An efficient synthesis of methyl 1,3-O-isopropylidene-α-D- fructofuranoside and 2,3:5,6-di-O-isopropylidene-D-glucose dimethyl acetal derivatives from sucrose

Article abstract of DOI:10.1016/j.carres.2005.07.023

Acetalation of sucrose with 2,2-dimethoxypropane in 1,4-dioxane in the presence of p-toluenesulfonic acid, followed by acetylation, afforded methyl 4,6-di-O-acetyl-1,3-O-isopropylidene-α-d-fructofuranoside and 4-O-acetyl-2,3:5,6-di-O-isopropylidene-d-gluc

Full text of DOI:10.1016/j.carres.2005.07.023

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 2494–2501
An efficient synthesis of methyl 1,3-O-isopropylidene-a-D-
fructofuranoside and 2,3:5,6-di-O-isopropylidene-D-glucose
dimethyl acetal derivatives from sucrose
Tadashi Hanaya,* Nobuaki Sato and Hiroshi Yamamoto
Department of Chemistry, Faculty of Science, Okayama University, Tsushima, Okayama 700-8530, Japan
Received 24 March 2005; accepted 20 July 2005
Available online 5 October 2005
Abstract—Acetalation of sucrose with 2,2-dimethoxypropane in 1,4-dioxane in the presence of p-toluenesulfonic acid, followed by
acetylation, afforded methyl 4,6-di-O-acetyl-1,3-O-isopropylidene-a-D-fructofuranoside and 4-O-acetyl-2,3:5,6-di-O-isopropylidene-
D-glucose dimethyl acetal as major products, while tosylation of the intermediate acetals provided methyl 6-O-tosyl-1,3-O-isoprop-
ylidene-a-D-fructofuranose.
Ó 2005 Elsevier Ltd. All rights reserved.
Keywords: Acetalation of sucrose; D-Fructofuranoside; D-Glucose dimethyl acetal; Isopropylidene acetal
1. Introduction
6-deoxy-6-phosphinoyl-D-fructoses.8,11,12 Although these
6-C-substituted derivatives have attracted considerable
interest as precursors for imino-,8 thio-,9,13 and phos-
pho-sugar analogs11,12 of D-fructopyranose, most of
them have been prepared by the use of enzymatic proce-
dures with D-fructose 1,6-diphosphate aldolase7–9 so far,
because of the lack of efficient chemical procedures for
the suitable starting materials.
Acetonation (isopropylidenation) is the most widely used
reaction for the initial step of carbohydrate derivatiza-
tion and many methods are known to accomplish this
reaction.1 Acetal exchange using 2,2-dimethoxypro-
pane2,3 or 2-methoxypropene4,5 in the presence of acid
catalyst is frequently used for introducing an isopropylid-
ene group, and affords different products from those by
the direct acetalation using acetone. For example, acetal
exchange of D-fructose with 2,2-dimethoxypropane
and 2-methoxypropene provides 1,2-O-isopropylidene-
b- (1)3 and 1,3-O-isopropylidene-a-D-fructofuranose (2),5
respectively, whereas acetalation of D-fructose with
acetone affords 1,2:4,5- and 2,3:4,5-di-O-isopropylid-
ene-b-D-fructopyranoses.6 Among these acetals, the D-
fructofuranoses, whose primary hydroxy group at C-1
and an anomeric hydroxy group are protected, can be
perceived as starting materials for the synthesis of
D-fructose derivatives substituted at C-6: such as 6-
deoxy-6-azido-,7,8 6-deoxy-6-amino-,8 6-thio-,9,10 and
HO
HO
O
HO
O
O
O
O
O
HO
O
O
O
OH
OMe
HO
HO
HO
1
2
3
As for D-fructofuranoses, the formation of 1 proceeds
in a low yield (28% as the corresponding triacetate) and
2 is needed further glycosidation for protection of the
12
anomeric OHgroup.
