Synthesis of β-D-fructopyranosides with N-phenyl trifluoroacetimidate donor

Article abstract of DOI:10.1016/j.tet.2012.11.058

Fructopyranosyl N-phenyl trifluoroacetimidate was demonstrated to be effective glycosyl donor for β-D-fructopyranosides preparation that exhibited good β-selectivity and good yields. X-ray data of two β-D-fructopyranosides were obtained and help to determ

Full text of DOI:10.1016/j.tet.2012.11.058

Tetrahedron 69 (2013) 1128e1132
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of
b-
D-fructopyranosides with N-phenyl
trifluoroacetimidate donor
,
b
,
b
,
a
a
Feng Lin a , Gaoyan Lian , Qiulong Xu , Xiaofeng Zhu
*
*
a State Key Laboratory of New Drugs & Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, 1111 Zhongshanbeiyi Road, Shanghai 200437, China
b State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, CAS, 345 Linlin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2012
Received in revised form 8 November 2012
Accepted 16 November 2012
Available online 23 November 2012
Fructopyranosyl N-phenyl trifluoroacetimidate was demonstrated to be effective glycosyl donor for
fructopyranosides preparation that exhibited good b-selectivity and good yields. X-ray data of two
fructopyranosides were obtained and help to determine the anomeric configuration of these ketoses.
b
b
-
-
D
-
-
D
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Glycosylation
Fructopyranoside
Trifluoroacetimidate donor
Ketose
Anomeric configuration
1. Introduction
Increasing works on fructopyranosides synthesis were reported
in recent years.20,21 Unfortunately, a general and effective glyco-
sylation method for fructopyranosides synthesis is not available
till now. Several fructopyranosyl donors, such as fluoride, 1-
propenyl, 1,2-sulfite, and 1,2-carbonate were investigated.22
Among them, fructopyranosyl fluoride provided the highest yield
D
-Fructose is the second most abundant simple sugar in nature,
and fructosides are involved in a wide range of biological proc-
esses.1e5 -pyranoid form6 and appears
-Fructose crystallizes in
mainly as mixtures of two pyranose and two furanose tautomers in
solution.7,8 In nature,
-fructosides generally appear as furanose, so
chemical approaches to fructosides are mostly relevant to the
D
b
D
with good
trisaccharide the yield was dropped to 22%. Unprotected
could be directly converted into alkyl -fructopyranosides by FeCl3,
b
-selectivity, but only 57% yield for disaccharide, and for
D-fructose
synthesis of fructofuranosides,9e13 and the reports of
D-frutopyr-
D
anoside synthesis are limited.14,15 However, fructopyranosides
demonstrate excellent bioactivity and pharmaceutical value.16 For
example, TopamaxÒ (1) was the Top-10 anticonvulsant drug with $
2.7 billion annual sale in 2008.17 It might also be used to treat
but the yield was low (w30%).21,23 The known fructopyranosyl
glycosylation all suffered from the low yield; and some general
donors, such as Schmidt’s imidate and bromide, could not be ap-
plied in this glycosylation, because of their instability in ketose.22
Lichtenthaler and co-workers’ study indicated that, under forced
acetylation condition, fructopyranosyl ring could be opened,24
which implied that fructopyranoside was more sensitive. But the
known fructopyranosyl glycosylations all required 1 equiv of Lewis
acid and the preparation of donor often required somewhat strong
condition. Under these conditions, some side reactions of fructo-
pyranoid likely occurred, which maybe the reason for the low yield
of some donors’ preparation and glycosylation.22 In order to de-
velop an effective and general method for fructopyranosides
synthesis, we aimed at developing a mild fructopyranosyl glyco-
sylation method, with mild condition for the corresponding donors’
preparation.
obesity.18 In 2010, n-butyl
b-D-frutopyranoside (2) isolated from
traditional Chinese medicine was reported to exhibit gastric cancer
inhibition activity19 (Fig. 1).
O
NH2
S
HO
HO
O
O
O
O
O
O
O
O
OH
OH
O
1
2
Fig. 1. Some fructopyranosides with pharmaceutical value.
Yu and co-workers recently developed N-phenyl tri-
fluoroacetimidate donor,25,26 which was successfully applied in
direct sialylation, glycosylation of primary amides, hydroxamic
* Corresponding authors. Tel.: þ86 21 65310547; fax: þ86 21 65169893; e-mail
addresses: linfeng@sioc.ac.cn (F. Lin), liangy@sioc.ac.cn (G. Lian).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.11.058

F. Lin et al. / Tetrahedron 69 (2013) 1128e1132
1129
acid, deoxysugars, and several total synthesis.27 In 2008, we re-
OR
H5
H4
OBz
OBz
OBz
BzO
ported an efficient fructofuranosylation employing N-phenyl tri-
fluoroacetimidate donor.28 We further investigate its application in
fructopyranosides synthesis.
