Construction Of Polycyclic Indole Skeleton Based On Metal Catalyzed Tandem Reaction And The Evaluation Of Biological Activities

Owing to their challenging structural complexity and interesting biological properties,polycyclic indole alkaloids have attracted much attention from synthetic and medicinal community.In this paper,we have carried out a series of work on the cataltyc synthesis of polycyclic indole alkaloids.A Ni（II）catalyzed asymmetric tandem reaction for the construction of continuous quaternary carbon centers and its application for the synthesis of polymeric cyclotryptamine alkaloids.Next,an Au（I）-catalyzed domino cyclization of 1,6-diynes incorporated with indole for the construction of indole-fused azabicyclo[3.3.1]nonanes.Lastly,these polycyclic indole compounds were screened for cytotoxic and antibacterial activities in vitro.（1）We have developed a chiral N,N’-dioxide/Ni（II）catalyzed enantioselective dearomative cyclization of tryptamine via tandem[4+2]cycloaddition/cyclization reaction,enabling the synthesis of contigous quaternary carbon centers with pyrroloindoline skeleton in one step.Reaction conditions optimization led to the discovery of L3 or L6/Ni（BF₄）₂·6H₂O as catalyst system,DIPEA as base,ethyl acetate or dichloromethane as solvent.This method featured mild reaction conditions,cheap nickel salts and easy preparation of ligands.It also showed a good substrate suitability for different tryptamine substrates and 3-bromo oxindole substrates.The asymmetric synthesis of the polycyclotryptamine alkaloids was subsequently explored based on this protocol.The Friedel-Craft alkylation and Ni（acac）₂/Zn catalyzed reduction coupling reaction were then investigated respectively for construction of C_3a-C₇,bond,and finally the asymmetric synthesis of trimeric cyclotryptamine alkaloids was achieved.Unfortunately,the NMR data of the final products was inconsistent with the natural products,and the follow-up research work is still in progress.（2）An Au-catalyzed domino cyclization of 1,6-diynes incorporated with indole was developed,efficiently constructing the framework of indole fused azabicyclo[3.3.1]nonane in one step via an cascade dearomatization/rearo-matization/dearomatization process.Through the screening of reaction conditions,we determined the optimal reaction conditions which were proceeded at 60 ^oC with（SPhos）Au Cl/Ag Cl O₄as catalyst and 1,2-dichloroethane as solvent.The advantages of the reaction included mild reaction conditions,good substrate tolerance,excellent diastereoselectiveities with good yields.This reaction is of great significance for the synthesis of polycyclic indole alkaloids and the tandem processes initiated by the Au（I）-catalyzed dearomatization of indole.（3）For the cytotoxic and antibacterial activities in vitro of the obtained polycyclic indole compounds were screened.The cytotoxic assay showed that compounds of 2-103j、3-49、4-93k、4-93p、4-94c、4-94k、4-94o、4-94p possessed remarkable inhibitions for the tested cancer cells of NCI-H522、SNB19、He La and uo-31,with less than 10μM IC₅₀ values.However,none of them showed significant antimicrobial activity in vitro.