New Alkene Chemistry for the Synthesis of Medicinally Relevant Compounds

用于合成医学相关化合物的新烯烃化学

基本信息

批准号：
9297349
负责人：
T V RAJANBABU
金额：
$ 29.79万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-06-30
项目状态：
已结题

项目摘要

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.

描述（由适用提供）：通过每种衡量标准，对对照的纯纯中间体的需求都在增加。发现新的催化反应，尤其是那些将通过高催化剂周转频率（即底物/催化剂/单位时间）产生实际水平的不对称诱导，将对医学和过程化学产生重大影响。在实际不对称合成中，催化剂和底物之间的手性转移方法的发明是发现的核心。通过一种主要依赖机械洞察力和对配体效应的系统检查的方法，已经发现了乙烯与各种烷烃的对映选择性异二聚反应的许多方案。在我们较早的尝试中无法正常工作的一类重要类别是1,3-二烯，这是最容易访问且可能有用的起始材料之一。它们的非对称反应的主要产物可以进一步阐述为更复杂的分子。然而，除了二烷 - alder反应外，很少有广泛适用的不对称催化，分子间碳碳键形成1,3-二烯的反应，部分原因是这些化合物的构象迁移率。我们最近发现了使用Ni（ii） - ，CO（ii） - 和RU（II） - 和RU（II）-Catalysts的不同类别的1,3-二烯，包括高度功能化的1,3-二烯，包括高度功能化的1,3-二烯，包括高度功能化的1,3-二烯，包括高度功能化的1,3-二烯。该化学完全实施后，将为多种无处不在的化学中间体提供途径。该提案的目的是探索这些反应的应用以及所得的中间体，用于合成具有可靠的生物学效率的化合物。所示的例子包括强大的抗微生物和抗肿瘤药，GABA类似物，金属蛋白酶酶抑制剂。提出了新发现的反应的应用，以对几种广泛的药物相关化合物的有效合成。总而言之，拟议的研究将通过揭示访问反应性启用启用启用的中间体的新方法，例如跳过1,4-二烯，烯醇，烯醇，烯醇，烯醇乙酸，乙烯基斯坦尼斯和乙烯基西兰氏菌，为生物学相关目标及其同类物的合成提供强大的工具。这些中间体对于制造新结构或众所周知的化合物的高级结构类似物可能很有用。我们希望发现的发现将缩短分子作为候选药物的概念化与其大规模合成之间的考虑距离。