Stereospecific synthesis of urea-tethered neoglycoconjugates starting from glucopyranosyl carbamates

Article abstract of DOI:10.1016/j.tet.2004.01.055

Silyl-assisted elimination reaction of glucopyranosyl carbamates has been established for the synthesis of α- and β-D-glucopyranosyl isocyanates and ureas. This method proved to be useful for the synthesis of urea-tethered neoglycoconjugates.

Full text of DOI:10.1016/j.tet.2004.01.055

Tetrahedron 60 (2004) 2621–2627
Stereospecific synthesis of urea-tethered neoglycoconjugates
starting from glucopyranosyl carbamates
*
Yoshiyasu Ichikawa, Taihei Nishiyama and Minoru Isobe
Laboratory of Organic Chemistry, School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
Received 26 September 2003; accepted 9 January 2004
Abstract—Silyl-assisted elimination reaction of glucopyranosyl carbamates has been established for the synthesis of a- and b-D-
glucopyranosyl isocyanates and ureas. This method proved to be useful for the synthesis of urea-tethered neoglycoconjugates.
q 2004 Published by Elsevier Ltd.
1. Introduction
glycopeptide mimetics, which proposed urea glycosyl bond
as the carbohydrate–peptide linkage.10 The synthesis of
urea glycosyl bond was planned to be constructed by the
reaction of glycopyranosyl isocyanates with amines.11
The importance of carbohydrates linked to the peptide
backbone of protein (glycopeptides) has become increas-
ingly appreciated in the bioorganic and/or medicinal
research work due to their involvement in various biological
events such as cellular recognition and adhesion.1 Glyco-
peptides have two main classes of glycosidic linkage which
involve either oxygen atom in the side chain of serine and
threonine, or nitrogen atom in the side chain of asparagine.2
Although synthetic chemists continue to explore the
synthesis of accurately sequenced glycopeptides for bio-
logical and structural studies, total synthesis of the native
glycopeptides still remain time-consuming and challenging
tasks. In parallel, there are also much efforts toward the
design and synthesis of glycopeptide mimetics which will
supply homogeneous, stable and readily accessible glyco-
peptide analogues for biological studies and applications as
potential therapeutic agents.3 For example, O-glycosidic
linkage is replaced by carbon–carbon,4 carbon–sulfur5 and
carbon–aminooxy units.6 With glycopeptide mimetics for
N-glycosidic linkage, the amide group in N-glycosides was
replaced by a retoamide subunit,7 and alanine–hydroxyl-
amine and alanine–hydrazine was employed as asparagine
surrogates.8 In addition to this rich area of glycopeptide
mimetics, multivalent glycoconjugates such as glycoclus-
ters and glycodendrimers have emerged as a new class of
compounds which bear a structural resemblance to poly-
saccharides.9 Such multivalent glycoconjugates are syn-
thetically available and have exactly defined structure,
which may be useful to explore the cluster effect of
glycosides. Recently, we proposed a new approach to
During this research endeavor, a new synthetic method for
the preparation of b-D-glucopyranosyl isocyanate 3 was
established as represented in Scheme 1. Following the
procedure reported by Ogawa,12 catalytic hydrogenation of
b-azide 1 gave b-amine 2, treatment of which with
triphosgene under Schotten–Baumann conditions afforded
a solution of b-isocyanate 3. Since isolation of pure 3 was
unsuccessful due to the highly reactive nature of the
isocyanate group,13 the resulting reaction mixture was
successively treated with cyclohexylamine to afford the
stable and easily isolable urea glucoside 4 as crystals.
While b-urea 4 was obtained with this simple method, many
attempts to prepare a-isomer using similar reaction
sequence failed. In fact, hydrogenation of a-azide 5 gave
Keywords: Carbamate; Carbohydrates; Neoglycoconjugates; Urea;
Synthetic methods.
*
Corresponding author. Tel.: þ81-5-2789-4115; fax: þ81-5-2789-4100;
Scheme 1. Synthesis of b-glucopyranosyl isocyanate and urea by the
reaction of b-glucopyranosyl amine with triphosgene.
e-mail address: ichikawa@agr.nagoya-u.ac.jp
0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.01.055