Meanwhile, Richardson and
co-workers obtained the diacetate of methyl 1,3-O-
isopropylidene-a-D-fructofuranoside (3) in 36% yield
from sucrose by the use of 2,2-dimethoxypropane and
p-toluenesulfonic acid in DMF followed by acetylation,
*
Corresponding author. Fax: +81 86 251 7853; e-mail: hanaya@
cc.okayama-u.ac.jp
0008-6215/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2005.07.023

T. Hanaya et al. / Carbohydrate Research 340 (2005) 2494–2501
2495
Table 1. Acetalation and subsequent acetylation of sucrose, D-glucose, and D-fructose
Entry Substrate Reaction condition of acetalationa Yields (%) of D-glucose derivatives
Yields (%) of D-fructose derivatives
14 (36)
1b
2
Sucrose
Sucrose
DMF, rt, 36 h
1,4-Dioxane, 80 °C, 2 h
4a (6.0), 7 (12.5), 9 (9.1), 11a,b (16)
4a (5.0), 4b (1.3), 5 (9.8), 6 (49), 7 (4.8), 8 (0.7), 14 (68)
9 (2.1), 10a (3.5), 10b (2.9), 12 (1.7), 13a (0.7)
4a (6.5), 4b (1.3), 5 (16), 6 (44), 7 (8.0), 8 (0.6), 14 (54)
9 (1.0), 10a (4.7), 10b (4.0), 12 (2.2), 13a (0.8)
4a (8.1), 4b (4.9), 5 (6.9), 6 (41), 7 (17), 8 (2.0),
9 (3.4), 12 (0.7), 13a (1.2), 13b (3.6)
3
4
5
Sucrose
DME, 80 °C, 4 h
D-Glucose 1,4-Dioxane, 80 °C, 2 h
D-Fructose 1,4-Dioxane, 80 °C, 2 h
14 (6.9), 15a,b (10), 16 (5.7),
17 (2.9), 18 (36), 19 (2.4), 20 (4.8)
a Catalytic amount of TsOH(0.3–0.4% w/v, 0.15 equiv) was used.
b Ref. 14.
together with D-glucose acetals (Table 1, entry 1).14 As
this compound was perceived as the most suitable for
our purposes, we attempted to modify the reaction con-
ditions to give 3 in satisfactory yield. We now describe
an improved procedure for compound 3 by treatment
of sucrose with 2,2-dimethoxypropane in 1,4-dioxane
solution (Scheme 1).
2. Results and discussion
Treatment of sucrose with 2,2-dimethoxypropane and p-
toluenesulfonic acid in 1,4-dioxane at 80 °C for 2 h
afforded a mixture of D-glucose and D-fructose deriva-
tives (Table 1, entry 2). These products were separated,
after having been converted into the corresponding
R2
R1
MeO
O
OMe
OAc
MeO
O
OMe
O
O
O
O
1) Me2C(OMe)2
TsOH
O
O
OAc
O
+
+
+
sucrose
or
O
O
O
O
O
O
OAc
O
O
2) Ac2O
pyridine
O
D-glucose
O
4a R1 = OMe, R2 = H
4b R1 = H, R2 = OMe
5
6
7
AcO
O
R2
R1
O
O
R2
O
O
O
O
OAc
O
AcO
O
OAc
O
O
O
+
+
+
+
+
R1
OAc
O
O
O
O
O
O
OMe
O
O
O
AcO
14
8
9
10a R1 = OMe, R2 = H
10b R1 = H, R2 = OMe
11a R1 = OAc, R2 = H
11b R1 = H, R2 = OAc
12 R1 = OMe, R2 = H
13a R1 = OAc, R2 = H
13b R1 = H, R2 = OAc
O
O
OAc
O
MeO
1) Me2C(OMe)2
TsOH
O
AcO
O
O
O
O
D-fructose
+
+
O
O
O
O
O
O
2) Ac2O
pyridine
OMe
AcO
14
15a,b
16
OMe
O
O
O
O
O
O
O
O
O
O
AcO
O
AcO
+
+
+
+
O
O
O
O
O
OAc
O
O
O
O
17
18
19
20
Scheme 1.

2496
T. Hanaya et al. / Carbohydrate Research 340 (2005) 2494–2501
acetates by treatment with acetic anhydride–pyridine.
By purification on a silica gel column, the crude prod-
ucts were separated into six fractions A–F, according
to the order of elution. The structures and the ratios
of all components in each fraction were determined on
fructofuranose (17) (2.9%), 1-O-acetyl-2,3:4;5-di-O-iso-
propylidene-b-D-fructopyranose (19)20 (2.4%), and
methyl 1,3:4,5-di-O-isopropylidene-b-D-fructopyrano-
side (20) (4.8%). As acyclic D-fructose derivatives,
(2R)- and (2S)-1,2:3,4:5,6-tri-O-isopropylidene-2-meth-
oxy-D-glucitol (15a,b) (10%) and 1-O-acetyl-3,4:5,6-di-
O-isopropylidene-D-fructose (16) (5.7%) were obtained.
