A new synthesis of α-arbutin via Lewis acid catalyzed selective glycosylation of tetra-O-benzyl-α-d-glucopyranosyl trichloroacetimidate with hydroquinone

Article abstract of DOI:10.1016/j.carres.2006.04.022

α-Arbutin has huge application potentials in the cosmetic industry, as its inhibitory effect on human tyrosinase is stronger than that of its naturally occurring anomer arbutin (4-hydroxyphenyl β-d-glucopyranoside). Enzymatic synthesis was preferred for α-arbutin previously, and now a new chemical synthesis is reported. The reaction of tetra-O-benzyl-α-d-glucopyranosyl trichloroacetimidate, as glycosyl donor, with hydroquinone was initiated by catalytic amounts of trimethylsilyl trifluoromethanesulfonate (TMSOTf), resulting in 4-hydroxyphenyl 2,3,4,6-tetra-O-benzyl-α-d-glucopyranoside with high stereoselectivity and yield, and then to α-arbutin quantitatively after deprotection.

Full text of DOI:10.1016/j.carres.2006.04.022

Carbohydrate Research 341 (2006) 1945–1947
Note
A new synthesis of a-arbutin via Lewis acid catalyzed
selective glycosylation of tetra-O-benzyl-a-D-glucopyranosyl
trichloroacetimidate with hydroquinone
Zhao-Xia Wang, Xiao-Xin Shi, Guo-Rong Chen,* Zhi-Hua Ren, Lei Luo and Jing Yan
Laboratory for Advanced Materials, Institute of Fine Chemicals, East China University of Science and Technology,
Shanghai 200237, PR China
Received 17 January 2006; received in revised form 7 April 2006; accepted 11 April 2006
Available online 15 May 2006
Abstract—a-Arbutin has huge application potentials in the cosmetic industry, as its inhibitory effect on human tyrosinase is stronger
than that of its naturally occurring anomer arbutin (4-hydroxyphenyl b-D-glucopyranoside). Enzymatic synthesis was preferred for
a-arbutin previously, and now a new chemical synthesis is reported. The reaction of tetra-O-benzyl-a-D-glucopyranosyl trichloro-
acetimidate, as glycosyl donor, with hydroquinone was initiated by catalytic amounts of trimethylsilyl trifluoromethanesulfonate
(TMSOTf), resulting in 4-hydroxyphenyl 2,3,4,6-tetra-O-benzyl-a-D-glucopyranoside with high stereoselectivity and yield, and then
to a-arbutin quantitatively after deprotection.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Keywords: a-Arbutin; Trichloracetimidate; Hydroquinone; Glycosylation
a-Arbutin (4-hydroxyphenyl a-D-glucopyranoside, 1) is
the anomer of the naturally occurring arbutin. It is a po-
tent suppressor of melanin synthesis in human skin
without apparent side effects.1–3 It was reported that
a-arbutin inhibited human tyrosinase much more effec-
tively than arbutin. The IC50 value of a-arbutin is
2.1 mM, whereas that of arbutin is higher than
30 mM.4 This indicates that a-arbutin is a more effective
skin-whitening agent than arbutin. Moreover, arbutin
inhibits normal cellular growth with increasing concen-
tration while a-arbutin does not,5 which suggests that
a-arbutin is more safe than arbutin.
a-Arbutin used to be produced by enzymatic synthe-
sis.6,7 There are very few reports on its chemical synthe-
sis. Kariyone et al. prepared a-arbutin in 16% yield by
reaction of penta-O-acetyl-b-D-glucopyranose and
hydroquinone at 120–130 ꢁC under diminished pres-
sure.8 Onodera et al. reported the direct acid-catalyzed
glycosylation of D-glucose with hydroquinone at
100 ꢁC for 10 h giving a-arbutin and its b-anomer in
11% and 4% yield, respectively.9 Cepanec et al. patented
recently a chemical synthesis of a-arbutin involving
reaction of penta-O-acetyl-a-D-glucopyranose and 4-
hydroxyphenyl acetate at reflux for about 3 days. a-
Arbutin was obtained in 27% yield after deacetylation.10
In all these methods, the reaction time was long and the
yields were low.
We now describe a synthesis of a-arbutin with high
stereoselectivity involving tetra-O-benzyl-a-D-glucopyr-
anosyl trichloroacetimidate11–13 as glucosyl donor in
reaction with hydroquinone to afford a-arbutin in two
steps and 65% yield (Scheme 1).
As could be seen in Table 1, the selectivity of glycosyl-
ation of 3 was greatly dependent on the catalyst and
reaction temperature. Dichloromethane was selected as
˚
the best solvent after screening. The presence of 4 A
molecular sieves was an important parameter since it
significantly improved the yield of glycosylation, though
it tended to give b-arbutin as a major product (entries 8–
10). Several Lewis acids have been tried for their impact
*
Corresponding author. Tel.: +86 21 64253016; fax: +86 21
64252758; e-mail: mrs_guorongchen@ecust.edu.cn
0008-6215/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2006.04.022

