新型氮杂环卡宾催化SN2'取代反应构筑手性季碳中心研究

Over the past decade, N-heterocyclic carbenes (NHCs) catalyzed organic reactions have attracted much attention, and some significant progress has been achieved. However, most of the reported NHC-catalyzed reactions are addition reactions; the substitution reactions remain sporadic, and there is no report on the asymmetric version. Recently, we have reported the first intramolecular NHC-catalyzed SN2' substitution reaction, further investigation revealed that cycloheptane thiazolium-derived NHCs containing N-aryl groups are crucial for this SN2' substitution reaction. Other NHCs such as imidazolium, triazolium salts didn’t match this reaction. When tri-substituted allylic aldehyde substrates were employed, the desired products were obtained with a quaternary carbon stereocenter. Unfortunately, there is no report on the preparation of such chiral NHCs. Thus, this project will design and synthesis of a series of new cycloheptane thiazolium-derived NHC precursors bearing axially chirality, the catalytic ability and the substitution reaction mechanism will be studied. Other intramolecular SN2' substitution reactions of α-leaving group substituted aldehydes and α,β-unsaturated aldehydes will be extended, as well as the intermolecular SN2' substitution reaction of fluorinated substrates. A series of catalytic system for the construction of quaternary carbon stereocenters will be developed based on the new NHCs catalyzed SN2' substitution reactions, which will provide new methods to incorporate quaternary stereocenters selectively in many organic molecules that are useful in medicine, agriculture and other areas.

氮杂环卡宾催化有机反应近年来取得了重要进展，但目前已报道的主要是加成反应；取代反应研究的较少，尚没有不对称催化取代体系报道。近期我们报道了首例氮杂环卡宾催化分子内SN2'取代反应，进一步研究发现N-芳基环庚烷并噻唑卡宾催化剂对SN2'取代反应具有独特的催化性能，其它如咪唑、三氮唑等类型卡宾催化剂不能匹配该反应。使用三取代烯丙基醛底物可以得到含季碳中心的预期产物，然而目前没有手性N-芳基环庚烷并噻唑卡宾催化剂的合成报道。基于此本项目拟发展一类新型含轴手性N-芳基环庚烷并噻唑卡宾催化剂，研究这类催化剂在取代反应中的反应性能及相关机理。考察其它底物如α位含离去基团的醛、α,β-不饱和醛的分子内SN2'取代反应，以及含氟底物的分子间SN2'取代反应。发展一系列基于新型氮杂环卡宾催化SN2'取代反应构筑手性季碳中心催化体系，为一些在医药、农业等领域有重要用途的含手性季碳中心化合物的制备提供新方法。

氮杂环卡宾催化有机反应近年来取得了重要进展，但目前已报道的主要是加成反应；取代反应研究的较少，尚没有不对称催化取代体系报道。本项目合成了一类新型含轴手性N-芳基环庚烷并噻唑卡宾催化剂，研究了这类催化剂在有机催化反应中的性能。首次实现了氮杂环卡宾催化三取代烯基醛的分子内不对称SN2‘’反应，高对映选择性的得到了一系列含有全碳季碳手性中心的苯并吡喃酮化合物。发展了氮杂环卡宾催化的α, β不饱和醛与亲电硫试剂的芳基硫醚化反应，氮杂环卡宾催化立体选择性糖苷化反应。以及氮杂环卡宾催化氢酰化/Stetter串联反应合成双苯并吡喃酮化合物，为含有此类骨架结构的天然活性产物提供了高效合成方法。基于有机小分子催化及构筑季碳手性发展了一些新的合成方法学，如有机催化萘酚不对称芳基化及硫芳基化去芳构化反应构筑手性季碳中心。手性磷酸催化的串联不对称Prins环化反应，[3+2]、[4+2]环加成反应及中心手性向轴手性转变，氧化脱氢环化反应等。本项目资助下，已发表研究论文20篇，包括Chem. Sci. (1篇)，Org. Lett. (11篇)，Chem. Eur. J. (2篇)，Adv. Syn. Cat. (2篇)，J. Org. Chem. (1篇)，应邀在Asian J. Org. Chem.和Chem. Asian J.撰写综述论文2篇；获中国发明专利授权3项。培养研究生12名，其中博士生3名，硕士生9名。