导向含氮杂环骨架构建的手性布朗斯特酸催化研究

Recently, the use of chiral Br?nsted acid catalysts has become a growing area of investigation. However, there are relatively few reports on catalytic asymmetric imine ion cyclization reactions by Br?nsted acid: successful cases were mostly concentrated in name organic reactions, and the range of substrates is also very limited. We wish to develop new asymmetric Br?nsted acid catalyzed iminium ion cyclization reactions that will allow the efficient and highly enantioselective construction of nitrogenous heterocylces from readily available starting meterials. This will constitute a new, powerful and broadly applicable organocatalytic asymmetric strategy to such target molecules. Conceptually our proposal is to exploit the high reactivity of iminium ions in cyclization reaction within the asymmetric environment of a catalytic quantity of an 'effecitive' chiral Br?nsted acid in a low polarity solvent. When there is sufficient facial differentiation in the ion pair between iminium ion and the chiral conjugate base of the Br?nsted acid, attack of the corresponding intramolecular nucleophile will give rise to enantioselectivity in the (irreversible) cyclization step. .Finally we wish to apply the developed chemistry as a key bond forming step in the total asymmetric synthesis of the alkaloid natural product. It would also provide assitance and relief in the diversity-oriented synthesis, biological activity studies, and structure-activity relationship studies of alkaloid. Furthermore, it is hoped that the more efficient and effective application of the developed chemistry will improve the drug discovery process.

近年来手性布朗斯特酸催化构建新的化学键已成为有机合成方法学研究的前沿和热点之一，但布朗斯特酸不对称催化亚胺离子环化反应研究报道较少，已有报道多集中在已知人名反应，底物的应用范围也很局限。本研究期望利用P,S为中心原子的手性Br?nsted酸围绕各种方式形成的亚胺离子和分子内尚未见报道的不同亲核试剂系统地进行单环到多环的N-杂环化合物构建研究。从概念上讲，我们利用环化反应中高活性的亚胺离子和催化量的手性布朗斯特酸作用形成离子对，当该离子对存在较大的面选择差异时，相应的分子内亲核试剂的进攻将导致环化反应得到高的对映选择性。拟通过该项目的实施发展有机催化的环化反应构建N-杂环化合物的方法，为生物碱的多样性合成、生理活性及构效关系研究、新的药物活性先导化合物的发现提供重要的基础。

光学纯含氮杂环化合物多出现在生物活性天然产物和药物分子中，而这些含氮杂环骨架在有机合成化学中常常作为关键中间体和合成砌块。在各种不同的合成方法中，手性Brønsted酸催化的高度对映选择性的含氮杂环化合物构建收到了广泛的关注。.本项目按照计划任务书从以下三个方面开展了工作：.第一：合成得到基于联萘酚、螺环二酚、联萘胺和螺环二胺骨架的各种取代手性布朗斯特酸催化剂。.第二：尝试了大量手性含氮杂环骨架的构建，成功实现了多类含氮杂环骨架（3-芳基苯并[1，4]噁嗪、2-芳基氢化喹啉、3-芳基异吲哚啉酮以及beta-咔啉等）的手性构筑。.第三：针对具体反应设计中使用到的两类氧化剂（过氧化类型氧化剂和高价碘试剂）进行了反应活性调研，同时有所突破，发现了多个新的有机反应，这些新反应的底物适用范围较广，并表现出很好的官能团耐受性，为我们重新认识和充分利用这两类氧化剂提供了实验基础。.在该项青年基金支持下，六篇SCI论文发表。