L-fructo-and D-psicofuranosylation reactions catalyzed by scandium triflate

Article abstract of DOI:10.3987/COM-10-11916

This paper describes the formation of L-fructo-and D-psicofuranosidic bonds by the scandium triflate catalyzed glycosidation. The reaction of the benzoylated L-fructofuranosyl acetate with an alcohol in the presence of 5 mol% scandium triflate in toluene

Full text of DOI:10.3987/COM-10-11916

HETEROCYCLES, Vol. 81, No. 5, 2010
1141
HETEROCYCLES, Vol. 81, No. 5, 2010, pp. 1141 - 1147. © The Japan Institute of Heterocyclic Chemistry
Received, 26th January, 2010, Accepted, 23rd March, 2010, Published online, 23rd March, 2010
DOI: 10.3987/COM-10-11916
L-FRUCTO-
AND
D-PSICOFURANOSYLATION
REACTIONS
CATALYZED BY SCANDIUM TRIFLATE
Takashi Yamanoi,*,1 Toshiaki Ishiyama,1,2 Yoshiki Oda,1 Sho Matsuda,1 and
Mikio Watanabe2
1The Noguchi Institute, 1-8-1 Kaga, Itabashi-ku, Tokyo, 173-0003, Japan:
2
tyama@noguchi.or.jp; Department of Chemistry, School of Science, Tokai
University, Kitakaname 1117, Hiratsuka, Kanagawa, 259-1292, Japan
Abstract
–
This paper describes the formation of L-fructo- and
D-psicofuranosidic bonds by the scandium triflate catalyzed glycosidation. The
reaction of the benzoylated L-fructofuranosyl acetate with an alcohol in the
presence of 5 mol% scandium triflate in toluene at room temperature for 3 h
stereoselectively afforded the corresponding α-L-fructofuranoside in good yields.
Several α-D-psicofuranosides were predominantly obtained in good yields by the
reactions between the benzoylated D-psicofuranosyl acetate and alcohols under
similar reaction conditions. This method successfully provided the sucrose mimics
composed of D-glucopyranose and L-fructofuranose or D-psicofuranose.
INTRODUCTION
Rare sugars are monosaccharides that occur in nature in very small quantities. About 50 kinds of them are
known. Although they have been only slightly available as research reagents, the discovery of a key
enzymatic reaction converting abundantly occurring monosaccharides into the rare sugars has allowed the
mass production of some of these rare sugars.1 This led to the elucidation of the physiological functions
of D-psicose and D-allose and has aroused much interest in rare sugar related compounds.2 We expected
that the glycosylation of the rare sugars would be an interesting approach to synthesizing new biologically
active compounds. The study of the chemical glycosidation of rare sugars, however, has been reported
only by Uenishi et al. regarding the synthesis of D-psicofuranosylceramide.3,4
D-fructose is known as one of the monosaccharides that abundantly exist in nature. Several glycosylation
reactions using D-fructofuranose derivatives, i.e., the D-fructofuranosylations, have been already
reported.5 We also developed a highly efficient D-fructofuranosylation method which used the benzylated
or benzoylated D-fructofuranosyl acetate derivative as the glycosyl donor and scandium triflate

