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: 7320569
• 负责人: T V RAJANBABU
• 金额: $ 23.7万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7320569
• 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; Condition; Cyclohexane; Cyclohexanes; Dependence; Development; Elements; Ethylene; Ethylenes; Facility Construction Funding Category; Frequencies; Generations; Glycosides; Goals; Heterodimerization; Ibuprofen; Ketones; LY 426965; Ligands; Literature; Measures; Methodology; Methods; Modification; Naproxen; Numbers; Object Attachment; Outcome Study; Pharmaceutical Preparations; 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; frondosin B; functional group; hypoxia inducible factor 1; improved; inhibitor/antagonist; insight; methyl group; novel strategies; phenserine; 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(申请人提供)：从每一项指标来看，用于合成手性医药产品的对映体纯中间体的需求都在不断增加。新的不对称反应的发现，特别是那些将产生实际水平的不对称诱导和高转换频率(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。通过一种主要依赖于机理洞察和对配体效应的系统研究的方法，我们发现了一些用于乙烯与乙烯、1，3-二烯和张力烯烃的对映选择性异二聚反应的方案。我们还发现了不对称生成全碳四元中心的反应，否则很难安装。温和的反应条件、对不同官能团的耐受性、分离的产率和反应的底物/催化剂比为100-1000和90-99%的对映体选择性表明，氢乙烯基化反应可以发展成为一种合成手性3-(烷基或芳基)-1-丁烯分子的实用工艺。许多重要的生物分子可以很容易地从这些中间体中获得。举例说明的例子包括强大的抗炎、抗肿瘤和抗结核病药物。在某些情况下，这是第一次对映体选择性合成，而在另一些情况下，模拟合成可能有助于临床研究，指出了这种方法相对于已知方法的相对优点。总的来说，该项目的目标有两个：(A)提高氢乙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芳烃、1，3-二烯和张力烯烃的氢乙烯基化反应的范围和应用，包括那些给出手性全碳四元中心的反应。这将包括：(B)不对称氢乙烯基化在天然产物全合成中的应用：(B)发现新的方案和用于这一严格反应的新手性配体。通过合成(-)-十二烯萜醇、甾体C/D环类似物、太阳孔蛋白、拟蝶呤和5-羟色胺拮抗剂LY426965，将说明安装外环手性中心这一经典问题的一般解决方案。这些化合物的立体选择性合成尤其重要，因为它们具有不同的生物活性(包括细胞毒性、抗炎和抗分支杆菌性质)，这些活性依赖于每个手性中心的构型，以及缺乏在C-C键形成过程中进行绝对立体化学控制的方法。氢乙烯基化在这方面提供了很好的机会。抛开应用不谈，我们希望对反应的研究将揭示新的控制元素，有助于开发新的、广泛适用的催化不对称合成工具。