Studies On The Synthesis Of Manzamine Marine Alkaloid Zamamiphidin A

Kobayashi and coworkers isolated a new manzamine related alkaloid zamamiphidin A from an Okinawan marine sponge Amphimedon sp.(SS-1231)in 2013,which poccesses moderate antibacterial activity against Staphylococcus aureus(MIC=32 ?g/m L).Architecturally,zamamiphidin A was characterized by an unprecedented heptacyclic framework containing a highly fused pentacyclic caged core,two11-membered rings,seven contiguous stereocenters including two quaternary centers,one aza-acetal structure as well as an unusual quaternary ammonium salt.To the best of our knowledge,the chemical synthesis of zamamiphidin A has not yet to be disclosed.This thesis is mainly focused on the total synthesis of zamamiphidin A and accomplished some advanced achievement.The easily prepared enamidomalonate 2-82 was applied to construct the C10 stereocenter through a key asymmetric Michael addition with N-tert-butanesulfinyl imidate 2-19,leading to preparation of 2-90.Then the rapid assembly of A ring compound 2-92 was realized by the strategy of Davis oxidation and oxygen anion cyclization.The formation of the AD-rings [4.3.0] compound 2-70 proceeded smoothly via an intramolecular Michael addition from 2-66,which was generated from 2-92.Subsequently,the hydrogenation and reduction reactions delivered the bicyclic compound 2-100 with the formation of the C3,C4 and C4 a stereocenters.The highly functionalized bicyclic intermediate 2-100 contains four contiguous stereocenters(C10,C3,C4 and C4a),C9 quaternary center,one aza-acetal motif and N2/N7 heteroatoms.Further transformations of related intermediates to zamamiphidin A were unfruitful,however,this research procedure provided certain references for its total synthesis.Based on the above exploration,another strategy should be taken into account.Highly stereoselective Diels-Alder reaction between diene 2-141 and dienophile 2-155 afforded intermediate 2-156(C ring).After deprotection,the key four-step cascade cyclization reaction(lactam opening/retro-aldol/aza-Michael addition/aldol)promoted by sodium methoxide successfully delivered the bridged bicyclic compound 2-194(CD rings).The subsequent functional group manipulations and the installation of C9 hydroxyl group provided the advanced intermediate 2-210.This compound possessed[3.3.1] bicycle system(CD rings),C8,C9 quaternary cennters and appropriate functional groups.This research work provided possible solutions for the total synthesis of zamamiphidin A.