H5
O
O
BzO
H
4
3 H
OBz
BzO
H3
OBz OR
1,3,4,5-Tetra-O-benzoyl-
trifluoroacetimidoyl chloride in the presence of K2CO3 in acetone to
afford
b-D
-fructose 324 reacted with N-phenyl
β-D-fructopyranoside
α-D-fructopyranoside
b
-trifluoroacetimidate 4 ( J3,4¼10.4 Hz) in 98% yield. The
2C5 Conformer
5C2 Conformer
solvent with a little moisture benefited the reaction (Table 1). The
fructopyranosyl imidate 4 was stable in storage at 4 C for weeks,
ꢀ
showing it a stable glycosyl donor (Scheme 1).
Nu
5
4
OBz
3
BzO
OBz
BzO
O
O
Table 1
Optimization of N-phenyl trifluoroacetimidate 4 preparation
4
BzO
5
BzO
Entry
Equiv of N-phenyl
trifluoroacetimidoyl
chloride
Solvent
Reaction
time
Yield
BzO
OBz
u
N
4
5
H Conformer A
Possible mechanism for Stereo-selectivity
H Conformer B
4
5
1
2
3
4
7
7
7
3
Anhydrous CH2Cl2
Hydrous CH2Cl2
Anhydrous acetone
AR grade acetone
20 h
8 h
16 h
2 h
10%
70%
40%
98%
Fig. 2. Conformers of
b or a-D-fructopyranoside and the possible mechanism for b-
selective fructopyranosylation.
OH
Cl
CF3
Ph
N
OH
OBz
O
BzO
BzO
BzO
N
O
Ph
O
5a
CF3
O
O
BzO
OBz
BzO
K2CO3
OBz
OBz
OBz
4
OBz
3
OBz
6a
Scheme 1.
Donor 4 and adamantanol 5a (1.5 equiv to donor 4) in CH2Cl2 at
ꢁ20 ꢀC with TMSOTf (0.06 equiv) provided adamantanyl
b-fructo-
pyranoside 6a stereoselectively in 91% yield (Table 2, entry 1). Re-
placement of CH2Cl2 with CH3CN or a mixed solvent of CH3CN/
CH2Cl2 (1:2) or THF/CH2Cl2 (1:2) resulted in the similar yield and
the same stereoselectivity (entry 2,3). When BF3$Et2O (0.2 equiv)
was used as promoter, the result was the same as TMSOTf’s case
(entry 4). Acetonitrile was used to affect the stereo outcome
through ‘solvent effect’ in aldose glycosylation;29 but in cases here,
solvent did not affect the stereo outcome. Addition of TMSOTf at
higher temperature (0 ꢀC) caused decomposition of donor 4 and
lowered the yield (entry 5); when 1 equiv of BF3$Et2O was used, 3
was the major product with 67% yields (entry 6). Because perben-
zoyl protected donor 4 should be the most inert donor of this type,
these above results indicated that strong conditions were un-
favorable for this type of donor. The anomeric configuration of 6a
was assigned as
ysis (Fig. 3).
b-D-fructopyranoside according to the X-ray anal-
Table 2
Optimization of glycosylation conditions with donor 4 and adamantanol
Fig. 3. ORTEP drawing of compound 6a.
Entry Lewis acid Solvent
T/ꢀC Product Yield
b
:a
determined by 1H NMR (entries 1, 3e6). For 5b and 5g, the yields
were good, the selectivity was about 3.2:1 (entries 2 and 7). For
2, 3, 4, 6-tetra-O-benzyl- -glucopyranose (5h), 39% -glucosyl
fructoside (indicated as
) 6h (J3,4¼10.5 Hz, J1 ,2 ¼3.3 Hz) was
isolated with 9:1 -glucosyl selectivity (entry 8). In this reaction,
only the major product stereomer could be isolated in pure
form, from four possible stereomers: and . The
1
2
3
4
5
6
0.06 equiv TMSOTf CH2Cl2
0.06 equiv TMSOTf CH3CN
ꢁ20 6a
ꢁ20 6a
91
90
87
88
76
67
b
b
b
b
b
only
only
only
only
only
b:a
D
a
b-
0.06 equiv TMSOTf THF/CH2Cl2 (1:2) ꢁ20 6a
0
0
a; b
0.2 equiv BF3$Et2O CH2Cl2
ꢁ20 6a
a/b
0.06 equiv TMSOTf CH2Cl2
0
ꢁ20
6a
3
1 equiv BF3$Et2O
CH2Cl2
d
a; b
a;
b,
b
;
b,
a;
a
b
;
a
a/b-
glucosyl selectivity was mainly affected by anomeric effect of 5h.