These results support the mechanism proposed by
Richardson and co-workers,14 namely, that acetalation
of primary hydroxy groups of sucrose with 2,2-dimeth-
oxypropane takes place at first to afford the 1,10,60-tri-
O-(1-methoxy-1-methylethyl) derivative. Next, the
cleavage of the linkage between D-glucose and D-fruc-
tose brings about the formation of the fructofuranosyl
oxycarbonium ion, which gives rise to the D-fructofur-
anoside (3) by the formation of the 1,3-O-isopropylidene
acetal and addition of a methoxy group to C-2. The 6-O-
(1-methoxy-1-methylethyl) group of D-fructose cleaves
without cyclization, but that of D-glucose effectively af-
fords the 5,6-O-isopropylidene derivatives (precursors of
compounds 4–7). It is noteworthy that the ratio of acy-
clic D-glucose derivatives (4–6) to furanoses and pyra-
noses is very high in entries 2 and 3. Such a tendency
has been observed in acetalation of D-xylose and 2-acet-
amido-2-deoxy-D-glucose with 2,2-dimethoxypropane in
dioxane.22
1
the basis of their 600 MHz HNMR spectra (see later).
From the first-eluting fraction A, (1S)-1,2:3,4:5,6-tri-
O-isopropylidene-1-methoxy-D-glucitol (4a)14,15 was ob-
tained in 5.0% yield (from sucrose), whereas methyl
2,3;4,5-di-O-isopropylidene-a-D-glucoseptanoside (12)16
was obtained in 1.7% yield from the next fraction (B).
The third fraction (C) gave an inseparable mixture of
(1R)-1,2:3,4:5,6-tri-O-isopropylidene-1-methoxy-D-gluc-
itol (4b)15 (1.3%), 6-O-acetyl-1,2:3,5-di-O-isopropylid-
ene-a-D-glucofuranose (8)16,17 (0.7%), and 1-O-acetyl-
2,3:4,5-di-O-isopropylidene-a-D-glucoseptanose (13a)17
(0.7%).
The fourth fraction (D) gave an inseparable mixture
of 2-O-acetyl-3,4:5,6-di-O-isopropylidene-D-glucose di-
methyl acetal (5) (9.8%), 3-O-acetyl-1,2:5,6-di-O-iso-
propylidene-a-D-glucofuranose (7)14,18 (4.8%), and
3-O-acetyl-1,2:4,6-di-O-isopropylidene-a-D-glucopyranose
(9)14 (2.1%).
The next fraction (E) gave 4-O-acetyl-2,3:5,6-di-O-iso-
propylidene-D-glucose dimethyl acetal (6) in 49% yield,
together with methyl 2,3-di-O-acetyl-4,6-O-isopropylid-
ene-a-D-glucopyranoside (10a)19 (3.5%) and its
b
The precise 1HNMR parameters for D-glucose and D-
fructose acetals 4–10, 12–20 are summarized in Tables 2
and 3. Since compounds 5, 6, 15, 16, 17, and 20 were
obtained for the first time in the present study, structural
assignments of them are discussed here in detail.
The NMR spectra of D-glucose acetals 5 and 6 re-
vealed the presence of two methoxy groups, two isoprop-
ylidene groups, and one acetyl group. The lowest-field
resonance of 5 was the H-2 signal (dd) at d 5.15 and that
of 6 was the H-4 signal (dd) at d 5.21. These data for 5
and 6 were consistent with the structures for 2-O-acetyl-
3,4:5,6-di-O-isopropylidene-D-glucose dimethyl acetal
and its 4-O-acetyl-2,3:5,6-di-O-isopropylidene analog,
respectively.
anomer (10b)19 (2.9%). No 1,2,3-tri-O-acetyl-4,6-O-isopro-
pylidene-a,b-D-glucopyranoses (11a,b)14 given in entry 1
were detected in this fraction. Compound 6 was isolated
by further column chromatography of this fraction.
From the slowest-eluting fraction (F), the desired
methyl 4,6-di-O-acetyl-1,3-O-isopropylidene-a-D-fructo-
furanoside (14)14 was obtained in 68% yield, and it was a
major product as well as the sole D-fructose derivative of
this reaction.
The acetalation of sucrose by the use of 1,2-dimeth-
oxyethane (DME) as a solvent required a longer reac-
tion time as compared with 1,4-dioxane (entry 3). The
resulting components are similar to those of entry 2,
with a slightly lower yield of 14.
We examined the acetalation and subsequent acetyla-
tion of both D-glucose and D-fructose under the same
conditions as those of entry 2. The conversion of D-glu-
cose resulted in the similar formation of D-glucose deriv-
atives with those from sucrose, except for the formation
of 1-O-acetyl-2,3:4,5-di-O-isopropylidene-b-D-glucosep-
tanose (13b)16 and the absence of methyl D-glucopyr-
anosides (10a,b) (entry 4).
