A new and facile synthesis of carbamate- and urea-linked glycoconjugate using modified Curtius rearrangement

Article abstract of DOI:10.1016/j.tetlet.2006.07.139

We describe a facile synthetic method of carbamate- and urea-linked glycoconjugates using sugar carboxylic acids by the modified Curtius rearrangement. This reaction is a simple one-pot procedure, and various nucleophiles including tertiary alcohols can b

Full text of DOI:10.1016/j.tetlet.2006.07.139

Tetrahedron Letters 47 (2006) 7219–7223
A new and facile synthesis of carbamate- and
urea-linked glycoconjugate using modified Curtius rearrangement
Daisuke Sawada, Shinya Sasayama, Hideyo Takahashi and Shiro Ikegami*
School of Pharmaceutical Sciences, Teikyo University, Sagamiko Kanagawa 199-0195, Japan
Received 5 July 2006; revised 23 July 2006; accepted 27 July 2006
Available online 17 August 2006
Abstract—We describe a facile synthetic method of carbamate- and urea-linked glycoconjugates using sugar carboxylic acids by the
modified Curtius rearrangement. This reaction is a simple one-pot procedure, and various nucleophiles including tertiary alcohols
can be utilized to afford desired compounds in moderate to high yields. And the stereospecific synthesis of the anomeric isomers is
achieved using the corresponding two stereoisomers of glycosyl carboxylic acid.
Ó 2006 Elsevier Ltd. All rights reserved.
There is a large number of glycosides in nature, namely,
glycoconjugates such as glycopeptides, glycolipids, and
nucleic acids. It is well known that the saccharide moiety
of the glycoconjugates plays important roles for their
biological activity.1 Also, there are other glycoconjugate
systems whose glycosidic linkage is linked with a carb-
amate or a urea instead of an acetal linkage.2 These
chemically more stable glycoconjugates3 are called neo-
glycoconjugates,2m and much attention has been paid to
their interesting biological activities. Recently, Ichikawa
and Prosperi reported the synthesis of such neoglyco-
conjugates,2k–o and these excellent works overcome
the most important problem in the oligosaccharide syn-
thesis, involving the stereoselective synthesis of the ano-
meric isomers. Their methods are based on an addition
of a nucleophile to a sugar isocyanate, and the stereo-
selective synthesis is achieved by the separation of the
anomeric isomers of the sugar isocyanide. We focused
on Curtius rearrangement, for one-pot synthesis of carb-
amate- or urea-linked glycoconjugates by the reaction
of sugar carboxylic acid and alcohol or amine using
diphenyl phosphoryl azide (DPPA).4 Curtius rearrange-
ment is known to proceed with retention of the
stereochemistry at the carbon connected with the carb-
oxylic acid moiety, and the stereospecific synthesis of
anomeric isomers should be accomplished by using the
corresponding two stereoisomers of the glycosyl carb-
oxylic acid. Moreover, chemical transformation of carb-
oxylic acids is simple, and that is advantageous for the
elongation of oligosaccharides. Here we report a new
and facile synthetic method of the neoglycoconjugate
using the modified Curtius rearrangement.
We started the Curtius rearrangement reaction using the
known D-glucuronic acid derivative (1).5 The general
conditions of Curtius rearrangement using DPPA are
to react a carboxylic acid and a nucleophile in the pres-
ence of triethylamine,4 and synthesis of a urea-linked
saccharide is easily accomplished owing to sufficient
nucleophilicity of an amine as shown in Scheme 1.
Compound 1 was refluxed with diphenylphosphoryl
azide (DPPA, 2 equiv) and triethylamine (2 equiv) for
1 h and then 1 equiv of piperidine was added to the reac-
tion mixture. Soon the reaction was completed to afford
the desired urea-linked saccharide (2) in 70% yield.
Next, for synthesis of a carbamate-linked saccharide,
compound
1 was similarly refluxed with DPPA
(2 equiv), triethylamine (2 equiv) and cyclohexanol
(1 equiv) as a nucleophile in benzene for 4 h. Unfortu-
nately, the reactivity decreased and the yield was not
satisfactory on account of the steric hindrance of the
O
H
O
OMe
OBn
N
N
O
OMe
OBn
HO
BnO
piperidine (1 eq)
DPPA (2 eq)
triethylamine (2 eq)
benzene
O
BnO
OBn
OBn
1
y. 70%
2
*
Corresponding author. Tel./fax: +81 42 685 3729; e-mail: somc@
pharm.teikyo-u.ac.jp
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.139

