Study On Total Synthesis Of Natural Products Sanjoseolide & Bavacoumestan C

The research content of this paper includes two parts:the total synthesis of natural products Sanjoseolide and Bavacoumestan C.The specific content is as follows:Chapter 1.Synthesis and Cytotoxic Evaluation of Sanjoseolide and Representative AnaloguesThe natural product Sanjoseolide is an isoprenyl side chain and a chiral center isolated from the Dalea frutescens A plant in 2016 by Professor Susan L.Mooberry of the University of Oklahoma,Texas.Otoketones.The authors used the SRB assay method to determine its antiproliferative activity and cytotoxicity to PC-3 and DU 145 prostate cancer cells,with corresponding IC₅₀0 values of 35.0?M and 25.5?M.By consulting relevant literature,we determined the synthetic route and based on retrosynthesis analysis.First,using 2,4-dihydroxyacetophenone as the starting material,the p-hydroxy group is selectively protected,and then 3-chloro-3-methyl-1-butyne is constructed on the o-hydroxy group through DBU and Cu I catalysis.The alkyne is reduced by hydrogenation,the Claisen rearrangement reaction on the benzene ring to construct the isopentenyl side chain,and the chloromethyl methyl ether protects the exposed hydroxyl group to obtain the intermediate 5.We also tried to synthesize intermediate 5 through iodine band,MOM protection,and Stille coupling.Next,the chiral center was constructed by Sharpless asymmetric dihydroxylation,and finally the basic skeleton of the chalcone compound was constructed by the Claisen-Schmidt reaction,and then the protective group was removed.Since Sanjoseolide good biological activity,we intend to synthesize 7analogues of Sanjoseolie and evaluate the biological activity,discuss the structure-activity relationship of the analogues,and finally found that compound 8e had an effect on RBE and HCCC-9810.For RBE,the IC₅₀ values of the synthetic analogues 8e and Sanjoseolide?1?for its inhibition were 12.8 and 15.7?M,and for HCCC-9810 were 12.7 and 15.6?M.The IC₅₀value of cytotoxicity inhibition rate of other compounds was higher than 20?M,and the inhibition effect was not obvious.Compared with the natural product Sanjoseolide?1?,it is not difficult to find that adding trifluoromethyl in the molecule has a better inhibitory effect on cytotoxic growth?8e and 1?.Of course,the benzene ring is also very significant?8b,8c and 1?.At present,our laboratory is also studying the cytotoxicity of analogues to other tumor cell lines.Chapter 2.Study on Total Synthesis of Natural Product Bavacoumestan CIn 2014,Bavacoumestan C,a coumarin compound,was isolated when Professor Jongheon Shin from the Institute of Natural Products,School of Pharmacy,Seoul National University,Korea,looked for bioactive compounds in Korean folk medicine.The molecule contains two chiral centers and a unique five-membered ring.The authors determined that the IC₅₀ value of SrtA was 119.0?M.Through the retrosynthesis analysis of natural product Bavacoumestan C,a synthetic route with 2,4-dihydroxyacetophenone and m-diphenol as starting materials was determined.First,the coumarin ring is constructed by 2,4-dihydroxyacetophenone through a carbonyl insertion reaction,and tetrabutylammonium bromide provide a bromine source to replace the hydroxyl group to synthesize the first fragment.The second fragment was synthesized by m-diphenol and 3,3-dimethacrylic acid catalyzed by fuchsylation under the catalysis of aluminum trichloride.Under the catalysis of potassium carbonate,the reaction was carried out under reflux of acetone to synthesize Intermediate 7.we did not detect compound 7.So we are exploring the synthesis of compound 7 and Bavacoumestan C.