Novel synthesis of oligosaccharides linked with carbamate and urea bonds utilizing modified Curtius rearrangement

Article abstract of DOI:10.1016/j.tet.2008.06.089

We describe a novel synthesis of various carbamate- and urea-linked disaccharides stereospecifically using sugar carboxylic acids and sugar alcohols or sugar amines by the modified Curtius rearrangement. In this reaction, the reactivity of each hydroxyl g

Full text of DOI:10.1016/j.tet.2008.06.089

Tetrahedron 64 (2008) 8780–8788
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel synthesis of oligosaccharides linked with carbamate and urea bonds
utilizing modified Curtius rearrangement
*
Daisuke Sawada, Shinya Sasayama, Hideyo Takahashi, Shiro Ikegami
School of Pharmaceutical Sciences, Teikyo University, Sagamiko, Sagamihara, Kanagawa 229-0195, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 June 2008
Received in revised form 21 June 2008
Accepted 24 June 2008
Available online 27 June 2008
We describe a novel synthesis of various carbamate- and urea-linked disaccharides stereospecifically
using sugar carboxylic acids and sugar alcohols or sugar amines by the modified Curtius rearrangement.
In this reaction, the reactivity of each hydroxyl group in glucose as an acceptor has been disclosed.
Furthermore, we applied this method to the synthesis of carbamate-linked oligosaccharides including
a dendritic molecule.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Carbamate
Urea
Carbohydrate
Rearrangement
Stereospecific synthesis
1. Introduction
utilized this reaction for stereospecific synthesis of these oligo-
saccharides. Here, we described the novel stereospecific synthesis
Oligosaccharides are essential constituents in our body and play
an important role in nature, often by conjugating the various
peptides and lipids and as nucleic acids.1 Many chemists have made
much effort for the stereoselective synthesis of oligosaccharides,
which has many problems even now. One of the reasons why oli-
gosaccharide synthesis still involves various difficulties is due to the
instability of the glycoside bond, which is acetal linkages. Recently,
the novel glycosaccharides in which sugars were linked each other
with carbamates or ureas other than acetals were reported,2 and
their bonds should be more stable than acetal bonds to provide the
more stable oligosaccharide analogs. So the carbamate- or urea-
linked glycosaccharides would make it possible to synthesize the
complex oligosaccharide, which could be good mimics of oligo-
saccharide biomolecules. Furthermore, these novel oligosaccha-
rides would be expected to show unique properties which could be
good tools for the chemical biology and material sciences. In this
time, we planed the synthesis of carbamate- and urea-linked oli-
gosaccharides using Curtius rearrangement with sugar carboxylic
acids and sugar alcohols or sugar amines in a stereospecific manner
(Scheme 1).3 Curtius rearrangement is known to proceed via an
isocyanate intermediate with retaining the configuration of the
chiral center adjacent to the reactive carboxylic acid, and we
of various types of carbamate- and urea-linked oligosaccharides by
the modified Curtius rearrangement.
2. Results and discussions
We started this synthetic method at obtaining the sugar
a- and
b-1-carboxylic acids stereospecifically, and the known lactones 1–
3,4 derived from glucose, galactose, and mannose, respectively,
were used for the synthesis of the carboxylic acids (Scheme 2).
According to Ref. 5, gluconolactone 1 and galactonolactone 2 were
transformed into both stereoisomers of alcohols 4–75 and they
were oxidized6 to carboxylic acids 9–12,5,7 the substrates for the
Curtius rearrangement. Mannolactone 3, however, gave only
cohol 8, which was oxidized to -carboxylic acid 14, because of the
steric hindrance of the 2 -benzyloxy group in the hydroboration
reaction. The inversion of the stereochemistry from the -carbox-
ylic acid 14 to the -carboxylic acid 13 was successfully achieved in
b-al-
b
b
b
a
the efficient conversion yield as shown in Scheme 3. Thus, we could
obtain both the stereoisomers of sugar 1-carboxylic acids 9–14
derived from glucose, galactose, and mannose.
Firstly, we investigated the synthesis of carbamate-linked di-
saccharides using the carboxylic acids 9–14 and alcohols 15–218
(Table 1). The typical reaction conditions are as follows: a carbox-
ylic acid and 2 equiv of an alcohol were refluxed in the presence of
2 equiv of diphenyl phosphorylazide (DPPA)9 and base.3 In some
cases, the additional catalyst, Ag2CO3, increased the yield (entries
* Corresponding author. Tel./fax: þ81 42 685 3714.
E-mail address: somc@pharm.teikyo-u.ac.jp (S. Ikegami).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.089

D. Sawada et al. / Tetrahedron 64 (2008) 8780–8788
8781
stereospecific synthesis of
carbamate- or urea-linked saccharides
OR
OR
O
OR
O
OR
RO
RO
RO
RO
RO
O
O
RO
RO
sugar-OH
O
or
RO
N
H
X
CO2H
NCO
OR
sugar-NH2
OR
OR
OR
OR
X = O or NH
OR
OR
O
OR
O
OR
O
RO
RO
RO
RO
RO
RO
O
O
RO
RO
sugar-OH
or
N
H
X
CO2H
NCO
OR
sugar-NH2
OR
OR
OR
OR
X = O or NH
Scheme 1.
O
O
O
TEMPO
O
O
BnO
BnO
OH
BnO
BnO
OH
OBn
1
2
1
2
1) Cp2TiCl2, MeLi
BnO
BnO
NaClO, NaClO2
4
4
Et2O, toluene
OBn
phosphate buffer
OBn
2) BH3·THF
H2O2, THF
CH3CN
OBn
OBn
OBn
4 (Glcα): 1α, 2α, 4α
5 (Glcβ): 1β, 2α, 4α
6 (Galα): 1α, 2α, 4β
7 (Galβ): 1β, 2α, 4β
8 (Manβ): 1β, 2β, 4α
9
(Glcα): 1α, 2α, 4α y. 95%
1 (Glc): 2α, 4α
2 (Gal): 2α, 4β
3 (Man): 2β, 4α
ref. 5
10 (Glcβ): 1β, 2α, 4α y. 99%
11 (Galα): 1α, 2α, 4β y. 98%
12 (Galβ): 1β, 2α, 4β y. 98%
14 (Manβ): 1β, 2β, 4α y.83%
Scheme 2. Synthesis of sugar carboxylic acid.
O
O
O
O
MeI
DBU
LiOH•H2O
BnO
BnO
OH
BnO
BnO
OH
OBn
DMF
y. 21%
(conv. y. 100%)
NaHCO3
DMF
y. 100%
MeOH, THF
H2O
y. 99%
OBn
OBn
OBn
14
13
Scheme 3. Synthesis of mannose derived b-carboxylic acid.
4–6, 8, 15, 17, 18). Although the carboxylic acids 9–14 gave similar
results, the -carboxylic acids 10, 12, and 14 showed better re-
activity and afforded better yield than the corresponding -car-
boxylic acids 9, 11, and 13, respectively. Also, the -carbamate
linkages seemed to be rather unstable than the -carbamate link-
To disclose the reactivity of each hydroxyl group in a sugar as an
acceptor, we planned such reaction procedure that carboxylic acid
10 was reacted with the mixture of each 1 equiv of sugar alcohols
16–19, for examining the reactivity of each hydroxyl group at the 2-
to 6-position in the glucose derivatives, respectively (Scheme 4).
The substrate 10 completely disappeared under the reaction con-
ditions and the carbamate-linked disaccharides 32–35 were
obtained in the ratio of 3.4:1.0:1.8:4.4 (32/33/34/35). This result
shows that the order of the reactivity of the each hydroxyl groups is
6-, 2-, 4-, 3-position, and also indicates the unique reactivity of
acceptors in this Curtius rearrangement.
