| Flavonoids are plant secondary metabolites and occur widespread in nature. 3-O-Substituted quercetin derivatives form a most commonly seen subclass of flavonoids, such as 3-O-Methylquercetin, Hirsutrin, Hyperside, Rutin, Quercetin-3-O-(2G-glucosyl)-rutinoside and CTN986, and so on. Interestingly, many of them have demonstrated a wide range of beneficial properties, for instance, radical-scavenging, anti-cancer, anti-virus, anti-microbial and anti-depressant biological activities, etc. Hence, the synthesis of this kind of compoudes has a vital significance.Perplexingly, Quercetin has multiple chemically similar hydroxyl groups. Therefore, regioselectivity of the synthetic method is one of the major challenges for the synthesis of 3-O-substituted quercetin. As for quercetin 3-O-glycoside, besides the problem of regioselectivity, the anomeric stereoselectivity of the glycosylation step causes further complication. Thus, the synthetic procedures are normally tedious and complex, and the overall yields are generally very low. Here, three typical 3-O-substituted quercetin derivatives, 3-O-Mthyl-quercetin, Hirsutrin and Quercetin-3-O-(2G-glucosyl)-rutinoside, had been selected as targets in our synthetic study, attempting to find facile methods for the synthesis of 3-O-substituted quercetin. For the first time, low-cost Rutin was converted into 7,3',4'-O-tribenzylquercetin. This compound is a versatile intermediate, since substituent groups can be attached specifically to its 3-OH position. On the basis, 3-O-Mthylquercetin and Hirsutrin had been synthesized in high yields with methods simpler than what had been reported. Moreover, the trisaccharide segment of quercetin-3-O-(2G-glucosyl)-rutinoside had also been constructed, underlying the synthesis of 3-O-glycosided quercetin with comolex sugar linkage. The results are summarized as follows:Preparation of 7,3' ,4' -0-tribenzyl quercet in Using rutin as the starting material, 7,3',4'-O- tribenzylquercetin was prepared for the first time with high yield via selective benzylation and mild acidic hydrolysis. Because of the strong chelaction the 5-OH with the 4-carbonyl group by intermolecular hydrogen bonding, following alkylation or glycosylation of this compound will arise selectively on the 3-OH site.Synthesis of 3-O-methylquercetin 3-O-Methylquercetin was syhthesized in two steps and in 76% overall yield, i.e. methylation of 7,3',4'-O-tribenzylquercetin with methyl iodide under the catalysis of K2CO3 ; then, cleavage of the benzyl groups by hydrogenolysis catalyzed by Pd/C.Synthesis of Hirsutrin Trichloroacetimide-group and acetyl-group had been used as activating group to connect differently protected glycosyl with the 3-OH of flavonoid aglycon under the catalysis of trimethylsilyl-tiflate (TMSOTf ) or boron trifluride etherate ( BF3.Et2O). All the efforts had failed to give the expected products. However, the glycosylation reaction succeeded by using 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide and gave 51% 48 % and 85% yields by catalysis of K2CO3 Ag2O or CTAB, respectively. Hirsutrin was obtained after removing the acetyl and benzyl protective groups.The tr i sacchar i de segment of quercetin-3-O-(2G-glucosyl)-rutinoside was synthesized as follow:Synthes i s of p-methoxyphenyl 3-O-benzyl -4, 6-0-benzylidene-B-D-gluco pyranos i de Acetylation of glucose of with acetic anhydride by the catalysis of anhydrous acetate sodium formed 1,2,3,4,6-penta-O-acetyl-B-D-glucopyranose.Reaction on of the product with p-methoxyphenol, using boron trifluride etherate as promoter, provided p-Methoxyphenyl 2,3,4,6-penta-O-acetyl-B-D-glucopyranoside, which was further transformed into p-Methoxyphenyl B-D-glucopyranoside by methanolysis in the present of catalytic amount of sodium methoxide. p-Methoxyphenyl 3-O-benzyl-4,6-O-benzylidene-B-D-glucopyranoside was accoplished by these manipulations, i.e. the formation-benzylidene of p-Methoxyphenyl-|3-D- glucopyranoside with benzaldehyde in formic acid and then regioselective benzylation via a dibutyl tin oxide-mediated...
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