Scandium triflate-catalyzed D-fructofuranosylation reactions using disaccharide units

Article abstract of DOI:10.3987/COM-12-S(N)66

This paper describes efficient D-fructofuranosylation reactions catalyzed by scandium triflate. The reactions used several benzoylated or benzylated glycosyl acylate derivatives from disaccharides containing the D-fructofuranose moiety at the reducing end

Full text of DOI:10.3987/COM-12-S(N)66

HETEROCYCLES, Vol. 86, No. 2, 2012
919
HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 919 - 925. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 28th June, 2012, Accepted, 21st August, 2012, Published online, 29th August, 2012
DOI: 10.3987/COM-12-S(N)66
SCANDIUM TRIFLATE-CATALYZED D-FRUCTOFURANOSYLATION
REACTIONS USING DISACCHARIDE UNITS†
Takashi Yamanoi1,* Noriko Misawa,1,2 Sho Matsuda,1 Mikio Watanabe,2 and
Yoshiki Oda1
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, 4-1-1 Kitakaname, Hiratsuka, Kanagawa, 259-1292, Japan
†Dedicated to Professor Dr. Ei-ichi Negishi on his 77th birthday.
Abstract – This paper describes efficient D-fructofuranosylation reactions
catalyzed by scandium triflate. The reactions used several benzoylated or
benzylated glycosyl acylate derivatives from disaccharides containing the
D-fructofuranose moiety at the reducing ends. Only 5 - 10 mol% scandium triflate
effectively promoted the D-fructofuranosylation reactions using the disaccharide
derivatives as the glycosyl donors. The structures and protecting groups of the
disaccharide donors and alcohol acceptor species influenced the stereoselectivity
and reactivity of the fructofuranosylation reactions. The fructofuranosylation
reactions could be applied to synthesize several non-reducing trisaccharides
containing a sucrose-like disaccharide unit.
D-Fructose is abundant in nature, and mostly occurs in the furanose form. It plays an important role in
several biological processes,1 and considerable attention is paid to fructosylated compounds and their
biological functions. For example, the non-reducing oligosaccharides, which contain the disaccharide unit
of D-glucopyranosyl-(1→2)-D-fructofuranoside, are classified as sucrose derivatives and mimics, and are
expected to have biological functions useful in food ingredients. They are also useful compounds to be
employed as synthetic targets.2 Consequently, several chemical glycosidations using D-fructofuranose
derivatives have been studied, i.e., D-fructofuranosylation reactions.3

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HETEROCYCLES, Vol. 86, No. 2, 2012
We have recently reported a highly efficient D-fructofuranosylation method catalyzed by scandium
triflate (Sc(OTf)3).4 This method utilized the 1,3,4,6-tetra-O-benzoyl-D-fructofuranosyl acetates (1) or
1,3,4,6-tetra-O-benzyl-D-fructofuranosyl acetates (2) as the glycosyl donor, as shown in Figure 1, and
Sc(OTf)3 as the activator. Only 5 mol% Sc(OTf)3 facilitated the smooth
1
RO
OR
completion of the fructofuranosylation reactions using 1 or 2. Compound 1
was slightly less reactive than 2 due to the effect of the electron-withdrawing
benzoyl groups. However, the reactions using 1 provided α-fructofuranosides
with higher stereoselectivities than those using 2. The high α-stereoselectivity
could be explained by the effect of the neighboring-group participation of the
benzoyloxy group at C-3 of 1.
O
RO
OAc
3
RO
R = Bz:
R = Bn:
1
2
Figure 1
Lacturose, malturose, and palatinose are disaccharides containing the D-fructofuranose moiety at the
reducing ends. They are commercially available reagents. Heijden et al. reported the glycosidation
reaction using these unprotected disaccharides and aliphatic alcohol solvents in the presence of the
MCM-41 catalyst.5 Although this method could only afford simple alkyl glycosides directly from the
unprotected disaccharides, it indicated the possibility that various novel fructosylated compounds could
be designed and synthesized by the fructofuranosylation technique using the glycosyl donors prepared
from these disaccharides.
We applied our Sc(OTf)3-catalyzed D-fructofuranosylation method to the glycosidation reaction, using
the glycosyl donors prepared from the disaccharides containing the D-fructofuranose moiety at the
reducing ends, in order to expand the versatility of our method and to demonstrate the synthesis of novel
fructofuranoside compounds from these disaccharides. We also studied the synthesis of the non-reducing
trisaccharides containing a sucrose-like disaccharide unit based on the fructofuranosylation strategy.
Figure 2 shows the disaccharide derivatives used as glycosyl donors, alcohols utilized as glycosyl
acceptors, and products. We first investigated the D-fructofuranosylation reactions using the fully
benzoylated disaccharides 3-5. Compounds 3-5 were readily prepared in 77%, 91%, and 84% yields with
α/β ratios of 72/28, 70/30, and 90/10 from lacturose, malturose, and palationose according to the general
benzoylation procedure by using benzoyl chloride and pyridine in dichloromethane.6 When the reaction
of 3 with 10 was examined using 5, 10, and 20 mol% Sc(OTf)3 in toluene at room temperature (Scheme
1), the corresponding fructofuranoside 15 was successfully obtained in the range 84% - 92% yield (Table
1, Entries 1-3). Only 10 mol% Sc(OTf)3 could sufficiently activate 3, and the C-2 benzoyloxy group of 3
acted as the good leaving group.
The α/β anomer ratios of 15 obtained from these reactions were 84/16, 83/17, and 84/16, respectively