Then, we tried the deprotection of the disaccharides 22–39
(Table 2). The representative method to remove a benzyl group
worked very well, and the deprotected disaccharides 41–57 were
obtained in excellent yield by Pd on carbon and H2 without af-
fecting both the carbamate bond and any stereochemistry, except
giving some unidentified decomposed product from 22.12
Next, we tried the synthesis of carbamate-linked oligosaccha-
rides on the basis of the previous observation. Carboxylic acid 583
and alcohol 593 are thought to be useful for the synthesis of the
linear oligosaccharide chain (Scheme 5). The same equivalent of 58
and 59 were reacted with 2 equiv of DPPA and triethylamine to give
the desired disaccharides 60 in 84% yield. Using compound 60, the
elongation both at the 1-carboxylic acid and/or at the 60-hydroxyl
b
a
a
b
ages under these reaction conditions, and, for example, in entries 3
and 6 in Table 1, the partial decomposition of the products took
place, and that would cause the relatively lower yields (56% yield in
entry 3 and 59% yield in entry 6). Among the acceptors 15–21, the
primary alcohol 19 (Glc-6-OH) showed the best reactivity and in-
terestingly the hemiacetal (Glc-1-OH) 15 gave the good results.10 It
seemed that the rate-determining step of the reaction was the
addition of the alcohol to the isocyanate intermediate, because the
transformation of the carboxylic acid to the isocyanate was thought
to be fast by the TLC analysis. Therefore, the reactivity should de-
pend on the steric hindrance of both an acceptor and a donor
dominantly, as shown in the evidence that alcohol 19 was the most
reactive among the acceptors. As a base, K2CO3 should be used for
the less reactive acceptors to accelerate their nucleophilicity.11 And
the additional catalyst, Ag2CO3, was also effective to promote the
addition of the acceptor by coordinating the isocyanate. Thus, it was
found that all of the
be obtained stereospecifically by the modified Curtius rearrange-
ment using - and -sugar carboxylic acids 9–14.
a- and b-carbamate-linked disaccharides could
a
b

8782
D. Sawada et al. / Tetrahedron 64 (2008) 8780–8788
Table 1
Synthesis of carbamate-linked disaccharides
OBn
O
OBn
OBn
OR
O
BnO
BnO
BnO
BnO
BnO
O
RO
RO
O
O
1'
1
N
H
O
OH
OBn
15: Glc-1-OH
BnO
CO2H
OR'
OBn
OBn
OR
22 ~ 30
9 (Glcα): 2α, 4α
11 (Galα): 2α, 4β
13 (Manα): 2β, 4α
DPPA, K2CO3 (2eq)
benzene, reflux
+
OR6
OBn
O
OBn
OR
R4O
R3O
BnO
BnO
BnO
O
O
RO
O
O
1'
1
OMe
N
H
O
BnO
CO2H
RO
OR'
OR2
OBn
OBn
OR
31 ~ 39
16 (Glc-2-OH ): 2α, 4α, R2 = H, R3~6 = Bn
17 (Glc-3-OH): 2α, 4α, R3 = H, R2,4~6 = Bn
18 (Glc-4-OH): 2α, 4α, R4 = H, R2~3,6 = Bn
19 (Glc-6-OH): 2α, 4α, R6 = H, R2~4 = Bn
20 (Gal-4-OH): 2α, 4β, R4 = H, R2~3,6 = Bn
21 (Man-2-OH): 2β, 4α, R2 = H, R3~6 = Bn
10 (Glcβ): 2α, 4α
12 (Galβ): 2α, 4β
14 (Manβ): 2β, 4α
Entry
Carboxylic acid
Alcohol
Time (h)
Yield (%)
Entry
Carboxylic acid
Alcohol
Time (h)
Yield (%)
1
2
3
9
9
9
9
9
9
9
11
13
15
16
17
18
19
20
21
19
19
12
20
34
29
29
29
29
50
15
82 (22: Glc
64 (23: Glc
56 (24: Glc
78 (25: Glc
66 (26: Glc
59 (27: Glc
65 (28: Glc
87 (29: Gal
a
a
a
a
a
10-Glc 1)
10-Glc 2)
10-Glc 3)
10-Glc 4)
10-Glc 6)
10
11
12
13
10
10
10
10
10
10
10
12
14
15
16
17
18
19
20
21
19
19
8
10
29
18
8
14
15
7
94 (31: Glc
73 (32: Glc
87 (33: Glc
89 (34: Glc
98 (35: Glc
79 (36: Glc
71 (37: Glc
95 (38: Gal
b
10-Glc 1)
b
b
b
b
b
10-Glc 2)
10-Glc 3)
10-Glc 4)
10-Glc 6)
10-Gal 4)
10-Man 2)
10-Glc 6)
10-Glc 6)
4a
5a
6a
7
14b
15a
16
a
10-Gal 4)
10-Man 2)
10-Glc 6)
a
b
b
8a
9
a
17a
18a
85 (30: Man
a
10-Glc 6)
6
92 (39: Man
b
a
Ag2CO3(0.1 equiv) was added.
Triethylamine was used as a base.
b
OR6
OR
OBn
OBn
DPPA, K2CO3 (2eq)
benzene, reflux
R4O
R3O
RO
RO
BnO
BnO
BnO
BnO
O
O
O
O
O
+
1'
1
N
H
O
OMe
OR'
CO2H
OR2
OR
OBn
OBn
mixture of 16 ~ 19
(1 eq each to 10)
10
32 : 33 : 34 : 35= 3.4 : 1.0 : 1.8 : 4.4
Scheme 4.
Table 2
Deprotection of carbamate-linked disaccharides
OH
OH
OBn
OR
HO
HO
BnO
BnO
O
O
RO
O
O
O
O
H2, Pd•C
1'
1
1'
1
HO
N
H
O
HO
MeOH/CH2Cl2
OR'
N
H
O
RO
OR'
OH
OH
OBn
OR
40 ~ 57
R' = Me (except 40 and 49)
22 ~ 39
Entry
Substrate
Yield (%)
Entry
Substrate
Yield (%)
1
2
3
4
5
6
7
8
9
22
23
24
25
26
27
28
29
30
- (40)
99 (41)
99 (42)
97 (43)
95 (44)
92 (45)
95 (46)
71 (47)
100 (48)
10
11
12
13
14
15
16
17
18
31
32
33
34
35
36
37
38
39
99 (49)
97 (50)
99 (51)
95 (52)
99 (53)
95 (54)
95 (55)
98 (56)
91 (57)

D. Sawada et al. / Tetrahedron 64 (2008) 8780–8788
8783
OMPM
OMPM
O
OH
BnO
DPPA, Et3N (2eq)
O
O
BnO
BnO
BnO
BnO
benzene, reflux
O
+
BnO
N
H
BnO
O
y. 84%
CO2H
CO2Me
OBn
OBn
OBn
58
O
60
59
BnO
CO2Me
OBn
OMPM
BnO
BnO
DPPA, K2CO3 (4eq)
Ag2CO3 (0.1eq)
benzene, reflux
O
O
OR1
N
H
O
OBn
R2O
R2O
59 (2eq)
y. 85%
BnO
O
O
O
LiOH, MeOH
THF, H2O
y. 95%
N
H
O
61
BnO
CO2H
OR2
OBn
R2O
(route a)
O
O
60
R2O
N
H
O
OH
OR2
(route b)
R2O
DDQ
CH2Cl2, H2O
y. 81%
BnO
BnO
O
O
O
R2O
CO2Me
DPPA, K2CO3 (4eq)
benzene, reflux
N
H
BnO
O
OR2
OBn
58 (2eq)
y. 88%
63: R1 = MPM, R2 = Bn
64: R1 = H, R2 = H
O
Pd•C, H2,
MeOH, CH2Cl2
y. 90%
62
BnO
CO2Me
OBn
Scheme 5. Synthesis of linear trisaccharide.
group would be possible, and disaccharide 60 was transformed into
the carboxylic acid 61 by hydrolysis (95% yield, route a) or into the
alcohol 62 by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
and H2O (81% yield, route b). The modified Curtius rearrangement
using the above carboxylic acids and alcohols, 59 and 61 (route a) or
58 and 62 (route b), afforded the same trisaccharide 63 in 85 and
88% yield, respectively. All the benzyl protections of 63 were re-
moved by Pd on carbon and H2 to give compound 64, and thus the
deprotected trisaccharide was obtained in the two independent
ways.