The disaccharide 6h is a derivative of sucrose. The anomeric carbon
Other acceptors (5beh) were investigated with the optimized
condition. This glycosylation method worked well with several
kinds of acceptors (Table 3). For acceptors 5a, 5cef, the -fructo-
pyranosides were obtained in high yields and high selectivity as
signal for
b-D-fructosyl group is 101.3 ppm; for a-D-glucopyranosyl
b
group is 91.7 ppm (Scheme 2).

1130
F. Lin et al. / Tetrahedron 69 (2013) 1128e1132
Optical activity, 13C NMR,23 HMQC, NOE,22 and 3J coupling between
C-1 and H-3 (so called JBCA method) were also used to determine
Table 3
Glycosylation with donor 4a
the anomeric configuration.31 It was reported that
b-D-fructopyr-
Entry
Acceptor
Product
Yieldb
91
b
:
ad
anoside usually adopts a 2C5 conformation in crystal and solu-
tions,24 therefore, J3,4 value are large (commonly 9e11 Hz) while J4,5
and the two J5,6 values are small (commonly 3e5 Hz). On the
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
b
b
b
b
b
b
b
b
only
59 (
63 (
73c
81
b
b
)
)
:
:
a
¼3.2:1
a¼10:1
only
only
only
contrary, for
small and one of the J5,6 values is large, indicating a 5C2 confor-
mation.24 Could this provide
simplified anomeric -de-
termination method for fructopyranoside?
a-D-fructopyranoside, J3,4 and J4,5 values (3e5 Hz) are
96
a
a,b
5g
5h
6g
6h
85(b
)
:
a¼3.2: 1
39 (a;
b)
mainlye
a
Condition: ꢁ20 ꢀC, 0.06 equiv TMSOTf, CH2Cl2, 30 min then rt 1 h.
Isolated yield.
Because the 3, 4, and 5-CH of tetra-O-benzoyl fructopyranosides
provide distinct chemical shift (usually>5.8 ppm, far from other
glycosyl CH) and coupling patterns, the key J3,4 and J4,5 values could
be obtained unambiguously from 1D 1H NMR. This advantage in our
b
c
Recovered 20% of 5d.
d
e
Determined by crude product 1H NMR.
With 9:1 a/b-glucosyl selectivity.
Ph
BzO
N
BzO
BzO
O
TMSOTf
O
OR
CF3
+
ROH
O
BzO
OBz
OBz
OBz
OBz
4
5a-5h
6a-6h
OH
O
HO
OH
OH
O
5b
5c
5d
5a
OMe
OH
O
O
OBn
O
O
O
O
O
BnO
BnO
O
O
O
BnO
OH
O
HO
5g
OH
5e
5f
5h
Scheme 2. Pyrano-type fructosylation with donor 4.
For most of known glycosylation of ketopyranosyl donors,
cases prompted us to evaluate the configuration determine
methods mentioned above.
1 equiv of catalyst was needed, such as Cp2ZrCl2eAgOTf for fluo-
ride,22 DICP for thioketoside.30 So this mild glycosylation, which
required catalytic amount of TMSOTf, is more environment-friendly
and effective.
Since the anomeric proton is lacking, the anomeric configura-
tion determination of fructopyranoside is relatively complicated.
We obtained two crystals: 6a and 6d. Their X-ray structural
analysis clearly indicated b
-pyranosides with 2C5 conformation32
(Figs. 3 and 4), in accordance well with the 1H NMR data (J3,4¼9.9
and 10.5 Hz, respectively). The major glycosyl products of 6beg
were assigned as b-D-fructopyranosides, according to their optical
Fig. 4. ORTEP drawing of compound 6d.

F. Lin et al. / Tetrahedron 69 (2013) 1128e1132
1131
rotation (between ꢁ70ꢀ and ꢁ111ꢀ)23 and C-2 anomeric 13C NMR
data (in the range of 99e102 ppm), and their J3,4 value was also in
found 790.65. Anal. Calcd for C42H32NF3O10: C, 65.71; H, 4.20, N,
1.82. Found: C, 65.94; H, 4.35; N, 1.75.
the range of 9e11 Hz. But 6g-a, whose a configuration was con-
firmed by NOE signals between H-1 and H-6ax, provided big J3,4
value (J3,4¼10.2 Hz) indicating a 2C5 conformation. We suggested
that because of the bulky secondary alcohol, the pyranoside most
likely adopted 2C5 conformation. To these cases, NOE must be done
to confirm the anomeric configuration. So the J value pattern of H-
3,4,5 provided the conformation information, but it was insufficient
to judge the anomeric configuration.