7220
D. Sawada et al. / Tetrahedron Letters 47 (2006) 7219–7223
Table 2. Additive conditions in Curtius rearrangement
nucleophile. Thus, we investigated at first the basic
conditions to activate the nucleophile (Table 1).
cyclohexanol (1 eq)
1
3
DPPA (2 eq), Et N (2 eq)
3
additive (2eq)
benzene, reflux, 4 h
Table 1. Base conditions in Curtius rearrangement
O
H
Run
Additive
Yield (%)
O
N
O
OMe
OBn
O
OMe
OBn
cyclohexanol (1 eq)
HO
BnO
1
2
3
4
5
6
7
8
9
10
11
12
13
14
BF3ÆOEt2
Ag2CO3
Ag2CO3
Ag2CO3
Ag2O
CuO
CuCl2
CoCl2
CoCl2
NiCl2
ZrCl4
ZrCl4
PdCl2
42
88
95a
74b
61
68
5
O
DPPA (2 eq)
base (2 eq)
benzene
BnO
OBn
OBn
reflux, 4 h
1
3
Run
Base
Yield (%)
1
2
3
4
5
6
7
8
Et3N
iPr2EtN
DBU
Li2CO3
Na2CO3
K2CO3
Cs2CO3
K3PO4
53a
30
56
5
52
69
40
59
5
47c
5
47
66a
15
20
La(OTf)3
a Additive: 0.1 equiv.
b Base: K2CO3.
c Additive was added after carboxylic acid was disappeared in TLC
analysis.
a 63% yield after 8 h reflux.
Organic bases resulted in moderate yields of the desired
carbamate, although the reactions did not complete and
several by-products were obtained by using DBU (runs
1–3). Then, we tried the inorganic bases in spite of their
poor solubility in benzene. Gratifyingly, the reaction
proceeded smoothly and the best result was obtained
by using K2CO3 (run 6). However, the isocyanate, inter-
mediate derived from the carboxylic acid in situ, seems
to remain as an unreacted form in the reaction mixture
with the TLC analysis. And the rate-determining step of
this reaction is considered to be an addition of the
nucleophile to this reactive isocyanate. Accordingly,
we investigated an additional promoter to activate the
isocyanate (Table 2). Various additives (2 equiv) were
tried with 1, cyclohexanol, DPPA, and triethylamine in
benzene, and in the case of Ag2CO3, the reactivity was
greatly improved (runs 2–4). The catalytic amounts of
Ag2CO3 gave the best yield, and a similar effect was also
observed with K2CO3 as a base. Using CoCl2, the yield
was only 5% (run 8); however, it was improved to 47%
by adding CoCl2 after confirming the disappearance of
carboxylic acid by TLC (run 9). And, a catalytic amount
of the additives also brought better results than 2 equiv
of them (runs 2, 3 and 11, 12). Therefore, it is suggested
that the metal reagents might have some influence on the
rearrangement of the carboxylic acid to the isocyanate.
Then, for the synthesis of various glycoconjugate, we
prepared both stereoisomers of glycosyl carboxylic acids
(Scheme 2). According to the reference,6 the sugar lac-
tone 47 was transformed into alcohols 5 and 6, which
were then oxidized to the desired carboxylic acids 7
and 8, respectively. Using compounds 1, 7, and 8, we
investigated the reactions with a series of nucleophiles
under the above modified Curtius rearrangement condi-
tions (Table 3).
At first, t-BuOH was used as a nucleophile. Because of
its steric hindrance, an excess amount of t-BuOH was
necessary to obtain the desired compound (run 1).
However, Ag2CO3 showed a great effect, and the Boc-
protected sugar 12 was obtained in 67% yield with
only 3 equiv of t-BuOH (run 3). Using K2CO3 as a
base caused the formation of t-BuOK in situ and that
resulted in some by-products and low yield (run 4).
Second, we attempted to obtain a Fmoc-protected sugar
using 9-fluorenemethanol (9-Fm) as a nucloephile. For
synthesis of a base-labile Fmoc carbamate using Curtius
rearrangement, 9-Fm is generally reacted with an iso-
lated isocyanate after excluding a base that remained
O
O
O
MPMO
BnO
OH
OBn
MPMO
BnO
OH
OBn
O
O
OBn
OBn
MPMO
BnO
ref. 6
TEMPO
5
7
y. 84%
O
OBn
NaClO, NaClO2
phosphate buffer
CH3CN
OBn
O
O
MPMO
BnO
OH
OBn
MPMO
BnO
OH
OBn
4
OBn
OBn
6
8
y. 95%
Scheme 2.

