New Alkene Chemistry for the Synthesis of Medicinally Relevant Compounds

 描述(由申请人提供)：从每一项指标来看，用于合成手性药物的对映体纯中间体的需求都在增加。新催化反应的发现，特别是那些将产生实际水平的不对称诱导和高催化剂周转频率(即底物/催化剂/单位时间)的反应，将对药物化学和过程化学产生重大影响。发明在催化剂和底物之间进行手性转移的新方法是在实际不对称合成中发现的核心。通过一种主要依赖于机理洞察和对配体效应的系统考察的方法，已经发现了许多用于乙烯与各种烯烃的对映选择性异二聚反应的方案。在我们之前的尝试中，一类重要的底物没有很好地发挥作用，那就是1，3-二烯，这是最容易获得和潜在有用的起始材料之一。它们的不对称反应的初级产物可以进一步细化为更复杂的分子。然而，在Diels-Alder反应之外，很少有人知道广泛适用的不对称催化的1，3-二烯分子间碳-碳键形成反应，部分原因是这些化合物的构象流动性。我们最近发现了使用Ni(II)-，Co(II)-和Ru(II)-催化剂对不同类别的1，3-二烯进行高区域和对映体选择性的不对称氢乙烯基化(乙烯加成)的创新方法，包括高官能化的1，3-二烯。这种化学，一旦完全实现，将提供获得各种对映纯的、无处不在的化学中间体的途径。这项提议的目的是探索这些反应和由此产生的中间体在合成具有公认生物功效的化合物方面的应用。例证包括强大的抗微生物和抗肿瘤药物、GABA类似物、金属蛋白酶抑制剂。建议将新发现的反应应用于几大类药物相关化合物的有效合成。总之，拟议的研究将通过揭示获得活性对映体纯中间体的新方法，如跳过的-1，4-二烯、烯醇醚、烯醇乙酸酯、乙烯基锡和乙烯基硅烷，为合成生物相关的目标及其同系物提供强有力的工具。这些中间体可用于制造新结构或用于测试的知名化合物的高级结构类似物。我们希望，这些发现将缩短分子作为候选药物的概念化和大规模合成之间的相当大的距离。

 DESCRIPTION (provided by applicant): By every measure the demand for enantiomerically pure intermediates for the synthesis of chiral pharmaceutical substances is increasing. Discovery of new catalytic reactions, especially those which would yield practical levels of asymmetric induction with high catalyst turnover frequencies (i.e., substrate/catalyst/unit time), will have significant impact on medicinal as well as process chemistry. Invention of new methods for chirality transfer between catalysts and substrates is at the heart of discovery in practical asymmetric synthesis. Through an approach that relies primarily on mechanistic insights and systematic examination of ligand effects, a number of protocols for the enantioselective heterodimerization reactions of ethylene with various alkenes have been discovered. An important class of substrates that did not work well in our earlier attempts is 1,3-dienes, which are among the most accessible and potentially useful starting materials. The primary products of their asymmetric reactions can be further elaborated into more complex molecules. Yet, outside Diels-Alder reactions, few broadly applicable asymmetric catalyzed, intermolecular carbon-carbon bond-forming reactions of 1,3-dienes are known, partly because of the conformational mobility of these compounds. We recently discovered innovative methods to effect highly regio- and enantio-selective asymmetric hydrovinylation (addition of ethylene) of different classes of 1,3-dienes, including highly functionalized ones, using Ni(II)-, Co(II)- and Ru(II)-catalysts. This chemistry, when fully implemented, will provide access to wide variety of enantio-pure, ubiquitous chemical intermediates. The goal of this proposal is to explore the applications of these reactions and the resulting intermediates for the synthesis of compounds with proven biological efficacy. Examples illustrated include powerful anti-microbial and anti-tumor agents, GABA analogs, metalloproteinase inhibitors. Applications of the newly discovered reactions for the efficient syntheses of several broad classes of medicinally relevant compounds are proposed. In summary, the proposed research will provide powerful tools for the synthesis of biologically relevant targets and their congeners, by revealing new ways of accessing reactive enantio-pure intermediates such as skipped-1,4-dienes, enol-ethers, enol-acetates, vinylstannes and vinylsilanes. These intermediates could be useful for making new structures or advanced structural analogs of well-known compounds for testing. We hope that the discoveries made will shorten the considerable distance between the conceptualization of a molecule as a drug candidate and its large-scale synthesis.