二氟与单氟重氮试剂的设计开发及其催化不对称化学反应研究

Fluorinated diazo compounds have received increasingly significant attention in organofluorine chemistry, inert bond activation, flow chemistry, and bio-catalysis in the past decade. In this context, despite remarkable progress achieved for 2,2,2-trifluorodiazoethane (CF3CHN2), investigations on difluorodiazoethane and monofluorodiazoethane remain rather limited. Specifically, utilization of these fluorinated building blocks in catalytic asymmetric synthesis remains an under-developed and challenging task. Therefore, the fundamental mission of this project is to design and develop two types of novel fluorinated diazo reagents: phenylsulfone difluorodiazoethane (Ps-DFA) and phenylsulfone monofluorodiazoethane (Ps-MFA and PT-MFA). The major focus of this project is to investigate the reactions between the developed fluorinated diazo reagents with various imines, aiming to establish Brønsted acid catalyzed versatile new chemical transformations that include enantioselective Mannich-type reactions, asymmetric aziridination reactions, and one-pot cascade ring-expansion reactions. The realization of these transformations will provide novel methods for the efficient construction of valuable chiral fluoroalkyl amines and fluoroalkyl heterocycles. Furthermore, synthetic transformations of afforded products will lead to the facile assembly of highly desirable chiral gem-difluoroallylic amines, chiral monofluoroallylic amines, etc. Meanwhile, mechanistic investigations on the catalytic modes and stereo-control patterns of chiral Brønsted acid catalyzed asymmetric transformations will also be carried out. Elucidating the differences between hydrogen-bonding catalysis and ion-pairing catalysis in such asymmetric reactions will be highly significant for the discovery of new asymmetric catalytic platforms.

含氟重氮化合物近年来在有机氟化学、惰性键活化、流体化学及生物催化等多个领域引起越来越多的关注，但有关二氟重氮乙烷及单氟重氮乙烷的研究仍非常有限，特别是此类含氟砌块在不对称催化合成中的应用仍亟待发展。基于此，本项目旨在：1）设计开发两种新型的含氟重氮试剂：磺酰基二氟重氮乙烷及磺酰基单氟重氮乙烷；2）探究利用Brønsted酸催化体系实现其与多种亚胺化合物的多样性化学转化新反应，主要包括不对称Mannich反应、不对称氮杂环丙烷化反应及一锅串联重排反应，从而为多种新型手性氟烷基胺和氟烷基含氮杂环化合物的合成提供有效方法，且产物合成转化可预期得到手性偕二氟烯丙胺及手性单氟烯丙胺等重要含氟功能分子；3）深入探索手性Brønsted酸在上述不对称反应中的催化模式及立体选择性控制机制（氢键型、离子对型等），以期指导新型手性催化体系的开发与建立。

含氟重氮化合物近年来在有机氟化学、惰性键活化、流体化学及生物催化等多个领域引起越来越多的关注，但有关二氟重氮乙烷及单氟重氮乙烷的研究仍非常有限，特别是此类含氟砌块在不对称催化合成中的应用仍亟待发展。基于此，本项目设计发展了新的含氟重氮试剂，并研究了其参与催化不对称反应与环加成反应等，取得的成果主要包括：（1）设计发展了四种含氟重氮新试剂，分别为苯磺酰二氟重氮乙烷、二苯磺酰基单氟重氮乙烷、二氟苯硫基重氮酮及二氟苯氧基重氮酮；（2）研究实现了手性Brønsted酸催化下，苯磺酰基二氟重氮乙烷与亚胺化合物的不对称Mannich、不对称氮杂环丙烷化反应及串联环加成反应，以良好的收率与立体选择性得到系列氟烷基手性胺、手性偕二氟烯丙胺与手性氟烷基氨基醇等重要含氟功能分子；（3）发现了手性磷酸/TEMPO及手性磺酰亚胺/苯硼酸两种新的协同催化体系，采用实验与理论计算相结合的方法对反应机理与立体选择性控制模式进行了探究；（4）实现了多种含氟重氮化合物与芳香重氮盐的[3 + 2]环加成反应，以优异的区域选择性得到了系列氟烷基四氮唑、三氮唑及吡唑化合物，并应用于多个含氟氨基酸及药物类似物的合成。.通过该项目的实施，发展了新的含氟重氮试剂，拓展了此类试剂的化学反应，提供了新的含氟化合物合成方法，形成了较好的研究特色与成果。已发表学术论文13篇，申请国家发明专利3项，授权国家发明专利1项。培养硕士毕业生1名，参与培养博士毕业生3名。