Development and Applications of Asymmetric Hydrovinylation of Alkenes

描述（由申请人提供）：无论如何，用于手性药物合成的对映体纯中间体的需求不断增加。发现新的不对称反应，特别是那些会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。通过一种主要依赖于机制见解和配体效应的系统检查的方法，我们已经发现了乙烯与乙烯烯、1,3-二烯和张力烯烃的对映选择性异二聚化反应的许多方案。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，分离产率>95%，底物/催化剂比100-1000，对各种反应的对映选择性为90-99% ee，这意味着加氢乙烯化可以发展成为一种实用的方法，用于合成手性3-（烷基或芳基）-1-丁烯基序分子。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。例子包括强效抗炎、抗肿瘤和抗结核药物。在某些情况下，这些是第一次对映体选择性合成，而在其他情况下，类似物合成可能有利于临床研究，这种方法相对于已知方法的相对优点被指出。总的来说，这个项目的目标有两个方面：(a)提高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，包括那些具有手性全碳四元中心的烯烃。这将涉及为这一精确反应发现新的方案和新的手性配体；(b)不对称加氢乙烯化在天然产物全合成中的应用。对于安装外环手性中心的经典问题的一般解决方案将通过合成(-)-月牙萜醇，类固醇C/D环类似物，helioporins和pseudoopterosins以及5 -羟色胺拮抗剂LY426965来说明。这些化合物的立体选择性合成尤其重要，因为它们具有多种生物活性（包括细胞毒性、抗炎和抗细菌特性），这些活性依赖于每个手性中心的构型，并且缺乏对C-C键形成的绝对立体化学控制的方法。加氢乙烯化在这方面提供了很好的机会。除了应用之外，我们希望对该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。

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.