不对称催化合成具有多官能团α-位手性季碳中心的α-氨基腈类及氰醇类化合物的新方法开发及应用研究

Nitriles are an important class of organic compounds, which are found in a number of pharmaceuticals, agrochemicals, and optoelectronic materials. In particular, highly functional α-amino nitriles and cyanohydrins bearing α-chiral quaternary carbon centers have received considerable attention, due to their unique role in organic synthesis and medicinal chemistry. Accordingly, the development of efficient asymmetric catalytic methods for these compounds has been a major topic in synthetic organic chemistry, which addresses a fundamentally important theme in organic chemistry in which chiral quaternary carbon centers are generated. The common approaches, such as asymmetric catalytic cyanation of ketones (cyanohydrin reaction) and ketimines (Strecker reaction) have been developed to construct these useful synthetic building blocks. However, these methods have always been problematic areas because of the main difficulties, for examples, the greater steric hindrance to cyanide attack on the carbonyl group or imine group, the lower electrophilicity of the carbonyl or imine group, and enhanced requirements for the stereodifferentiating properties of the catalyst et al. The utilization of nitrile-stabilized carbanions to effect C-C bond-forming reaction occupies a unique position in organic synthesis, ideally suited for installing hindered quaternary centers. Although nitrile-stabilized carbanions are extremely important synthetic intermediates, and widely used in the generation of multiple polyfunctional structures, asymmetric catalytic version of these processes have never been developed. In this proposal, we envisioned that α-amino nitriles and cyanohydrins bearing an α-hydrogen could be used as potential pro-nucleophilic reagents to construct these densely functional quaternary carbon centers in high stereoselective manner via asymmetric organocatalysis (Lewis base or Br?nsted base ) or cooperative catalysis of organocatalysts and metal catalysts. In this manner, a variety of functional groups can be introduced efficiently. Based on these, several novel multicomponent tandem reactions are also designed accordingly. Furthermore, the potential applications of these compounds with incorporated densely functional quaternary carbon centers are proposed. Firstly, we plan to develop a Lewis base-promoted asymmetic intramolecular cyanofunctionalization of these compounds which could provide a unique access to densely functionalized compounds bearing β-quaternary carbon centers with the remarkable feature that both α- and β-positions of activated alkene are functionalized. Secondly, we propose to employ these compounds to construct unsaturated β-，γ-，δ- lactone or lactam moiety in asymmetric fashion, which are common in nature, usually display a wide variety of biological activities.

具有α-位季碳手性中心（含杂原子O, N）并具有高度官能团化的腈类结构单元在有机合成、生物化学和药学研究中具有很高的应用价值。本项目拟利用手性有机催化剂和金属催化的协同作用策略解决构建该类季碳手性中心的催化效率和立体控制等难题；计划利用具有α-位氢的氰醇以及α-氨基腈类衍生物作为潜在的亲核试剂，基于此发展新的不对称催化方法，高效、高立体选择性的构建该结构单元，并在此基础上力图探索新型、高效、原子经济性的多组分串联反应等合成策略。同时，对于所构建的具有该类季碳手性中心的腈类化合物，根据其自身结构特点，拟设计、开发系列新颖的键的断裂以及形成反应，并据此发展新型、高效的合成方法学，探索、研究其在有机合成及相关领域中的应用。

具有α-位季碳手性中心（含杂原子O, N）并具有高度官能团化的腈类结构单元在有机合成、生物化学和药学研究中具有很高的应用价值。因此，发展高原子经济性、高效的合成方法来快速构建具有结构多样性的含有α-季碳手性中心（含杂原子O， N）的腈类结构单元，具有重要的学术研究意义和应用价值。在本项的研究中，首先我们从原子经济性角度出发，利用手性有机催化剂或金属催化剂以及其的协同作用等策略解决构建该类季碳手性中心的催化效率和立体控制等难题。通过采用具有α-位氢的氰醇以及α-氨基腈类衍生物作为潜在的亲核试剂，发展了系列新型、高效的催化合成方法，对映选择性的构建了具有多样性、高度官能团化的手性季碳中心（含杂原子O， N）的腈类衍生物如：具有连续手性中心的3-氰基-3,3-二取代苯酞（ee up to 99%）、二氢萘醌 （es up to 99%）、2,2二取代-1,2-二氢吡啶（ee up to 99%）以及多取代的吡啶衍生物（es up to 99%）等；非对映选择性的构建了具有连续季碳、叔碳手性中心的二氢呋喃以及Pyrrolo[2,1-a]isoquinoline等衍生物。其次，通过对上述方法及策略的进一步拓展，我们不仅发展了多种新型的多组分串联合成方法如：烯丙基烷基化/环化反应、烯丙基烷基化/环加成反应、硫迈克尔加成引发的串联反应等方法高立体选择性的合成了α-亚甲基γ-丁内酯、2,4-二取代四氢吡咯以及具有喹啉以及异喹啉杂芳环结构并具有季碳中心的有机硫化合物等衍生物，而且通过对官能团化腈类化合物结构与性质的深入研究和理解，还发展了具有α-氨基腈结构单元并具有缺电子烯烃参与的1,7-烯炔环化反应以及分子内钯催化的C-H键对氰基的加成反应，首次多样性合成了氮杂二环[4，1，0]庚二烯、4,5-二氢-3H-氮杂七元环吖庚因、咔唑等重要杂环衍生物。此外，我们对上述化合物的生物活性也进行了研究，并取得了初步进展，为进一步拓展上述合成方法及策略在生物及医药领域的应用奠定了良好的基础。