HETEROCYCLES, Vol. 86, No. 2, 2012
921
(Entries 1-3). In addition, the reaction of 3 with several types of acceptor alcohols 11-13 under similar
reaction conditions also afforded the corresponding fructofuranosides 16-18 in excellent yields of 88%,
80%, and 86%, and their α/β anomer ratios were 84/16, 84/16, and 88/12, respectively (Entries 4-6).
Although these reactions mainly produced α-anomers, β-anomers were also produced in small amounts.
The predominance of the α-stereoselectivity was attributed to the effect of the neighboring-group
participation of the benzoyloxy group at C-3. This indicated that the α-stereoselectivity of
fructofuranosylation using 3 was slightly poorer than that using 1. We assumed that the steric hindrance
of the benzoylated β-D-galactopyranosyl moiety at C-4 of 3 would slightly reduce the α-stereoselectivity
of the fructofuranosylation reactions.
OR2
R2O
OR2
OR1
R2O
OR2
O
1
O
O
R2O
OR2
OR1
R2O
R2O
O
R2O
O
R2O
OR1
OR2
R2O
6
1
OR2
O
R2O
R2O
O
OR2
OR1
R2O
O
O
OR2
3
R2O
O
OR2
OR2
OR2
OR2
O
R2O
O
R2O
R2O
R1 = R2 = H: palatinose
R2O
R1 = R2 = H: lacturose
R1 = R2 = H: malturose
R1 = OH; R2 = Bn:
6
Glycosyl donor
1 = R2 = Bz:
R1 = Ac; R2 = Bn:
R
1 = R2 = Bz:
3
R1 = Ac; R2 = Bn:
R
1 = R2 = Bz:
4
5
R
7
R1 = Ac; R2 = Bn:
8
9
Product
R1 = PhCH2CH2-; R2 = Bz: 19
R1 = n-Octyl; R2 = Bz: 20
R1 = PhCH2CH2-; R2 = Bz: 22
R1 = CH2=CHCH2-; R2 = Bz: 23
R1 = PhCH2CH2-; R2 = Bz: 15
R1 = PhCH2CH2-; R2 = Bn: 28
R1 = CH2=CHCH2-; R2 = Bz: 16
O
R1
=
=
; R2 = Bn:
BnO
29
30
BnO
R1 = n-Octyl; R2 = Bz: 24
R1 = n-Octyl; R2 = Bz: 17
O
BnO
R1
; R2 = Bz:
OMe
BnO
=
OMe
21
BnO
BnO
OAc
O
O
R1
=
=
; R2 = Bz: 25
OMe
OAc
O
BnO
R1
=
; R2 = Bz: 18
OMe
OAc
BnO
BnO
AcO
AcO
BnO
R1
; R2 = Bn:
BnO
BnO
AcO
O
O
R1
; R2 = Bn: 32
AcO
AcO
AcO
AcO
R1
=
; R2 = Bz:
26
AcO
AcO
R1 = OH; R2 = Bz:
OAc
27
O
R1
=
; R2 = Bn: 31
AcO
AcO
AcO
Alcohol
OAc
O
OH
O
AcO
AcO
PhCH2CH2OH
BnO
BnO
CH2=CHCH2OH
CH3CH2CH2CH2CH2CH2CH2CH2OH
AcO
14
OH
BnO
10
11
12
OMe
Figure 2. Disaccharide derivatives and alcohols utilized in this study, and products

