Studies On The Total Synthesis Of Sesquiterpenoids (+)-Cuparene,(+)-Tochuinyl Acetate,Herbertenolide And Fissistigmatin & The Evaluation Of Biological Activities

Sesquiterpenoid is one of the most abundant natural products with diverse skeleton structures,and exhibits excellent biological activies,such as antitumor and antibacterial.It remains highly desirable for chemists to develop an artificial synthetic strategy.This thesis mainly focuses on the synthesis of aromatic sesquiterpenoids and sesquiterpenoid hybrid flavonoids to support the subsequent chemical biology studies.The synthesis of the cuparane-type sesquiterpenoids?+?-Cuparene,?+?-Tochuinyl acetate and herbertane-type sesquiterpenoid Herbertenolide were described in the first part of this dissertation.Structurally,these molecules all possess continuous quaternary carbon centers.Moreover,the chiral continuous quaternary all-carbon center of?+?-Tochuinyl acetate and Herbertenolide is a pair of diastereomers.Usually only one specific diastereoisomer is accessible via previously developed methodologies.In this regard,a general protocol that enables stereospecific construction of all stereoisomers of contiguous quarternary carbon centers is of high importance for the collective synthesis of those type of natural products.Inspired by our recent work on the oxidative rearrangement of malondialdehyde,we illustrated the oxidative ring contraction of?-formyl cyclic ketones mediated by H₂O₂,which provides a facile access to the stereospecific construction of contiguous quaternary carbon centers.This reaction was carried out by using H₂O₂ as oxidant and ethyl acetate as solvent at room temperature.This method featured mild reaction conditions,convenient operations and no need of pecious metal catalyst.By oxidative extrusion of formic acid,contiguous quaternary all-carbon centers were forged stereospecifically from enantioenriched?-formyl cyclic ketone.This method enabled construction of all stereoisomers of chiral continuous quaternary all-carbon center from enantiopure cyclohexanone.The asymmetric total synthesis of the cuparane-type sesquiterpenoids?+?-Cuparene and?+?-Tochuinyl acetate were then executed via this oxidative ring-contraction reaction.Initially,gram-scale synthesis of chiral cyclohexanone was smoothly realized via a one-pot 3-exo iodo-cyclo-etherification/Wagner-Meerwein rearrangement process developed by us.The other quarternary carbon center was established via formylation and methylation process.Oxidative ring contraction of the enantioenriched?-formylcyclohexanone mediated by H₂O₂ yielded corresponding cyclopentanoic acid.Eventually,asymmetric total synthesis of?+?-Cuparene and?+?-Tochuinyl acetate were efficiently accomplished via a series of transformations.Furthermore,the diastereoselective synthesis of herbertane-type sesquiterpenoid Herberte-nolide was also realized via similar strategy.The asymmetric synthetic studies of sesquiterpenoid hybrid flavonoid Fissistigmatin was described in the second part of this dissertation.Fissistigmatins are a novel type of sesqui-terpenoid hybrid flavonoid isolated from Fissistigma bracteolatum Chatt.?Annonaceae?containing a flavonoid and an eudesmane-type sesquiterpenoid fragment connected by the C4-C1''bond.To date,no synthesis or synthetic study of Fissistigmatin has ever been reported.To construct the key C4-C1''bond of Fissistigmatin,we developed a bioinspired enantio-selective addition of aldehyde to 2-hydroxychalcone promoted by co-operative organo-catalysts driven by visible light.This reaction was carried out by using R-TRIP and chiral imidazolidinone A4 as co-operative organocatalysts and diethyl ether as solvent at room temperature under the irradiation of 24 W compact fluorescent light.The chiral 4H-chromenes could be obtained in 93%yield with up to 99%ee and 20:1 dr.Moreover,the organocatalysts could be recycled for 10 times without noticeable loss of reactivity,which is of great significance for the synthetic study of Fissistigmatins.The results for the preliminary screening of antibacterial activity indicated that the chiral 4H-chromenes 5-54 showed inhibitory activity against Bacillus subtilis,which provided a reference for further research on the antibacterial activity of this kind of skeleton.The flavonoid framework of Fissistigmatin was subsequently constructed by taking advantage of this novel protocol in 93%yield with 98%ee and>20:1 dr on the gram scale synthesis.Finally,the decalin skeleton of sesquiterpenoid fragment was forged via intra-molecular Diels–Alder reaction from this key building block.