Total Syntheses Of Natural Products By Sp~2 C-H Activation:Total Syntheses Of Berberine And Illudalanes And Synthetic Study Towards Arnamial

The structural diversity of natural products endows them with rich biological activities,such as anti-cancer,anti-malaria,anti-bacterial,promoting nerve growth and antilipemic.Therefore,natural products have always been playing an important role of drug discovery,and catch the attention of pharmacists and chemists.Our group has been devoting to the total synthesis of natural products with important bioactivities.We apply frontier chemistry technology,such as C-H functionalization,to total synthesis of natural products for achieving breakthroughs in synthetic strategies and synthetic efficiency.In this dissertation,effieient and divergent total syntheses of berberine and norchelerythrine and five illudalane sesquiterpenes have been achieved with sp2 C-H functionalization as a key strategy.And the synthetic studies towards antineoplastic protoilludane sesquiterpene amamial is also elaborated.Berberine is a quaternary amoniun alkaloid isolated from traditional Chinese medicine Coptis chinensis,Phellodendron chinensis,etc.Berberine exhibits broad-spectrum antimicrobial activities.Recent research also reveals that berberine is a novel cholesterol-lowering agent and it also exhibits anti-tumor activity.It contains a 5,6-dihydroisoquinolino[3,2a]isoquinolinium core.Chelerythrine is one of the main active ingredients of traditional Chinese medicinal plant celandine.It's a protein kinase inhibitor.It contains a benzophenanthridine core.We have developed a novel strategy,featuring a pyridine-directed aromatic C-H vinylation and an aza-6? or all carbon-6?electrocyclization for the synthesis of azapolycycles,and also demonstrated the synthetic utility of this strategy by concise syntheses of berberine and norchelerythrine.Arnamial is a protoilludane sesquiterpene benzoate discovered from liquid cultures of Armillaria mellea FR-P75.It exhibits significant cytotoxicity against several human cancer cell lines.Arnamial contains a 5/6/4 tricyclic core and an orsellinic acid moiety.The high strained four-membered ring makes it a challenging target for total synthesis.Our synthetic strategy features an intermolecular[2+2+2]cycloaddition and a dearomative alkylation for the synthesis of the 5/6/4 tricyclic core skeleton.The tetrasubstituted phenyl ring was constructe through intermolecular[2+2+2]cycloaddition from symmetrical terminal diyne and asymmetrical monoyne.Installation of phenolic hydroxyl group by lactone-directed aromatic C-H oxygenation and methyl group via Suzuki reaction generated challenging hexasubstituted benzene intermediate.The dearomative alkylation to construct four-membered ring is currently underway.Moreover,five illudalane sesquiterpenoids were selected as targets for total synthesis,including radulactone,granulolactone,echinolactone A,calomelanolactone and riparol B.Starting from the above hexasubstituted benzene intermediate in arnamial synthesis,the total synthesis of granulolactone was completed in two-step.And the other four natural products were also synthesized from key intermediate granulolactone.We have developed a protecting-group-free,divergent total syntheses of five illudalane sesquiterpenes in 6 to 8 steps.Furthermore,the absolute configuration of radulactone have been assigned on the basis of our total synthesis.