Then, we embarked on the synthesis of a sugar dendritic mol-
ecule as an application of the present methodology (Scheme 6). The
BnO
BnO
MP
O
DPPA (8.0 eq)
DPPA (8.0 eq)
K2CO3 (8.0 eq)
10 (4.0 eq)
MP
O
O
K2CO3 (8.0 eq)
Et3SiH (5.0 eq)
TFA (5.0 eq)
O
O
O
10 (4.0 eq)
O
O
BnO
N
H
O
O
OAllyl
CH2Cl2
benzene, reflux
benzene, reflux
OBn
O
O
HO
OAllyl
OBn
OBn
y. 98%
y. 89%
OH
y. 84%
HN
OBn
OBn
66
65
(α: 59%)
(β: 25%)
OBn
OBn
BnO
OBn
OBn
BnO
BnO
BnO
BnO
BnO
OBn
O
O
O
O
BnO
O
OBn
H
N
BnO
HN
O
O
NH
BnO
HN
O
O
O
OBn
OBn
OBn
DPPA (12.0 eq)
Et3N (12.0 eq)
10 (6.0 eq)
O
BnO
BnO
BnO
OBn
OBn
BnO
BnO
O
O
O
O
O
O
O
H
N
Ag2CO3 (0.6 eq)
N
O
O
O
O
N
O
O
OR
OBn
OBn
H
H
OBn
O
benzene, reflux
OBn
O
O
OBn
O
HN
OBn
HN
OBn
y. 77%
O
OBn
OBn
BnO
BnO
PdCl2 (2.4 eq),
CH2Cl2, H2O
y. 86%
67: R = Allyl
68: R = H
69
Scheme 6. Synthesis of a dendritic molecule.

8784
D. Sawada et al. / Tetrahedron 64 (2008) 8780–8788
known monosaccharide 65,13 which is soluble in benzene was
reacted with 4 equiv of 10 and 8 equiv of DPPA and K2CO3 to afford
the trisaccharide 66 in 84% yield. Compound 66, which had
equipped two carbamate linkages in one step, was a mixture of
anomeric isomers, which could be separated by column chroma-
3. Conclusion
We have developed a novel stereospecific synthesis of the a-
and b-carbamate- and urea-linked disaccharides by the modified
Curtius rearrangement. In these reactions, the reactivity of each
hydroxyl group of glucose as an acceptor has been disclosed.
Furthermore, we demonstrated the oligosaccharide syntheses by
applying this method and the trisaccharide 64 could be easily
synthesized in two different ways. Finally, the synthetic challenge
to the dendritic molecule 69 involving one-step construction of
two carbamate linkages has been accomplished. Hopefully, this
methodology would make it possible to synthesize more complex
and new glycoconjugates exhibiting interesting properties, and
contribute to the chemical biology and material science.
tography, and the major a-isomer was used for the further syn-
thesis for precise structural evidence. The deprotection of the
methoxybezylidene group of 66 was achieved by Et3SiH and tri-
fluoroacetic acid in 98% yield, and the resultant 4,6-diol was reacted
with 10 as the above reaction to afford the pentasaccharide 67 in
89% yield. The removal of the allyl group in compound 67 resulted
in the partial decomposition of the substrate under various con-
ditions. Fortunately, it was found that the deprotection using PdCl2
in CH2Cl2 and H2O proceeded smoothly and the desired hemiacetal
68 was obtained in 86% yield. We investigated the final Curtius
rearrangement to 68, however, it was difficult due to the steric
hindrance around the reactant hemiacetal group. After many at-
tempts, the reaction with 6 equiv of compound 10, 12 equiv of
DPPA, triethylamine, and 0.6 equiv of Ag2CO3 successfully afforded
the hexasaccharide 6914 in 77% yield. As above, we have finally
developed the new way for the synthesis of unique dendritic
molecule having a sugar core.
Now we established the synthetic methodology of carbamate-
linked saccharides, then we shifted the next investigation to
explore the synthesis of urea-linked saccharides using Curtius
rearrangement with aminosugars 7015 and 7116 as acceptors
(Scheme 7). To form a urea linkage from a carboxylic acid and an
amine, a carboxylic acid must be converted to the intermediate
isocyanate before reacting an amine, to avoid the transformation of
the amide. So, we refluxed the carboxylic acid 9 or 10 with 2 equiv
of DPPA and triethylamine for 1 h in advance, and then 1.5 equiv of
amine 70 or 71 was added to the reaction mixture. The whole
mixture was further refluxed until the intermediate isocyanate
disappeared by the TLC analysis (1–5 h) and finally the urea-linked
disaccharides 72–75 were obtained in excellent yield. With the
aminosugar 70, CH3CN was used as a co-solvent, because of the
insoluble property of 70 in benzene, in which 2-amino group se-
lectively reacted with the isocyanate. The removal of all the benzyl
groups and the benzylidene group of the disaccharides was suc-
cessfully achieved by Pd on carbon and H2 in MeOH and CH2Cl2
without affecting the urea linkage. As above, it was found that both
4. Experimental
4.1. General procedures
Infrared (IR) spectra were measured on a Jasco FT/IR-8000
Fourier transform infrared spectrometer. Proton nuclear magnetic
resonance (1H NMR) spectra and carbon nuclear magnetic reso-
nance (13C NMR) spectra were recorded with a JEOL JNM-GSX400,
600 (400, 600 MHz) pulse Fourier transform NMR spectrometer in
CDCl3 solution. Low-resolution mass spectra (MS) and high-reso-
lution (HR) mass spectra were obtained with a JEOL JMS-SX102A
mass spectrometer. Optical rotations were determined using a Jasco
DIP-370 digital polarimeter. Thin-layer chromatography (TLC) was
performed on precoated plates (Merck TLC aluminum sheets silica
60 F254) with detection by UV light or with phosphomolybdic acid
in ethanol/H2O followed by heating. Except for special cases as
mentioned, column chromatography was performed using SiO2
(Wakogel C-300, Wako).
4.2. General procedure for the oxidation of sugar alcohols
The reaction of 4 is described as a representative example.
4.2.1. 1-(2,3,4,6-Tetra-O-benzyl-a-D-glucopyranosyl)formic acid (9)
To the solution of 4 (524 mg, 0.944 mmol) in CH3CN (4.7 mL)
were added TEMPO (21 mg, 0.13 mmol) and NaH2PO4 (0.67 M,
3.5 mL), and the mixture was warmed at 35 ꢀC. A solution of NaClO
(0.47 mL, 0.25%) and NaClO2 (0.94 mL, 2 M) was added to the
mixture over a period of 1 h. Then, saturated aqueous Na2S2O3 was
the a- and b-urea-linked disaccharides could be obtained stereo-
specifically by Curtius rearrangement using
a- and b-sugar
carboxylic acids 9 and 10.
Ph
Ph
O
OBn
O
OH
O
O
OH OH
O
BnO
BnO
HO
HO
HO
HO
O
O
O
O
1'
1'
O
O
HO
OMe
N
H
N
H
N
H
N
H
NH2
OBn
OMe
OH
OMe
OBn
O
70 (Glc-2-NH2)
72: 1'α y. >99%
73: 1'β y. 99%
76: 1'α y. >99%
77: 1'β y. >99%
BnO
BnO
DPPA, Et3N (2eq)
benzene, (CH3CN)
reflux
H2, Pd•C
MeOH/CH2Cl2
+
CO2H
OBn
NH2
OBn
OH
9 (Glcα)
10 (Glcβ)
BnO
BnO
BnO
BnO
HO
HO
O
O
O
O
O
1'
1'
O
OMe
OBn
O
OMe
OH
OMe
N
H
N
H
BnO
N
H
N
H
HO
OBn
OBn
OH
71 (Glc-6-NH2)
OBn
OH
78: 1'α y. >99%
79: 1'β y. 99%
74: 1'α y. >99%
75: 1'β y. 92%
Scheme 7. Synthesis of urea-linked disaccharides.

D. Sawada et al. / Tetrahedron 64 (2008) 8780–8788
8785
carefully added to the mixture at 0 ꢀC and the whole mixture was
4.3.1. Methyl 2,3,6-tri-O-benzyl-4-O-[(N-2,3,4,6-tetra-O-benzyl-
-glucopyranosyl)carbamoyl]- -glucopyranoside (25)
To the mixture of carboxylic acid 9 (38 mg, 0.066 mmol) and
a-
stirred at room temperature. After 30 min, 2 N HCl was added to the
mixture, which was acidified (pH 2). The aqueous layer was
extracted with AcOEt (20 mL, three times) and the combined or-
ganic layers were washed with brine, dried over Na2SO4, and con-
centrated to give a residue, which was purified by silica gel flash
chromatography (hexane/AcOEt, 1:1) to afford the desired product
D
a-D
alcohol 18 (63 mg, 0.132 mmol) in benzene (7 mL) were added
K2CO3 (18 mg, 0.132 mmol), DPPA (0.029 mL, 0.132 mmol), and
Ag2CO3 (1.8 mg, 0.0066 mmol) and the whole mixture was
refluxed for 29 h. Then, saturated aqueous NH4Cl was added to
the mixture at 0 ꢀC followed by the addition of AcOEt (20 mL).
