Total Synthesis Of Bergenin And Bergenin-related Natural Products

The C-glycoside compounds are defined as compounds in which the exo-cyclic oxygen atom of an 0-glucoside has been replaced by a carbon atom. For their exhibit various bioactivities. During the last two decades, the C-glycosides has become one of sources of new structure drugs, so the synthesis of C-glycosides has been of considerable interest.Bergenin , is a member of natural aryl C-glycoside with the chemical name: 3, 4, 8, 10-Tetrahydroxy-2-hydroxymethyl-9-methoxy-3, 4, 4a, 10b-tetrahydro-2H -pyrano[3,2-c]isochromen-6-one and its structure has free hydroxybenzene and lactone with relieve a cough, calm asthma, protect liver , anti-inflammation, anti-tumors and anti-virural bioactivities. In our institute it has also been isolated from the Chinese medicine WOX, bergenin displays anti-inflammation and anti-tumors bioactivities. In order to study C-glycoside synthesis, we design methods to total synthesis of Bergenin. In the base of bergenin, its related ramifications as well as, are been composed. This serves as a basis for testing their bioactivities, revealing the relationships between structure and bioactivity and developing new medicines.Retrosynthetically , bergenin can be logically C-glycosylated with glycosyl donor and aglycone, but in fact, it's a challenge for directly glycosylation because of gallic acid's (aglycone) strong draw- electron carbonylo So we must replace draw-electron group with push-electron , then the glycosylate reaction is successfully accurs. There is three steps for the design idea : (1) Deoxidize carbonyl, and the phenol hydroxyl protect group using push-electron, to improve aglycone's activity; (2) C- glycosylation through intramolecular aglycon delivery; (3) Oxygenation of methylene, then synthesize Bergenin.Firstly we design Frises like rearrangement reaction routeto synthesis of Bergenin. Using highly activity benzyl trichloroacetimide as glycosyl donor and moreprotective group hydroxybenzene as glycols acceptor, under the catalyse of Trimethylsilyl trifluoromethane sulfonate(TMSOTf). But this method is defeated. The causation may be the lowerly activityof protective group hydroxybenzene.Then we adopt Friedel -Crafts like arylation , come through gallic acid and through mainly 11 steps in an oerall yield of 17.5%. The aglycone was readily obtained in an overall yield of 61.4% via five steps by using gallic acid acetylester as the starting material. The glucopyranose was readily obtained in an overall yield of 44.8% via six steps by using glucoside as the starting material. The aglycone and the glucopyranose are aetherylated, oxidation with ruthenium trichlorine and kalium tetraoxide into the corresponding lactone , then the lactone is ruptured by LiOH in reflux THF, the results compound is isomerizated with DBU in reflux THF, and at last, hydrolysis by PoVC, the final target bergenin is eventually obtained. Its four new derivates and 8 ramification and 3 Aryl intermediates C-glycoside are also synthesized using this methods. All the intermediates are identified correctly by 'H-NMR, I3C-NMR, 1R and the solid-stated materials are also measured melt point. The analytical data for the synthesized bergenin are identical in all respects to thosed reported for the natural material such as IR, 'H-NMR, I3C-NMR.In conclusion, a highly convergent approach for the total synthesis of bergenin and its related ramifications has been first developed successfully, which paved the way to easily access to the diversified analogues of bergenin.