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HETEROCYCLES, Vol. 81, No. 5, 2010
(Sc(OTf)3) as the activator.6 Only 5 mol% Sc(OTf)3 smoothly promoted the reactions of these
D-fructofuranosyl acetates with alcohols to produce the corresponding D-fructofuranosides. A high
α-stereoselectivity was found when the benzoylated D-fructofuranosyl acetate derivative was utilized as
the glycosyl donor. This could be attributed to the effect of the neighboring group participation of the
benzoyl group at C-3. In addition, we successfully synthesized several non-reducing disaccharides by
D-fructosylation of 1-hydroxy aldopyranose derivatives. They are synthetic mimics of sucrose of which
the glucopyranose moiety is replaced with a different kind of aldopyranose. They are expected to have
biological functions useful as novel food ingredients.
We postulated that our D-fructofuranosylation system would be applicable for the glycosidation of the
L-fructo- and D-psicofuranoses which are the available rare sugars and are the isomers of D-
fructofuranose.7,8 This paper describes the L-fructo- and D-psicofuranosylations catalyzed by Sc(OTf)3,
and the synthesis of novel sucrose mimics by glycosylating these rare sugars with a 1-hydroxy
glucopyranose derivative.
RESULTS AND DISCUSSION
１．Preparation of glycosyl donors
We investigated the preparation of 1,3,4,6-tetra-O-benzoyl-L-fructofuranosyl acetate (1) and
1,3,4,6-tetra-O-benzoyl-D-psicofuranosyl acetate (2) as the glycosyl donors. These compounds were
prepared from L-fructose and D-psicose as shown in Scheme 1. The reaction of L-fructose with benzoyl
chloride (5 equiv.) in pyridine and dichloromethane at room temperature for 3 h9 afforded the
corresponding benzoylated L-fructofuranose 3 and L-fructopyranose 4 in 64% and 25% yields,
respectively. Similar reaction conditions gave the benzoylated D-psicofuranose 5 and D-psicopyranose 6
from D-psicose in 54% and 12% yields, respectively. The subsequent acetylation of 3 using Ac2O and
o
n-BuLi (1.3 equiv.) in THF at -30 C for 3 h afforded the desired 1 in 79 % yield with an α/β mixture
having the isomer ratio of 85/15. The acetate 2 (isomer ratio= 13/87) was obtained from 5 in 75% yield
using a similar acetylation procedure.
BzO
OBz
OBz
OBz
BzO
O
O
O
OBz
OBz
O
OBz
benzoyl chloride
pyridine-CH2Cl2
benzoyl chloride
pyridine-CH2Cl2
D-psicose
L-fructose
+
+
OH
OH
BzO
OH
OBz
BzO
BzO
OH
OBz
BzO OBz
OBz
6
4
5
3
n-BuLi, Ac2O
BzO
THF
OAc
n-BuLi, Ac2O
THF
OAc
O
O
OBz
OBz
BzO OBz
BzO
OBz
OBz
1
2
Scheme 1

HETEROCYCLES, Vol. 81, No. 5, 2010
1143
2. L-Fructo- and D-psicofuranosylation reactions
We investigated the Sc(OTf)3-catalyzed L-fructofuranosylation using 1 as shown in Scheme 2 according
to our previously reported D-fructofuranosylation system.6 The reaction of 1 with 1 equiv. of phenethyl
alcohol (7) using 5 mol% Sc(OTf)3 in the presence of the dry reagent, CaSO4 in toluene at room
temperature for 3 h stereoselectively afforded the corresponding phenethyl α-L-fructofuranoside 8 in 88%
yield with no production of its β-isomer. The neighboring group effect of the benzoyl group at the C-3 of
1 seemed to promote the α-stereoselective L-fructofuranosylation reaction, which corresponded to our
former observation of the D-fructofuranosylation reaction.
Compound 1 was smoothly glycosylated into 2,3,4,6-tetra-O-benzyl-D-glucopyranose (9) under the same
reaction conditions to produce the novel sucrose mimics 10a and 10b in a good total yield of 88%. The
two isomers from the L-fructofuranosidic/D-glucopyranosidic linkages wereα/α and α/β, and the isomer
ratio from the D-glucopyranosidic linkage was 65/35. These observations almost corresponded to those
from our former D-fructofuranosylation study. These results are shown in Table 1.10
OAc
OR
O
OBz
O
OBz
5 mol% Sc(OTf)3
PhMe, CaSO4
ROH
+
OBz
OBz
BzO
BzO
OBz
OBz
8, 10
7, 9
1
Scheme 2
Table 1. L-Frucotofuranosylation reaction using 1
Entry
Acceptor
Product
Isomer ratio
Yield (%)
1
2
7
9
8
-
88
10a and 10b
65/35b)
88c)
a) Molar ratio: 1: 7 (or 9): Sc(OTf)3= 1: 1 (0.5): 0.05. Reaction time: 3h. b) Ratio of 10a/10b. c) Total yield of 10a and 10b.
BnO
OBn
OBn
O
1'
Ph
BnO