The organic layer was separated and the aqueous layer was fur-
ther extracted twice with AcOEt (20 mL). The combined organic
layers were washed with brine, dried over Na2SO4, and con-
centrated to give a residue, which was purified by silica gel flash
chromatography (hexane/AcOEt, 4:1) to afford the desired prod-
uct 25 (53 mg, 78%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
9 (508 mg, 95%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
d 9.18
(m, 1H), 7.32–7.15 (m, 20H), 4.83 (d, J¼11.2 Hz, 1H), 4.77 (d,
J¼11.0 Hz, 1H), 4.75–4.73 (m, 1H), 4.73 (d, J¼11.7 Hz, 1H), 4.70 (d,
J¼11.7 Hz, 1H), 4.62–4.59 (m, 2H), 4.50–4.47 (m, 2H), 4.31–4.28 (m,
1H), 3.99–3.91 (m, 2H), 3.73–3.65 (m, 3H); 13C NMR (100 MHz,
CDCl3) d 172.72, 137.95, 137.76, 137.47, 136.79, 128.17, 128.13, 128.10,
128.02, 127.92, 127.83, 127.74, 127.67, 127.56, 127.51, 127.49, 127.45,
80.89, 77.24, 76.74, 74.71, 74.23, 74.10, 73.70, 73.32, 73.22, 72.79,
d
7.27–7.01 (m, 35H), 5.53 (d, J¼5.1 Hz, 1H), 5.48 (m, 1H), 4.96
68.45; MS (FABdNBAþNaI): m/z 591 (MþNa)þ; HRMS (FABdN-
(t, J¼9.5 Hz, 1H), 4.85 (d, J¼11.0 Hz, 1H), 4.79 (d, J¼11.5 Hz, 1H),
4.77–4.68 (m, 4H), 4.67 (d, J¼11.0 Hz, 1H), 4.58–4.56 (m, 2H),
4.55–4.28 (m, 6H), 3.90 (t, J¼9.5 Hz, 1H), 3.81 (m, 1H), 3.70 (dd,
J¼5.1, 9.3 Hz, 1H), 3.63–3.53 (m, 7H), 3.45 (dd, J¼5.9, 10.8 Hz, 1H),
24
BAþNaI): calcd for C35H36NaO7 591.2359, found 591.2348; [
a]
D
ꢁ9.70 (c 0.26, CHCl3); IR (neat, cmꢁ1): 1734 (C]O).
4.2.2. 1-(2,3,4,6-Tetra-O-benzyl-
a-
D-mannopyranosyl)formic acid
3.36 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 154.65 (C]O), 138.50,
(13)
138.20, 137.96, 137.89, 137.76, 137.74, 136.87, 128.38, 128.35,
128.34, 128.32, 128.28, 128.25, 128.19, 128.11, 128.07, 127.96,
127.91, 127.87, 127.83, 127.78, 127.73, 127.68, 127.64, 127.58, 127.48,
127.41, 127.36, 127.33, 98.07, 81.81, 79.19, 77.21, 77.04, 76.88,
75.52, 75.25, 74.94, 73.60, 73.53, 73.49, 73.42, 72.11, 70.71, 69.30,
68.89, 55.35; MS (FABdNBAþNaI) m/z 1052 (MþNa)þ; HRMS
To the solution of 14 (305 mg, 0.536 mmol) in DMF (4 mL) were
added NaHCO3 (86 mg, 1.07 mmol) and methyl iodide (95 L,
m
1.61 mmol), and the mixture was stirred at ambient temperature
for 19 h. Then, water was added to the mixture, extracted with
AcOEt (20 mL three times), and the combined organic layers were
washed with brine, dried over Na2SO4, and concentrated to give
a residue, which was purified by silica gel flash chromatography
(hexane/AcOEt, 5:1) to afford the ester (312 mg, 100%) as a colorless
oil. The ester was successively used in the next step. To the solution
of the ester (71 mg, 0.122 mmol) in DMF (1 mL) was added DBU
(FABdNBAþNaI) calcd for
C63H67NNaO12 1052.4561, found
24
1052.4536; [
a
]
D
þ8.17 (c 0.55, CHCl3); IR (neat, cmꢁ1) 1721
(C]O), 3285 (NH).
4.4. General procedure for the deprotection of carbamate-
linked disaccharides
(40 mL, 0.268 mmol) and the mixture was stirred at ambient tem-
perature for 48 h. Then, saturated aqueous NH4Cl was added to the
mixture at 0 ꢀC followed by the addition of AcOEt (20 mL). The
organic layer was separated and the aqueous layer was further
extracted twice with AcOEt (20 mL). The combined organic layers
were washed with brine, dried over Na2SO4, and concentrated to
give a residue, which was purified by silica gel flash chromatogra-
The reaction of 26 is described as a representative example.
4.4.1. Methyl 6-O-[(N-a-D-glucopyranosyl)carbamoyl]-a-D-
glucopyranoside (44)
To the solution of carbamate 26 in dichloromethane (1 mL) and
methanol (6 mL) was added Pd on carbon (3.3 mg), and the mixture
was stirred under hydrogen for 26 h. Then, the mixture was evap-
orated and the residue was purified by silica gel flash chromatog-
raphy (dichloromethane/methanol, 4:1) to afford the desired
product 44 (12 mg, 95%) as a white powder: 1H NMR (600 MHz,
phy (hexane/AcOEt, 6:1–5:1) to afford the
a colorless oil with the recovered substrate,
The -ester was successively used in the next step. To the solution
of the -ester (60 mg, 0.103 mmol) in THF (1 mL), MeOH (1 mL), and
b-ester (15 mg, 21%) as
a-ester (56 mg, 79%).
b
b
water (0.3 mL) was added LiOH$H2O (9 mg, 0.206 mmol) at 0 ꢀC,
and the mixture was stirred for 10 h at ambient temperature. Then,
1 N HCl was added to the mixture at 0 ꢀC followed by the addition
of AcOEt (20 mL). The organic layer was separated and the aqueous
layer was further extracted twice with AcOEt (20 mL). The com-
bined organic layers were dried over Na2SO4 and concentrated to
give a residue, which was purified by silica gel flash chromatogra-
phy (hexane/AcOEt, 1:1) to afford the desired carboxylic acid 13
CD3OD)
d
5.36 (d, J¼5.2 Hz, 1H), 4.65 (d, J¼3.6 Hz, 1H), 4.37–4.35
(m, 1H), 4.27 (dd, J¼5.8, 11.8 Hz, 1H), 3.75 (dd, J¼2.2, 11.8 Hz, 1H),
4.72–3.69 (m, 1H), 3.67–3.56 (m, 4H), 3.45–3.43 (m, 1H), 3.41–3.38
(m, 4H), 3.32–3.28 (m, 2H); 13C NMR (150 MHz, CD3OD)
d 159.03,
101.27, 80.71, 74.98, 74.79, 74.06, 73.46, 71.79, 71.60, 71.32, 65.57,
62.73, 55.75; MS (FABdNBAþNaI) m/z 422 (MþNa)þ; HRMS
(FABdNBAþNaI) calcd for
C14H25NNaO12 422.1275, found
24
(58 mg, 99%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
d
7.50–
422.1274; [
a]
þ13.1 (c 0.37, CH3OH); IR (neat, cmꢁ1) 1711 (C]O),
D
7.26 (m, 18H), 7.18–7.14 (m, 2H), 4.86 (d, J¼11.0 Hz, PhCH2, 1H), 4.74
(d, J¼12.2 Hz, 1H), 4.70–4.57 (m, 3H), 4.29 (m, 1H), 4.01–3.92 (m,
2H), 3.76 (m, 2H), 3.61 (dd, J¼2.7, 8.6 Hz, 1H); 13C NMR (100 MHz,
3738–3030 (OH).