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HETEROCYCLES, Vol. 86, No. 2, 2012
(R2O)2
OR2
OR2
(R2O)2
OR2
OR2
OR'
O
cat. Sc(OTf)3
O
R2O
R2O
R2O
R2O
R'OH
+
OR1
PhMe, CaSO4
O
O
O
O
10-14
R2O
R2O
3-5, 7-9
15-26, 28 -32
Scheme 1
Table 1. D-Fructofuranosylation reactions using the disaccharide derivatives
Entrya)
Donor
Acceptor
10
Sc(OTf)3 (mol%) Product
Yield (%)
84
α/β Anomer ratiob)
1
3
3
3
3
3
3
4
4
4
5
5
5
5
3
7
7
7
8
9
5
15
15
15
16
17
18
19
20
21
22
23
24
25
26
28
29
30
31
32
84/16
83/17
84/16
84/16
84/16
88/12
83/17
80/20
77/23
α
2
10
10
20
10
10
10
10
10
10
10
10
10
10
10
5
91
3
10
92
4
11
88
5
12
80
6
13
86
7
10
81
8
12
71
9
13
55
10
11
12
13
14
15d,e)
16d,e)
17d,f)
18d,f)
19d,f)
10
83
11
90
α
12
86
α
13
84
α
14
trace
87
N.D.c)
61/39
73/27
10
13
5
82
14
5
53
α
α
α
(65/35)g)
(68/32)g)
(65/35)g)
14
5
48
14
5
47
a) Molar ratio: donor/acceptor = 1/1; Reaction time = 1 h - over night; Temp. = rt b) Determined by 1H NMR. c) N.D. =
Not determined. d) Temp. = 0 ºC e) Reaction time = 20 min. f) Reaction time = 30 – 90 min. g) α/β Anomer ratio of the
glucopyranosyl moiety at C-1”. The fructofuranosidic linkage = α only.
Next, we investigated the fructofuranosylation reactions using 4 and 5 with the benzoylated
α-D-glucopyranose moiety at C-4 or C-6 in order to clarify their influence on the fructofuranosylation
stereoselectivities. When the reactions between 4 and alcohols 10, 12, and 13 were conducted under
similar reaction conditions, the corresponding fructofuranosides 19-21 were obtained in 81%, 71%, and