On the other hand, the conversion of D-fructose affor-
ded the methyl furanoside (14) as a minor component
(in 6.9% yield), together with a number of other
products. As for the cyclic D-fructose derivatives, 3-O-
acetyl-1,2:4;5-di-O-isopropylidene-b-D-fructopyranose
(18)20,21 was obtained as a major product (36% yield),
along with 3-O-acetyl-1,2:4;6-di-O-isopropylidene-b-D-
The NMR spectrum of an inseparable mixture of D-
fructose acetals 15a,b indicated a set of C-2 epimers
for tri-O-isopropylidene monomethyl acetal. The values
0
0
(8.3–9.7 Hz) of the geminal couplings J1,1 and J6,6 for
15a,b suggested that each of their C-1 and C-6 was in-
2
cluded in a dioxolane ring (namely, JCH ¼ 8:3–9:3 H z
2
in the dioxolane ring of 4–7 and 18 versus
2JCH ¼ 10:8–12:2 Hz in the dioxane ring of 9, 10, and
2
14). These facts show that 15a,b have the structure of
1,2:3,4:5,6-tri-O-isopropylidene-D-fructose monomethyl
The data for the reported compounds (4, 7–10, 12–14, 18, and 19) are
also listed, because no complete assignments for 4, 8, 13, 14, 18, and
19 were available in the previous reports14–17,20 or the measurement
for 7, 9, 10, and 12 was done in different solvents (benzene-d6 or
acetone-d6).14,16,19

T. Hanaya et al. / Carbohydrate Research 340 (2005) 2494–2501
Table 2. 1HNMR parameters for D-glucose derivatives (4–13) in CDCl3
2497
Compound
Chemical shifts/d
H-1
H-2
H-3
H-4
H-5
H-6
H0-6
MeO
AcO
Me2C
4a
4b
5
5.09
4.97
4.52
4.34
5.99
5.86
5.52
4.87
4.43
4.88
6.29
5.76
4.15
4.02
5.15
3.83
4.57
4.48
4.04
4.84
4.91
3.64
3.76
3.77
4.06
4.11
4.26
4.20
4.22
5.23
5.08
5.37
5.11
4.48
4.485
4.14
3.93
3.83
3.64
5.21
4.32
4.185
3.695
3.67
3.71
4.32a
4.37
4.25
4.06
4.12
4.05
4.27
3.76
4.20
3.81
3.725
3.33
4.28
4.31
4.25
4.12
4.08
4.10
3.99
4.29
4.06
3.95
3.89
3.95
3.73
3.76
4.01
3.95
3.96
3.92
3.90
4.15
4.00
3.69
3.74
3.78
3.41a
3.51
3.80
3.41
3.34
3.42, 3.33
3.415, 3.41
—
—
—
3.37
3.48
3.45
—
—
—
2.11
2.12
2.08
2.09
2.10
2.06, 2.035
2.04, 2.03
—
2.16
2.14
1.48, 1.475, 1.42, 1.41, 1.38, 1.33
1.53, 1.44, 1.42, 1.415, 1.41, 1.36
1.40, 1.39, 1.37, 1.31
1.41, 1.39, 1.38, 1.34
1.49, 1.37, 1.35, 1.32
1.50, 1.39, 1.31, 1.29
1.57, 1.455, 1.37, 1.34
1.46, 1.37
6
7
8
9
10a
10b
12
13a
13b
1.46, 1.37
1.46, 1.45, 1.44, 1.36
1.47, 1.45, 1.41, 1.35
1.52, 1.44, 1.42, 1.36
—
Coupling constants/Hz
0
0
J6,6
J1,2
J2,3
J3,4
J4,5
J5,6
J5,6
4a
4b
5
3.2
3.4
7.8
6.1
3.7
3.7
4.6
3.7
7.8
2.7
2.7
7.6
3.9
8.3
2.0
7.6
0
7.3
7.6
7.3
2.0
2.7
3.9
8.6
9.3
9.5
7.6
7.8
8.1
8.5
6.6
7.8
5.9
8.1
7.3
9.9
9.7
9.5
7.3
7.8
—
6.1
6.3
6.4
6.3
5.6
3.2
5.4
5.6
5.4
10.5
10.8
2.7
4.9
6.6
4.9
5.9
4.6
8.6
8.3
8.6
8.8
8.5
12.0
10.8
11.0
11.0
12.8
13.2
13.9
6
7
8
0
6.9
9
4.2
9.8
9.3
9.8
9.8
9.8
10.2
10.2
10.2
3.7
3.4
5.4
10a
10b
12
13a
13b
a
0
J4,6 1.0 Hz.
