Cation-Controlled Enantioselective and Diastereoselective Synthesis of Indolines: An Autoinductive Phase-Transfer Initiated 5-endo-trig Process

A catalytic enantioselective approach to the synthesis of indolines bearing two asymmetric centers, one of which is all-carbon and quaternary, is described. This reaction proceeds with high levels of diastereoselectivity (>20:1) and high levels of enantioselectivity (up to 99.5:0.5 er) in the presence of CsOH·H2O and a quinine-derived ammonium salt. The reaction most likely proceeds via a delocalized 2-aza-pentadienyl anion that cyclizes either by a suprafacial electrocyclic mechanism, or through a kinetically controlled 5-endo-trig Mannich process. Density functional theory calculations are used to probe these two mechanistic pathways and lead to the conclusion that a nonpericyclic mechanism is most probable. The base-catalyzed interconversion of diastereoisomeric indolines in the presence of certain quaternary ammonium catalysts is observed; this may be rationalized as a cycloreversion–cyclization process. Mechanistic investigations have demonstrated that the reaction is initiated via a Mąkosza-like interfacial process, and kinetic analysis has shown that the reaction possesses a significant induction period consistent with autoinduction. A zwitterionic quinine-derived entity generated by deprotonation of an ammonium salt with the anionic reaction product is identified as a key catalytic species and the role that protonation plays in the enantioselective process outlined. We also propose that the reaction subsequently occurs entirely within the organic phase. Consequently, the reaction may be better described as a phase-transfer-initiated rather than a phase-transfer-catalyzed process; this observation may have implications for mechanistic pathways followed by other phase-transfer-mediated reactions.

本文报道了一种催化对映选择性合成含两个手性中心的吲哚啉（indolines）的方法，其中一个手性中心为全碳季碳中心。该反应在一水合氢氧化铯（CsOH·H₂O）与奎宁衍生铵盐（quinine-derived ammonium salt）存在下进行，展现出优异的非对映选择性（>20:1）与对映选择性（最高可达99.5:0.5 er）。该反应大概率经由离域的2-氮杂戊二烯阴离子（2-aza-pentadienyl anion）中间体进行，该中间体可通过同面电环化机制（suprafacial electrocyclic mechanism）完成环化，亦可经由动力学控制的5-endo-trig曼尼希过程实现环化。研究人员通过密度泛函理论（Density functional theory, DFT）计算对这两条反应路径进行了探究，最终得出非周环反应机制（nonpericyclic mechanism）为最可能反应路径的结论。实验中还观察到，在特定季铵盐催化剂存在下，碱可催化非对映异构吲哚啉（diastereoisomeric indolines）发生相互转化，该过程可通过逆环化-环化（cycloreversion–cyclization）过程进行合理解释。机理研究表明，该反应通过类似马科扎（Mąkosza）的界面过程引发；动力学分析显示，反应存在显著的诱导期，与自诱导（autoinduction）现象一致。研究人员鉴定出一种关键催化物种：由反应产物阴离子与铵盐发生去质子化反应生成的奎宁衍生两性离子实体（zwitterionic quinine-derived entity），并阐明了质子化在该对映选择性反应过程中的作用。我们进一步提出，后续反应完全在有机相内进行，因此该反应更适合被描述为相转移引发（phase-transfer-initiated）而非相转移催化（phase-transfer-catalyzed）过程；这一发现可为其他相转移介导反应的机理研究提供参考。