Total Synthesis And Biological Study Of The Analogue Of Cyanolide A

Cyanolide A,isolated from the extracts of a Papua New Guinea collection of Lyngbya bouillonii in 2010 by Gerwick and co-workers,has been shown to possess highly molluscicidal activity.Synthetically,Cyanolide A is a dimeric glycosidic macrolide,consisting of a central 16-membered macrocycle that was fused with two tetrahydropyrans and two xylose residues.In this thesis,based on the structure of Cyanolide A,we obtained the analogue of Cyanolide A via a unique and novel total synthetic route,and the subsequently tested the anticancer activity of the synthesized analogue,which showed that the analogue had no anti cancer activity.The synthetic route was commenced with methyl acetoacetate.We first employed a double negative ion reaction to add the carbon chain,and install the first hydroxyl.Then,in the presence of BEt₃,syn-1,3-diol was selectively constructed via the reduction of carbonyl,which was protected using p-anisaldehyde dimethyl acetal.Next,withe treating with DIBAL-H,the ester group was reduced to aldehyde that was immediately subjected to alkoxy-directed Mukaiyama Aldol reaction to construct anti-1,3-diol in the presence of Ti（O-i-Pr）₂Cl₂.With the anti-1,3-diol in hand,we could obtain the key tetrahydropyran intermediate via few steps including protection of the newly formed hydroxyl group,deprotection of the acetal group,and oxa-Michael addition alkaline condition.Afterward,16-membered macrolide was synthesized via a hydrolysis of the ester of and the following dimerization under Yamaguchi’s lactonization condition.Finally,we could accomplish the total synthesis of Cyanolide A analogue via the deprotection of hydroxyl group and the glycosylation reaction.Subsequent biological tests of this analogue showed no anticancer activity because we got less than 50%inhibition of human lung cancer cell A549,human hepatocellular carcinoma HepG2 and human prostate cancer cell PC-3.In this thesis,we employed a linear synthetic strategy to synthesize the analogue of Cyanolide A.The route has the many advantages,suhc as cheap and easily obtained starting material,simple operation of experiment,relatively high yield and relatively short steps.The synthetic strategy also provided an impotant reference for the synthesis of other Cyanolide A analogues.