Studies On Total Synthesis Of Natural Product Neobraclactone A And Related Gold Catalyst Methodology

Natural product is the major source of medicine and the treasure house of diverse structures.Total synthesis of natural product is not only the science of discovering medicine,but also the precise art.The natural product Neobraclactone A had a better activity(GI50=0.40μM)against K562 than the positive control drug gambogic acid(GI50=0.56 μM),and showed potential anti cancer activity.This thesis was aimed at the total synthesis of Neobraclactone A based on DTS strategy,building up the bank of analogues of Neobraclactone A,screening the activities,discovering lead compound.We summarized the reasons of former fails on synthesis of the skeleton of Neobraclactone A,and proposed a synthetic route to the C,D,E rings of Neobraclactone A starting with L-(-)-carvone.After two generations’ exploration,we finally achieved the synthesis of 3-20 which is the former skeleton of C,D,E rings,summarized the experiences and laid the roots for future study.We employed the ethylenediamine mediated tandem cyclization to build up the A,B,C rings of Neobraclactone A.Inspired by this strategy we designed and completed the methodology of ’A Au(I)-catalyzed hydrogen bond-directed tandem strategy to synthesize indeno-chromen-4-one and indeno-quinolin-4-one derivatives’.This methodology started with some simple and non-cycle materials,under the double action of gold catalysis and hydrogen bond-directing,built up the indeno-chromen-4-one and indeno-quinolin-4-one derivatives in one step and one pot respectively.It had the advantages of mild reacting conditions,wide substrate scope and high yields.At the same time we discussed its mechanism by isolating the intermediates and computer-assisted calculation.Moreover,the activities against K562 of intermediates in synthesis of 3-20 were between 20-40μM,much lower than Neobraclactone A.And the activities against IMPDH of some indeno-chromen-4-one compounds were tested.Compound 2j had the 1/49 activity of positive control drug MPA,and better selectivity against IMPDH II compared to MPA.2j and 2n had the potential to be lead compound by structure derivatization.