Total Synthesis Of Natural Products Bavachinone A-C And Bavaflavone A And Their Biological Activities

The natural products Bavachinone A-C and Bavaflavone A were isolated from the plant Psoralea corylifolia and its fruits by the groups of Prof.Jongheon Shin at the College of Pharmacy,Seoul National University,Korea,Prof.Choi Long at the College of Pharmacy,Peking University and Prof.Yang Xiuwei at the College of Pharmacy,Peking University in2015,2018 and 2022,respectively.The compounds in this class have similar 5/6/6 polycyclic systems,benzofuran and benzopyrone moieties containing 1-2 chiral centers.Biological activity studies have shown that Bavachinone A possessing good anti-inflammatory activity;Bavachinone B inhibits Str A and SIRT1,which were key enzymes required for invasion of host cells by Gram-positive bacteria,as well as diacylglycerol acyltransferase 1(DGAT1)andα-glucosidase,which play a key role in triacylglycerol synthesis,thus the Bavachinone B could be a lead compound for the treatment of diabetes.Bavachinone C and Bavaflavone A act through the estrogen receptor(ER)pathway and have a good activity on osteogenic differentiation and mineralization in MC3T3-E1 cells,which could be used as lead compounds for the treatment of osteoporosis.To date,no asymmetric total synthesis of the natural products has been reported in the literature.By retrosynthetic analyzing the structures of Bavachinone A-C and Bavaflavone A,we decided to adopt a tandem synthesis strategy,aiming to complete the total synthesis of the above four natural products with simple methods and the shortest synthesis steps.Therefore,we decided to use commercially available 2,4-dihydroxyacetophenone as the starting material.Firstly,we introduced the isopentenyl side chain by Claisen rearrangement reaction,followed by epoxidation off the five-membered ring to complete the construction of the benzodifuran structure in Bavachinone A and Bavaflavone A.The construction of the benzodifuran moiety in Bavachinone C or Bavachinone B can also be completed by oxidation of benzodifuran or catalytic coupling with alkynyl alcohol.The oxy-michael addition reaction or the oxidation cyclization reaction under iodine catalytic conditions were used to complete the construction of the skeletons of benzopyrones and benzodipyrones in four molecules.Finally,we completed the racemic synthesis of the natural product Bavachinone A-C.Unfortunately,the removal of protecting groups in the synthesis of Bavaflavone A caused great difficulties due to electronic effects,the synthesis of this molecule is still under investigation.For the construction of chiral centers in the above molecules,we successfully introduced chiral centers on the benzodiofuran ring using the Sharpless asymmetric dihydroxylation reaction,and on the dihydropyranone ring by Michael addition reaction with chiral amine catalysts,but the enantioselectivity is relatively low and this part of the research is still in progress.We examined the inhibitory activity of the natural product Bavachinone A-C racemate against Fusarium oxysporum,Phytophthora infestans,Cladosporium fulvum,Rhizoctonia solanikuhn,Botrytis cinerea and Fusarium graminearum using the mycelium growth rate method.The results showed that only Bavachinone A and C had inhibitory activity against the Botrytis cinerea.