Studies On The Synthesis Of Polycyclic Spiroindolines

Polycyclic spiroindolines are the core skeletons of many bioactive natural products and pharmaceuticals.Therefore,the development of highly efficient and selective methods for their synthesis is of great significance.In this thesis,two novel strategies for the construction of polycyclic spiroindolines from simple materials via intramolecular or intermolecular tandem cyclization reactions have been developed.The details are as follows:Firstly,we developed a Bi_Cl3-mediated tandem cyclization reaction of（hetero）aryl-substituted tryptamine-ynamides in ClCH₂CH₂Cl at 100℃ in the presence of 5 ?MS as the additive,which led to the formation of a series of structurally diverse polycyclic spiroindoline scaffolds in moderate to excellent yields（27-93%）.Interestingly,the fused tricyclic indole derivatives instead of the polycyclic spiroindolines were obtained for alkyl-substituted ynamides under the same reaction conditions presumably due to the lack of a nucleophilic group to promote the Mannich-type cyclization reaction to complete.The reaction could be scaled up to a gram scale with no deterioration of yield.In addition,some selective reduction reactions could be conducted with polycyclic spiroindoline products by just varying the reaction conditions.Considering that both pentacyclic spiroindoline and tricyclic indole derivatives are privileged structures in drug discovery,the products obtained in this work may have potential medicinal value.Sencondly,we developed a rhodium-catalyzed cascade cross-coupling/spirocycliczation/formal[4+2]cycloaddition reaction of 3-（2-isocyanoethyl）indoles with aromatic azides,providing a general synthetic protocol to polycyclic spiroindolines bearing a pentasubstituted guanidine moiety with moderate to excellent yields.This transformation is highly efficient since one C-C,one C=N,three C-N bonds as well as two new rings are constructed in a single step.The polycyclic spiroindolines bearing a pentasubstituted guanidine could serve as versatile building blocks for the synthesis of complex compounds that are otherwise difficult to synthesize using the known approaches.More importantly,this work represents a new reactivity pattern of 3-（2-isocyanoethyl）indole,and thus provides a new development direction for 3-（2-isocyanoethyl）indole chemistry.