HETEROCYCLES, Vol. 86, No. 2, 2012
923
55% yields with α/β anomer ratios of 83/17, 80/20, and 77/23, respectively (Entries 7-9). The
stereoselectivities of these reactions using 4 almost corresponded with those using 3. The reactions of 5
with 10-13 under similar reaction conditions produced the corresponding fructofuranosides 22-25 in high
yields of 83%-90% (Entries 10-13). All these reactions only produced α-anomers. The stereoselectivities
of the reactions using 5 were slightly different from those using 3 and 4, and the high α-stereospecificity
corresponded with our past results for the reactions using 1. These observations exhibited a high
possibility that the steric hindrance of the benzoylated carbohydrate moieties at C-4 in the disaccharide
donors 3 and 4 may partially prevent the acceptor alcohols from α-attacking.
Furthermore, we attempted to synthesize the non-reducing trisaccharides containing the
D-glucopyranosyl-(1→2)-D-fructofuranoside unit by the fructofuranosylation reactions using the
disaccharide donors. When the fructofuranosylation of 14 using 3 was examined under similar reaction
conditions, the desired non-reducing trisaccharide 26 was obtained in trace amounts, and compound 27
having an anomeric hydroxyl group was the main product (Entry 14). It appeared that compound 14 was
much less reactive than alcohols 10-13.
We additionally investigated the fructofuranosylation reactions using the benzyl group-protected
disaccharide 7 containing the C-2 acetoxy group as the leaving group. The disaccharide derivative 7 was
expected to act as a highly reactive glycosyl donor because of the effect of the electron-donating benzyl
groups. Compound 7 was obtained in 75% yield with an α/β ratio of 73/27 by the acetylation of 67 using
n-butyllithium and acetic anhydride in THF at -30 ºC. Subsequently, we examined the reactions of 7 with
the alcohols 10, 13, and 14 under similar reaction conditions using 5 mol% Sc(OTf)3 in toluene at 0 ºC.
The corresponding fructofuranosides 28 and 29 were obtained in excellent yields of 87% and 82% with
α/β anomer ratios of 61/39 and 73/27 (Entries 15 and 16). It was noteworthy that the reaction between 7
and 14 smoothly proceeded to give the desired non-reducing trisaccharide 30 in a satisfactory yield of
53% with both isomers (Entry 17).
The results using 7 urged us to prepare two new disaccharide donors 8 and 9 from lacturose and
palatinose, and to use them in the synthesis of the non-reducing trisaccharides. The benzyl
group-protected 8 and 9 containing the C-2 acetoxy group were prepared from 16 and 23 by the following
synthetic steps: deprotection of the benzoyl groups of 16 and 23 using NaOMe in MeOH-CHCl3 and
subsequent benzylation using BnBr-NaH in DMF (87%, 45%); deprotection of the allyl group using 75%
aqueous H2SO4-1,4-dioxane7 (88%, 95%); and subsequent acetylation using n-BuLi and Ac2O in THF
(82%, 83%). The fructofuranosylation of 14 using the disaccharide donors 8 and 9 under similar reaction
conditions succeeded in providing the desired trisaccharides 31 and 32 in 48% and 47% yields with both
isomers, respectively (Entries 18 and 19). Thus, we successfully synthesized the non-reducing
trisaccharides 31 and 32 by the fructofuranosylation method.

924
HETEROCYCLES, Vol. 86, No. 2, 2012
The NMR spectra showed that all fructofuranosidic linkages of 30, 31, and 32 were α,8 and the α/β ratios
of the formed glucopyranosidic linkages were 65/35, 68/32, and 65/35, respectively (Entries 17-19). The
13C NMR data of each anomeric carbons in the fructofuranosides 15-25, and 28-32 are shown in Table 2.
Table 2. Chemical shift (δ/ppm) of each anomeric carbons in the fructofuranoside producta)
Entry Product
C-2 of fructose
C-1’ of galactose (Gal) or glucose (Glc)
C-1” of Glc
1
15
16
17
18
19
20
21
22
23
24
25
28
29
30
31
32
106.8 [α], 102.2 [β]
107.1 [α], 103.1 [β]
106.8 [α], 103.0 [β]
106.9 [α], 102.2 [β]
107.0 [α], 102.7 [β]
107.1 [α], 102.8 [β]
106.8 [α], 103.2 [β]
106.7 [α]
102.1 and 101.7 [βGal]
102.1 and 101.7[βGal]
102.1 and 101.7 [βGal]
102.7 and 101.1[βGal]
95.8 and 96.9 [αGlc]
95.8 and 96.8 [αGlc]
96.4 and 97.0 [αGlc]
95.8 [αGlc]
-
2
-
3
-
4
97.3, 96.4 [α]
5
-
6
-
7
97.4, 96.4 [α]
8
9
107.2 [α]
95.9 [αGlc]
10
11
12
13
14
15
16
107.9 [α]
95.9 [αGlc]
-
107.1 [α]
95.8 [αGlc]
97.5 [α]
108.3 [α], 104.1 [β]
108.7 [α], 103.6 [β]
109.4 and 108.8 [α]
108.8 and 108.9 [α]
109.3 and 108.6 [α]
94.2 and 99.1 [αGlc]
94.2 and 99.9 [αGlc]
94.4 and 95.2 [αGlc]
104.7 and 103.8 [βGal]
97.1 and 97.2 [αGlc]
-
97.7, 96.7 [α]
88.8 [α], 93.9 [β]
89.6 [α], 94.3 [β]
89.0 [α], 94.0 [β]
a) The empirical chemical shift value (δC/ppm) of the C-2 of fructofuranoside; α = 107-109 ppm: β = 103-105 ppm. See
Ref. 8.
C-2
OR2
C-2
OR2
(R2O)2
OR2
(R2O)2
OR2
O
O
R2O
R2O
R2O
R2O
OAc
OAc
OAc
O
O
O
O
O
O
C-1"
O
R2O
BnO
BnO
R2O
AcO
BnO
C-1"
OMe
C-1'
C-1'
30 - 32
18, 21, 25, 29
In summary, we developed efficient Sc(OTf)3-catalyzed D-fructofuranosylation reactions using several
benzoylated or benzylated disaccharide derivatives as the glycosyl donors. Only 5 – 10 mol% Sc(OTf)3

