A practical synthesis of 2,3,4,6-Tetra-O-acetyl-1-O-(2-propenyl)-β-D- glucopyranoside using ZnCl2

Article abstract of DOI:10.1021/op0300488

2,3,4,6-Tetra-O-acetyl-1-O-(2-propenyl)-β-D-glucopyranoside (1a), which is a useful raw material in the synthesis of a bioactive agent, has been synthesized in 50% yield by reacting β-D-glucose pentaacetate and 3 mol equiv of an allyl alcohol with 0.9 mol equiv of ZnCl₂ in toluene at 80°C for 2 h followed by recrystallization from diisopropyl ether. This method is suitable for the large-scale preparation of 1a due to its efficiency, safety, and cost-effectiveness.

Full text of DOI:10.1021/op0300488

Organic Process Research & Development 2004, 8, 405−407
A Practical Synthesis of
2,3,4,6-Tetra-O-acetyl-1-O-(2-propenyl)-â-D-glucopyranoside Using ZnCl2
Yoko Yuasa† and Yoshifumi Yuasa*,‡
School of Pharmacy, Tokyo UniVersity of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392,
Japan, and Technical Engineering Department, Takasago International Corporation, 1-5-1 Nishiyawata, Hiratsuka,
Kanagawa 254-0073, Japan
a
Table 1. Results of the allylation of 2 by SnCl4
Abstract:
2,3,4,6-Tetra-O-acetyl-1-O-(2-propenyl)-â-D-glucopyranoside (1a),
which is a useful raw material in the synthesis of a bioactive
ratio of
temp reaction 1a/1b by
isolated
yield
allyl alcoholb
mol equiv
solvent (°C) time (h) HPLC of 1a (%)
agent, has been synthesized in 50% yield by reacting â- -glucose
D
pentaacetate and 3 mol equiv of an allyl alcohol with 0.9 mol
equiv of ZnCl2 in toluene at 80 °C for 2 h followed by
recrystallization from diisopropyl ether. This method is suitable
for the large-scale preparation of 1a due to its efficiency, safety,
and cost-effectiveness.
1
2
1.0
2.0
CH2Cl2 25
toluene 35
2
3
75/25
40/60
32
c
a 1.0 mol equivalent of SnCl4 for 2 (50 mmol) was used. b Mole equivalent
value of allyl alcohol for 2. c 1a was not isolated.
Table 2. Results of the allylation of 2 in various amounts of
a
ZnCl2
Introduction
ratio of
isolated
yield
ZnCl2
temp reaction 1a/1b by
2,3,4,6-Tetra-O-acetyl-1-O-(2-propenyl)-â-D-glucopyra-
noside (1a) is known to be a useful raw material in the
syntheses of a bioactive agent, an irreversible inhibitor of
yeast hexokinase,1 and recently reported, 3-(6-deoxy-6-
sulfoglucopyranosyl)acylglycerol derivatives as immuno-
suppressants.2 Some syntheses of 1a have been reported.
For example, Lee has reported the synthesis of 1a from
2,3,4,6-tetra-O-acetyl-R-D-glucopyranosyl bromide, excess
allyl alcohol, and 1.1 equiv of mercuric cyanide in 74.5%
yield.3 A previous report used a catalytic amount of silver
oxide, instead of mercuric cyanide, with chloroform as the
solvent to produce 1a in 65% yield.4
Furthermore, â-D-glucose pentaacetate (2) in dichlo-
romethane or in refluxing benzne was alkylated by the
various alcohols in the presence of stannic chloride to give
alkyl â-D-glucopyranoside tetraacetates.5,6 Upon the reaction
with an allyl alcohol in the presence of stannic chloride in
dichloromethane, â-D-mannose pentaacetate produced the
corresponding allyl glycosides as a mixture of R-/â-anomers.7
However, these reported methods are considered unsuit-
able due to the toxicity of the reagents and economic and
mol equiv solvent (°C) time (h)
HPLC of 1a (%)
1
2
3
1.0
0.9
0.8
benzene 80
benzene 80
benzene 80
2
2
2
90/10
92/8
90/10
40
45
41
a 3.0 mol equiv of allyl alcohol for 2 (50 mmol) was used.