BnO
BnO
OBn
O
O
1
1
O
OBz

Ph
O

BnO
O
2
BnO

BnO
BnO
HO
O
O
O
OBz
OBz
BzO
BnO
OBz
OBz
OBz
2'
7
OBz
2'
OH
BzO
BzO
OBz
OBz
10b
9
8
10a
Our next investigation was the D-psicofuranosylation using 2 in the presence of Sc(OTf)3 as shown in
Scheme 3. As compound 2 had a poor solubility in toluene, dichloromethane was used as the solvent. The
reaction of 2 with 7 using 5 mol% Sc(OTf)3 in dichloromethane at room temperature for 3 h afforded the
corresponding phenethyl α- and β-D-psicofuranoside 11a and 11b with an isomer ratio of 32/68 in a total
yield of 81%. We found that the D-psicofuranosylation also smoothly proceeded under the above stated
reaction conditions and predominantly produced the β-isomer. The preferential formation of the
β-D-psicofuranosidic bond appeared to be attributed to the neighboring group participation of the C-3

1144
HETEROCYCLES, Vol. 81, No. 5, 2010
benzoyl group of 2. However, this effect was insufficient and could not prevent the formation of the
-D-psicofuranosidic bond.
Next, the effect of the solvents was examined using diisopropyl ether and acetonitrile. The reactions using
these solvents afforded 11a and 11b with isomer ratios of 22/78 and 67/33 in total yields of 73% and 66%,
respectively. Diisopropyl ether slightly increased the β-stereoselectivity, while acetonitrile considerably
increased the α-stereoselectivity.11
OAc
OR
BzO
BzO
O
O
5 mol% Sc(OTf)3
solvent, CaSO4
ROH
+
OBz
BzO OBz
OBz
BzO OBz
7, 9, 12, 13
11, 14-16
2
Scheme 3
Table 2. D-Psicofuranosylation reaction using 2
Entrya) Acceptor Solvent
Product
Isomer ratio
Total yield (%)
1
7
CH2Cl2
i-Pr2O
11a and 11b
32/68b)
22/78b)
67/33b)
25/75c)
31/69d)
20/8/28/44f)
81
73
66
72
50
80
2
7
11a and 11b
3
7
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
11a and 11b
4
12
13
9
14a and 14b
5
6e)
15a and 15b
16aa, 16ab, 16ba and 16bb
a) Molar ratio: 2: acceptor: Sc(OTf)3= 1: 1: 0.05. Reaction time: 3h. b) Ratio of 11a/ 11b. c) Ratio of 14a/ 14b. d) Ratio of 15a/ 15b.
e) Molar ratio: 2: acceptor: Sc(OTf)3= 1: 0.5: 0.05. f) Ratio of 16aa/ 16ab/ 16ba/ 16bb.
OMe
OBn
1'
OBz
O
1'
Ph
BzO
1'
O
BzO
OBz
BzO
O
OBn
OBn
OH
O
OBn
O
OMe
OBn
2
O
O



O
2
O
2
BnO
BnO
HO
BnO
BzO
O
O

O
1'
OBz
BzO OBz
Ph
2
BnO
BnO
BzO OBz
BzO OBz
OMe
OBn
OBn
OMe
OBz
12
13
11a
11b
14a
BzO OBz
14b
BnO
OBn
OBn
OBn
O
OBn
O
BnO

BzO
OBz
BnO

OBz
BzO
BnO
O
1
BzO
O
OBz

O

1
OBn
OBn

O
2'
O
BnO
O

OBn
1'
1
BzO
BnO
2 
2'
2
O
BzO
O
OBn
O
O
BzO
BnO
O
BnO
O
OMe
O
O
2'
1'
O
BnO
2'

OBz
BzO OBz
BnO
16ba

OBz
BzO OBz
1
O
BzO OBz
OBz
BzO OBz
BnO
OBn
OBn
OBn
OMe

BzO OBz
BzO OBz
16bb
15a
15b
16aa
16ab
Several sugar alcohols were used as glycosyl acceptors. The reactions of 2 with methyl
2,3,4-tri-O-benzyl-α-D-glucopyranoside (12) and methyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside (13) in
dichloromethane in the presence of 5 mol% Sc(OTf)3 afforded the corresponding α- and
β-psicofuranosides 14a and 14b, and 15a and 15b. The isomer ratios and total yields of 14a and 14b, and
15a and 15b were 25/75 and 72%, and 31/69 and 50%, respectively. Compound 2 was also smoothly