4.4.2. [2,3,4-Tri-O-benzyl-6-O-{(N-2,3,4-tris-O-benzyl-6-O-(4-
CDCl3)
d
173.46, 137.95, 137.85, 137.83, 137.59, 128.43, 128.34,
methoxybenzyl)-b-D-glucopyranosyl)carbamoyl}-b-D-
128.28, 128.26, 128.25, 127.93, 127.89, 127.85, 127.72, 127.63, 127.55,
80.08, 77.32, 76.07, 75.06, 74.00, 73.91, 73.30, 72.17, 71.89, 69.28; MS
glucopyranosyl]formic acid methyl ester (60)
To the mixture of carboxylic acid 58 (38 mg, 0.066 mmol) and
alcohol 59 (63 mg, 0.132 mmol) in benzene (7 mL) were added
triethylamine (18 mg, 0.132 mmol) and DPPA (0.029 mL,
0.132 mmol), and the whole mixture was refluxed for 29 h. Then,
saturated aqueous NH4Cl was added to the mixture at 0 ꢀC followed
by the addition of AcOEt (20 mL). The organic layer was separated
and the aqueous layer was further extracted twice with AcOEt
(20 mL). The combined organic layers were washed with brine,
dried over Na2SO4, and concentrated to give a residue, which was
purified by silica gel flash chromatography (hexane/AcOEt, 4:1) to
(FABdNBAþNaI) m/z 591 (MþNa)þ; HRMS (FABdNBAþNaI) calcd
20
for C35H36O7Na 591.2315, found 591.2337; [
a]
ꢁ1.41 (c 1.35,
D
CHCl3); IR (neat, cmꢁ1) 1730 (C]O).
4.3. General procedure for the synthesis of carbamate-linked
disaccharides
The reaction of 9 and 18 is described as a representative
example.

8786
D. Sawada et al. / Tetrahedron 64 (2008) 8780–8788
afford the desired product 60 (53 mg, 78%) as a colorless oil: 1H
NMR (400 MHz, CDCl3) 7.33–7.24 (m, 30H), 7.12 (m, 2H), 6.83 (m,
4.4.5. [2,3,4-Tri-O-benzyl-6-O-{(N-2,3,4-tris-O-benzyl-6-O-(N-
2,3,4-tris-O-benzyl-6-O-(4-methoxybenzyl)- -gluco-
pyranosyl)carbamoyl)- -glucopyranosyl}carbamoyl]-
glucopyranosyl]formic acid methyl ester (63)
d
b-D
2H), 5.12 (d, J¼9.0 Hz, 1H), 4.92–4.77 (m, 7H), 4.72 (d, J¼9.2 Hz, 1H),
4.68 (d, J¼8.8 Hz, 1H), 4.63–4.56 (m, 4H), 4.47 (d, J¼10.7 Hz, 1H),
4.40 (d, J¼11.0 Hz, 1H), 4.25 (m, 1H), 3.95–3.59 (m, 8H), 3.75 (s, 3H),
3.72 (s, 3H), 3.50 (m, 3H), 3.33 (t, J¼8.54 Hz, 1H); 13C NMR
b-
D
b-D-
Route a. The general procedure for the synthesis of carbamate-
linked disaccharides was followed by using 61 (29 mg,
0.027 mmol), 2 equiv of 59 (27 mg, 0.054 mmol), 2 equiv of K2CO3
and DPPA, and 0.1 equiv of Ag2CO3 to afford 63 (36 mg 85%) as
(100 MHz, CDCl3)
d 169.04, 159.04, 155.16, 138.24, 138.05, 137.90,
137.52, 137.24, 129.71, 129.56, 128.86, 128.82, 128.37, 128.31, 128.26,
128.17, 128.13, 128.06, 128.02, 127.87, 127.79, 127.74, 127.64, 127.60,
127.54, 113.61, 86.07, 85.79, 81.64, 80.03, 79.73, 78.85, 78.10, 77.78,
77.54, 77.41, 76.09, 75.57, 75.19, 75.00, 74.79, 74.70, 73.02, 67.56,
63.93, 55.10, 52.36; MS (FABdNBAþNaI) m/z 1110 (MþNa)þ; HRMS
a colorless oil: 1H NMR (400 MHz, CDCl3)
d 7.32–7.21 (m, 45H), 7.11–
7.09 (m, 2H), 6.82–6.80 (m, 2H), 5.17–5.10 (m, 2H), 4.92–4.68
(m,17H), 4.55 (d, J¼6.6 Hz,1H), 4.53 (d, J¼6.6 Hz,1H), 4.60–4.52 (m,
2H), 4.47 (d, J¼10.26 Hz, 1H), 4.38–4.32 (m, 4H), 4.27–4.22 (dd,
J¼3.7, 11.6 Hz, 2H), 3.87 (d, J¼9.5 Hz, 1H), 3.68–3.61 (m, 6H), 3.74 (s,
3H), 3.68 (s, 3H), 3.57 (m, 1H), 3.52–3.42 (m, 4H), 3.34–3.28 (m,
(FABdNBAþNaI) calcd for
C65H69NNaO14 1110.4616, found
20
1110.4628; [
3284 (NH).
a
]
þ4.3 (c 2.75, CHCl3); IR (neat, cmꢁ1) 1705 (C]O),
D
2H); 13C NMR (100 MHz, CDCl3)
d 169.24, 159.19, 155.35, 155.21,
138.41, 138.24, 138.19, 137.76, 137.66, 137.51, 137.35, 129.92, 129.66,
128.57, 128.51, 128.46, 128.44, 128.42, 128.40, 128.39, 128.31, 128.20,
128.17, 128.13, 128.02, 127.97, 127.91, 127.88, 127.79, 127.75, 127.67,
127.62, 113.72, 86.14, 86.11, 85.83, 85.68, 81.79, 81.58, 80.33, 80.16,
79.90, 79.79, 78.13, 78.02, 77.82, 77.57, 77.50, 77.40, 76.20, 75.73,
75.62, 75.24, 75.16, 75.09, 75.06, 74.86, 74.80, 73.07, 67.69, 64.02,
63.72, 61.81, 60.37, 55.15, 52.44, 52.41; MS (FABdNBAþNaI) m/z
4.4.3. [2,3,4-Tri-O-benzyl-6-O-{(N-2,3,4-tris-O-benzyl-6-O-(4-
methoxybenzyl)- -glucopyranosyl)carbamoyl}-
glucopyranosyl]formic acid (61)
b-
D
b-D-
Compound 60 was dissolved in methanol, THF, and H2O, and
LiOH$H2O was added to the solution. After stirring for 4 h at room
temperature, saturated aqueous NH4Cl was added to the mixture at
0 ꢀC followed by the addition of AcOEt (20 mL). The organic layer
was separated and the aqueous layer was further extracted twice
with AcOEt (20 mL). The combined organic layers were washed
with brine, dried over Na2SO4, and concentrated to give a residue,
which was purified by silica gel flash chromatography (hexane/
AcOEt, 4:1) to afford the desired product 61 (53 mg, 78%) as a col-
1586 (MþNa)þ, HRMS (FABdNBAþNaI) calcd for C93H98N2NaO20
26
1585.6613, found: 1585.6617; [
a
]
ꢁ2.23 (c 0.7, CHCl3); IR (neat,
D
cmꢁ1) 1738 (C]O), 3328 (NH).
Route b. The general procedure for the synthesis of carbamate-
linked disaccharides was followed by using 62 (14 mg,
0.0145 mmol), 2 equiv of 58 (17 mg, 0.029 mmol), and 4 equiv of
K2CO3 and DPPA to afford 63 (20 mg, 88%) as colorless oil.
orless oil: 1H NMR (400 MHz, CDCl3)
d 7.32–7.25 (m, 30H), 7.10 (m,
2H), 6.91 (m, 2H), 5.42 (br s, 1H), 4.92–4.73 (m, 13H), 4.57 (m, 2H),
4.45 (m, 2H), 4.37 (d, J¼10.0 Hz, 1H), 4.27 (m, 1H), 3.98 (m, 1H),
3.82–3.29 (m, 10H), 3.72 (s, 3H), 3.34 (m, 1H); 13C NMR (100 MHz,
4.4.6. [6-O-{(N-6-O-(N-
glucopyranosyl}carbamoyl-b-D-glucopyranosyl]formic acid methyl
b
-
D
-Glucopyranosyl)carbamoyl)-
b-D-
CDCl3)
d
159.07, 155.51, 138.26, 138.02, 137.88, 137.59, 137.31, 139.64,
ester (64)
129.55, 128.39, 128.33, 128.27, 128.20, 128.05, 128.90, 127.80,127.69,
127.66, 127.58, 127.52, 113.66, 85.76, 85.51, 81.74, 80.18, 79.33, 77.50,
77.21, 76.00, 75.58, 75.45, 75.05, 74.81, 74.69, 72.92, 67.64, 63.60,
56.88, 55.12; MS (FABdNBAþNaI) m/z 1097 (MþNa)þ; HRMS
The general procedure for the deprotection of carbamate-linked
disaccharides was followed by using 63 (19 mg 0.012 mmol) to
afford 64 (6.9 mg 90%) as a colorless oil: 1H NMR (400 MHz, D2O)
d
4.83–4.80 (m, 3H), 4.50–4.45 (m, 2H), 4.28–4.24 (m, 2H), 4.05–
4.02 (m, 1H), 3.91–3.83 (m, 2H), 3.74–3.74 (m, 4H), 3.56 (s, 3H),
3.58–3.35 (m, 7H); 13C NMR (100 MHz, D2O)
171.05, 170.45,
(FABdNBAþNaI) calcd for
C64H67NNaO14 1096.4459, found
25
1096.4442; [
3280 (NH).
