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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/9297349
• 关键词: Acetates; Acids; Alkenes; Biological; Carbon; Chemicals; Chemistry; Cobalt; Complex; Development; Diels Alder reaction; Economics; Ethers; Ethylenes; Frequencies; Goals; Heart; Heterodimerization; Ligands; Literature; Measures; Metalloproteases; Metals; Methodology; Methods; Molecular Conformation; Nickel; Outcome; Pharmacologic Substance; Procedures; Process; Protocols documentation; Reaction; Reporting; Research; Route; Structure; Succinic Acids; Synthesis Chemistry; Testing; Time; Variant; analog; antimicrobial; antitumor agent; butyrolactone; catalyst; diene; drug candidate; enol; gamma-Aminobutyric Acid; inhibitor/antagonist; innovation; insight; invention; novel; pi bond; public health relevance; tool; vinylsilane

 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（由申请人提供）：通过各种措施，对合成手性药物的对映体纯中间体的需求正在增加。发现新的催化反应，特别是那些将产生具有高催化剂周转频率的实际水平的不对称诱导的催化反应（即，底物/催化剂/单位时间）的变化将对药物以及工艺化学产生显著影响。在催化剂和底物之间进行手性转移的新方法的发明是实际不对称合成发现的核心。通过主要依赖于机理的见解和配体效应的系统检查的方法，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。在我们早期的尝试中没有很好工作的一类重要底物是1，3-二烯，它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加工成更复杂的分子。然而，在狄尔斯-阿尔德反应之外，很少有广泛适用的不对称催化的、分子间碳-碳键形成的1，3-二烯反应是已知的，部分原因是这些化合物的构象移动性。我们最近发现了创新的方法来实现高度区域和对映选择性的不对称加氢乙烯化（乙烯加成）的不同类别的1，3-二烯，包括高度官能化的，使用Ni（II），Co（II）和Ru（II）催化剂。这种化学，当充分实施时，将提供获得各种各样的对映体纯，无处不在的化学中间体。本提案的目标是探索这些反应的应用以及合成具有已证实生物功效的化合物的所得中间体。举例说明的例子包括强大的抗微生物和抗肿瘤剂，GABA类似物，金属蛋白酶抑制剂。应用新发现的反应，有效地合成了几个广泛的类别的药用相关化合物的建议。 总之，拟议的研究将提供强大的工具，为生物相关的目标和它们的同系物的合成，通过揭示新的方式获得反应性的对映体纯中间体，如跳过-1，4-二烯，烯醇醚，烯醇乙酸酯，乙烯基锡和乙烯基硅烷。这些中间体可用于制备用于测试的已知化合物的新结构或高级结构类似物。我们希望这些发现将缩短作为候选药物的分子概念化与其大规模合成之间的距离。