Table 3. 1HNMR parameters for D-fructose derivatives (14–19) in CDCl3
Compound
Chemical shifts/d
H-1
H0-1
H-3
H-4
H-5
H-6
H0-6
MeO-2
AcO
Me2C
14
3.91
4.105
4.13
5.05
4.00
3.94
4.41
3.93
3.89
3.98
4.04
4.92
3.95
3.83
4.18
3.60
4.07
4.01
4.07
4.46
5.31
5.11
4.30
3.88
4.86
4.18
4.10
4.25
4.05
4.28
4.60
4.27
4.15
4.26
4.275
4.19
4.33
4.22
4.23
4.29
4.42
4.035
4.045
4.10
4.00
4.13
3.90
4.01
4.27
3.98
3.99
3.96
3.88
4.09
3.76
3.90
3.29
3.385b
3.36b
—
—
—
2.095, 2.09
—
—
2.16
2.13
2.13
2.10
—
1.38, 1.43
15aa
15ba
16
1.56, 1.435, 1.425, 1.41, 1.40, 1.36c
1.54, 1.435, 1.43, 1.40, 1.39, 1.355c
1.46, 1.42, 1.39, 1.34
17
18
1.54, 1.48, 1.36, 1.34
1.55, 1.48, 1.39, 1.35
1.54, 1.48, 1.40, 1.34
1.55, 1.52, 1.49, 1.36
19
20
—
3.31
Coupling constants/Hz
0
0
0
J6,6
J1,1
J3,4
J4,5
J5,6
J5,6
14
12.2
9.7
9.5
17.8
9.0
9.3
0.7
6.8
6.6
5.9
6.6
8.1
2.7
7.8
3.9
5.4
4.9
6.6
6.0
5.4
7.8
5.6
3.9
6.6
6.4
6.3
7.1
2.7
2.0
1.3
6.6
6.8
6.4
5.1
5.9
0.7
0.7
3.2
11.7
8.3
8.3
15a
15b
16
8.8
17
18
12.5
13.4
12.9
13.2
19
20
11.7
12.7
a C-2 epimers: the correlation of coupled protons was confirmed by 2D-COSY measurements.
b ,c
The assignment of methoxy and isopropylidene signals may be interchanged.
acetal, although the anomeric configurations of them are
still ambiguous.
The NMR spectra of D-fructose derivatives 16 and 17
indicated the presence of two isopropylidene groups and

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T. Hanaya et al. / Carbohydrate Research 340 (2005) 2494–2501
one acetyl group. The acyclic structure having 1-O-ace-
tyl-3,4:5,6-di-O-isopropylidene unit for 16 was derived
from the appearance of H2-1 signals at a lower field (d
which is an important precursor for introducing vari-
ous substituents at C-6. Thus, treatment of 3 with
1.2 equiv of tosyl chloride in pyridine afforded 22
(84%) together with a small amount of the 4,6-di-O-
tosyl compound (23) (5%). As an alternative route for
preparation of 22, acetalation of sucrose, followed by
direct tosylation was attempted. The mixture obtained
by using the same conditions of acetalation as used in
entry 2 in Table 1 was treated with 1.0 equiv of tosyl
chloride to give 22 (48% from sucrose). The D-glucose
acetals were difficult to tosylate owing to the absence
of free primary hydroxy groups. The monotosylate 22
was easily separated from the mixture of D-glucose
derivatives by column chromatography. The use of an
excess (1.5 equiv) of tosyl chloride resulted in the for-
mation of ditosylate 23 (13%) and a lower yield of 22
(39%).
In conclusion, we have developed an efficient proce-
dure for the preparation of methyl 1,3-O-isopropylid-
ene-a-D-fructofuranoside and 2,3:5,6-di-O-isopropyl-
idene-D-glucose dimethyl acetal from sucrose. The
former is readily isolated as 6-O-tosylate, which is a
potentially useful precursor for 6-C-substituted D-fruc-
tose derivatives.
0
5.05 and 4.92) and the magnitude of the J6,6 value
(8.8 Hz), whereas the furanose structure having 3-O-ace-
tyl-1,2:4,6-di-O-isopropylidene unit for 17 was assigned
from the appearance of the H-3 signal at a lower field
0
(d 5.31), and the magnitude of the J1,1 (9.0 Hz) and
0
J6,6 values (12.5 Hz).