There are three interesting aspects of the stereoselectivity of this
ketose glycosylation. First, there are two neighboring benzoyl
groups: on 1 and 3 position. The neighboring group participation
2.2. Adamantan-1-yl 1,3,4,5-tetra-O-benzoyl-b-D-fructopyr-
anoside (6a)
Yield: 91%. [
a
]
25 ꢁ102 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3):
D
d
8.21e7.23 (m, 20H, Bz), 6.35 (d, 1H, J¼9.9 Hz, H-3), 5.82 (m, 2H, H-
4 and H-5), 5.16 and 4.27 (AB, 2H, J¼11.1 Hz, H-1), 4.40 and 4.06 (AB,
2H, J¼13.2 Hz, H-6), 2.22e2.03 (m, 9H, OAda), 1.71 (br s, 6H, OAda).
13C NMR (100 MHz, CDCl3):
d 165.8, 165.7, 165.6, 165.5, 133.1e128.2,
101.5, 77.2, 70.1, 69.8, 68.0, 63.5, 61.9, 44.2, 36.0, 30.9. HRMS (ESI)
calcd for C44H42O10Na 753.2670, found 753.2672. Anal. Calcd for
(NGP) of 3-OBz will result in 2,3-trans structure, that is,
while NGP of 1-OBz will result in - or -glycosylation. The excel-
lent -selectivity shown in Table 3 indicated that the selectivity was
a
-glycoside,
C )
44H42O10: C, 72.31; H, 5.79. Found: C, 72.44; H, 5.62. IR (cmꢁ1
a
b
nmax¼2919, 1721, 1270, 1107, 711.
b
less likely affected by NGP of 3-OBz. Second, if NGP occurred in this
glycosylation, some kind of ortho-ester will be formed and could be
captured. Experiments were designed to capture the ortho-ester
intermediate,33 but only normal glycosylation product or hydro-
lyzed product 3 was obtained. We noticed that Crich and the co-
workers used O-BOC protected glycosides to trap the participa-
tion groups.34 Further works should be done to investigate the
possible NGP of 1, 4 or 5-OBz, to provide us more information on
2.3. n-Butyl 1,3,4,5-tetra-O-benzoyl-
D
-fructopyranoside (6b)
25
Yield: 59%.
b
:a
¼3.2:1; for
b
-anomer: [
a
]
ꢁ69.2 (c 1.0, CHCl3),
D
1H NMR (300 MHz, CDCl3):
d
8.11e7.18 (m, 20H, Bz), 6.26 (d, 1H,
J¼10.5 Hz, H-3), 5.82 (dd,1H, J¼10.5, 3.6 Hz, H-4), 5.75e5.73 (m,1H,
H-5), 4.76 and 4.24 (AB, 2H, J¼11.7 Hz, H-1), 4.05 (AB, 2H, J¼13.2,
1.5 Hz, H-6), 3.79e3.51 (m, 2H), 1.75e1.60 (m, 2H), 1.58e1.40 (m,
2H), 0.94 (t, 3H); 13C NMR (100 MHz, CDCl3):
d 165.8 (C, 2C), 165.7
this interesting
b
-glycosylation. Third, the conformation analysis of
(C), 165.6(C), 133.2e128.3 (CHarom), 99.41 (C), 70.10, 69.63, 68.43,
62.98 (CH2), 61.95 (CH2), 61.60 (CH2), 32.04 (CH2), 19.57 (CH2),
13.93; HRMS (ESI) calcd for C38H36O10Na 675.2207, found 675.2190.
Anal. Calcd for C38H36O10: C, 69.93; H, 5.56. Found: C, 69.79; H, 5.33.
the keto-oxonium ion (Fig. 2) indicated that 4H5 conformer A was
preferred over 5H4 conformer B (OBz group at C-3 favors equatorial
position, while C-4,5 favor axial position).35 The stereoelectronic
preference for nucleophilic addition of conformer B, which pro-
vides
Nucleophilic addition from the stereoelectronic preferred face of
conformer A, which is also less hindered, resulted in -anomer
product. So the stereoelectronic factors may be the major reason for
excellent -selectivity of this glycosylation.
