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）：从各个方面来看，用于合成手性药物物质的对映体纯中间体的需求都在增加。新催化反应的发现，特别是那些能够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，将对医药和过程化学产生重大影响。催化剂和底物之间手性转移新方法的发明是实际不对称合成发现的核心。通过主要依赖于配体效应的机制见解和系统检查的方法，已经发现了乙烯与各种烯烃的对映选择性异二聚反应的许多方案。在我们早期的尝试中效果不佳的一类重要底物是 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主要产物可以进一步加工成更复杂的分子。然而，除了狄尔斯-阿尔德反应之外，很少有广泛适用的 1,3-二烯不对称催化、分子间碳-碳键形成反应，部分原因是这些化合物的构象迁移性。我们最近发现了使用 Ni(II)-、Co(II)- 和 Ru(II)- 催化剂实现不同类别 1,3-二烯（包括高度官能化的 1,3-二烯）的高度区域和对映选择性不对称氢乙烯基化（乙烯加成）的创新方法。这种化学反应完全实施后，将提供多种对映体纯、普遍存在的化学中间体。该提案的目标是探索这些反应的应用以及由此产生的中间体，用于合成具有经过验证的生物功效的化合物。举例说明的例子包括强效抗微生物剂和抗肿瘤剂、GABA 类似物、金属蛋白酶抑制剂。提出了新发现的反应在几大类医学相关化合物的有效合成中的应用。 总之，拟议的研究将通过揭示获得反应性对映纯中间体（例如跳过的1,4-二烯、烯醇醚、烯醇乙酸酯、乙烯基锡烷和乙烯基硅烷）的新方法，为合成生物学相关目标及其同系物提供强大的工具。这些中间体可用于制造新结构或众所周知化合物的高级结构类似物以进行测试。我们希望所取得的发现将缩短候选药物分子的概念化与其大规模合成之间的相当大的距离。