D. Sawada et al. / Tetrahedron Letters 47 (2006) 7219–7223
Table 3. Synthesis of various carbamate and urea-linked glycoconjugates
7221
O
R'OH or R'NH (x eq)
RCOOH
(1, 7, 8)
(X = O or NH)
DPPA (2 eq), benzene
condition A ~ D
R
N
X R'
H
{condition A: Et3N (2eq), B: Et3N (2eq) + Ag2CO3 (0.1eq), C: K2CO3 (2eq) D: K2CO3 (2eq) + Ag2CO3 (0.1eq)}
Run
Condition
RCOOH
R0OH/R0NH (x)
Product
Time (h)
Yield (%)
H
1
2
3
4
A
B
Ba
C
1
1
1
1
t-BuOH (excess)
t-BuOH (3)
t-BuOH (3)
24
30
21
18
58
35
67
5
BocN
O
OMe
OBn
12
BnO
t-BuOH (3)
OBn
O
H
FmocN
OMe
5
6
C
D
1
1
9-Fm (2)
9-Fm (2)
5.5
3.5
71
78
13
BnO
OBn
OBn
H
N
O
O (CH2)13CH3
O (Cholesteryl)
O (1-adamantyl)
14
MPMO
7
8
9
A
C
C
8
8
8
Tetradecanol (2)
5
15
22
92
94
70
O
BnO
OBn
OBn
H
N
O
MPMO
BnO
H
O
15
16
OBn
(2)
H
H
OBn
HO
H
N
OH
O
MPMO
BnO
O
(3)
OBn
OBn
OBn
O
OMe
H
N
BnO
BnO
HO
BnO
O
O
OMe
OBn
10
11
12
13
C
A
D
A
1
1
7
8
9 (2)
8
16
16
7
80
64
81
86
17
18
O
OBn
O
BnO
OBn
O
OMe
OBn
O
H
N
OH
O
O
OMe
OBn
BnO
BnO
BnO
10 (2)
O
OBn
BnO
OBn
BnO
OBn
OBn
OBn
H
O
OMe
OBn
O
N
O
19
MPMO
BnO
9 (2)
9 (2)
O
BnO
OBn
OBn
OBn
H
N
O
OMe
OBn
O
O
MPMO
BnO
20
O
BnO
OBn
OBn
OBn
H
N
CO2tBu
NHBoc
21
O
O
O
MPMO
BnO
14
15
C
A
7
8
Boc-L-Ser-Ot-Bu (2)
Boc-L-Ser-Ot-Bu (2)
4.5
83
90
O
OBn
OBn
O
H
N
CO2tBu
NHBoc
22
MPMO
BnO
13
O
OBn
OBn
O
23
H
N
H
N
CO2Et
MPMO
BnO
16
A
8
HClÆGly-OEt (2)
0.5
93
O
OBn
OBn
(continued on next page)