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Y. Ichikawa et al. / Tetrahedron 60 (2004) 2621–2627
a-amine 6, which rapidly isomerized into the thermodyna-
mically more stable b-isomer 2 during work-up (Scheme 2).
To avoid such an anomerization problem, we developed a
method utilizing the oxidation of glucopyranosyl isonitrile 7
for the preparation of a-glucopyranosyl urea 9 (Scheme 3).
p-nitrophenyl b-N-glucopyranosyl carbamate 12 as a
precursor to b-glucopyranosyl isocyanate 3.
Initial attempts to synthesize 12 by the reaction of b-amine
2 with p-nitrophenyl chloroformate in the presence of
triethylamine were unsuccessful; only bis-urea 13 was
isolated (Scheme 5). We reasoned that use of triethylamine
caused elimination of the initially formed p-nitrophenyl
carbamate 12 to afford isocyanate 3, which spontaneously
reacted with the remaining amine 2. This rationalization led
us to employ a weaker base; the combination of p-nitro-
phenyl chloroformate and pyridine successfully suppress
the elimination to furnish 12 as pale yellow crystals. As
expected, base-catalyzed elimination of p-nitrophenyl
carbamate 12 occurred quite readily; reaction of 12 in
dichloroethane with diisopropylethylamine (iPr2NEt) at
room temperature spontaneously afforded an yellow
solution containing b-isocyanate 3, which was successively
treated with cyclohexylamine to yield urea glucoside 4 in
84% yield for two steps. Although we were delighted with
these results, we found the problem associated with 12,
which slowly decomposed even in a refrigerator. Moreover,
purification of 12 by silica-gel chromatography was
accompanied with partial formation of 13 to result in the
decreased recovery of 12.
Scheme 2. A rapid anomerization of a-glucopyranosyl amine.
Scheme 3. Synthesis of a-glucopyranosyl isocyanate and urea starting from
a-glucopyranosyl isonitrile.
While this protocol established a stereospecific synthesis of
a- and b-D-glucopyranosyl isocyanates and ureas, we felt
that more convenient method uncovered. Herein, we report
the full detail of our second-generation synthesis of
glucopyranosyl isocyanates and ureas starting from gluco-
pyranosyl carbamates.14
Scheme 5. Synthesis of p-nitrophenyl glucopyranosyl carbamate and its use
for the preparation of glucopyranosyl urea.
We next turned our attention to the more stable methyl
carbamate 14, which was prepared from 1 in 98% yield
(Scheme 6).
2. Results and discussion
Bender proposed that p-nitrophenyl N-methylcarbamate 10
undergoes alkaline hydrolysis via elimination–addition
mechanism, which involves methyl isocyanate 11 as an
intermediate15 (Scheme 4). This report inspired us to set
Scheme 6. Synthesis of methyl glucopyranosyl carbamate.
Although 14 was sufficiently stable to be stored at room
temperature for several weeks, the base-catalyzed elimin-
ation of methyl carbamate 14 (iPr2NEt, 1,2-dichloroethane,
reflux temperature, overnight) did not occur. To solve this
problem, we explored the silyl-promoted elimination
reaction of carbamates.16 Although such elimination of
carbamates are well-established transformations, no
example of this reaction with a-alkoxy carbamate is
Scheme 4. Elimination–addition mechanism of carbamate hydrolysis and
evolution of a new synthetic plan for glucopyranosyl isocyanate starting
from glucopyranosyl carbamate.

