactions we work on had been carried out using precious metals (Rh, Ir, Pd). We expect, when fully devloped, cobalt (which is up to 200 time cheaper than Rh for example), will be able to catalyze some of these basic reactions. Rapid assays of selectivity (-chemo-, regio- and enantioselectivities) are essential for the success of these projects and HPLC is one of the most critical instruments we use. Through this submission we request funds for replacement of an aging instrument (now more than 20 years old) that has been declared obsolete by the manufacturer, thus becoming increasingly difficult to service and maintain.

项目概要/摘要 发现全新的催化反应，特别是对映选择性反应，表明 高周转频率（即底物/催化剂/单位时间），使用现成的前体， 将对药物和过程化学产生重大影响。通过一种依赖的方法 我们重点关注机制见解和随之而来的配体设计，我们的目标是发现新的 烯烃和炔烃的对映选择性反应。例如，使用低价手性(L*)钴 配合物使得多种 1,3-二烯、乙烯和 丙烯酸烷基酯，其为原料。这些反应的产物是合成的 有价值的手性 1,4-跳跃二烯（产率和 ee > 90%），可以转化为 药学相关类别的化合物。引用的例子包括抗微生物和抗 肿瘤和抗真菌剂、GABA 类似物和金属蛋白酶抑制剂。正在进行中 机理研究强烈表明阳离子 [(P~P)Co(L)]+X– 物种在这些中的中介作用 在环境条件下进行的异常选择性的 C-C 键形成反应。最多 值得注意的是，我们最近（2020/2021）发现手性阳离子 Co(I) 与定制的络合物 设计的配体催化炔烃和乙烯基-X衍生物的对映选择性[2+2]-加成， 可以说，开辟了获得对映体纯 3-取代环丁烯（潜在的前体）的最佳途径 许多其他有价值的化合物。与 1,3-二烯形成鲜明对比的是，1,3-烯炔最初形成， 乙烯基环丁烯，然后以串联方式，具有全功能的高官能化环丁烷 碳四元中心。这种反应非常有效且不常见。初步结果 还表明手性阳离子 Co(I) 配合物催化至少 4 种其他类型的对映选择性 反应（前手性 1,3-二烯的硼氢化、氢化酰化和氢化硅烷化，以及， 1,6-烯炔的环化/氢乙烯基化）。我们计划探索一些组合如何 反应可以串联进行，试图充分发挥新钴化学的潜力 有机合成。从历史上看，我们研究的一些反应是使用珍贵的 金属（Rh、Ir、Pd）。我们预计，当钴完全开发出来时（比钴便宜 200 倍） 例如 Rh），将能够催化其中一些基本反应。选择性快速测定 （化学选择性、区域选择性和对映选择性）对于这些项目的成功至关重要，而 HPLC 是 我们使用的最重要的工具之一。通过此提交，我们请求资金 更换已宣布报废的老化仪器（现已使用 20 多年） 由制造商制造，因此维修和维护变得越来越困难。