Study On The Synthesis And Bioactivities Of Analogs Of Shuangkangsu-an Anti-virus Principle Of Jinyinhua

Shuangkangsu, a new component with an unusual 1,2-dioxine skeleton first isolated by our group from a TCM (traditional Chinese medicine) named Jinyinhua, has a significant activity of inhibition of influenza virus in chicken embryo and respiratory syncytial virus in cells. The particular skeleton of the leading compound is valuable for new drug research and development.For studying the total synthesis of Shuangkangsu and its analogs, in this work, the methods for the formation and glucosylation of 1,4-Dihydro-[1,2]dioxine-1,4-diol as well as the method for removal of acetyl protective group in compounds 37, 38 have been studied. Synthesis of 1,3,5-triene had been further studied and analogs of Shuangkangsu were synthesized before tested for bioactivities including antiviral activitives and antitumor activities in vitro. Meanwhile, some new synthetic methods have been found and some of the related reactions in this work have also been studied.1. The ameliorative method for the formation of 1,4-Dihydro-[1,2]dioxine-1,4-diol, which is an intramolecular addition of hydrogen peroxide to 1,2-dialdehyde was established. This ameliorative method was used to simplify the procedure and improve the yield of the reaction, all these are important for the consequent reactions. Two new 1,4-Dihydro-[1,2]dioxine-1,4-diols with seven-member-circularity 1,3,5-triene 92 and 101 were prepared by this method. Two 1,2-dialdehydes with seven-member-circularity 1,3,5-triene 91 and 100 as key intermediates of 92 and 101 were firstly prepared and discussed.2. The optical pure isomers 39, 40, 95, 96, 104 and 105 of Shuangkangsu were successfully synthesized respectively from compound 1, 92, 101. The glucosylation methods for hydroxyl of substrate 1 was developed: The substrate 1 can be reacted with the alkyl thioglycoside donor by treat with N-Iodosuccinimide and Silver Trifluoromethanesulfonate, be reacted with the glycosyl trichloroacetimidate donor by treat with boron trifluoride ether complex or be reacted with the glycosyl trichloroacetimidate donor catalyzed by trimethylsilyl triflate (TMSOTf) to produce compounds 37 and 38 (optical pure isomers). The methods for removing the acetyl protective group in 3,6-O-glycosyl-[1,2]dioxane was also studied. Dibutyltin oxide was the proper reagent to remove the acetyl protective group in compounds 37, 38, 93, 94, 102 and 103. By comparing the CD spectra of compounds 39, 40, 95, 96, 104 and 105 with 6, 7 and/or Shuangkangsu of which the absolute configurations were specific, the absolute configuration of 39,40, 95, 96,104 and 105 were determined to (1R, 4R), (1S, 4S), (1R, 4R) and (1S, 4S). Some reactions' mechanisms were discussed.3. Some analogs of Shuangkangsu and some intermediates were tested for antiviral activities and antitumor activities, the structure-activity relationship (SAR) and antiviral mechanism of this kind of compounds were also discussed.4. The decomposition mechanisms of the peroxides under acidic or basic conditions were further discussed.5. The synthesis of 1,3,5-triene was further studied and a new method to prepare (2Z, 4Z, 6Z)-diethyloxepine-4, 5-dicarboxylate just by one-step was disclosed. Synthesis of two alkyl-substituted analogues, an alky-/acyl-substitute analogue and some 1H-azepine analogues are also described. The property of this kind of reaction is firstly discussed in detail as followed.6. In this work, 121 compounds including 41 new ones were synthesized. Among these compounds, 22 including 15 new ones are peroxides and 99 including 26 new ones are other types of compounds. And 17 of the peroxides are optical pure isomers including 10 new ones.