a
]
þ15.3 (c 2.5, CHCl3); IR (neat, cmꢁ1) 1710 (C]O),
d
D
165.54, 152.08, 76.17, 74.07, 72.42, 71.88, 71.62, 71.41, 71.27, 70.85,
70.51, 62.23, 66.14, 65.92, 65.65, 65.55, 63.73, 63.52, 54.82; MS
4.4.4. [2,3,4-Tri-O-benzyl-6-O-{(N-2,3,4-tris-O-benzyl-
b-
D-
(FABdNBAþNaI) m/z 655 (MþþNa)þ; HRMS (FABdNBAþNaI) calcd
23
glucopyranosyl)carbamoyl}-
b
-D-glucopyranosyl]formic acid
for C22H36N2NaO19 655.1811, found: 655.1807; [
a]
ꢁ52.6 (c 0.92,
D
methyl ester (62)
H2O); IR (neat, cmꢁ1) 1717 (C]O), 3326.
To the solution of carbamate 60 in dichloromethane (8 mL) and
H2O (3 mL) was added DDQ (10 mg), and the mixture was stirred
for 26 h. Then, saturated aqueous NH4Cl was added followed by
the addition of dichloromethane (20 mL). The organic layer was
separated and the aqueous layer was further extracted twice with
dichloromethane (20 mL). The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated to give
a residue, which was purified by silica gel flash chromatography
(dichloromethane/methanol, 60:1) to afford the desired product
62 (41 mg, 100%) as a colorless oil: 1H NMR (400 MHz, CDCl3)
4.4.7. Allyl 2,3-di-O-[(N-2,3,4,6-tetra-O-benzyl-
glucopyranosyl)carbamoyl]-4,6-O-(4-methoxybenzylidene)-
glucopyranoside (66 ) and allyl 2,3-di-O-[(N-2,3,4,6-tetra-O-
benzyl- -glucopyranosyl)carbamoyl]-4,6-O-(4-
methoxybenzylidene)- -glucopyranoside (66
To the mixture of carboxylic acid 10 (671 mg, 1.24 mmol) and
alcohol 65 (104 mg, 0.31 mmol) in benzene (50 mL) were added
K2CO3 (339 mg, 2.48 mmol) and DPPA (0.52 mL, 2.48 mmol), and
the whole mixture was refluxed for 17 h. Then, saturated aqueous
NH4Cl was added to the mixture at 0 ꢀC followed by the addition of
AcOEt (100 mL). The organic layer was separated and the aqueous
layer was further extracted twice with AcOEt (100 mL). The com-
bined organic layers were washed with brine, dried over Na2SO4,
and concentrated to give a residue, which was purified by silica gel
flash chromatography (hexane/AcOEt, 3:1) to afford the desired
b-D-
a-D-
a
b-D
b-D
b)
d
7.38–7.22 (m, 30H), 5.48 (d, J¼8.8 Hz, 1H), 4.95–4.74 (m, 12H),
4.62 (d, J¼10.3 Hz, 1H), 4.61 (d, J¼10.3 Hz, 1H), 4.44 (d, J¼11.5 Hz,
1H), 4.35 (m, 1H), 3.96 (d, J¼9.3 Hz, 1H), 3.91–3.58 (m, 9H), 3.66 (s,
3H), 3.47 (m, 1H), 3.36 (t, J¼9.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
169.25, 155.40, 138.16, 138.03, 137.81, 137.53, 137.49, 137.30,
128.41, 128.39, 128.36, 128.31, 128.28, 128.02, 127.91, 127.85, 127.78,
127.75, 127.73, 127.60, 127.55, 86.02, 85.59, 81.61, 80.44, 79.95,
78.01, 77.64, 77.37, 76.68, 75.67, 75.62, 75.25, 75.09, 74.93, 74.73,
63.72, 61.36, 52.37; MS (FABdNBAþNaI) m/z 990 (MþNa)þ; HRMS
product 66
25%) as white powder. Compound 66
7.41–7.10 (m, 42H), 6.82–6.80 (m, 2H), 5.95–5.89 (m, 1H), 5.56 (t,
a
(264 mg, 59%) as a white powder and 66
b (116 mg,
a
: 1H NMR (600 MHz, CDCl3)
d
(FABdNBAþNaI) calcd for
C
75H61NNaO13 990.4041, found
J¼9.6 Hz, 1H), 5.44 (s, 1H), 5.34 (dd, J¼1.4, 17.3 Hz, 1H), 5.34 (dd,
J¼1.1, 10.5 Hz, 1H), 5.12–5.10 (m, 2H), 4.94–4.92 (m, 1H), 4.85–4.73
(m, 8H), 4.71 (d, J¼11.3 Hz, 1H), 4.68–4.46 (m, 9H), 4.33–4.31 (m,
25
990.4045; [
3288 (NH).
a]
þ0.15 (c 2.9, CHCl3); IR (neat, cmꢁ1) 1707 (C]O),
D

D. Sawada et al. / Tetrahedron 64 (2008) 8780–8788
8787
1H), 4.28 (dd, J¼5.0, 10.5 Hz, 1H), 4.21 (dd, J¼5.2, 12.9 Hz, 1H), 4.04–
4.4.9. 1,2,3,4,6-Penta-O-[(N-2,3,4,6-tetra-O-benzyl-
b-D-
3.99 (m, 2H), 3.78–3.76 (m, 1H), 3.76 (s, 3H), 3.69–3.55 (m, 8H),
glucopyranosyl)carbamoyl]- -glucopyranoside (69)
D
3.39–3.38 (m, 1H), 3.35–3.33 (m, 1H), 3.29 (t, J¼8.0 Hz, 1H), 3.20 (t,
To the solution of 67 (43 mg, 0.017 mmol) in dichloromethane
(2 mL) and H2O (0.135 mL) was added PdCl2 (7.4 mg, 0.04 mmol),
and the mixture was stirred at ambient temperature for 32 h. Then,
H2O was added to the mixture at 0 ꢀC followed by the addition of
AcOEt (20 mL). The organic layer was separated and the aqueous
layer was further extracted twice with AcOEt (20 mL). The com-
bined organic layers were washed with brine, dried over Na2SO4,
and concentrated to give a residue, which was purified by silica gel
flash chromatography (hexane/AcOEt, 1:1) to afford the desired
product 68 (37 mg, 86%) as a white powder, and this compound was
immediately used in the next step. To the mixture of carboxylic acid
10 (14 mg, 0.024 mmol) and hemiacetal 68 (10 mg, 0.004 mmol) in
benzene (4 mL) were added triethylamine (0.007 mL, 0.048 mmol),
DPPA (0.011 mL, 0.048 mmol), and Ag2CO3 (0.7 mg, 0.0024 mmol),
and the whole mixture was refluxed for 5 h. Then, saturated
aqueous NH4Cl was added to the mixture at 0 ꢀC followed by the
addition of AcOEt (20 mL). The organic layer was separated and
the aqueous layer was further extracted twice with AcOEt (20 mL).