The NMR spectrum of the D-fructose derivative 20
indicated the presence of two isopropylidene groups
0
and one methyl group. The magnitude of J1,1 value
(12.7 Hz) suggested a six-membered isopropylidene ring,
whereas the resemblance of other coupling constants of
20 with those of 18 suggested the pyranose structure
2
having the C5 conformation. The anomeric configura-
tion of 20 is likely to be beta, based on the nature of
the fused-ring system and anomeric effect, thus indicat-
ing that compound 20 is methyl 1,3:4,5-di-O-isopropyl-
idene-b-D-fructopyranoside.
Two major products 14 (68% yield from sucrose) and
6 (49%) of the present work were, respectively, con-
verted into de-O-acetylated compounds 314 and 2115,23
by treatment with sodium methoxide in methanol in al-
most quantitative yield (Scheme 2). The D-glucose acetal
(21) fully protected except for 4-OHis also an important
substrate, similar to 3, for conversion into various
compounds. No convenient synthesis of 21 has been
reported, to the best of our knowledge, although the
4-O-benzoyl derivative of 21 was prepared by Curtis
and Jones (ꢀ40% yield from D-glucose dimethyl dithio-
acetal)23 and Stevens (34% yield from D-glucose).15b
As an extension of this work, the D-fructofuranoside
(3) was converted into the 6-O-tosyl derivative (22),
3. Experimental
3.1. General methods
All reactions were monitored by TLC (Merck silica gel
60F, 0.25 mm) with an appropriate solvent system [(A)
1:3, (B) 1:1 EtOAc–hexane, and (C) EtOAc]. Column
chromatography was performed on Katayama Silica
Gel 60K070. The components were detected by exposing
the plates to UV light and/or spraying them with 20%
H2SO4–EtOH(with subsequent heating). Optical rota-
tions were measured with a JASCO P-1020 polarimeter
in CHCl3. The 1HNMR spectra were measured in
CDCl3 with Varian Unity Inova AS600 (600 MHz) at
23 °C. Chemical shifts are reported as d values relative
to CHCl3 (7.26 ppm) as an internal standard.
MeO
O
OMe
O
NaOMe
MeOH
6
OH
O
O
21
3.2. Acetalation and subsequent acetylation of sucrose
O
HO
O
O
NaOMe
MeOH
14
To a solution of sucrose (500 mg, 1.46 mmol) in dry 1,4-
dioxane (10 mL) were added 2,2-dimethoxypropane
(2.5 mL, 20 mmol) and p-toluenesulfonic acid monohy-
drate (40 mg, 0.21 mmol). The mixture was stirred at
80 °C for 2 h, neutralized with pyridine at rt, and then
concentrated in vacuo. The residue was dissolved in
dry pyridine (7.5 mL) and acetic anhydride (2.5 mL,
26 mmol) was added at 0 °C. The mixture was stirred
at rt for 12 h, diluted with a small amount of cold water,
and then concentrated in vacuo. The residue was dis-
solved in CHCl3, washed with water, dried (Na2SO4),
OMe
TsCl
pyridine
HO
3
O
O
TsO
O
1) Me2C(OMe)2
TsOH, 1,4-dioxane
sucrose
OMe
RO
2) TsCl
pyridine
22 R = H
23 R = Ts
Scheme 2.

T. Hanaya et al. / Carbohydrate Research 340 (2005) 2494–2501
2499
and evaporated in vacuo. The residue was separated by
column chromatography with a gradient eluent of 1:7–
1:3 EtOAc–hexane into six fractions, A–F.
Fraction D [Rf 0.35–0.32 (A)] gave an inseparable
mixture of 5 (66.6 mg, 6.9%), 7 (143 mg, 17%), and 9
(28.5 mg, 3.4%).
Fraction A [Rf 0.58 (A)] gave (1S)-1,2:3,4:5,6-tri-O-
isopropylidene-1-methoxy-D-glucitol (4a)14,15 (24.3 mg,
5.0% from sucrose) as a colorless syrup: HNMR, see
Fraction E [Rf 0.28 (A)] gave 4-O-acetyl-2,3:5,6-di-O-
isopropylidene-D-glucose dimethyl acetal (6) (398 mg,
41%) as a colorless syrup.
1
Table 2.
Fraction F [Rf 0.22 (A)] gave 1-O-acetyl-2,3:4,5-di-O-
isopropylidene-b-D-glucoseptanose (13b)16 (30.0 mg,
3.6%) as colorless prisms: mp 98–99 °C (lit.16 mp 99–
Fraction B [Rf 0.45 (A)] gave methyl 2,3:4,6-di-O-iso-
propylidene-a-D-glucoseptanoside (12)16 (6.7 mg, 1.7%)
as a colorless syrup (lit.16 mp 64–65 °C): HNMR, see
100 °C); HNMR, see Table 2.