Y. Ichikawa et al. / Tetrahedron 60 (2004) 2621–2627
2623
known. Accordingly, we were concerned about the behavior
of the plausible intermediate, N-silylated species such as II
(Scheme 7), which is critical to the origin of the
stereoselectivity in this elimination reaction. If intermediate
II is configurationally stable and undergoes the elimination
reaction, complete retention of the anomeric stereochem-
istry in the starting material I will be observed. On the other
hand, if equilibrium between II and N-carbamoylimine
intermediate III occurs via reversible ring-opening reaction,
then the product distribution will be determined by the
relative stability of the a- and b-anomers II and/or the rates
of their elimination and equilibration. In this sense, we were
especially worried about the fate of II having a-anomer
configuration, because a-N-glycosides are expected to be
less stable than b-isomers.
the carbamates, we have prepared trichloroethyl (Troc) and
phenyl carbamates 15 and 16 by treatment of 2 with 2,2,2-
trichloroethyl chloroformate and phenyl chloroformate in
78 and 89% yields, respectively (Scheme 8). While
elimination of the Troc carbamate 15 was sluggish and
excess reagents were necessary, phenyl carbamate 16
underwent smooth elimination (1.5 equiv. of MeSiCl3,
4.0–5.0 equiv. of iPr2NEt, 1,2-dichloroethane, 75 8C, 5 h)
to afford glucopyranosyl isocyanate 3. Successive treatment
of the reaction mixture containing 3 with cyclohexylamine
(2.0 equiv.) afforded b-urea glucoside 4 in 82% yield after
chromatographic purification.17
Scheme 8. Synthesis of Troc and phenyl glucopyranosyl carbamates and
their use for the synthesis of b-urea glucoside.
Encouraged by this result, a-phenyl carbamate 17 was also
prepared from a-azide 5 (Scheme 9). Catalytic hydrogen-
ation of a-azide 5 followed by immediate treatment of the
reaction mixture with phenyl chloroformate and pyridine
afforded a 4:1 mixture of phenyl carbamates with the
desired a-isomer 17 predominating in 87% yield. Although
a mixture of these anomers could be separated by careful
silica-gel chromatography, a-isomer 17 was much more
conveniently purified by recrystallization.18 Using a pro-
cedure similar to that given in Scheme 8, silyl-promoted
elimination of a-carbamate 17 was carried out, and the
corresponding a-urea glucoside 9 was isolated in 83% yield.
According to 1H NMR analysis of the crude reaction
products, any b-isomer 4 has never been detected, which
clearly showed that elimination of a-carbamate 17 pro-
ceeded stereospecifically without anomerization. It should
be noted that while our previous method using glucopyra-
nosyl isonitriles gave slightly better yields (Scheme 3) than
the present procedure, both glucopyranosyl carbamates 16
Scheme 7. A plausible reaction mechanism for the silyl-promoted
elimination of glucopyranosyl carbamates.
After screening several chlorosilanes and solvents, we have
finally found that trichloromethylsilane (CH3SiCl3) and
trichlorophenylsilane (PhSiCl3) in 1,2-dichloroethane or
acetonitrile are effective for this transformation as rep-
resented in Table 1. However, we soon realized a serious
drawback; a large excess of cyclohexylamine (5 to 7 equiv.)
was necessary to obtain a good yield of urea glucoside 4.
For example, when only 2 equiv. of cyclohexylamine was
employed, the yield of isolated urea glucoside 4 dropped
appreciably (ca. 30%). Since this problem appeared to arise
from excess chlorosilane used which would interfere with the
reaction of glucopyranosyl isocyanate 3 with cyclohexyl-
amine, we turned our attention to the more reactive
glucopyranosyl carbamates with moderate stability.
Since it is expected that the extent and rate of elimination
depend on pKa values of the leaving alkoxy substituents in
Table 1. Silyl-promoted elimination of b-methyl glucopyranosyl carba-
mate 14
Entry
Chlorosilane
Solvent
Conditions
Yield (%)
A
B
C
D
MeSiCl3
PhSiCl3
MeSiCl3
PhSiCl3
CH2ClCH2Cl
CH3CN
CH2ClCH2Cl
CH3CN
80 8C/4 h
45 8C/3 h
80 8C/5 h
50 8C/6 h
90
85
90
89
Scheme 9. Synthesis of a-phenyl glucopyranosyl carbamate and urea
glucoside.

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Y. Ichikawa et al. / Tetrahedron 60 (2004) 2621–2627
Table 2. Synthesis of urea-tethered neoglycoconjugates
Entry
R
A
B
C
D
E
a-Urea glucosides (yield, %)a
b-Urea glucosides (yield, %)a
18a (89%)b
19a (82%)b
18b (80%)b
19b (78%)b
18c (84%)b
19c (82%)b
18d (80%)b
19d (81%)b
18e (93%)c
19e (94%)c
a
Isolated yield after chromatographic purification.
Glucopyranosyl carbamate (1.0 equiv.) and amine (2.0 equiv.) were employed. Yield based on glucopyranosyl carbamate.
Glucopyranosyl carbamate (1.5 equiv.) and amine (1.0 equiv.) were used. Yield calculated based upon L-phenylalanine methyl ester hydrochloride.
b
c
and 17 can be readily prepared from glucopyranosyl azides
in two steps using commercially available reagents. More-
over, a practical merit for the purification of a-phenyl
glucopyranosyl carbamate 17 is noticed in its easy
crystallinity.
With a new route to glucopyranosyl ureas established, we
undertook to examine the utility of glucopyranosyl
carbamates as glycosyl donors for the synthesis of urea-
tethered neoglycoconjugates. The results are summarized in
Table 2, in which a variety of urea-glucosides are prepared
by the reaction with five different amines. It is notable that
even sterically hindered amine, such as diisopropylamine
(entry C), as well as low nucleophilic amine, such as aniline
(entry D), gave satisfactory yields (.80%).
Scheme 10. Lindhorst synthesis of thio-bridged cluster of b-glucoside.
opportunity to compare glucopyranosyl isocyanate with
isothiocyanate counterpart. Furthermore, we expected that
the synthesis of a-urea-bridged glucopyranosyl cluster
appeared to be more appealing than the b-isomer synthesis,
because the corresponding a-thiourea analogue is difficult
to be synthesized.22 Scheme 11 summarizes our approach to
the urea-tethered a-glucopyranosyl cluster.
The first synthesis of both glucopyranosyl isocyanate 3
and isothiocyanate 21 was announced in 1914 by
Fischer.19 Although many syntheses of neoglycoconju-
gates using glucopyranosyl isothiocyanate has been
reported,20 little attention has been paid to glucopyrano-
syl isocyanate 3. This miserable situation for 3 may be
due to the difficulties associated with the preparation of
the more reactive glucopyranosyl isocyanate 3. Since a
reliable synthetic method for the preparation of both a-
and b-D-glucopyranosyl isocyanates has been established,
we turned our attention upon comparing glucopyranosyl
isocyanate with isothiocyanate counterpart in the context
with the neoglycoconjugates synthesis. In this sense, we
were interested in the report of Lindhorst,21 who
synthesized thio-bridged cluster of b-glucoside 22 by
the reaction of tris(2-aminoethyl)amine 20 with b-
glucopyranosyl isothiocyanate 21 (Scheme 10). In this
case, the base-catalyzed O!N migration of acyl groups
from the acetyl-protected glucosyl isothiocyanates onto
the amino termini of the trivalent amine proved to be
troublesome. To avoid this problem, reaction conditions
using diluted solution and reflux temperature (CH2Cl2)
were carefully employed.
Using a procedure similar to that in Scheme 9, a-carbamate
17 was transformed into a-isocyanate 8. Subsequent
treatment of the resulting reaction mixture containing 8
with tris(2-aminoethyl)amine 20 resulted in low yields of
product. After some experimentation, it was finally found
that aqueous work-up was necessary. In fact, after silyl-
promoted elimination of 17, rapid and careful work-up gave
the crude isocyanate 8,23 which was immediately dissolved
in dichloroethane. Treatment of the resulting solution with
20 furnished the multivalent glucoside 23 in 89% yield.24 It
should be noted that any migration of acetyl group in 8 was
not observed, which appears to reflect the more reactive
nature of glucopyranosyl isocyanate. Further deprotection
of 23 with a mixture of triethylamine and methanol gave
water-soluble glucodendrimer 24. Any anomerization of
urea-glucoside linkage did not occur during hydrolysis of
acetates in 23, which was confirmed by acetylation of 24 to
afford 23.25
This report led us to examine the reaction of glucopyranosyl
isocyanate with trivalent amine, which would offer an