HETEROCYCLES, Vol. 81, No. 5, 2010
1145
glycosylated into 9 under similar reaction conditions to produce the novel sucrose mimics 16aa, 16ab,
16ba, and 16bb in a good total yield of 80%. The isomer ratio was 20/8/28/44. These results are
summarized in Table 2.10
In summary, this paper reported the Sc(OTf)3-catalyzed L-fructo- and D-psicofuranosylation reactions
using 1 and 2. We observed that the α-stereoselective L-fructofuranosylation using 1 smoothly proceeded
with 5 mol% Sc(OTf)3 in toluene at room temperature for 3 h and similar reaction conditions promoted
the β-predominant D-psicofuranosylation using 2. The L-fructo- and D-psicofuranosylations converting 1
and 2 into 9 successfully afforded the novel sucrose mimics.
ACKNOWLEDGEMENT
We thank Fushimi Pharmaceutical Co., Ltd. for the gifts of L-fructose and D-psicose.
REFERENCES AND NOTES
1. K. Izumori, Naturwissenschaften, 2002, 89, 120.
2. Y. Asada, Y. Kawanami, and S. Tajima, “Rare sugars II”, Proceeding of the Third Symposium of
International Society of Rare Sugars, Art-Printing Co., Ltd.
3. J. Uenishi and A. Ueda, Heterocycles, 2009, 77, 1297.
4. J. Uenishi and A. Ueda, Tetrahedron: Asymmetry, 2008, 19, 2210.
5. See Ref. 6.
6. T. Yamanoi, N. Misawa, and M. Watanabe, Tetrahedron Lett., 2007, 48, 6458.
7. H. Itoh and K. Izumori, J. Ferment. Bioeng., 1996, 81, 351.
8. H. Itoh, T. Sato, and K. Izumori, J. Ferment. Bioeng., 1995a, 80, 101.
9. A. Bouali, G. Descotes, D. F. Ewing, A. Grouiller, J. Lefkidou, A.-D. Lespinasse, and G. Mackenzie,
J. Carbohydr. Chem., 1992, 11, 159.
10. A typical glycosidation procedure: To a stirred suspension of Sc(OTf)3 (3.9 mg, 0.008 mmol) and 7
(19 μL, 0.16 mmol) in toluene (3 mL) was added 1 (100 mg, 0.16 mmol) in the presence of
anhydrous CaSO4 (ca. 100 mg) under an Ar atmosphere and stirred for 3 h. The reaction was then
quenched by the addition of a saturated aqueous NaHCO3 solution (5 mL). The reaction mixture was
extracted with EtOAc, and the organic layer was washed with water and a saturated aqueous NaCl
solution. After the organic layer was dried over anhydrous Na2SO4, the solvent was evaporated
under reduced pressure. The crude product was purified using a preparative silica gel TLC (PTLC;
EtOAc/hexane = 1/2) to give the desired glycoside 8 (91 mg, 88%) as an amorphous solid.
1
Compound (8): H NMR (CDCl3, 600 MHz):  2.86~2.93 (2H, m, H-2’), 3.87~3.89 (1H, m, H-5),
3.91~3.94 (1H, m, H-1’a), 3.97~4.00 (1H, m, H-1’b), 4.40 (1H, d, J = 11.7 Hz, H-1a), 4.55 (1H, dd,