1
1
Table 2.
Fraction C [Rf 0.40 (A)] gave a colorless syrup, which
consisted of (1R)-1,2:3,4:5,6-tri-O-isopropylidene-1-
methoxy-D-glucitol (4b)15 (6.5 mg, 1.3%), 6-O-acetyl-
1,2:3,5-di-O-isopropylidene-a-D-glucofuranose (8)16,17
(2.9 mg, 0.7%), and 1-O-acetyl-2,3:4,5-di-O-isopropylid-
ene-a-D-glucoseptanose (13a)16 (2.9 mg, 0.7%), the ratio
3.4. Acetalation and subsequent acetylation of D-fructose
By use of the same procedures already described, D-fruc-
tose (500 mg, 2.78 mmol) was treated with 2,2-dimeth-
oxypropane (2.5 mL) and p-toluenesulfonic acid
monohydrate (40 mg) and then acetylated. The products
were separated by column chromatography into five
fractions, A–E.
Fraction A [Rf 0.53 (A)] gave an inseparable mixture
(1:1) of (2R)- and (2S)-1,2:3,4:5,6-tri-O-isopropylidene-
2-methoxy-D-arabino-hexitols (15a,b) (92.3 mg, 10%
from D-fructose) as a colorless syrup: 1HNMR, see
Table 3.
1
being estimated by HNMR: 1HNMR, see Table 2.
Fraction D [Rf 0.35–0.32 (A)] gave a colorless syrup,
which consisted of 2-O-acetyl-3,4:5,6-di-O-isopropylid-
ene-D-glucose dimethyl acetal (5) (49.6 mg, 9.8%), 3-
O-acetyl-1,2:5,6-di-O-isopropylidene-a-D-glucofuranose
(7)14,18 (21.1 mg, 4.8%), and 3-O-acetyl-1,2:4,6-di-O-iso-
propylidene-a-D-glucopyranose (9)14 (9.2 mg, 2.1%),
1
the ratio being estimated by HNMR: 1HNMR, see
Fraction B [Rf 0.42 (A)] gave 3-O-acetyl-1,2:4,5-di-O-
isopropylidene-b-D-fructopyranose (18)20,21 (301 mg,
36%) as colorless needles: mp 76–77 °C (lit.21 mp 76–
Table 2.
Fraction E [Rf 0.28–0.25 (A)] gave a colorless syrup,
which consisted of 4-O-acetyl-2,3:5,6-di-O-isopropylid-
ene-D-glucose dimethyl acetal (6) (247 mg, 49%), methyl
2,3-di-O-acetyl-4,6-O-isopropylidene-a-D-glucopyrano-
side (10a)19 (16.3 mg, 3.5%), and its b-D-glucopyrano-
side (10b)19 (13.4 mg, 2.9%), the ratio being estimated
by 1HNMR: 1HNMR, see Table 2. Rechromatography
1
77 °C); HNMR, see Table 3.
Fraction C [Rf 0.35 (A)] gave a colorless syrup, which
consisted of 1-O-acetyl-3,4:5,6-di-O-isopropylidene-D-
fructose (16) (48.0 mg, 5.7%) and 1-O-acetyl-2,3:4,5-
di-O-isopropylidene-b-D-fructopyranose (19)20 (20.2 mg,
2.4%), the ratio being estimated by 1HNMR: 1H
NMR, see Table 3.
21
of this fraction afforded 6 as a colorless syrup: ½aꢁD
+2.28 (c 1.62). Anal. Calcd for C16H28O8: C, 55.16; H,
8.10. Found: C, 55.09; H, 8.16.
Fraction D [Rf 0.26 (A)] gave a colorless syrup, which
consisted of 3-O-acetyl-1,2:4,6-di-O-isopropylidene-b-D-
fructofuranose (17) (24.5 mg, 2.9%) and methyl 1,3:4,5-
di-O-isopropylidene-b-D-fructopyranoside (20) (36.4 mg,
4.8%), the ratio being estimated by 1HNMR: 1HNMR,
see Table 3.
Fraction F [Rf 0.16 (A)] gave methyl 4,6-di-O-acetyl-
1,3-O-isopropylidene-a-D-fructofuranoside (14)14 (316
17
mg, 68%) as a colorless syrup: ½aꢁD +29.6 (c 1.02)
20
1
[lit.14 ½aꢁD +35.5 (c 1, CHCl3)]; HNMR, see Table 3.