environmental concerns. Large-scale production is needed
using an efficient, safe, and cost-effective process. We have
studied the allylation of 2, and we now report the practical
synthesis of 1a for a raw material for synthesis of 3-(6-deoxy-
6-sulfoglucopyranosyl)acylglycerol derivatives as immuno-
suppressants.2
Results and Discussion
Initially, we attempted the coupling reaction of â-D-
glucose pentaacetate 2 and allyl alcohol in dichloromethane
with SnCl4, according to the above-described literature.5 The
result was not practically acceptable with regard to the
selectivity of the R/â-anomeric ratio and the isolated yield
(run 1 in Table 1). In the case of changing to toluene as the
solvent, the selectivity and yield were not improved (run 2
in Table 1). We next used ZnCl2 as a Lewis acid, which is
classified as borderline acid8 and easier to handle than SnCl4.
The amount of ZnCl2 in benzene as a solvent has been
investigated, and 0.9 mol equiv of ZnCl2 gave the best result
(run 2 in Table 2). The solvent and reaction temperature were
fixed in benzene at 80 °C, according to a previous report,5a,6
because this reaction did not proceed at temperatures below
50 °C in toluene. Furthermore, the optimal amount of allyl
* To whom correspondence should be addressed. Telephone: 81-463-21-
7516. Fax: 81-463-21-7413. E-mail: yoshifumi_yuasa@takasago.com.
† Tokyo University of Pharmacy and Life Science.
‡ Takasago International Corporation.
(1) Bessell, E. M.; Westwood, J. H. Carbohydr. Res. 1972, 25, 11.
(2) Yamazaki, T.; Sugawara, F.; Ohta, K.; Masaki, K.; Nakamura, K.;
Sakaguchi, K.; Sato, N. WO 0053190, 2000. Chem. Abst. 133, 208124r,
2000.
(3) Lee, R. T.; Lee. Y. C. Carbohydr. Res. 1974, 37, 193.
(4) Talley, E. A.; Vale, M. D.; Yanovsky, E. J. Am. Chem. Soc. 1945, 47,
2037.
(5) (a) Hanessian, S.; Banoub, J. Carbohydr. Res. 1977, 59, 261. (b) Hanessian,
S.; Banoub, J. In Methods in Carbohydrate Chemistry; Whistler, R. L.,
BeMiller, J. N., Eds.; Academic Press: New York, 1980.
(6) Hanessian, S.; Shylux, N. P. Can. J. Chem., 1953, 31, 3543.
(7) RajanBabu, T. V.; Fukunaga, T.; Reddy, G. S. J. Am. Chem. Soc. 1989,
111, 1759.
(8) Ho, T.-L. Hard and Soft Acids and Bases Principle in Organic Chemistry;
Academic Press: New York, 1977.
10.1021/op0300488 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/26/2004
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405

Table 3. Results of the allylation of 2 in various mol equiv
The R-anomer, 1b could be purified by silica gel column
chromatography, and its spectra were obtained (shown in
Experimental Section).
In large-scale production, we have produced 7.55 kg of
1a with 99% purity in 50% yield from 15.0 kg of 2 using
the above-described method without difficulty.
of the allyl alcohola
reaction ratio of
isolated
allyl alcohol
temp time 1a/1b by yield of 1a
mol equiv solvent (°C)
(h)
HPLC
(%)
1
2
3
4
5
6
7
1.1
1.1
2.0
3.0
3.0
3.0
3.0
benzene 80
benzene 80
benzene 80
benzene 80
benzene 80
2
9
2
2
20
2
80/20
68/32
82/18
92/8
59/41
93/7
32
20
40
45
15
47
b
Experimental Section
â-D-Glucose pentaacetate was purchased from Tokyo
Kasei. All reagents and solvents were obtained from com-
mercial sources and used without further purification. For
determining the melting points, a Yanagimoto micro melting
apparatus was used, and the values are uncorrected. The
boiling points are uncorrected values. NMR was run on a
toluene
toluene
80
80
10
46/54
a 0.9 mol equiv of ZnCl2 for 2 (100 mmol) was used. b 1a was not isolated.