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HETEROCYCLES, Vol. 81, No. 5, 2010
J = 4.8 Hz, J = 12.4 Hz, H-6a), 4.70 (1H, dd, J = 2.8 Hz, J = 11.7 Hz, H-6b), 4.91 (1H, d, J = 12.4
13
Hz, H-1b), 5.45 (1H, d, J = 5.5 Hz, H-4), 5.86 (1H, d, J = 1.4 Hz, H-3): C NMR (CDCl3, 150
MHz):  36.2 (C-2’), 59.6 (C-1), 62.5 (C-1’), 63.4 (C-6), 78.9 (C-4), 81.1 (C-5), 81.3 (C-3), 107.0
1
(C-2), 164.8~166.1 (C=O). Compounds (10a and 10b): isomer mixture: H NMR (CDCl3, 600
13
MHz):  4.99 (1H, d, J = 8.2 Hz, H-1b), 5.39 (1H, d, J = 3.4 Hz, H-1a): C NMR (CDCl3, 150
MHz):  91.4 (C-1a), 95.3 (C-1b), 107.6 (C-2’b), 107.9 (C-2’a). Compound (11a): 1H NMR (CDCl3,
600 MHz):  2.90~2.98 (2H, m, H-2’), 3.92~3.96 (1H, m, H-1’a), 4.11~4.14 (1H, m, H-1’b), 4.31
(1H, dd, J = 2.9 Hz, J = 6.2 Hz, H-5), 4.54 (1H, d, J = 12.0 Hz, H-1a), 4.55 (1H, dd, J = 3.8 Hz, J =
12.0 Hz, H-6a), 4.63 (1H, d, J = 12.0 Hz, H-1b), 4.68 (1H, dd, J = 2.8 Hz, J = 12.0 Hz, H-6b),
13
5.70~5.72 (2H, m, H-3, H-4): C NMR (CDCl3, 150 MHz):  36.5 (C-2’), 62.5 (C-1), 62.6 (C-1’),
63.9 (C-6), 71.0 (C-4), 73.2 (C-3), 80.5 (C-5), 103.5 (C-2), 165.2~166.2 (C=O). Compound (11b):
1H NMR (CDCl3, 600 MHz):  2.83 (2H, t, J = 6.2 Hz, H-2’), 3.82~3.86 (1H, m, H-1’a), 3.90 (1H,
dt, J = 6.9 Hz, J = 8.9 Hz, H-1’b), 4.19 (1H, dd, J = 6.2 Hz, J = 11.7 Hz, H-6a), 4.34 (1H, dd, J = 4.1
Hz, J = 11.7 Hz, H-6b), 4.45 (1H, d, J = 12.4 Hz, H-1a), 4.71~4.74 (1H, m, H-5), 4.89 (1H, d, J =
12.4 Hz, H-1b), 5.90~5.93 (1H, m, H-4), 5.97 (1H, d, J = 4.8 Hz, H-3): 13C NMR (CDCl3, 150
MHz):  36.1 (C-2’), 59.2 (C-1), 62.8 (C-1’), 64.8 (C-6), 72.8 (C-4), 75.1 (C-3), 79.2 (C-5), 107.3
(C-2), 164.7~166.0 (C=O). Compound (14a): 1H NMR (CDCl3, 600 MHz):  3.16 (3H, s, Me), 3.27
(1H, dd, J = 3.4 Hz, J = 9.6 Hz, H-2’), 3.54 (1H, t, J = 9.6 Hz, H-4’), 3.75~3.78 (1H, m, H-5’),
3.90~3.96 (3H, m, H-3’, H-6’), 4.41 (1H, d, J = 3.4 Hz, H-1’), 4.50~4.53 (2H, m, H-1a, H-6a),
4.58~4.61 (3H, m, H-1b, H-6b, CH2Ph), 4.66~4.69 (2H, m, H-5, CH2Ph), 5.71~5.72 (1H, m, H-4),
5.77 (1H, d, J = 7.6 Hz, H-3): 13C NMR (CDCl3, 150 MHz):  54.8 (Me), 61.4 (C-6’), 63.1 (C-1 or
C-6), 63.7 (C-1 or C-6), 69.6 (C-5’), 70.9 (C-4), 73.2 (C-3), 77.9 (C-4’), 80.2 (C-5, C-2’), 81.8
1
(C-3’), 97.6 (C-1’), 103.7 (C-2), 165.1~166.1 (C=O). Compound (14b): H NMR (CDCl3, 600
MHz):  3.34 (3H, s, Me), 3.60 (1H, dd, J = 3.4 Hz, J = 9.6 Hz, H-2’), 3.65 (1H, t, J = 8.9 Hz, H-4’),
3.75~3.77 (1H, m, H-5’), 3.86 (1H, dd, J = 3.4 Hz, J = 10.3 Hz, H-6a), 3.95 (1H, t, J = 8.9 Hz, H-3’),
4.10 (1H, dd, J = 1.4 Hz, J = 10.3 Hz, H-6b), 4.44 (1H, d, J = 12.4 Hz, H-1a), 4.64~4.81 (7H, m,
H-1’, H-6’, CH2Ph), 4.83~4.86 (1H, m, H-5), 4.89 (1H, d, J = 12.4 Hz, H-1b), 5.96~5.98 (1H, m,
13
H-4), 6.03 (1H, d, J = 4.1 Hz, H-3): C NMR (CDCl3, 150 MHz):  55.1 (Me), 60.0 (C-6), 60.2
(C-1), 65.7 (C-6’), 69.4 (C-5’), 73.3 (C-4), 75.1 (C-3), 77.4 (C-4’), 79.6 (C-5), 80.3 (C-2’), 81.8
1
(C-3’), 97.7 (C-1’), 107.3 (C-2), 164.7~166.1 (C=O). Compound (15a): H NMR (CDCl3, 600
MHz):  3.44 (Me), 3.59~3.63 (2H, m, H-4’, H-6’a), 3.84~3.89 (3H, m, H-3’, H-5’, H-6’b), 4.03
(1H, t, J = 9.6 Hz, H-2’), 4.10~4.19 (2H, m, H-1a, H-5), 4.25~4.27 (2H, m, H-1b, H-6a), 4.63 (1H, d,
J = 4.1 Hz, H-1’), 5.05 (1H, d, J = 12.4 Hz, H-6b), 5.71 (1H, dd, J = 2.7 Hz, J = 5.5 Hz, H-4), 5.93

