氮杂卡宾、光协同催化的单电子转移策略介导烯醛的不对称反应

This project is focused on developing a synergistic process based on N-heterocyclic carbene catalysis and photocatalysis. This strategy promoted a single-electron transfer event of the homoenolate equivalent which was mediated by NHCs, and realized the functionalization of the β-position of enal substrates. It represented the first combination of “umpolung catalysis” and the reductive quenching cycle of ruthenium, and the concurrent impetus delivered the formation of homoenolate radical cation intermediate for the sequential transformation. The catalytic cycle was highly depended on the balance between all the bond dissociation energies and reduction potentials of the relative components. Without the addition of stoichiometric oxidants, the reaction was performed in an atom-economy manner and avoided the limitation of products caused by the exogenetic oxidants. In the model reaction, homoenolate radical cation intermediate generated a β-chiral center through asymmetric hydrogen transfer, and the in-suit generated radical species oxidized the photosensitizer and complete the photocatalytic cycle. The desired ester product was manufactured in moderate yield and enantioselectivity. The preliminary mechanism study proved the indispensable assistance of both NHCs catalysis and photocatalysis in the aforementioned transformation. And the strategy was also detected in the combination of deferent nucleophiles other than hydroxyl compounds and generated the carboxylic acid and acyl sulfide respectively. Also the modification of the β-substituents of enals and the trail for deferent radical source will extend the application of this strategy and afford some original conversions. We also set up the target for the construction of some potential pharmaceutical skeletons for further applications.

本项目基于氮杂卡宾与光催化协同介导的单电子氧化策略，促进高烯醇中间体的单电子转移历程，从而实现烯醛化合物β位的不对称官能团化。项目的创新点在于，首先将氮杂卡宾的极反转催化循环与钌的还原淬灭循环正交地结合在一起，协同催化自由基正离子中间体的生成；其次所设计的催化循环通过平衡反应体系中相关化学键的解离能及活性物种的还原电势，以原子经济性较高的化学转化规避了当量级别的氧化剂，同时避免了氧化剂对产物结构的限制。在预设的模板反应中，自由基正离子通过不对称氢转移得到目标手性中心，原位生成的氢源自由基氧化光敏剂的还原态完成了光催化循环，以中等收率及对映选择性得到饱和酯产物。初步的机理实验证明氮杂卡宾的催化循环与光催化的循环均是不可或缺的反应条件。基于相同策略，在方法学拓展应用中通过对不同亲核试剂的选择、烯醛β位的官能团修饰、自由基源的选择，实现其他高效的不对称转换。

质子迁移历程是诸多生命进程及化学转化的标准范式，往往可作为模版用以探索并拓宽亲电官能团化反应的阈值空间，然而质子作为体积最小的亲电体，其不对称版本的壁垒又异常突出。围绕本项目的立项依据，我们对β-双取代烯醛的不对称氢迁移进行系统探索，首次构建诸多不对称版本的化学转化。利用氮杂卡宾（NHC）作为极反转催化剂，原位产生烯醛的高烯醇式中间体，经由催化剂骨架的手性信息传导，实现远程不对称质子迁移的面选择性控制。同时使用含桥头三级氮的Brønsted碱作为质子迁移催化剂，与适当的Lewis酸或质子酸原位制备质子梭，精准识别高烯醇中间体β位点的手性信息，从而高效构建β-手性硫酯化合物库。并基于这一模版反应，探索非手性NHC催化剂与手性磷酸（CPA）、手性三级胺协同催化的可能性。.除此之外，项目组利用手性NHC催化剂活化β-双取代烯醛化合物，基于仿生不对称质子迁移策略，以咪唑或吡唑作为转酰基试剂，通过“瞬时稳态”酰胺中间体，解决了碱性脂肪胺对高对映选择质子迁移历程的无序干扰，同时避免醛胺缩合反应的发生。瞬时稳态的β-手性酰基咪唑物种亦可被非氮源亲核试剂捕获，实现诸多类别β-手性羧酸衍生物的高效合成；各种氨基酸酯亦可作为兼容底物，为短肽氮端提供独特的修饰策略；多种官能团可在氧化还原中性的反应条件下兼容，为复杂药物骨架提供后期修饰的切入点；其中β-手性酰肼类产物可高效转化为多种杂环骨架，初步论证此类关键合成子的应用价值。以此为模板，项目组亦探索氧化还原中性条件下烯醛化合物串联不对称官能团化的可能性，首次实现不对称氢氟化反应。