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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

基本信息

批准号：
7858243
负责人：
T V RAJANBABU
金额：
$ 17.56万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7858243
关键词：
Acids Address Alkenes Alzheimer&apos s Disease Analgesics Anti-Inflammatory Agents Anti-inflammatory Antimycobacterial Agents Antitubercular Agents Ascorbic Acid Betula Genus Biological Biological Factors Carbon Chemistry 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

项目摘要

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）：从各个方面来看，用于合成手性药物产品的对映体纯中间体的需求不断增加。新的不对称反应的发现，特别是那些能够产生实际水平的不对称诱导和高周转频率（即底物/催化剂/单位时间）的反应，将对药物和过程化学产生重大影响。通过主要依赖于配体效应的机理见解和系统检查的方法，我们发现了许多乙烯与乙烯基芳烃、1,3-二烯和应变烯烃的对映选择性异二聚反应的方案。我们还发现了全碳四元中心的不对称生成反应，否则很难安装。温和的反应条件、对各种官能团的耐受性、分离收率>95%、底物/催化剂比为100-1000以及各种反应的对映选择性为90-99% ee，这意味着氢乙烯基化可以发展成为合成具有手性3-（烷基或芳基）-1-丁烯基序的分子的实用方法。许多生物学上重要的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效抗炎、抗肿瘤和抗结核药物。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，模拟合成可能有利于临床研究，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) 改进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、1,3-二烯和应变烯烃（包括那些提供手性全碳四元中心的烃）的氢乙烯基化的范围和应用。这将涉及新方案的发现，以及用于这种严格反应的新手性配体，(b)不对称氢乙烯基化在天然产物全合成中的应用。通过 (-)-月桂萜醇、类固醇 C/D 环类似物、日光孔蛋白和拟珊瑚素以及血清素拮抗剂 LY426965 的合成来说明安装环外手性中心的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、抗炎和抗分枝杆菌特性），这些活性依赖于每个手性中心的构型，并且缺乏对 C-C 键形成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绝佳的机会。除了应用之外，我们希望对该反应的研究能够揭示新的控制元件，有助于开发新的、广泛适用的催化不对称合成工具。