HETEROCYCLES, Vol. 81, No. 5, 2010
1147
13
(1H, d, J = 6.2 Hz, H-3): C NMR (CDCl3, 150 MHz):  55.1 (Me), 62.5 (C-6), 64.3 (C-1), 69.4
(C-6’), 70.2 (C-5’), 71.4 (C-4), 71.7 (C-3), 72.3 (C-2’), 79.7 (C-5), 80.1 (C-4’), 80.8 (C-3’), 97.4
(C-1’), 105.2 (C-2), 165.2~165.9 (C=O). Compound (15b): 1H NMR (CDCl3, 600 MHz):  2.99 (1H,
dd, J = 4.1 Hz, J = 9.7 Hz, H-2’), 3.31 (3H, s, Me), 3.40 (1H, dd, J = 7.6 Hz, J = 10.3 Hz, H-6’a),
3.76 (1H, t, J = 9.6 Hz, H-4’), 3.83~3.88 (3H, m, H-3’, H-5’, H-6’b), 4.37 (1H, d, J = 3.4 Hz, H-1’),
4.59~4.64 (3H, m, H-1a, H-5, H-6a), 4.80~4.90 (2H, m, H-1b, CH2Ph), 5.34 (1H, d, J = 11.7 Hz,
H-6b), 5.90 (1H, d, J = 6.9 Hz, H-3), 5.94 (1H, dd, J = 4.1 Hz, J = 6.2 Hz, H-4): 13C NMR (CDCl3,
150 MHz):  55.0 (Me), 63.7 (C-6), 64.8 (C-1), 69.9 (C-5’), 70.2 (C-6’), 70.8 (C-4), 71.1 (C-4’),
75.0 (C-3), 79.8 (C-3’), 80.3 (C-5), 80.9 (C-2’), 97.1 (C-1’), 107.5 (C-2), 164.6~166.1 (C=O).
1
Compounds (16aa, 16ab, 16ba, and 16bb): isomer mixture: H NMR (CDCl3, 600 MHz):  5.02
(1H, d, J = 7.6 Hz, H-1ba), 5.06 (1H, d, J = 8.3 Hz, H-1bb), 5.55 (1H, d, J = 3.4 Hz, H-1ab), 5.65
(1H, d, J = 2.8 Hz, H-1aa): 13C NMR (CDCl3, 150 MHz):  90.6 (C-1aa), 90.9 (C-1ba), 95.2
(C-1bb), 96.9 (C-1ab), 104.0 (C-2’aa), 104.4 (C-2’ab), 107.2 (C-2’ba), 107.8 (C-2’bb).
11. Similar solvent effect using acetonitrile was reported. a) A. Ishiwata and Y. Ito, Synlett, 2003, 1339;
b) T. Yamanoi, R. Inoue, S. Matsuda, K. Iwao, Y. Oda, A. Yoshida, and K. Hamasaki, Heterocycles,
2009, 77, 445.