1946
Z.-X. Wang et al. / Carbohydrate Research 341 (2006) 1945–1947
OH
HO
OBn
BnO
OBn
BnO
OBn
O
O
O
HO
HO
BnO
BnO
BnO
BnO
O
iii
i
ii
BnO
BnO
O
O
NH
CCl3
BnO
OH
O
OH
OH
1
2
3
4
Scheme 1. Synthesis of a-arbutin (1). Reagents and conditions: (i) CCl3CN/DBU/CH2Cl2; (ii) hydroquinone, TMSOTf, ꢁ60 ꢁC ! rt; (iii) Pd–C, H2.
Table 1. Glycosylation of 3 and 3b with hydroquinone
Entry
Donor
Catalysts
Temperature (ꢁC)
Time (h)
Yield (%)
Isomer distribution (a:b)
˚
˚
˚
˚
˚
˚
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3
TMSOTf/4 A ms
rt
ꢀ1
ꢀ1
ꢀ1
ꢀ1
ꢀ1
ꢀ1
ꢀ1
ꢀ1
ꢀ1
ꢀ1
ꢀ1
ꢀ1
ꢀ1
ꢀ1
ꢀ3
ꢀ3
ꢀ3
86
83
82
80
81
81
79
86
79
78
85
89
96
86
58
56
23
2:1
1:1
1:2
1:1
4:1
2:3
5:1
1:4
1:4
2:9
3:2
1:1
2:3
2:5
5:1
5:1
1:2
3
TMSOTf/4 A ms
0 to rt
ꢁ20 to rt
ꢁ40 to rt
ꢁ60 to rt
ꢁ80 to rt
ꢁ60 to rt
rt
0 to rt
ꢁ60 to rt
rt
3
TMSOTf/4 A ms
3
TMSOTf/4 A ms
3
TMSOTf/4 A ms
3
TMSOTf/4 A ms
3
TMSOTf
˚
3
4 A ms
˚
3
4 A ms
˚
3
4 A ms
˚
3
BF3ÆEt2O/4 A ms
˚
˚
˚
3
ZnCl2/4 A ms
ZnCl2/4 A ms
ZnCl2/4 A ms
40
rt
3
3
ꢁ30 to rt
ꢁ60 to rt
rt
3b
3b
3b
TMSOTf
BF3ÆEt2O
ZnCl2
rt
on selectivity and yield. TMSOTf, BF3ÆEt2O and ZnCl2
gave good yields, but only TMSOTf gave a good a-selec-
tivity (entries 5 and 7). The best a-selectivity was
achieved using TMSOTf as the catalyst in the absence
of 4 A molecular sieves (entry 7). Low yields were ob-
tained when Lewis acids such as AlCl3, TiCl4, YCl3
and LaCl3 were used as catalysts.
2,3,4,6-Tetra-O-benzyl-b-D-glucopyranosyl trichloro-
acetimidate14 (3b) was also used as donor in reaction
with hydroquinone (entries 15–17), but the reaction pro-
ceeded slowly (ꢀ3 h) and the yields were not so high.
1.2. 4-Hydroxyphenyl 2,3,4,6-tetra-O-benzyl-a-D-gluco-
pyranoside (4)
At ꢁ60 ꢁC, under Ar, a soln of hydroquinone (49.5 mg,
0.45 mmol) and 3 (205.4 mg, 0.30 mmol) in anhyd
CH2Cl2 (15 mL) was treated with TMSOTf (33.3 mg,
0.15 mmol), and the mixture was stirred for 20 min.
The temperature was gradually allowed to rise to room
temperature over a period of 1 h. The reaction was
quenched by the addition of aq saturated NaHCO3
(2 mL) and stirring was continued for ꢀ10 min, and
then saturated aq NaCl was added. The mixture was
extracted with CH2Cl2 (3 · 5 mL), and the organic layer
was dried over anhyd MgSO4. The solvent was evapo-
rated under diminished pressure, and the residue was
chromatographed on a silica gel column (10:1 petroleum
ether–EtOAc) to give 4 (125.1 mg, 66%) and its anomer
4b (24.6 mg, 13%) both as oily materials.
˚
1. Experimental
1.1. General
1
Melting points are uncorrected. H NMR spectra were
20
obtained on a DRX-500 equipment using TMS as inter-
nal standard. IR spectra were recorded on a Nicolet
5SXC equipment with KBr films. ESIMS spectra were
recorded on a HP-5989A spectrometer. Elementary
analyses were done on Elementar Vario EL III. Optical
rotations were measured on a WZZ-1S polarimeter.
Chromatography was performed on silica gel (200–300
Compound 4: ½aꢂD +84.0 (c 1,CHCl3); IR (KBr): m
3350, 2930, 2870, 1450, 1210, 1080 cmꢁ1 1H NMR
;
(500.13 MHz, CDCl3): d 7.25 (m, 20H, 4-Ar), 6.93 (d,
2H, J 8.8 Hz, ArH), 6.68 (d, 2H, J 8.8 Hz, ArH), 5.33
(d, 1H, J 3.4 Hz, 1-H), 5.04 (d, 1H, –CH2), 4.96 (br s,
1H, –OH), 4.89–4.39 (m, 7H, –CH2), 4.18 (dd, 1H, J
9.3 Hz, J 9.3 Hz, 3-H), 3.92–3.55 (m, 5H, H-2,4-6,60);
ESIMS: m/z 632 [M]+, 655 [M+Na]+, 671 [M+K]+,
mesh). TLC was performed on Silica Gel HSGF254
.