The combined organic layers were washed with brine, dried over
Na2SO4, and concentrated to give a residue, which was purified by
silica gel flash chromatography (hexane/AcOEt, 2:1) to afford the
desired product 69 (9.6 mg, 77%) as a white powder: 1H NMR
J¼8.3 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 159.76, 154.74, 154.53,
138.28, 138.03, 137.98, 137.71, 137.67, 137.60, 133.25, 129.43, 128.85,
128.77, 128.73, 128.58, 128.29, 128.25, 128.21, 128.11, 127.88, 127.83,
127.63, 127.59, 127.53, 127.48, 117.74, 113.33, 101.33, 96.24, 85.95,
85.89, 81.60, 81.56, 79.57, 78.46, 78.38, 78.35, 77.49, 77.42, 77.21,
76.13, 76.02, 75.55, 74.79, 74.74, 74.19, 73.97, 73.49, 73.39, 72.00,
70.33, 68.75, 68.72, 68.20, 68.10, 68.09, 62.49, 55.20; MS
(FABdNBAþNaI): m/z 1491 (MþNa)þ; HRMS (FABdNBAþNaI)
24
calcd for C87H92N2NaO19 1491.6192, found 1491.6199; [
a]
þ8.48 (c
D
1.27, CHCl3); IR (neat, cmꢁ1): 1746 (C]O), 3339 (NH). Compound
66 7.38–7.10 (m, 42H), 6.83–6.81 (m,
b
: 1H NMR (600 MHz, CDCl3)
d
2H), 5.89–5.85 (m,1H), 5.46 (s,1H), 5.32–5.29 (m, 2H), 5.18–5.16 (m,
1H), 5.05 (t, J¼8.3 Hz, 1H), 4.94–4.84 (m, 6H), 4.81–4.67 (m, 7H),
4.63–4.61 (m, 2H), 4.54–4.46 (m, 4H), 4.39–4.31 (m, 4H), 4.10 (dd,
J¼5.3, 12.9 Hz, 1H), 3.82 (t, J¼10.1 Hz, 1H), 3.76 (s, 3H), 3.72–3.65
(m, 6H), 3.62–3.56 (m, 3H), 3.34–3.26 (m, 3H); 13C NMR (100 MHz,
CDCl3)
d 159.76, 154.57, 154.27, 138.23, 138.22, 138.05, 137.66,
137.63, 137.52, 133.20, 129.24, 129.13, 128.62, 128.24, 128.19, 128.16,
128.14, 127.89, 127.79, 127.55, 127.46, 117.46, 113.33, 101.22, 100.40,
86.11, 86.04, 81.60, 81.51, 78.54, 77.70, 77.43, 77.41, 77.38, 75.90,
75.87, 75.87, 75.85, 75.57, 74.64, 74.62, 73.92, 73.84, 73.49, 73.37,
73.10, 72.74, 70.20, 68.45, 67.99, 66.14, 55.15; MS (FABdNBAþNaI):
(600 MHz, CDCl3) d 7.41–7.04 (m, 100H), 5.88 (m, 1H), 5.71 (m, 1H),
m/z 1491 (MþNa)þ; HRMS (FABdNBAþNaI) calcd for C87H92N2NaO19
5.54 (m, 1H), 5.39 (m,1H), 5.31–5.29 (m,1H), 5.19 (m,1H), 5.11–5.02
(m, 3H), 4.90–4.39 (m, 47H), 4.16 (m, 1H), 3.93 (m, 1H), 3.79 (m, 1H),
3.47–3.68 (m, 23H), 3.33 (m, 1H), 3.26–3.23 (m, 1H), 3.10–3.19 (m,
24
1491.6192, found 1491.6196; [
a
]
ꢁ169.2 (c 2.52, CHCl3), IR
D
(neat, cmꢁ1): 1748 (C]O), 3385 (NH).
3H); 13C NMR (150 MHz, CDCl3)
d 155.04, 154.39, 153.28, 138.56,
4.4.8. Allyl 2,3,4,6-tetra-O-[(N-2,3,4,6-tetra-O-benzyl-
glucopyranosyl)carbamoyl]- -glucopyranoside (67)
To the solution of 66 (14 mg, 0.01 mmol) in dichloromethane
b
-
D
-
138.44, 138.33, 138.22, 138.12, 138.08, 138.02, 137.95, 137.77, 137.43,
129.07,128.97,128.72,128.62,128.59,128.49,128.35,128.29,128.24,
128.15, 128.03, 127.85, 127.79, 127.71, 127.63, 127.53, 127.49, 92.90,
86.00, 85.90, 85.71, 82.15, 81.69, 80.56, 80.33, 77.89, 77.47, 76.41,
75.80, 75.67, 75.47, 74.96, 74.86, 74.81, 74.76, 74.48, 74.18, 73.46,
a-D
a
(2 mL) were added triethylsilane (0.008 mL, 0.05 mmol) and tri-
fluoroacetic acid (0.004 mL, 0.05 mmol) at 0 ꢀC, and the mixture
was stirred for 1.5 h at room temperature. Then, saturated aqueous
NaHCO3 was added to the mixture at 0 ꢀC followed by the addition
of AcOEt (20 mL). The organic layer was separated and the aqueous
layer was further extracted twice with AcOEt (20 mL). The com-
bined organic layers were washed with brine, dried over Na2SO4,
and concentrated to give a residue, which was purified by silica gel
flash chromatography (hexane/AcOEt,1:1) to afford the diol (13 mg,
98%) as a colorless oil. The product was successively used in the
next step. To the mixture of carboxylic acid 10 (206 mg,
0.362 mmol) and diol 66 (123 mg, 0.091 mmol) in benzene (30 mL)
were added K2CO3 (100 mg, 0.725 mmol) and DPPA (0.156 mL,
0.725 mmol), and the whole mixture was refluxed for 24 h. Then,
saturated aqueous NH4Cl was added to the mixture at 0 ꢀC followed
by the addition of AcOEt (100 mL). The organic layer was separated
and the aqueous layer was further extracted twice with AcOEt
(100 mL). The combined organic layers were washed with brine,
dried over Na2SO4, and concentrated to give a residue, which was
purified by silica gel flash chromatography (hexane/AcOEt, 5:1) to
afford the desired product 67 (201 mg, 89%) as a colorless oil: 1H
73.24, 68.51, 68.15. Anal. Calcd for C181H187N5O36: C, 72.26; H, 6.27;
24
N, 2.33. Found: C, 72.12; H, 6.46; N, 2.20; [
a
]
þ4.19 (c 0.42, H2O);
D
IR (neat, cmꢁ1) 1746 (C]O), 3317.
4.5. General procedure for the synthesis of urea-linked
disaccharides
The reaction of 9 and 70 is described as a representative
example.
4.5.1. Methyl 4,6-O-benzylidene-2-deoxy-2-[(N0-2,3,4,6-tetra-O-
benzyl-a-D-glucopyranosyl)ureido]-a-D-glucopyranoside (72)
To the solution of carboxylic acid 9 (28 mg, 0.048 mmol) and in
benzene (3.5 mL) were added triethylamine (0.013 mL,
0.092 mmol), and DPPA (0.021 mL, 0.092 mmol), and the mixture
was refluxed for 1 h. Next, amine 70 (20 mg, 0.072 mmol) in CH3CN
(1.5 mL) was added at room temperature and the whole mixture
was further refluxed for 5 h. Then the mixture was cooled to 0 ꢀC
and saturated aqueous NH4Cl was added followed by the addition
of dichloromethane (20 mL). The organic layer was separated and
the aqueous layer was further extracted twice with dichloro-
methane (20 mL). The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated to give a residue, which
was purified by silica gel flash chromatography (dichloromethane/
methanol, 60:1) to afford the desired product 72 (41 mg, 100%) as
NMR (600 MHz, CDCl3)
d 7.34–7.10 (m, 80H), 5.91 (m, 1H), 5.76 (m,
1H), 5.32–5.29 (m, 2H), 5.52 (t, J¼9.3 Hz, 1H), 5.35 (m, 1H), 5.07 (m,
1H), 4.94–4.39 (m, 42H), 4.18 (m, 1H), 4.11–4.07 (m, 3H), 3.72–3.48
(m, 20H), 3.28 (m, 3H), 3.14 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
154.98, 154.64, 154.45, 154.35, 138.30, 138.20, 137.97, 137.81,
137.76, 137.68, 137.63, 133.14, 129.56, 128.68, 128.51, 128.33, 128.22,
128.17, 128.13, 128.13, 127.88, 127.79, 127.73, 127.68, 127.55, 127.46,
117.69, 95.11, 85.84, 85.70, 81.96, 81.43, 80.02, 77.20, 76.18, 75.86,
75.47, 74.76, 74.66, 74.51, 74.20, 73.95, 73.39, 73.23, 73.12, 68.56,
68.05, 67.36; MS (FABdNBAþNaI) m/z 2504 (MþNa)þ; HRMS
a colorless oil: 1H NMR (400 MHz, CDCl3)
d 7.53–7.51 (m, 2H), 7.38–
7.28 (m, 21H), 7.17–7.15 (m, 2H), 5.84 (br s, 1H), 5.56 (s, 1H), 5.53 (br
s, 1H), 5.24 (br s, 1H), 4.86 (t, J¼11.0 Hz, 1H), 4.79 (d, J¼11.0 Hz, 1H),
4.73 (d, J¼11.0 Hz, 1H), 4.64–4.42 (m, 6H), 4.26 (dd, J¼10.7, 15.9 Hz,
1H), 4.04 (m, 1H), 3.83–3.65 (m, 8H), 3.54–3.49 (m, 2H), 3.23 (s,
(FABdNBAþNaI) calcd for C149H156N4O30Na 2504.0697, found
24
2504.0694; [
a
]
D
þ6.04 (c 0.53, CHCl3); IR (neat, cmꢁ1): 1746
3H); 13C NMR (100 MHz, CDCl3)
d
158.77, 138.21, 138.03, 137.41,
(C]O), 3325 (NH).
