Development and Applications of Asymmetric Hydrovinylation of Alkenes

描述（由申请人提供）：通过各种衡量标准，对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。发现新的不对称反应，特别是那些将产生实际水平的不对称诱导和高转换频率的反应（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。通过一种方法，主要依赖于机械的见解和系统的检查配体的影响，我们已经发现了一些协议的乙烯与乙烯基芳烃，1，3-二烯和应变烯烃的对映选择性异二聚反应。我们还发现了不对称生成全碳季中心的反应，否则很难安装。温和的反应条件、对各种官能团的耐受性、> 95%的分离产率、100-1000的底物/催化剂比和90- 99%ee的各种反应的对映选择性意味着加氢乙烯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大的抗炎，抗肿瘤和抗结核药物。在某些情况下，这些是第一个对映体选择性合成，而在其他情况下，类似物的合成可能有利于临床研究，这种方法相对维斯已知的方法的相对优点被指出。概括地说，该项目的目标有两个方面：（a）提高加氢乙烯化的选择性和范围。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的加氢乙烯化的范围和应用，包括那些产生手性全碳季中心的加氢乙烯化。这将涉及发现新的方案和用于该严格反应的新的手性配体。（B）不对称氢化乙烯基化在天然产物的全合成中的应用。环外手性中心的安装的经典问题的一般解决方案将说明与合成（-）-劳伦二萜醇，类固醇C/D环类似物，helioporins和pseudopterosins和5-羟色胺拮抗剂LY 426965。这些化合物的立体选择性合成是特别重要的，因为它们的不同的生物活性（包括细胞毒性，抗炎和抗分枝杆菌的性能），这些活动的依赖于每个手性中心的构型，和缺乏的方法，绝对立体化学控制在C-C键的形成。加氢乙烯化在这方面提供了极好的机会。除了应用程序，我们希望该反应的研究将揭示新的控制元素，用于开发新的，广泛适用的，催化不对称合成的工具。

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.