In conclusion, fructopyranosyl trifluoroacetimidate 4 exhibited
good glycosyl donor properties. With mild condition and good
yield, this new glycosylation method will be a general method for
a
-glycoside, is unfavorable because of the big hindrance.
2.4. t-Butyl 1,3,4,5-tetra-O-benzoyl-
D
-fructopyranoside (6c)
25
b
Yield: 63%.
b
:
a
¼10:1; for
b
d
-anomer: [
8.18 (d, 2H, J¼8.1 Hz), 7.96 (t, 4H,
a]
ꢁ107.8 (c 1.0, CHCl3),
D
1H NMR (300 MHz, CDCl3):
b
J¼2.7 Hz), 7.84 (d, 2H, J¼3.3 Hz), 7.62e7.22 (m, 12H), 6.35 (d, 1H,
J¼12.0 Hz, H-3), 5.85e5.80 (m, 2H, H-4 and H-5), 5.12 and 4.28 (AB,
2H, J¼11.1 Hz, H-1), 4.33 and 4.07 (AB, 2H, J¼11.4, 1.8 Hz, H-6), 1.53
(s, 9H); 13C NMR (100 MHz, CDCl3):
d 165.9 (C), 165.8 (C), 165.7 (C),
fructopyranoside synthesis. The
b
-selectivity of glycosylation may
165.6 (C), 133.2e128.2 (CHarom), 101.4 (C), 70.2, 70.0, 68.2,
63.2(CH2), 61.8(CH2), 30.7; HRMS (ESI) calcd for C38H36O10Na
675.2207, found 675.2190.
be mainly determined by the stereoelectronic factors, following the
CurtineHammet principle, while NGP effect of 2-OBz did not work.
Further work should be done to evaluate the possible NGP effect of
1,4 or 5-OBz. Two crystals of
b
-
D
-fructopyranosides 6a and 6d with
2.5. Diosgenin-3-yl-1,3,4,5-tetra-O-benzoyl-b-D-fructopyr-
anoside (6d)
2C5 conformation were obtained. Several empirical anomeric de-
termination methods were checked and discussed, but none of
them alone could clearly judge the anomeric configuration.
Yield: 73%.
CDCl3):
b
only; [
a
]
25 ꢁ94.1 (c 1.0, CHCl3), 1H NMR (300 MHz,
D
d
8.10e7.25 (m, 20H), 6.34 (d, 1H, J¼10.5 Hz), 5.88 (dd, 1H,
J¼10.8, 3.3 Hz), 5.79 (m, 1H), 5.29 (m, 1H), 4.86 and 4.30 (AB, 2H,
J¼12 Hz), 4.48e4.36 (m, 2H), 4.11e3.94 (m, 1H), 3.82 (m, 1H),
3.52e3.34 (m, 2H), 2.54 (t, 1H, J¼14.4 Hz), 2.35e2.20 (m, 1H),
2.04e0.80 (m, 22H), 1.12 (s, 3H), 0.98 (d, 3H, J¼6.9 Hz), 0.81e0.78
2. Experimental section
2.1. 1,3,4,5-Tetra-O-benzoyl-
nyl)-trifluoroacetimidate (4)
b-D-fructopyranosyl-2-(N-phe-
(m, 6H). 13C NMR (100 MHz, CDCl3):
d 165.8 (2C), 165.7, 165.6, 140.2
(C, C-5), 133.2e128.3 (CHarom), 122.2 (C-6),109.3 (C, C-22), 100.4 (C,
C-20), 80.8 (C-16), 72.6, 70.2, 69.6, 68.2, 66.8 (CH2, C-26), 63.2 (CH2),
62.3 (CH2), 62.1, 56.4, 50.0,41.6, 41.3 (CH2), 40.3 (C), 39.7 (CH2), 37.4
(CH2), 36.7 (C), 32.1 (CH2), 31.9, 31.5, 31.4 (CH2), 30.3, 30.3 (CH2),
28.8 (CH2), 20.9 (CH2), 19.5, 17.1, 16.3, 14.5; HRMS (ESI) calcd for
To 1,3,4,5-tetra-O-benzoylfructose 3 (594 mg, 1 mmol) and N-
phenyl trifluoroacetimidoyl chloride (0.45 mL, 3 mmol) in acetone
(AR grade, 8 mL) was added K2CO3 (410 mg, 3 mmol), and the
mixture was stirred at rt for 2 h. The mixture was filtered, con-
centrated, and the residue was purified by column chromatography
(hexane/EtOAc 7:1) to obtain 4 as white foam (756 mg, 98%).
