有机分子催化立体选择性反应合成含氟杂环的研究

The synthetic methods for preparation of monofluorinated or trifluormethylated heterocycles has received much attention since the fluorine-containing heterocycles usually show interesting biological activities with potential for applications in the medicinal and agricultural fields. Compared with the directed fluorination, the fluorinated building-block strategy has received increasing interest due to their mild reaction conditions with highly selectivity. On the other hand,the use of small chiral organic molecules as enantioselective catalysts, with the associated advantages of their easy availability and of carrying out asymmetric transformations in a metal free-environment and under mild and simple reaction conditions, has lately experienced an impressive growth. Therefore, asymmetric organocatalysis is now considered the "third pillar" of enantioselective catalysis, together with biocatalysis and metal catalysis, and is being increasingly used in organic synthesis. This project focuses on the study of the asymmetric reactions involving the fluorinated substrates catalyzed by asymmetric organocatalysts. Thus, a series of monofluorinated or trimethylfluorinated heterocycles with stereoselectivity are expected to be obtained, based on our recent investigations. Moreover, the stereoselective MCRs involving the fluorinated substrates, acted as one component in MCRs, catalyzed by asymmetric organocatalyst will also be investigated.

含单氟和三氟甲基的杂环化合物因其具有特殊的生理活性，其合成方法是当今的一个研究热点。与直接氟化相比，砌块法克服了反应条件苛刻、选择性差等缺点，从而具有反应条件温和，选择性好等优点而愈受重视。另一方面，手性有机分子催化剂由于具有简单易得、在无金属催化剂的环境中并在相对温和的反应条件下具有很好的对映选择性等优点，最近越来越受化学家的关注。在具有对映选择性的催化体系中，不对称有机分子催化体系被认为是除了生物催化、金属催化以外的第三种重要的催化体系，在有机合成中应用越来越广。本项目的提出结合了含氟砌块法和不对称有机分子催化剂具有高的立体选择性的特点，研究不对称有机分子催化剂催化含氟底物的反应性能，在现有工作的基础上，以期合成一系列含单氟或含三氟甲基具有立体选择性的含氟杂环化合物，并进一步拓展不对称有机分子催化剂在催化含氟底物的一锅法、多组分立体选择性反应中的应用.

项目主要研究了以含单氟代和含三氟甲基的化合物为含氟砌块，通过与合适底物的反应，构筑一系列结构新颖的具有潜在生理活性的含单氟或含三氟甲基的杂环化合物，所得到的产物的立体化学进一步用X-Ray晶体结构分析予以确定，晶体结构分析结果表明：由于分子中存在典型的异头碳效应，以及有明显的分子内氢键存在，这二种因素决定了产物分子的立体化学。此部分工作丰富了含氟杂环化合物合成的方法学。于此同时，我们也初步探索了有机小分子催化的不对称合成四氢喹啉类化合物。研究结果发现：通过对常用的一些有机小分子催化剂的筛选，用手性联萘酚磷酸酯类催化剂时，其不对称催化效应最为明显。值得一提的是：反应体系中加入催化量的Lewis酸添加剂，可以提高反应的ee值以及产率。这一结果为后续研究提供了一定的基础。

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