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

项目概要/摘要 发现了全新的催化反应，特别是对映选择性反应， 较高的周转频率（即，底物/催化剂/单位时间），使用容易获得前体， 将对医药和工艺化学产生重大影响。通过一种方法， 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 复合物使得能够在宽范围的1，3-二烯和乙烯之间进行异二聚化， 作为原料的丙烯酸烷基酯。这些反应的产物是合成的 有价值的手性1，4-跳跃的二烯（以>90%的产率和ee生产），其可以转化为 药学相关类别的化合物。所引用的例子包括抗微生物和抗微生物。 肿瘤和抗真菌剂、GABA类似物和金属蛋白酶抑制剂。正在进行 机理研究强烈表明，阳离子[（P~P）Co（L）]+X-物种在这些 在环境条件下进行的异常选择性的C-C键形成反应。最 值得注意的是，我们最近（2020/2021）发现，手性阳离子Co（I）与定制- 设计的配体催化炔和乙烯基-X衍生物的对映选择性[2+2]-加成， 可以说，打开了获得对映体纯的3-取代的环丁烯的最佳途径， 许多其他有价值的化合物。与1，3-二烯形成鲜明对比，1，3-烯炔最初形成， 乙烯基环丁烯，然后以串联方式，高度官能化的环丁烷与全- 碳四元中心这种反应是非常有效和罕见的。初步结果 还表明手性阳离子Co（I）-络合物催化至少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，和， 1，6-烯炔的环化/加氢乙烯基化）。我们计划探索一些组合如何 反应可以串联进行，试图利用新的钴化学的全部潜力， 有机合成从历史上看，我们研究的一些反应是用珍贵的 金属（Rh、Ir、Pd）。我们预计，当完全开发后，钴（比钴便宜200倍）将成为全球最大的钴生产商。 例如Rh），将能够催化这些基本反应中的一些。选择性快速测定 （-化学-，区域-和对映体选择性）是这些项目的成功必不可少的，HPLC是 我们使用的最重要的工具之一。通过这份文件，我们要求资金， 更换已宣布过时的老化仪器（现已超过20年） 因此变得越来越难以维修和维护。

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.