磺酰氯与亚胺和缺电子烯烃的反应研究

Beta-Sultams and trimetylene sulfone derivatives are key sulfur analogs of antibiotic beta-lactams. They have been widely applied in development and discovery of new drugs. Reactions of sulfonyl chlorides and unsaturated compounds are important synthetic methods for construction of four-membered heterocyclic compounds containing sulfonyl group. Although reaction of sulfonyl chlorides and imines have been reported for synthesis of beta-sultams, their formation mechanism is still not clear and remains unraveling problem, limiting their application. In addition, only reactions of sulfonyl chlorides and strong electron-rich olefins (such as enamines and genimal dialkoxylolefins) have been investigated, reactions of sulfonyl chlorides and electron-deficient olefins have not been studied till now. In this project, the formation mechanism of beta-sultams and the factors in controlling their stereoselectivity in the reaction of sulfonyl chlorides and imines will be investigated. First, the formation mechanism is proposed. Studies on the influence of bases on the reaction, the cyclization of sulfonamides and aldehydes, reaction of sulfonyl chlorides and cyclic imines will be conducted to verify our proposed mechanism experimentally. On the other hand, reactions of sulfonyl chlorides and electron-deficient olefins to generate adducts and cycloadducts will be explored. Some novel C2 symmetric optically active tertiary amines have been designed and will be synthesized and applied as nucleophilic catalysts in the reactions of sulfonyl chlorides with imines and electron-deficient olefins. Finally, the application of the adducts and cycloadducts will be explored in synthesis of novel compounds containing sulfonic acid groups, such as 1,2-disubstituted 3-aminopropanesulfonic acids and 4-aminobutanesulfonic acids. The results will provide useful information on the application of sulfonyl chlorides in organic synthesis.

beta-磺内酰胺和环丙砜衍生物是具有抗菌活性的beta-内酰胺的重要含硫类似物，广泛用于药物开发研究中。磺酰氯与含不饱和双键化合物的反应是合成含有磺酰基和砜基四元杂环化合物的重要方法。虽然已有磺酰氯与亚胺形成beta-磺内酰胺反应的报道，但其形成机理仍存在许多疑点没有解决，限制了该反应的应用。另外，人们只研究了磺酰氯与强富电子烯烃的环加成反应，尚未探索磺酰氯与缺电子烯烃的反应。该项目拟揭示磺酰氯与亚胺形成beta-磺内酰胺反应的机理及影响该反应立体选择性的因素，提出了可能的合理机理。拟通过研究碱性对反应的影响、磺酰胺中间体的环化、环状亚胺的反应等实验来证实提出的机理。还拟设计合成具有C2对称性的新型光学活性三级胺催化剂，来研究磺酰氯与缺电子烯烃的不对称(环)加成反应。实现磺酰氯与亚胺和缺电子烯烃的可控立体选择性合成，以及(环)加成产物在合成中的应用研究,为在有机合成中的应用奠定基础。

β-磺内酰胺衍生物是具有抗菌活性的β-内酰胺的重要含硫结构类似物，广泛用于药物开发研究中。磺酰氯与亚胺类化合物的反应是合成含有β-磺内酰胺类四元杂环化合物的重要方法。在该项目中，通过研究揭示了磺酰氯与亚胺形成β-磺内酰胺反应的机理及影响该反应立体选择性的因素，提出了合理的反应机理。通过研究碱对磺酰氯与亚胺反应的影响、环状亚胺参与反应形成的β-磺内酰胺的立体选择性等实验证实了提出的机理。揭示了控制磺酰氯与亚胺反应立体选择性合成β-磺内酰胺的因素。在研究过程中还发现烯砜和烯酮都可以与两分子亚胺反应形成相应的六元杂环产物，也可以两分子烯砜或烯酮二聚，再与一分子亚胺反应形成相应的六元杂环产物，分别揭示了这几类形成六元杂环产物的反应机理，并确定了六元环产物的立体化学，还提出了成环选择性(annuloselectivity)的概念。还通过碱和温度的调控分别实现了对烯砜和烯酮与亚胺成环选择性的控制。最后，还研究了硫代烯酮与亚胺反应的机理、立体选择性和成环选择性，还比较了Staudinger、thio-Staudinger和sulfa-Staudinger反应中间体的反应活性。此外，还实现了磺酰氯与缺电子不饱和化合物偶氮二甲酸酯的加成反应，得到了α-氯代磺酰基肼二甲酸酯；探索了磺酰氯与缺电子烯烃的加成反应，尽管尝试了多种类型的缺电子烯烃和亲核试剂，均未能实现磺酰氯与缺电子烯烃的加成反应。这可能也是该类反应至今未见一例报道的原因。