7222
D. Sawada et al. / Tetrahedron Letters 47 (2006) 7219–7223
Table 3 (continued)
Run
17
Condition
RCOOH
R0OH/R0NH (x)
Product
Time (h)
1
Yield (%)
84
H
H
N
24
CO2Me
NHZ
A
8
Z-L-Lys-OMeÆHCl (1.2)
O
N
MPMO
BnO
O
OBn
OBn
O
N
O
NBz
25
H
N
O
O
BzN
(2)
MPMO
BnO
18
19
A
A
8
8
13
82b
O
O
N
OBn
H
OBn
O
OBn
OBn
OBn
H
N
H
N
26
BnO
N
MPMO
BnO
0.5
87
11 (1.2)
O
BnO
OBn
OBn
OBn
OBn
OBn
a 2 equiv of Ag2CO3 was added.
b The prereflux to convert RCOOH into RNCO could be omitted.
in the reaction.8 With K2CO3, however, the Fmoc-pro-
tected sugar 13 was fortunately obtained in a simple
one-pot procedure (run 5), and the yield was improved
to 78% with additional catalytic amounts of silver car-
bonate (run 6).9 Tetradecanol, cholesterol, and 1-ada-
matanol reacted with 8 under the modified and
unmodified Curtius rearrangement conditions, and the
corresponding carbamate-linked glycoconjugates were
obtained in 92% yield (run 7, condition A), 94% yield
(run 8, condition C), and 70% yield (run 9, condition
C), respectively. Compound 14 is thought to be an ana-
log of a glycolipid, and as such examples, various
pseudosaccharides, which are linked through a carba-
mate, would be produced from aglycons under these
Curtius rearrangement conditions. Similarly, sugar alco-
hols 9 and 10 worked as a nucleophile to afford the
carbamate-linked disaccharides (runs 10–13). The
stereospecific synthesis of both anomeric isomers of
disaccharide 19 and 20 could be achieved with the ster-
eoisomers of glycosyl carboxylic acid 7 and 8.10 Using
an amino acid, Boc-L-Ser-Ot-Bu as a nucleophile, a
carbamate-linked sugar–amino acid complex was
successfully obtained: Boc-L-Ser-Ot-Bu and 7, 8 were
transformed into 21 and 22 in 83% yield by condition
C (run 14) and in 90% yield by condition A (run 15),
respectively. Judging from the above experiments, the
reaction conditions should be chosen as follows: condi-
tion A, the general Curtius rearrangement condition in
which triethylamine is used as a base, is suitable for
reactive carboxylic acids and alcohols (runs 7 and 13
in Table 3). In the case of less reactive carboxylic acids
or alcohols, K2CO3 should be employed as a base, and
additional Ag2CO3 is often effective both with triethyl-
amine and K2CO3. In some cases, decomposition of sub-
strates or isocyanates by either K2CO3 or Ag2CO3 is
observed, resulting in low yield.
Next, we tried the urea-linked saccharide synthesis by
various amines as nucleophiles. Amino acid derivatives,
HClÆGly-OEt and Z-L-Lys-OMeÆHCl reacted smoothly
to give the desired compounds (runs 16 and 17). Com-
pounds 21, 22, and 24 are applicable to the synthesis
of N- or O-linked glycopeptide analogs. 3-N-Benzoyl-
thymine11 successfully afforded the desired compound
25 in 82% yield (run 18), which would be applied to syn-
thesize nucleic acid derivatives. Azasugar 1112 was also
utilized as a nucleophile, and urea-linked disaccharide
26 was obtained in 87% yield (run 19).
Then, we investigated further transformation of the neo-
glycoconjugate. The removal of the MPM group of
compound 23 afforded an alcohol (27), and also a carb-
oxylic acid (28) was obtained by the hydrolysis of 23.
These compounds 27 and 28 will be utilized for elonga-
tion of glycoconjugates (Scheme 3).
In summary, we have accomplished a facile synthesis of
carbamate- and urea-linked glycoconjugates with sugar
carboxylic acids and alcohols or amines by the modified
Curtius rearrangement. This reaction is a simple one-pot
procedure, and various nucleophiles including tertiary
alcohols can be utilized to afford moderate to high yields
of desired compounds. And the stereospecific synthesis
of the anomeric isomers was also achieved using the
corresponding two stereoisomers of glycosyl carbo-
xylic acids. The synthesis and application of more
complex neoglycoconjugates are now on-going in our
laboratory.
H
H
H
H
O
N
N
CO2Et
O
N
N
CO2H
HO
BnO
MPMO
BnO
LiOH•H2O
DDQ
O
O
23
CH2Cl2
H2O
OBn
MeOH
H2O
OBn
OBn
OBn
27
28
Scheme 3.

D. Sawada et al. / Tetrahedron Letters 47 (2006) 7219–7223
7223
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Acknowledgments
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Partial financial support for this research from the
Ministry of Education, Culture, Sports, Science, and
Technology of Japan, and Uehara Memorial Founda-
tion to D.S. are gratefully acknowledged.
8. (a) Spino, C.; Gobdout, C. J. Am. Chem. Soc. 2003, 125,
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9. Typical experimental procedure (Table 3, run 6): Com-
pound 1 (44 mg, 0.092 mmol) was refluxed with 9-Fm
(36 mg, 0.184 mmol), DPPA (40 lL, 0.184 mmol), trieth-
ylamine (25 lL, 0.184 mmol), and silver carbonate
(2.5 mg, 0.0092 mmol) in benzene for 3.5 h. The reaction
mixture was cooled to at 0 °C, and satdNH4Claq (20 mL)
was added to the reaction mixture, and extracted with
ethyl acetate (20 mL) for three times. The combined
organic phase was washed with brine and dried with
Na2SO4. Filtration and evaporation of the organics gave
the crude product, which was purified with silica gel
chromatography (Wakogel C-300, Wako, hexane/ethyl
acetate 6/1–4/1) to give the desired compound 13 in 78%
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.07.139.
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