新型手性胺双功能催化剂的设计、合成及其在不对称催化反应中的应用研究

In this application, we designed three kinds of novel chiral bifunctional organocatalysts. Firstly, we introduce thiourea group into the organocatalysts which have been synthesized before. The "chiral amine-thiourea-pyridine" catalysts are obtained which will promote the formation of hydrogen-bonding to activate substrates more effectively. Next, we combine chiral primary amine and phosphate into one small organic molecule. A new kind of "chiral primary amine-cyclic phosphate" catalysts with six member and seven member ring structure are obtained. These bifunctional organocatalysts will be applied more kinds of reactions, high enantioselectivity will be obtained through strong activation of the substrates by both of primary amine and br?nsted acid. Thirdly, we introduce crown ethers, which are often employed as effective phase-transfer catalysts, into the chiral amine organocatalysts. New bifunctional organocatalysts "chiral amine-crown ethers" are obtained. The crown ethers group in the catalyst will assist the chiral amine to activate substrates and stabilize transition state through efficient hydrogen-bonding interactions. These new bifunctional organocatalysts will be evaluated in asymmetric C-C bond formation reactions and relate domino reactions, and the dual activation model for the transition state will also be studied. The aiming is at broadening the application of bifunctional organocatalysts in asymmetric synsthesis, providing new synthetic strategy for the synthesis of natural products, chiral drugs, pesticides, and other fine optical activity chemicals.

在本申请中，我们共设计了三种类型的新型双功能催化剂。首先，在我们原有较优催化剂的基础上引入了硫脲，合成了"手性胺-硫脲-吡啶"催化剂，通过形成氢键进一步提高催化剂对底物活化的能力；其次，我们将手性伯胺和磷酸结合在同一分子中，形成一类新型的、具有六元环状和七元环状结构的"手性伯胺-环状磷酸"双功能催化剂，通过两部分基团共同对底物进行活化，来拓展催化反应的类型、提高立体选择性；第三，我们将具有相转移作用的冠醚引入到手性胺催化剂中，得到"手性胺-冠醚"催化剂，利用冠醚部分的相转移功能及其与底物形成一定氢键的能力，达到对底物进行活化和稳定过渡态的作用。这些新型的双功能催化剂主要用于不对称C-C键的形成反应及相关的串联反应中，并对催化剂的双活化机理进行探讨,旨在扩展双功能有机催化剂在不对称合成中的应用，为天然产物、手性药物、农药及其它光学活性中间体的合成提供新方法。

在此项目执行期间，我们合成得到了多种高效的双功能催化剂。其中最有代表性的是基于三乙烯二胺骨架的催化剂，它们在多种类型串联反应中，如：Kabachnik–Fields反应、串联Knoevenagel–Michael反应、串联Friedel–Crafts烷基化以及多米诺Michael反应等中，均显现了较高的催化活性。并且，我们利用这些串联反应合成了具有各种重要生物活性的化合物，如：双萘酚甲烷、双吲哚甲烷、双烯醇、二芳基氧化吲哚、β-磷酸酯丙二腈和α-氨基磷酸酯等衍生物。另外，合成这些化合物的反应过程具有明显的优点，如：操作简单、反应时间短、反应条件温和、产率高、选择性好以及不涉及金属催化等。我们还合成了一种由苯乙烯支载的DABCO非均相催化剂，并用于催化Knoevenagel-P杂-Michael加成反应中。此项目中所有的催化剂都能够很容易的回收使用。最后，基于这些双功能催化剂，我们还设计了一个连续流动反应模型，使他们用于未来化工生产成为可能。