C
C
61H68O12Na 1015.4603, found 1015.4603. Anal. Calcd for
61H68O12: C, 73.77; H, 6.90. Found: C, 73.49; H, 7.06. IR (cmꢁ1
)
n
[
a]
25 ꢁ120 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3):
d
8.05e7.82
2951, 1731, 1449, 1278, 1065, 711.
D
(m, 8H, Ar), 7.60e7.24 (m, 14H, Ar), 7.09 (t, 1H, J¼7.6 Hz, Ar), 6.77 (d,
1H, J¼7.6 Hz, Ar), 6.41 (d, 1H, J3,4¼10.4 Hz, H3), 5.95 (dd, 1H, J¼10.4,
2.8 Hz, H4), 5.92 (m, 1H, H5), 5.33 and 4.97 (AB, 2H, J¼11.6 Hz, H-
2.6. 40-Methoxyphenyl-1,3,4,5-tetra-O-benzoyl-
b-D
-fructopyr-
anoside (6e)
6),4.33 (s, 2H, H1). 13C NMR (75 MHz, CDCl3):
d 165.6, 165.5, 165.3,
165.2, 143.0, 141.0 (q, J¼36 Hz, C]NPh), 133.5, 133.4, 133.3, 133.1,
129.8e128.3 (CHarom), 124.5, 118.9, 115.9 (q, J¼287 Hz, CF3) 104.9,
69.1, 68.1, 63.6, 62.9 ESIMS (m/z) calcd for C42H32NF3O10Na 790.19,
Yield: 81%.
CDCl3):
b
only; [
a
]
25 ꢁ107.8 (c 1.0, CHCl3), 1H NMR (300 MHz,
D
d
8.52e6.78 (m, 24H), 6.38 (d,1H, J¼10.5Hz, H-3), 5.99(dd,1H,
J¼10.5, 3.6 Hz, H-4), 5.82(m,1H, H-5), 4.60and 4.15 (AB, 2H, J¼11.7 Hz,

1132
F. Lin et al. / Tetrahedron 69 (2013) 1128e1132
H-1), 4.50 and 4.20 (AB, 2H, J¼12.9, 2.4 Hz, H-6), 3.70 (s, 3H); 13C NMR
1141.40. Anal. Calcd for C68H62O15: C, 72.97; H, 5.58. Found: C, 72.67,
H, 5.53. IR (cmꢁ1
nmax¼2923, 1731, 1267, 1101, 711.
(100 MHz, CDCl3):
d
165.7 (C), 165.6 (C), 165.5 (C, 2C), 156.4 (C), 146.7
)
(C), 133.9e114.8 (CHarom), 102.0 (C), 70.0, 69.5, 67.9, 62.7 (CH2), 62.5
(CH2), 55.6; HRMS (ESI) calcd for C41H34O11Na 725.1985, found
Acknowledgements
725.1982. IR (cmꢁ1
)
nmax¼1731, 1508, 1270, 1238, 1021, 716.
This work was supported by the Committee of Science
and Technology of Shanghai (10QB1403900), the National
Natural Science Foundation of China (20902059 & 21102170), and
MOST (2009ZX09301-007).
2.7. 1,3,4,5-Tetra-O-benzoyl- -fructopyranosyl-(2/6)-1,2:3,4-
b-D
di-O-isopropylidene- -galactopyranoside (6f)
a-D
Yield: 96%.
b
only; [
a
]
25 ꢁ139.3 (c 1.0, CHCl3), 1H NMR (300 MHz,
D
CDCl3):
d
8.10e7.26 (m, 20H), 6.35 (d, 1H, J¼10.5 Hz, H-30), 5.87 (dd,
Supplementary data
1H, J¼10.5, 3.6 Hz, H-40), 5.60e5.78 (m, 1H, H-50), 5.55 (d, 1H,
J¼4.8 Hz, H-1), 4.98 (d, 1H, J¼11.7 Hz), 4.71 (dd, 1H, J¼7.8, 2.1 Hz),
4.40e3.90 (m, 8H), 1.57, 1.50, 1.43, 1.36 (4s, 12H). 13C NMR (100 MHz,
1H and 13C NMR spectra and CIF files for compound 6a and 6d.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.11.058.
