Studies On The Design And Synthesis Of Isosteviol Derivatives

Isosteviol and its derivatives, being tetracyclic diterpenoid with a beyerane skeleton, have attracted scientific attention because of their remarkably broad spectrum of biological activities. In this thesis, thirty-nine isosteviol based bioactive derivatives were designed and synthesized with a natural available stevioside as starting materil, via hydrolysis, esterification, oxidation, reduction, Beckmann rearrangement and craking, Baeyer-Villiger rearrangement, nucleophilic addition and condensation reaction, etc. Thirty-two of those derivatives had never been reported in literature. All of the new compounds were respectively characterized by IR,NMR,HRMS spectra as well as X-ray crystal structures determination. Based on the bioactive substructure of isosteviol, some research efforts were put forward on the derivativation of isosteviol in order to find useful prodrug molecules. The corresponding work is described as follows:1. Ethyl ent-15a-hydroxymethyl-16-oxobeyeran-19-oate (5) and ethyl ent-15-hydroxymethylene-16-oxobeyeran-19-oate (6) were regioselectively synthesized via steps from stevioside. The effects of different oxidants on the selective oxidation of ethyl ent-15a-hydroxymethyl-16β-hydroxybeyeran-19-oate were also studied. A series of isosteviol derivatives were designed and synthesized by opening or enlarging the D-ring of isosteviol via Beckmann rearrangement and fragmentation. It was found that the ratio of the rearrangement and fragmentation products could be significantly affected by different acids, such as proton acid and Lewis acid. The mechanism of the Beckmann reaction was further confirmed. The absolute configuration of compound 6 was confirmed by X-ray crystallographic analysis. 2. Ethyl ent-15-hydroxymethylene-16-oxobeyeran-19-oate (6) reacted with phenylhydrazine and phenylhydrazine hydrochloride to produce a series of hydrazones and pyrazolyl derivatives. The yields of target products were significantly affected by using proton acid as catalyst. Two useful procedures were developed for the formation of pyrazole ring attached to the isosteviol 15,16-position. The X-ray crystal structure analysis of compound 19 confirmed the position of the substituent on the pyrazole ring. The relationship of yields and the electronic effects of substituents was also discussed. 3. Some spiral type isosteviol derivatives with thiadiazoline moiety were designed and synthesized via steps from ethyl ent-16-oxobeyeran-19-oate (3) in good yields. The desired synthesis route is valuable to prepare isosteviol derivatives containing thiadiazoline moiety in simple and general condition. A possible mechanism for the MnO2 oxydized Oxydation-Cycization reaction was suggested and the structures of the new compounds were also studied.4. Some bishydroxy isosteviol derivatives were designed and synthesized via Baeyer-Villiger rearrangement, selective reduction as well as bimolecule condensation reaction. A novel method for the synthesis of lactone type sulphonic acid ester with sulphuric acid was found and the proposed mechanism of the reaction was put forward. The diethyl ent-16,16'-dihydroxybeyeran-19,19'-oate was first synthesized by bimolecular condensation and reduction free radical reaction of ethyl ent-16-oxobeyeran-19-oate and some conditions were further investigated. The X-ray crystal structures of compounds 35 and 38 were determined.5. Studies on biological activities of the synthesized isosteviol derivatives are ongoing.