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

项目摘要/摘要 发现了全新的催化反应，特别是对映体选择性的催化反应 高周转频率(即底物/催化剂/单位时间)，使用容易获得的前体， 将对药物和过程化学产生重大影响。通过一种依赖于 在机械洞察和随之而来的配体设计方面，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 络合物使大范围的1，3-二烯和，乙烯和 烷基丙烯酸酯，这是原料。这些反应的产物是人工合成的 有价值的手性1，4-跳过二烯(产率和ee为90%)，可转化为 药学上相关的化合物类。列举的例子包括抗微生物和抗菌素 肿瘤和抗真菌药物、GABA类似物和金属蛋白酶抑制剂。正在进行中 机理研究有力地表明了阳离子[(P~P)Co(L)]+X-物种在这些化合物中的中介作用 在环境条件下进行的特别选择性的C-C成键反应。多数 值得注意的是，我们最近(2020/2021)发现了自定义的手性阳离子钴(I)配合物。 设计的配体催化炔烃和乙烯-X衍生物的不对称[2+2]-加成反应， 可以说，开环是获得对映体3-取代环丁烯的最佳途径，环丁烯是环丁烯的潜在前体 还有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，以串联的方式，高度官能化的环丁烷与所有- 碳的第四系中心。这样的反应效率很高，而且很少见。初步结果 手性阳离子钴(I)络合物至少催化4种其他类型的对映选择性 反应(前手性1，3-二烯的氢硼化、氢酰化和氢硅化，以及， 1，6-烯炔的环合/氢乙烯基化反应)。我们计划探索一些组合是如何 反应可以串联进行，以尝试开发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使用珍贵的 金属(Rh、Ir、Pd)。我们预计，当完全开发时，钴(比 例如，RH)，将能够催化其中一些基本反应。选择性快速测定法 (化学选择性、区域选择性和对映体选择性)对于这些项目的成功是必不可少的，而高效液相色谱法是 这是我们使用的最关键的工具之一。通过此提交，我们请求资金用于 更换已宣布过时的老化仪器(现已有20多年的历史) 因此，维修和维护变得越来越困难。

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.