Polycyclic Indole Synthesis Via Annulation Strategy

Polycyclic indole belongs to an important class of nitrogen-containing heterocycles, which was first derived from organic base in the field of biology. Several natural products and therapeutic agents possessing this heterocyclic motif exhibit remarkable biological and pharmacological activities. The polycyclic indole scaffold is regarded as the "privileged" structural motif for discovering novel medicinally relevant compounds. The chemical synthesis of these core structures has drawn extensive interests from synthetic community. As a consequence, focusing on the synthesis of polycyclic oxindole derivatives by development of novel reagents and exploration of efficient strategies would be very impressiving and challenging. In this dissertation, we have highlighted the efficient synthesis of fused polycyclic indoles and spirooxindoles via simple cycloadditions. The key discoveries are listed below:1. An expedient and efficient synthesis of coumarin-fused tetrahydrocarbazoles via Diels-Alder reaction between3-nitrocoumarins and21vinylindoles has been reported. The simplest thiourea was used as the Bransted acid to promote this process. Based on the X-ray structure and1H NMR spectral experiments (NOESY and HSQC), a plausible transition state was proposed to explain the observed stereocontrol. An endo-selective Diels-Alder cycloaddition might be favored.2. Based on the previous work, we have successfully developed an enantioselective [4+2] cycloaddition of2-vinylindoles with3-nitro-2H-chromenes catalyzed by a Zn(OTf)2/bis(oxazoline) complex, which provides a convenient and novel approach to chiral fused heterocycles in highly chemo-and enantioselectivities. It is worth to note that when the reaction was fully complete, we can obtain almost optically active product (>99%ee) through a simple filtration of the reaction mixture, while less effect was observed on the yield. This procedure indicated that the reaction has a potential utility in industry.3. We have delivered a highly efficient organocatalyzed Michael addition/cyclization cascade reaction of3-isothiocyanato oxindoles with3-ylideneoxindoles (up to99%yield,>99%ee,>95:5dr). This method allows efficient and rapid synthesis of highly functionalized bispirooxindole products bearing three contiguous stereogenic centers with two quaternary stereocenters in a single operation. Notably, these products could be readily converted into other useful functional molecules, such as spiro oxazoline oxindole and y-lactam derivative.4. On the basis of previous work, herehin we further improved the applications of3-isothiocyanato oxindoles. An unprecedented Zn(OTf)2-catalyzed asymmetric Michael addition/cyclization cascade of3-isothiocyanato oxindoles with3-nitro-2H-chromenes has been disclosed. This transformation provides an efficient access to various synthetically important polycyclic spirooxindoles in a highly stereoselective manner (up to99%yield,>99%ee,>95:5dr). Moreover, in addition to various3-nitro-2H-chromenes, acyclic nitroalkenes, such as β-methyl-β-nitrostyrene, could also be successfully employed in this transformation and afforded the desired product (82%yield,99.5%ee,6:1dr). In the case of β-nitrostyrene, the corresponding product was obtained in only29%yield with3:1dr and4%ee. Perhaps more significantly, a novel bifunctional Lewis acid/base activation model was proposed based on control experiments, wherein the Zn(Ⅱ) moiety serves as a Lewis acid and the N atom of the free NH group acts as a Lewis base via a hydrogen-bonding interaction.