1
Bruker DRX-500. The H and 13C NMR were measured at
Scheme 1. Allylation of â-D-glucose pentaacetate 2 using
ZnCl2
500 and 125 MHz, respectively. The NMR spectra were
recorded in CDCl3 with TMS as the internal standard. The
chemical shifts were given in δ (ppm). IR: Nicolet Avatar
360 FT-IR. MS: Hitachi M-80A mass spectrometer at 70
eV. HPLC: Hitachi L-6200; column: Cosmosil 5C-18AR-
II, 4.6 mm × 250 mm; eluent: CH3CN/0.2% aqueous H3-
PO4 (60/40); flow rate: 1.0 mL/min; detector: Hitachi
L-4000 (220 nm). Retention times 1a 9.8 min, 1b 10.2 min.
Scale-Up Procedure for 2,3,4,6-Tetra-O-acetyl-1-O-(2-
propenyl)-â-D-glucopyranoside (1a). In a 200-L glass
vessel, toluene (120 L) was added with stirring, and then
ZnCl2 (5.23 kg, 38.18 mol), â-D-glucose pentaacetate 2 (15.0
kg, 38.43 mol), and the allyl alcohol (6.7 kg, 115.33 mol)
were added. The mixture was heated at 80 °C for 2 h and
immediately cooled to 5 °C. Then water (30 L) was added.
The organic layer was separated and washed with 5% Na2-
CO3 solution (30 L) and 5% NaCl solution (30 L). After the
solvent was removed under reduced pressure, an oily residue
(13.8 kg) was obatined. The residue was dissolved in
diisopropyl ether (60 L) at 50 °C and cooled to 15 °C. The
formed crystalline material was filtered and dried at 40 °C
under reduced pressure (35 Torr) to give 2,3,4,6-tetra-O-
acetyl-1-O-(2-propenyl)-â-D-glucopyranoside (1a) (7.55 kg,
50%) as colourless crystals. Purity was 99% by HPLC. Mp
85-86 °C (lit.1 86 °C, lit.3 88 °C). [R]23D ) -25.0° (c ) 1,
CHCl3) (lit.3 [R]25D ) -25.8° (c ) 5, CHCl3). 1H NMR 2.01
(3H, s, CH3CO2), 2.04 (3H, s, CH3CO2), 2.05 (3H, s, CH3-
CO2), 2.09 (3H, s, CH3CO2), 3.63-3.72 (1H, m, OCH2-
CHd), 4.06-4.14 (1H, m, OCH2CHd), 4.16 (1H, d, J )
2.5 Hz, H-5), 4.26 (1H, dd, J ) 12.3, 4.8 Hz, H-6), 4.35
(1H, dd, J ) 13.2, 4.8 Hz, H-6′), 4.56 (1H, d, J ) 2.5 Hz,
H-1), 5.02 (1H, dd, J ) 9.6, 8.0 Hz, H-3), 5.10 (1H, dd, J
) 9.9, 9.5 Hz, H-4), 5.20-5.23 (2H, m, H-2, CHdCH2),
5.28 (1H, dd, J ) 17.3, 1.7 Hz, CHdCH2), 5.82-5.86 (1H,
m, CHdCH2); 13C NMR 20.56 (CH3), 20.58 (CH3), 20.63
(CH3), 20.70 (CH3), 61.94 (CH2), 68.44 (CH), 69.99 (CH2),
71.28 (CH), 71.77 (CH), 72.85 (CH), 99.55 (CH), 117.62
(CH2), 133.28 (CH), 169.29 (CO), 169.36 (CO), 170.26
(CO), 170.64 (CO); IR (CHCl3) 3020, 2972, 2878, 2401,
1751, 1648 cm-1; SI-MS (m/e): 411 [M + Na]+, 389 [M +
H]+, 331, 307, 289, 271, 243, 229, 211.
