| Among the 2,4,5-trisubstituted piperidine derivatives, the one containing indole moiety at 2-position can be frequently found as intriguing core structure in a number of indole alkaloids belonging to different skeletal types with promising biological activities. However, despite extensive efforts, the synthesis of 2-indolyl-4-carboxylate piperidine has proven extremely challenging, and the asymmetric version of which is undeveloped.First, we obtained the best reaction conditions via solvent screening and additive screening. We identified the best reaction conditions of diaryprolinol silyl ether catalysed reaction between hemiacetal and nitroolifen by HPLC analysis. The most suitable solvent is benzene, while the most suitable additive is benzoic acid. Afterwards, we have applied 16 nitroolifens and 6 hemiacetals in the reaction, and all the materials can smoothly reacted with ideal results. The ee values in all reactions ranged from 96% to 99%.Based on the retrosynthetic analysis, we envisioned that the methodology of enamine-based organocatalytic enantioselective reaction catalyzed by diaryphenyl silyl ether between 5-substituted racemic tetrahydrofuran-2-ol and nitroolefins would be a facile asymmetric entry route to chiral lactol, which could in situ generate 3,5-disubstituted lactone via simple oxidation reaction. Under the ring-opening conditions, nitroalcohol could be produced from lactone, and the subsequent oxidation and intramolecular reductive amination led to 2-indolyl-4-amide piperidine unit.Herein, we directly use substituted racemic lactols to react with nitroolefins via enamine-based asymmetric organocatalyzed Michael addition providing efficient access to highly substituted lactones with excellent stereoselectivity as one single, which could be finally transformed into 2,4,5-trisubstituted piperidine derivatives with high diastereo- and enantioselectivities. |
