Penta-O-benzoyl-D-glucose: an efficient glycosyl donor for the synthesis of a-arbutin and a-aromatic-O-glucosides

Abstract a-arbutin, an inhibitor of tyrosinase is characterized as a- aromatic glucoside. The paper reports a facile glycosylation between penta-O-benzoyl-D-glucoside 3 and a series of aromatic aglycons 4a-4f catalyzed by BF₃·Et₂O forming a-arbutin intermediate 5a and other aromatic glucosides 5b-5f with good yields 91% and 75%-96%. Deprotection of 5a gives a-arbutin in 66% yield over 4 steps from glucose. Both the yield and stereoselectivity (a/b=6.2) exceed the present method. The hitherto unknown compounds 5a-5f are determined by ¹H-NMR and EI-MS.
Keywords a-Arbutin; Penta-O-benzoyl-D-glucose; 1, 2-cis-O- glycosylation; Stereoselective synthesis

b-arbutin 1 is a nature product that extracted from blueberry leaves. Recently its synthetic anomer a-arbutin 2 has attracted more interests for its low histotoxicity ^[1] (IC₅₀=2.1, b-arbutin IC₅₀≥30). Therefore a-arbutin has prospective future in medical and cosmetic application ^[2].

Fig. 1 Structures of a- and b- arbutin

    The stereoselective formation of 1,2-cis-glycosidic linkage and the poor nucleophilicity of phenols under glycosylation condition are two aspects that challenge the synthesis of α-arbutin ^[3]. Its selective synthesis requires extra efforts due to neighboring participation, solvent effect, steric hindrance, and catalyst as well as temperature and reaction time ^[4]. Present method ^[5], starting from methyl glucoside only affords α-arbutin in 32% yield (a/b=5). Such a low overall yield is mainly due to the further modification of penta- benzoyl glucoside to provide C-2 none participated and anomeric center activated trichloroacetimidate with yield 40%~50% by two steps from methyl glucose. Therefore the study of efficient 1, 2-cis-O-glycosylation not only contributes to the industrial application but also the synthesis methodology.
    Traditionally, per-benzoylated glucoside is so "disarmed" that it is rarely used as glycosyl donor. To our best knowledge, there are only two related documents ^{[6, 7]} reporting its application in aromatic glycosylation. In contrast, another kind of glycosyl ester: glycosyl acetate is widely used, but 1, 2-trans glycoside is preferred. Attracted by the easy accessibility of penta-O-benzoyl-D-glucose compared with the multi-steps and low yield of preparing C-2 non-participating group protected trichloroacetimidate glycosyl donor, we reconsider the application of penta-O-benzoyl-D-glucoside in 1, 2-cis-glycosylation.

Fig. 2 1, 2-cis-O-glycosylation using penta-O-benzoyl-D-glucoside as donor

    As shown in Fig. 2, a series of cis-O-glycosides are synthesized. Under N₂, a solution of compound 3 2.5g (3.6mmol) and phenols 4a-4f (7.2mmol) in CH₂Cl₂ (25ml) are stirred magnetically. The mixture is cooled to 0℃, treated with BF₃·Et₂O 1.9ml (14.4mmol) then allow the temperature raise to r.t. in 1~2hrs. The mixture is kept under refluxing for another 48hrs then quenched with saturated aq. NaHCO₃, diluted with 10ml CH₂Cl₂ and stirring was continued for 20min, the organic layer is washed by 2×20ml Na₂CO₃ and 20ml aq. NaCl, dried with anhydr. Na₂SO₄. The solvent is evaporated under diminished pressure, and the residue is chromatographed by silica gel column (1:6~1:2.5 = ethyl acetate: petroleum ether) to give single isomer or mixture. Yields, a/b ratio and characterizations are listed in Table 1. Without purification, deprotection of 5a to afford α-arbutin 2 is conducted under standard condition with sodium methoxide in methanol. The overall yield of α-arbutin counting from glucose is 66% determined by HPLC using external standard method ^[8].