Z.-X. Wang et al. / Carbohydrate Research 341 (2006) 1945–1947
1947
1287 [2M+Na]+. Anal. Calcd for C40H40O7: C, 75.95;
References
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20
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;
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1.3. 4-hydroxyphenyl a-D-glucopyranoside (a-arbutin, 1)
A soln of 4 (316 mg, 0.5 mmol) and 10% Pd–C (50 mg)
in EtOAc (5 mL) and EtOH (5 mL) was stirred at room
temperature for 1.5 h under H2. After filtering the cata-
lyst, the filtrate was concentrated to give 1 (133.5 mg,
98%) as white crystals; mp 195–196 ꢁC, lit.8 195.5–
20
196 ꢁC. Rf 0.16 (1:1 EtOAc–Me2CO); ½aꢂD +155.07 (c
1, CHCl3); 1H NMR (500.13 MHz, D2O): d 6.96 (d,
2H, J 8.9 Hz, ArH), 6.77 (d, 2H, J 8.9 Hz, ArH), 5.38
(d, 1H, J 3.7 Hz, 1-H), 3.81–3.37 (m, 6H, H-2,3,4,5,6,60).
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This work was supported by the Natural Science Foun-
dation of China (No. 20576034) and Shanghai Science
and Technology Community. (Grant No. 044307011).