Total Synthesis Of Monoterpenoid Indole Alkaloids Enabled By Enantioselective Tandem Michael Addition And Evaluationof Biological Activities

Monoterpenoid indole alkaloids are widely distributed in nature,with polycyclic scaffold and diverse biological activities,which also pose significant synthetic challenge.This dissertation focuses on developing a highly enantioselective tandem Michael addition reaction to construct enantioenriched spiro[pyrrolidine-3,3'-oxindole].Relying on this method,the asymmetric synthesis of several monoterpenoid alkaloids is achieved,which paves the way for further biochemical studies.Spiro[pyrrolidine-3,3'-oxindole]has been recognized as a privileged skeleton widely present in indole alkaloids and pharmaceutical molecules with important biological activities.Therefore,the development of a concise and efficient synthetic method is of great significance.Although a variety of methods have been reported for the construction of this skeleton,enantioselective construction of spiro[pyrrolidine-3,3'-oxindole]remains an unsolved challenge.A highly enantioselective tandem Michael addition of tryptamine-derived oxindoles to alkynones was developed by taking advantage of Feng's chiral N,N'-dioxide/Sc?OTf?₃.The reaction enabled the facile preparation of enantioenriched spiro[pyrrolidine-3,3'-oxindole]skeleton.Systematic screening of ligands,solvents and bases,the combination of L₁,1,2-dichloroethane and Na₂CO₃ was identified as the optimal reaction condition.A broad range of oxindoles and alkynones with different functionalities were well tolerated with this reaction condition,showing synthetic potential in the asymmetric synthesis of pharmaceutical molecules and natural products.Strychnos alkaloids possess polycyclic structure and potent biological activities.The total synthesis of Strychnos alkaloids has attracted much attention from synthetic chemists.Based on the asymmetric tandem Michael addition reaction,we designed a new synthetic strategy for the asymmetic synthesis of?-?-Tubifoline,?-?-Tubifolidine and?-?-Dehydrotubifoline.The synthesis commenced with the preparation of spirooxindole on decagram scale using the tandem Michael addition reaction.Due to the easy racemization of the spirooxindole,intramolecular condensation proved to be quite challenging.By activation of the amide and ketone with Meerwein salt and TBSOTf respectively,the tetracyclic product was prepared on gram scale without loss of enantiopurity.The construction of the bridged D ring was unexpectedly problematic because of a ring opening/cyclization process via reversible Mannich reaction,which led to racemization.This process could be totally suppressed by a SnCl₄-promoted allylic substitution.The asymmetic synthesis of the Strychnos alkaloids?-?-Tubifoline,?-?-Tubifolidine,?-?-Dehydrotubifoline were achieved in 10 to 11 steps.Kopsiyunnanine M is a Strychnos-Strychnos type bisindole alkaloid isolated from the aerial part of K.arborea in 2016.At present,no synthetic study has been reported.Due to the structural complexity and biological activity of bisindole alkaloids,we commenced the synthesis of Kopsiyunnanine M.According to the proposed biogenetic pathway of Kopsiyunnanine M,a biomimetic Diels-Alder synthetic strategy was employed.At present,we focused on the asymmetric synthesis of diene fragment.Efficient synthesis of the spirooxindole could be achieved by taking advantage of the tandem Michael addition reaction.Upon activation of the amide with Meerwein salt,oxidation with IBX,simultaneously promoted the intramolecular condensation to deliver the tetracyclic product.The construction of bridged D ring was subsequently completed with SnCl₄-promoted deprotection/cyclization cascade reactions.Finally,the reductive ring-opening reaction enabled the construction of the diene fragment.We performed primary screening of anti-inflammatory,antibacterial,anti-tumor and immunosuppressive activities in vitro on synthetic spiropyrrolidine oxindoles and Strychnos alkaloids.Tubifoline and Akuammicine exhibited inhibitory activities on LPS-induced NO production,and further evaluation of neuritis inhibitory activity was still in progress.