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: 10320911
• 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/10320911
• 关键词: Acrylates; Address; Alkenes; Alkynes; Antifungal Agents; Benign; Carbon; Cations; Chemistry; Clinical Trials; Cobalt; Complex; Custom; Cyclobutanes; Economics; Education; Ethylenes; Frequencies; Future; Heterodimerization; Ligands; 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; success; time use; 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 最近对生物活性分子和反应的批判性分析最常用于其 制备表明，饱和碳的分数和手性中心的存在与 作为一种化合物，从发现到临床试验，再到批准的药物，都取得了成功。关于一个 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 仍然需要解决的问题是将具有成本效益的药物推向市场。因此发现了全新的 催化反应，特别是对映体选择性反应，表现出高转换频率(即， 底物/催化剂/单位时间)，使用容易获得前体，将对 药物化学和过程化学。通过一种严重依赖机械洞察力的方法 我们致力于发现新的烯烃和炔烃的对映选择性反应。例如，使用 低价的手性(L*)钴配合物使大范围的 1，3-二烯，以及乙烯和烷基丙烯酸酯，它们是原料。这些产品的产品 反应是具有合成价值的手性1，4-跳过的二烯(在&gt；90%的产率和ee中产生) 它们可以转化为与药物相关的一类化合物。列举的例子包括 抗微生物、抗肿瘤和抗真菌药物、GABA类似物和金属蛋白酶 抑制剂。正在进行的机理研究强烈表明阳离子的中间性。 这些异常选择性的C-C成键反应中的{[P~P]Co(L)+}个X-物种 在环境条件下。最值得注意的是，我们最近(2018/2019)发现手性阳离子 具有定制配体的钴(I)配合物催化炔烃的不对称[2+2]-加成反应 和乙烯-X衍生物，可以说是合成对映体3-取代环丁烯的最佳途径， 潜在的前体和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，乙烯基环丁烯，然后，在串联的方式，高度官能化的环丁烷与一个 全碳第四纪中心。这样的反应效率很高，而且很少见。初步 结果还表明，手性阳离子钴(I)络合物至少催化4种其他类型的反应 (前手性1，3-二烯的氢硼化、氢酰化和氢硅化，以及1，6-二烯的环化/高压 Enynes)。我们计划探索有多少种反应组合可以同时进行， 试图在有机合成中充分开发新的钴化学的潜力。从历史上看 我们研究的一些反应是使用贵金属进行的。我们预计，什么时候 完全开发的钴(例如，它比Rh便宜100到200倍)将能够 催化其中的一些基本反应。这里提出的工作的跨学科性质 为培养各个层次的未来科学家提供了绝佳的机会。