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: 10544730
• 负责人: T V RAJANBABU
• 金额: $ 38.4万
• 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/10544730
• 关键词: Acrylates; Address; Alkenes; Alkynes; Antifungal Agents; Benign; Carbon; Chemistry; Clinical Trials; Cobalt; Complex; Custom; Cyclobutanes; Economics; Education; Ethylenes; Frequencies; Future; Heterodimerization; Ligands; Marketing; Medicine; Metalloproteases; Metals; Methods; Nature; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Process; Reaction; Research; Route; Running; Scientist; Time; Training; Work; analog; antimicrobial; catalyst; cost effective; design; diene; drug candidate; gamma-Aminobutyric Acid; inhibitor; insight; large scale production; manufacture; success; tool; tumor

Project Summary/Abstract A recent critical analysis of biologically active molecules and reactions most often used for their preparation suggests that fraction of saturated carbons and presence of chiral centers correlate with success as a compound moves from discovery, through clinical trials to an approved drug. About a third of the compounds had at least one chiral center. In addition, practical aspects of manufacturing still need to be addressed to market a cost effective drug. Thus 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 we strive 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 (2018/2019) 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 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 reactions (hydroboration, hydroacylation and hydrosilylation of prochiral 1,3-dienes, and, cyclizaion/HV of 1,6- enynes). We plan to explore how many 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. We expect, when fully devloped, cobalt (which is 100 to 200 time cheaper than Rh for example), will be able to catalyze some of these basic reactions. The interdisciplinary nature of the work proposed here provides outstanding opportunities to train future scientists at every level of their education.

项目摘要/摘要 对生物活性分子和反应的最新批判性分析最常用于其 制备表明，饱和碳的比例和手性中心的存在与 作为化合物的成功从发现转变为临床试验转变为批准的药物。大约 三分之一的化合物至少有一个手性中心。此外，制造业的实际方面 仍然需要解决一种经济有效的药物。从根本上发现的新发现 催化反应，尤其是对映选择性反应，表现出较高的周转频率（即 使用易于可用前体的基板/催化剂/单位时间）将对 药物和过程化学。通过一种严重依赖机械见解的方法 我们努力发现烷烃和炔烃的新对映选择性反应。例如，使用 低价性手性（L*）钴络合物已在广泛的范围内实现异二聚化 1,3-二烯，以及乙烯和烷基丙烯酸酯，它们是原料材料。这些产品 反应在合成的手性手性1,4键词字典（以> 90％的产量和EE产生）是 可以将其变成具有物理相关的化合物类。引用的例子包括 抗微生物，抗肿瘤和抗真菌剂，GABA类似物和金属蛋白酶酶 抑制剂。正在进行的机械研究强烈表明阳离子的中间体 {[p〜p）co（l）]+} x-物种在这些异常选择性的C-C键形成反应中进行 在环境条件下。最引人注目的是，我们最近（2018/2019）发现手性阳离子 CO（i）具有自定义设计的配体的复合物催化对映选择性[2+2] - 炔烃的成果 和乙烯基X衍生物，可以说，可以说是对对映体3-取代环丁烯的最佳途径， 潜在的前体其他有价值的化合物。与1,3-二烯，1,3-enynes形式形成鲜明对比， 最初，乙烯基环丁烯，然后以串联的方式，具有高度官能化的环形机构 全碳四元中心。这样的反应高效且不常见。初步的 结果还表明，手性阳离子CO（i） - 复合物催化至少4种其他类型的反应 （术前1,3-二烯的水力恢复，水酰化和氢化化，以及1,6--的环体/HV/HV Enynes）。我们计划探索可以同时运行多少反应组合 试图探索有机综合症新钴化学的全部潜力。历史上 我们进行的一些反应是使用贵金属进行的。我们期望什么时候 完全开发的钴（例如，比RH便宜100到200时间）将能够 催化其中一些基本反应。这里提出的工作的跨学科性质 提供了出色的机会，可以在他们的各个级别的教育中培训未来的科学家。