HETEROCYCLES, Vol. 86, No. 2, 2012
925
successfully activated these disaccharide donors to effectively promote fructofuranosylations.9 The
structures and protecting groups of the disaccharide donors and alcohol acceptor species influenced the
stereoselectivity and reactivity of the fructofuranosylation reactions. We succeeded in establishing the
synthetic protocol to produce several non-reducing trisaccharides containing a sucrose-like disaccharide
unit based on the fructofuranosylation strategy.
REFERENCES AND NOTE
1. (a) P. J. Looijesteijn, I. C. Boels, M. Kleerebezem, and J. Hugenholtz, Appl. Environ. Microbiol.,
1999, 65, 5003; (b) E. Wiame, G. Delpierre, F. Collard, and E. Van Schaftingen, J. Biol. Chem.,
2002, 277, 42523; (c) See Ref. of 3a.
2. (a) J. Seibel, R. Moraru, S. Gotze, K. Buchholz, S. Na’amnieh, A. Pawlowski, and H.-J. Hecht,
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7081; (c) B. Yu and Y. Z. Hui, Chinese Chem. Lett., 1993, 4, 285; (d) J. Uenishi and A. Ueda,
Tetrahedron: Asymmetry, 2008, 19, 2210.
3. (a) G. Liana, Q. Gaob, and F. Lin, Carbohydr. Res., 2008, 343, 2992; (b) See Ref. 4.
4. T. Yamanoi, N. Misawa, and M. Watanabe, Tetrahedron Lett., 2007, 48, 6458.
5. A. M. van der Heijden, T. C. Lee, F. van Rantwijk, and H. van Bekkum, Carbohydr. Res., 2002, 337,
1993.
6. A. Bouali, G. Descotes, D. F. Ewing, A. Grouiller, J. Lefkidou, A.-D. Lespinasse, and G. Mackenzie,
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8. S. Oscarson and F. W. Sehgelmeble, J. Am. Chem. Soc., 2000, 122, 8869.
9. A typical glycosidation procedure is as follows: To a stirred suspension of Sc(OTf)3 (4.3 mg, 0.009
mmol) and 10 (10.3 μL, 0.09 mmol) in toluene (5 mL), 3 (101.5 mg, 0.09 mmol) was added at rt in
the presence of drierite (ca. 100 mg). The resulting mixture was then stirred for 4.5 h. The reaction
was then quenched by the addition of a sat. aq. NaHCO3 solution (5 mL). The reaction mixture was
extracted with EtOAc, and the organic layer was washed with water and a sat. aq. NaCl solution.
After the organic layer was dried over Na2SO4, the solvent was evaporated under reduced pressure.
The crude product was purified by preparative silica gel TLC (EtOAc/hexane = 1/2) to give 15 as a
colorless oil (92.1 mg, 91%, Entry 2 of Table 1).