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

项目总结/摘要 最近对生物活性分子和最常用于其 制备表明，饱和碳的分数和手性中心的存在与 一个化合物的成功是从发现，通过临床试验，到被批准的药物。大约一 三分之一的化合物具有至少一个手性中心。此外，制造业的实际方面 仍然需要解决以销售成本有效的药物。从而发现了一种全新的 催化反应，特别是对映选择性反应，显示出高的转换频率（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。通过一种严重依赖于机械见解的方法 我们致力于发现烯烃和炔烃的新的对映选择性反应。例如使用 低价手性（L *）钴络合物已经使得能够在宽范围的 1，3-二烯和乙烯和丙烯酸烷基酯，它们是原料。这些产品 反应是合成上有价值的手性1，4-跳过的二烯（以> 90%的产率和ee生产） 其可以转化为药学上相关的化合物类别。列举的例子包括 抗微生物和抗肿瘤和抗真菌剂、GABA类似物和金属蛋白酶 抑制剂的正在进行的机械研究强烈表明，阳离子的中间性 {[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。最值得注意的是，我们最近（2018/2019）发现，手性阳离子 Co（I）配合物催化炔的对映选择性[2 + 2]加成反应 和乙烯基-X衍生物，可以说，打开了获得对映体纯的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1，3-二烯形成鲜明对比，1，3-烯炔形成， 首先，乙烯基环丁烯，然后，以串联方式，高度官能化的环丁烷， 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）-配合物催化至少4种其他类型的反应 （前手性1，3-二烯的硼氢化、氢酰化和硅氢化，以及1，6-二烯的环化/HV） enynes）。我们计划探索有多少种反应组合可以串联运行， 试图开发新的钴化学在有机合成中的全部潜力。历史上 我们研究的一些反应是用贵金属进行的。我们预计，当 完全开发的钴（例如比Rh便宜100到200倍）将能够 催化这些基本反应。这里提出的工作的跨学科性质 提供了优秀的机会，培养未来的科学家在他们的教育的各个层次。

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.