Development and Applications of Asymmetric Hydrovinylation of Alkenes

烯烃不对称氢乙烯基化的研究进展及应用

• 批准号: 7623571
• 负责人: T V RAJANBABU
• 金额: $ 23.6万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7623571
• 关键词: Acids; Address; Alkenes; Alzheimer' s Disease; Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Antimycobacterial Agents; Antitubercular Agents; Ascorbic Acid; Betula Genus; Biological; Biological Factors; Carbon; Chemistry; Classification; Clinical Research; Complex; Cyclohexanes; Dependence; Development; Elements; Ethylenes; Frequencies; Generations; Glycosides; Goals; Heterodimerization; Ibuprofen; Ketones; Ligands; Literature; Measures; Methodology; Methods; Modification; Naproxen; Outcome Study; Pharmacologic Substance; Process; Property; Protocols documentation; Reaction; Relative (related person); Route; Scheme; Serotonin Antagonists; Side; Solutions; Steroids; Synthesis Chemistry; Time; analog; aphanorphine; base; catalyst; cytotoxic; design; diene; drug candidate; frondosin B; functional group; hypoxia inducible factor 1; improved; inhibitor/antagonist; insight; methyl group; novel strategies; phenserine; pi bond; pseudopterosins; stereochemistry; success; tetralin; tool

DESCRIPTION (provided by applicant): By every measure the demand for enantiomerically pure intermediates for the synthesis of chiral pharmaceutical products keeps mounting. Discovery of new asymmetric reactions, especially those which would yield practical levels of asymmetric induction and high turnover frequencies (i.e., substrate/catalyst/unit time), will have significant impact on medicinal as well as process chemistry. Through an approach that relies primarily on mechanistic insights and systematic examination of ligand effects, we have discovered a number of protocols for the enantioselective heterodimerization reactions of ethylene with vinylarenes, 1,3-dienes and strained olefins. We have also uncovered reactions for the asymmetric generation of all-carbon quaternary centers, which are otherwise difficult to install. Mild reaction conditions, tolerance to various functional groups, isolated yields >95%, substrate/catalyst ratios of 100-1000 and enantioselectivities of 90-99% ee for various reaction imply that hydrovinylation could be developed into a practical process for the synthesis of molecules with a chiral 3-(alkyl or aryl)-1-butene motif. Many biologically important molecules can be easily accessed from these intermediates. Examples illustrated include powerful anti-inflammatory, antitumor and antituberculosis agents. In some cases these are the first enantioselective syntheses, while in others, where analog synthesis could benefit clinical studies, the relative merits of this approach vis-a-vis known methods are pointed out. Broadly, the goals of this project are two fold: (a) Improvements in the selectivity and scope of hydrovinylation. Following our preliminary results, we want to explore and expand the scope, and applications of the hydrovinylation of vinyl arenes, 1,3-dienes and strained olefins, including those give chiral all-carbon quaternary centers. This would involve the discovery of new protocols, and of new chiral ligands for this exacting reaction, (b) Application of asymmetric hydrovinylation in total synthesis of natural products. A general solution to the classical problem of installation of exocyclic chiral centers will be illustrated with synthesis of (-)-laurenditerpenol, steroid C/D ring analogs, helioporins and pseudopterosins and serotonin antagonist LY426965. Stereoselective syntheses of these compounds are especially important because of their varied biological activities (including cytotoxic, anti-inflammatory and antimycobacterial properties), dependence of such activities on the configuration of each of the chiral centers, and paucity of methods for absolute stereochemical control in C-C bond formations. Hydrovinylation offers outstanding opportunities in this regard. Applications aside, we hope that the study of the reaction would reveal new control elements useful for the development of new, broadly applicable, tools for catalytic asymmetric synthesis.

描述（由申请人提供）：通过每种衡量指标，对对照纯净的中间体的需求，用于合成手性药物的产品的需求不断增加。发现新的不对称反应，尤其是那些将产生实际水平的不对称诱导和高离职频率（即底物/催化剂/单位时间）的反应，将对药用化学和过程化学产生重大影响。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，我们发现了乙烯与乙烯基烯烯，1,3-二烯和碳纤维的对照选择性异二焦二聚反应的许多方案。我们还发现了对全碳四元中心不对称产生的反应，否则这些中心很难安装。轻度反应条件，对各种官能团的耐受性，分离的屈服> 95％，底物/催化剂比为100-1000，对各种反应的对照组为90-99％EE，这意味着可以将水旋苷化发展为分子与chiral 3-（chiral 3-（烷基）合成的实际过程，这些中间体可以很容易地访问许多具有生物学上重要的分子。所示的例子包括强大的抗炎，抗肿瘤和抗结核药。在某些情况下，这些是第一个对映选择性合成，而在其他情况下，模拟合成可以使临床研究受益，这种方法的相对优点相对于已知方法。从广义上讲，该项目的目标是两个方面：（a）提高氢旋烯基化的选择性和范围。根据我们的初步结果，我们希望探索和扩大乙烯基领域，1,3-二烯和紧张的烯烃的氢化素化的范围，包括给人手性全碳季心中心的烯烃。这将涉及发现新方案的发现，以及对这种严格反应的新手性配体的发现，（b）在天然产物的总合成中应用不对称的氢苷化。通过（ - ） - 月桂素甲醇，类固醇C/D环类似物，螺旋蛋白和假霉胞素和羟色胺拮抗剂LY426965的合成，将说明外生手性中心安装经典问题的一般解决方案。这些化合物的立体选择合成尤其重要，因为它们的生物学活性各异（包括细胞毒性，抗炎和抗菌特性），这种活动对每个手性性中心的构型的依赖性，以及对于C-C键形成中绝对刻板控制方法的方法。 Hydrovinylation在这方面提供了出色的机会。除了应用外，我们希望对反应的研究能够揭示新的控制元素，可用于开发新的，广泛适用的催化不对称合成工具。