Fraction E [Rf 0.16 (A)] gave 14 (60.9 mg, 6.9%) as a
colorless syrup.
3.3. Acetalation and subsequent acetylation of D-glucose
By use of the same procedures just described, D-glucose
(500 mg, 2.78 mmol) was treated with 2,2-dimethoxy-
propane (2.5 mL) and p-toluenesulfonic acid monohy-
drate (40 mg) and then acetylated. The products were
separated by column chromatography into six fractions,
A–F.
Fraction A [Rf 0.58 (A)] gave 4a (74.4 mg, 8.1% from
D-glucose) as a colorless syrup.
Fraction B [Rf 0.45 (A)] gave 12 (5.2 mg, 0.7%) as a
colorless syrup.
3.5. Methyl 1,3-O-isopropylidene-a-D-fructofuranoside
(3)14
To a solution of 14 (231 mg, 0.276 mmol) in dry MeOH
(5.0 mL) was added, with stirring, a 28% methanolic
solution of NaOMe (0.03 mL, 0.15 mmol) at 0 °C. After
having been stirred at rt for 1 h, the mixture was neutral-
ized with Amberlite IR-120(H+). The resin was filtered
off and washed with MeOH. The filtrate was evaporated
in vacuo and the residue was purified by column chro-
matography to give 3 (167 mg, 98%) as a colorless syrup:
Fraction C [Rf 0.40 (A)] gave an inseparable mixture
of 4b (45.6 mg, 4.6%), 8 (17.1 mg, 2.0%), and 13a
(10.0 mg, 1.2%).
20
20
½aꢁD +41.9 (c 1.11) [lit.14 92% yield, ½aꢁD +42.5 (c 1,

2500
T. Hanaya et al. / Carbohydrate Research 340 (2005) 2494–2501
1
MeOH)]; Rf 0.07 (B), 0.32 (C); HNMR: d 1.39, 1.48
dimethoxypropane (2.5 mL, 20 mmol) and p-toluene-
sulfonic acid monohydrate (40 mg, 0.21 mmol). The
mixture was stirred at 80 °C for 2 h. The mixture
was neutralized with pyridine at rt and concentrated
in vacuo. The residue was treated with tosyl chloride
(278 mg, 1.46 mmol) and dry pyridine (7.5 mL) with
the procedures already described. The products were
separated by column chromatography with a gradient
eluent of 1:3–1:1 EtOAc–hexane. After elution of the
fractions [Rf 0.58–0.10 (A), 0.84–0.46 (B)], which con-
sisted of D-glucose acetals (380 mg), the slowest-eluting
fraction [Rf 0.32 (B)] gave 22 (274 mg, 48%) as a color-
less syrup.
(3Heach, 2s, CMe 2), 2.35 (2H, br s, HO-4,6), 3.33
0
0
(3H, s, MeO-2), 3.80 (1H, dd, J6,6 11.7, J5,6 5.4 Hz,
H0-6), 3.86 (1H, dd, J5,6 3.2 Hz, H-6), 3.93 (1H, d, J1,1
0
12.2 Hz, H,H0-1), 3.99 (1H, dd, J4,5 2.5, J3,4 0.5 Hz, H-
4), 4.05 (1H, d, H-3), 4.16 (1H, ddd, H-5).
3.6. 2,3:5,6-Di-O-isopropylidene-D-glucose dimethyl
acetal (21)15
By use of the same procedures already described, com-
pound 6 (98.6 mg) was treated with NaOMe to give 21
20
(83.3 mg, 96%) as a colorless syrup: ½aꢁD ꢂ8.17 (c 2.16)
22
[lit.15b ½aꢁD ꢂ15 (c 3.1, MeOH)]; Rf 0.13 (A); 1H
NMR: d 1.36, 1.42, 1.43, 1.435 (3Heach, 4s, CMe ),
2
2.14 (1H, br s, HO-4), 3.42, 3.43 (3H each, 2s, MeO-
Acknowledgements
1), 3.61 (1H, br d, H-4), 4.02 (1H, dt, J4,5 8.1, J5,6 5.4,
J5,6 5.4 Hz, H-5), 4.07 (2H, d, H,H0-6), 4.125 (1H, dd,
0
We are grateful to the SC-NMR Laboratory of
Okayama University, for the NMR measurements.
J2,3 8.3, J1,2 6.6 Hz, H-2), 4.18 (1H, dd, J3,4 1.2 Hz, H-
3), 4.40 (1H, d, H-1).
3.7. Methyl 1,3-O-isopropylidene-6-O-tosyl-a-D-fructo-
furanoside (22) and its 4,6-di-O-tosyl analog (23)
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