CDCl3):
d 165.8 (C), 165.71 (C), 165.70 (C), 165.6 (C), 133.2e128.3
(CHarom),109.5 (C),108.7 (C), 99.7 (C), 96.3 (CH, C-1), 71.0, 70.73, 70.69,
70.1, 69.6, 68.1, 66.7, 62.9 (CH2), 62.4 (CH2), 61.0 (CH2), 26.1 (CH3), 26.0
(CH3), 25.0 (CH3), 24.6 (CH3), ESIMS m/z calcd for C46H46O15Na 861.27,
found 861.20. Anal. Calcd for C46H46O15: C, 65.86; H, 5.53. Found: C,
References and notes
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65.90; H, 5.73. IR (cmꢁ1
)
n
2988, 1725, 1271, 1070, 705.
chim. Biophys. Acta 2001, 1510, 307.
3. Reddy, B. S. J. Nutr. 1999, 129, 1478S.
2.8. 1,3,4,5-Tetra-O-benzoyl-
b-D
-fructopyranosyl-(2/3)-1,2:5,
4. Taper, H. S.; Lemort, C.; Roberfroid, M. B. Anticancer Res. 1998, 18, 4123.
5. Huo, C.-X.; Wang, C.; Zhao, M.; Peng, S.-Q. Chem. Res. Toxicol. 2004, 17, 1112.
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12. Mueller, T.; Schneider, R.; Schmidt, R. R. Tetrahedron Lett. 1994, 35, 4763.
13. Yu, B.; Hui, Y. Chin. Chem. Lett. 1993, 4, 285.
6-di-O-isopropylidene-
D
-glucofuranoside (6g)
25
Yield: 85%,
NMR (300 MHz, CDCl3):
b
:
a
¼3.2:1.
b
anomer: [
a
]
D
ꢁ90.4 (c 1.0, CHCl3), 1H
d
8.10e7.13 (m, 20H), 6.29 (d,1H, J¼10.5 Hz,
H-30), 5.85 (dd, 1H, J¼10.5, 3.0 Hz, H-40), 5.82 (m, 1H, H-50), 5.65 (d,
1H, J¼3.3 Hz, H-1), 4.81 and 3.99 (AB, 2H, J¼13.2, 1.2 Hz, H-60), 4.75
and 4.32 (AB, 2H, J¼12.0 Hz, H-10), 4.60 and 4.48 (AB, 2H, J¼3.3 Hz,
H-6), 4.58e4.55 (m, 1H), 4.28 (dd, 1H, J¼8.7, 6.3 Hz), 4.17 (dd, 1H,
J¼8.7, 3.3 Hz), 4.05e4.01 (m, 1H),1.45 (s, 3H), 1.44 (s, 3H), 1.42 (s,
3H), 1.17 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 165.8 (C), 165.7 (C),
14. Raaijmakers, H. W. C.; Arnouts, E. G.; Zwanenburg, B.; Chittenden, G. J. F. Car-
bohydr. Res. 1994, 257, 293.
165.52 (C), 165.48 (C), 133.4e128.3 (CHarom), 112.2 (C), 110.0 (C),
104.8 (CH, C-1), 100.7 (C, C-20), 84.7, 81.8, 74.7, 71.7, 70.3, 70.0, 68.4
(CH2), 68.3, 64.1 (CH2), 62.5 (CH2), 26.9 (CH3), 26.3 (CH3, 2C), 25.5
(CH3); ESIMS m/z calcd for C46H46O15Na 861.27, found 861.21. Anal.
Calcd for C46H46O15: C, 65.86; H, 5.53. Found: C, 65.71; H, 5.68. IR
15. Tatibouet, A.; Yang, J.; Morin, C.; Holman, G. D. Bioorg. Med. Chem. 2000, 8, 1825.
16. Haraguchi, Y.; Yagi, A.; Koda, A.; Inagaki, N.; Noda, K.; Nishiokaf, I. J. Med. Chem.
1982, 25, 1495.
17. Cross, J. H.; Riney, C. J. In Treatment of Epilepsy, 3rd ed.; Shorvon, S., Perucca, E.,
Engel, J., Jr., Eds.; Wiley-Blackwell: Oxford, UK, 2009; pp 673e683.
18. Witkamp, R. F. Pharm. Res. 2010, 28, 1792.
19. Yang, J. Faming Zhuanli Shenqing 2010, CN 101856364A 20101013.
20. Sung’hwa, F.; Strik, A.; Regeling, H.; Zwanenburg, B.; Chittenden, G. J. F. Car-
bohydr. Res. 2006, 341, 846.