137.02, 129.09, 128.49, 128.35, 128.30, 128.27, 128.18, 128.11, 128.07,

8788
D. Sawada et al. / Tetrahedron 64 (2008) 8780–8788
127.85, 127.79, 127.62, 126.25, 101.86, 98.84, 81.92, 81.76, 78.02,
77.91, 76.78, 75.72, 74.99, 73.61, 72.94, 70.53, 70.06, 68.86, 67.93,
62.22, 55.01; MS (FABdNBAþNaI) m/z 869 (MþNa)þ; HRMS
References and notes
1. Dwek, A. R. Chem. Rev. 1996, 96, 683–720.
´
´
2. (a) Laupichler, L.; Thiem, J. Synlett 1992, 159; (b) Garcıa Fernandez, J. M.; Mellet,
C. O.; Dı´az Pe´rez, V. M.; Fuentes, J.; Kova´cs, J.; Pinte´r, I. Tetrahedron Lett. 1997, 38,
4161–4164; (c) Prosperi, D.; Ronchi, S.; Panza, L.; Rencurosi, A.; Russo, G. Synlett
2004, 1529–1532; (d) Ichikawa, Y.; Matsukawa, Y.; Nishiyama, T.; Isobe, M. Eur.
J. Org. Chem. 2004, 586–591; (e) Ichikawa, Y.; Nishiyama, T.; Isobe, M. Synlett
2000, 1253–1256; (f) Ichikawa, Y.; Nishiyama, T.; Isobe, M. J. Org. Chem. 2001,
66, 4200–4205; (g) Nishiyama, T.; Ichikawa, Y.; Isobe, M. Synlett 2003, 47–50;
(h) Prosperi, D.; Ronchi, S.; Lay, L.; Rencurosi, A.; Russo, G. Eur. J. Org. Chem.
2004, 395–405; (i) Ichikawa, Y.; Matsukawa, Y.; Isobe, M. J. Am. Chem. Soc. 2006,
128, 3934–3938.
(FABdNBAþNaI) calcd for
C49H54N2O11Na 869.3625, found
23
869.3640; [
a
]
D
þ83.4 (c 1.9, CHCl3); IR (neat, cmꢁ1) 1562, 1651
(C]O), 3275 (NH).
4.6. General procedure for the deprotection of urea-linked
disaccharides
The reaction of 72 is described as a representative example.
3. (a) Sawada, D.; Sasayama, S.; Takahashi, H.; Ikegami, S. Tetrahedron Lett. 2006,
47, 7219–7223; (b) Sawada, D.; Sasayama, S.; Takahashi, H.; Ikegami, S. Eur. J.
Org. Chem. 2007, 1064–1068.
4. (a) Kuzuhara, H.; Fletcher, H. G., Jr. J. Org. Chem. 1967, 32, 2531–2534; (b) Lewis,
M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976–4977.
5. (a) Csuk, R.; Gla¨nzer, B. I. Tetrahedron 1991, 47, 1655–1664; (b) RajanBabu, T. V.;
Reddy, G. S. J. Org. Chem. 1986, 51, 5458–5461; (c) Griffin, F. K.; Paterson, D. E.;
Taylor, R. J. K. Angew. Chem., Int. Ed. 1999, 38, 2939.
4.6.1. Methyl 2-deoxy-2-[(N0-
a-D-glucopyranosyl)ureido]-a-D-
glucopyranoside (76)
To the solution of carbamate 72 in dichloromethane (8 mL) and
methanol (3 mL) was added Pd on carbon (10 mg), and the mixture
was stirred under hydrogen for 26 h. Then, the mixture was evap-
orated and the residue was purified by silica gel flash chromatog-
raphy (dichloromethane/methanol, 4:1) to afford the desired
product 76 (12 mg, 100%) as a white powder: 1H NMR (600 MHz,
6. Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski, E. J. J.; Reider, P. J.
J. Org. Chem. 1999, 64, 2564–2566.
7. Lockhoff, O. Angew. Chem., Int. Ed. 1998, 37, 3436–3439.
8. Alcohol 15: Pravdic, N.; Danilov, B. Carbohydr. Res. 1974, 36, 167–180; Alcohol
16: Lecourt, T.; Herault, A.; Pearce, J. A.; Sollogoub, M.; Sinay¨, P. Chem.dEur. J.
2004, 10, 2960–2971; Alcohols 17, 18: Koto, S.; Takeda, Y.; Zen, S. Bull. Chem.
Soc. Jpn. 1972, 45, 291–293; Alcohol 19: Falck, J. R.; Barma, D. K.; Venkatara-
man, S. K.; Baati, R.; Mioskowski, C. Tetrahedron Lett. 2002, 43, 963–966;
Alcohol 20: Garegg, P. J.; Hultberg, H.; Wallin, S. Carbohydr. Res. 1982, 108,
97–101; Alcohol 21: Franks, N. E.; Montgomery, R. Carbohydr. Res. 1968, 6,
286–298.
CD3OD)
d
5.32 (d, J¼5.2 Hz, 1H), 4.73 (d, J¼9.1 Hz, 1H), 4.63 (m, 2H),
4.55 (br s, 1H), 3.78 (m, 2H), 3.72 (m, 2H), 3.66–3.57 (m, 4H), 3.50–
3.44 (m, 5H), 3.30 (m, 2H), 3.27 (s, 3H), 3.12 (m, 1H); 13C NMR
(150 MHz, CD3OD) d 160.76, 100.26, 82.45, 79.10, 75.11, 74.33, 73.92,
73.81, 73.51, 73.41, 72.02, 71.44, 62.68, 55.56; MS (FABdNBAþNaI)
9. Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94, 6203–6204.
10. Using 15, which is a mixture of the stereoisomers at the 1-position in the ratio
m/z 421 (MþNa)þ; HRMS (FABdNBAþNaI) calcd for C14H26N2O11Na
26
421.1433, found 421.1447; [
a
]
þ101.7 (c 0.75, CH3OH); IR (neat,
of 3:1 (
a
/
b
), 22 was exclusively obtained with 1-
b
-linkage, and 31 was obtained
). The
D
cmꢁ1) 1559, 1649 (C]O), 3580–3060 (OH).
as a mixture of the stereoisomers at the 1-position in the ratio of 1:10 (a/b
stereochemistry of 22 and 31 were determined by the analysis of the coupling
constants in the 1H NMR.
11. In entry 14 in Table 1, both 10 and 19 are so reactive that the yield of this
reaction by Et3N is slightly better than that using K2CO3 as a base.
12. Using 22, the reaction should afford the desired product, however, some
unknown decomposed products were included, which were difficult to be
separated.
Acknowledgements
This work was partially supported by the Ministry of Education,
Culture, Sports, Science, and Technology of Japan and Uehara
Memorial Foundation (to D.S.).
13. Oka, T.; Fujiwara, K.; Murai, A. Tetrahedron 1998, 54, 21–44.
14. The stereochemistry at the 1-position of the core sugar in 69 should be
b
-linkage on the basis of the results in Table 1, and a trace amount of the
stereoisomer might be isolated, whose structure was not determined.
15. Emmerson, D. P. G.; Hems, W. P.; Davis, B. G. Tetrahedron: Asymmetry 2005, 16,
213–221.
16. Reitz, A. B.; Tuman, R. W.; Marchione, C. S.; Jordan, A. D.; Bowden, C. R.;
Maryanoff, B. E. J. Med. Chem. 1989, 32, 2110–2116.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.06.089.