alcohol was investigated, and thus 3 mol equiv of allyl
alcohol gave the best result (run 4 in Table 3). Once again,
the solvent was changed to toluene instead of benzene (run
6 in Table 3), because benzene has a higher toxicity than
toluene. Thus, â-D-glucose pentaacetate, 3 mol equiv of allyl
alcohol, and 0.9 mol equiv of ZnCl2 in toluene at 80 °C for
2 h produced 2,3,4,6-tetra-O-acetyl-1-O-(2-propenyl)-â-D-
glucopyranoside (1a) and 2,3,4,6-tetra-O-acetyl-1-O-(2-pro-
penyl)-R-D-glucopyranoside (1b) in a 93/7 ratio by HPLC.
Purification by recrystallization from alcohols was not
successful, but recrystallization from diisopropyl ether gave
1a with 99% purity in 47% isolated yield (shown in
Experimental Section). The rationalization of this reaction
could be explained according to the literature;5a,9 thus, in
the presence of allyl alcohol and ZnCl2, 2 gave the corre-
sponding 1,2-trans-glucoside 1a, presumably via the forma-
tion of a 1,2-orthoesther intermediate, and subsequent
rearrengement (Scheme 1). The extension of reaction times
led to increasing proportions of R-anomer 1b due to
anomerisation (run 7 in Table 3).
2,3,4,6-Tetra-O-acetyl-1-O-(2-propenyl)-r-D-glucopy-
ranoside (1b). A small amount of the mother liquor of
recrystallized 1a was concentrated in a vacuum and purifi-
(9) Banoub, J.; Bundle, D. R. Can. J. Chem. 1979, 57, 2085.
406
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cated by column chromatography (silica gel, eluent: ethyl
acetate/n-hexane ) 1:15) to give 2,3,4,6-tetra-O-acetyl-1-
O-(2-propenyl)-R-D-glucopyranoside (1b). Purity was 98%
by HPLC. Mp 51-54 °C (lit.1 55-56 °C). [R]23D ) +131.8°
(c ) 1.1, CHCl3) (lit.1 [R]30D ) +141° (c ) 1, CHCl3)). 1H
NMR 2.01 (3H, s, CH3CO2), 2.03 (3H, s, CH3CO2), 2.07
(3H, s, CH3CO2), 2.09 (3H, s, CH3CO2), 3.99-4.11 (3H,
m, H-6, OCH2CHd), 4.16-4.22 (1H, m, H-5), 4.27 (1H,
dd, J ) 12.3, 4.5 Hz, H-6′), 4.90 (1H, dd, J ) 10.3, 3.7 Hz,
H-2), 5.07 (1H, dd, J ) 10.1, 9.7 Hz, H-3), 5.11 (1H, d, J
) 3.7 Hz, H-1), 5.23 (1H, dd, J ) 10.4, 1.4 Hz, CHdCH2),
5.32 (1H, dd, J ) 16.4, 1.6 Hz, CHdCH2), 5.51 (1H, dd, J
) 10, 9.7 Hz, H-4), 5.82-5.92 (1H, m, CHdCH2); 13C NMR
20.51 (CH3), 20.57 (CH3), 20.58 (CH3), 20.61 (CH3), 61.80
(CH2), 67.28 (CH), 68.49 (CH), 68.71 (CH2), 70.08 (CH),
70.66 (CH), 94.77 (CH), 118.05 (CH2), 133.02 (CH), 169.50
(CO), 169.97 (CO), 170.01 (CO), 170.52 (CO); IR (CHCl3)
3023, 2970, 2401, 2877, 1741, 1647 cm-1; SI-MS (m/e): 411
[M + Na]+, 389 [M + H]+, 331, 307, 289, 271, 243, 229,
211.
Received for review November 12, 2003.
OP0300488
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