(cmꢁ1
anomer; 1H NMR (400 MHz, CDCl3):
d 8.10e7.23 (m, 20H), 6.34
) n 2986, 1728, 1274, 1069, 708.
a
(d, 1H, J¼10.2 Hz, H-30), 6.05 (d, 1H, J¼3.6 Hz, H-1), 5.88 (dd, 1H,
J¼10.2, 3.6 Hz, H-40), 5.78 (m, 1H, H-50), 4.81 (d, 1H, J¼12 Hz), 4.63
(m, 2H), 4.38e4.26 (m, 3H), 4.09e3.84 (m, 4H), 1.52 (s, 3H), 1.41 (s,
21. Goursaud, F.; Benvegnu, T. Carbohydr. Res. 2009, 344 136.
22. Kaji, E.; Kurimoto, E.; Saiga, R.; Matsuura, A.; Harada, K.; Nishino, T. Heterocycles
2005, 66, 453.
3H), 1.40 (s, 3H), 1.36 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 165.74
ꢀ
23. Ferrieres, V.; Benvegnu, T.; Lefeuvre, M.; Plusquellec, D.; Mackenzie, G.; Wat-
son, J. W.; Haley, J. A.; Goodby, J. W.; Pindak, R.; Durbin, M. K. J. Chem. Soc.,
Perkin Trans. 2 1999, 951.
24. Lichtenthaler, F. W.; Klotz, J.; Flath, F.-J. Liebigs Ann. 1995, 2069.
25. Yu, B.; Tao, H. Tetrahedron Lett. 2001, 42, 2405.
26. Yu, B.; Tao, H. J. Org. Chem. 2002, 67, 9099.
27. Yu, B.; Sun, J. Chem. Commun. 2010, 4668 and references therein.
28. Lian, G.; Gao, Q.; Lin, F. Carbohydr. Res. 2008, 343, 2992.
29. Schmidt, R. R.; Michel, J.; Roos, M. Liebigs Ann. Chem. 1984, 1342.
30. (a) Heskamp, B. M.; Veeneman, G. H.; van der Marel, G. A.; van Boeckel, C. A. A.;
van Boom, J. H. Tetrahedron 1995, 51, 5657; (b) Heskamp, B. M.; Noort, D.; van
der Marel, G. A.; van Boom, J. H. Synlett 1992, 713.
(2C), 165.50, 165.3, 133.0e128.1, 112.1, 106.3 (CH, C-1), 100.8, 99.3,
84.1, 79.0, 75.1, 71.2, 70.1, 69.5, 68.2, 62.9, 62.4, 62.2, 29.4, 27.3, 26.7,
22.7; ESIMS m/z calcd for C46H46O15Na 861.27, found 861.23. Anal.
Calcd for C46H46O15: C, 65.86; H, 5.53. Found: C, 65.64; H, 5.51.
2.9. 1,3,4,5-Tetra-O-benzoyl-
b-D-fructopyranosyl-(2/1)-2, 3,
4, 6-tetra-O-benzyl- -glucopyranoside (6h)
a-D
Yield: 39%. 1H NMR (300 MHz, CDCl3):
d 8.20e7.15 (m, 40H), 6.47
31. Matsumori, N.; Kaneno, D.; Murata, M.; Nakamura, H.; Tachibana, K. J. Org.
Chem. 1999, 64, 866.
(d, 1H, J¼10.5 Hz, H-30), 5.80e5.76 (m, 2H, H-40 and H-50), 5.51 (d,
1H, J¼3.3 Hz, H-1), 4.96e4.51 (m, 10H), 4.28e4.01 (m, 4H),
32. Allscher, T.; Klufers, P. Acta Crystallogr. 2010, C66, o321.
33. Compound 4 and 5b in CH2Cl2, THF or Et2O at ꢁ60 ꢀC with TMSOTf (0.06 equiv)
for 30 min, TLC showed 50% conversion, quench at ꢁ60 ꢀC by NEt3, after col-
umn chromatography, no ortho-ester was obtained, but only normal glycosyl-
ation product or hydrolyzed product.
34. Crich, D.; Hu, T.; Cai, F. J. Org. Chem. 2008, 73, 8942.
35. Lucero, C. G.; Woerpel, K. A. J. Org. Chem. 2006, 71, 2641 and references therein.
3.79e3.66 (m, 4H). 13C NMR (100 MHz, CDCl3):
d 165.6 (C),165.5 (C),
138.0e127.6 (CHarom), 101.3 (C, C-20), 91.7 (CH, C-1), 82.8, 78.8, 77.9,
76.0 (CH2), 75.3 (CH2), 74.3 (CH2), 73.5 (CH2), 72.0, 69.9, 68.9 (CH2),
67.3, 63.5 (CH2). ESIMS (m/z) calcd for C68H62O15Na 1141.40, found