Y. Ichikawa et al. / Tetrahedron 60 (2004) 2621–2627
2625
Elemental analysis was performed by Analytical Laboratory
at Graduate School of Bioagricultural Sciences, Nagoya
University. For thin-layer chromatography (TLC) analysis,
Merck precoated TLC plates (silica gel 60 F254, 0.25 mm)
were used. Column chromatography was performed on
silica gel (silica gel 60) supplied by E. Merck. Preparative
TLC separation was made on plates prepared with a 2 mm
layer of silica gel (Silica gel PF254) obtained from E. Merck.
Reactions were run under atmosphere of nitrogen when the
reactions were sensitive to moisture or oxygen. Dichloro-
˚
methane (CH2Cl2) was dried with molecular sieves 3 A.
Pyridine and triethylamine (Et3N) were stored over
anhydrous KOH. All other commercially available reagents
were used as received.
4.1.1. Synthesis of p-nitrophenyl-2,3,4,6-tetra-O-acetyl-
b-D-glucopyranosyl carbamate 12 and its use for the
preparation of glucopyranosyl urea. A solution of
glucopyranosyl azide 1 (1.50 g, 4.02 mmol) and palladium
on activated carbon (2%, 350 mg) in THF (100 mL) was
vigorously stirred under hydrogen atmosphere for 3 h. The
mixture was filtered through Celite and concentrated under
reduced pressure. The resulting amine 2 (1.50 g) was
dissolved in a mixture of pyridine (1.30 mL, 16.1 mmol)
and CH2Cl2 (30.0 mL), and then treated with p-nitrophenyl
chloroformate (1.62 g, 8.04 mmol) at room temperature.
After being stirred for 30 min, the mixture was poured into
aqueous saturated ammonium chloride solution, and the
separating aqueous layer was extracted with AcOEt. The
combined organic layers were washed with brine, dried
(Na2SO4) and then concentrated. The resulting residue was
passed through a short column of silica-gel (AcOEt–
hexane, 2:1) to afford p-nitrophenyl glucopyranosyl carba-
mate 12 (1.97 g, 96%) as pale yellow solids. Since we have
not succeeded in purifying 12, the crude material was
successively employed for the next reaction. IR (KBr)
nmax¼3358, 1753, 1527, 1225; dH(CDCl3); 2.05 (3H, s),
2.06 (3H, s), 2.10 (3H, s), 2.13 (3H, s), 3.87 (1H, ddd, J¼10,
4.5, 2 Hz), 4.14 (1H, dd, J¼12.5, 2 Hz), 4.35 (1H, dd,
J¼12.5, 4.5 Hz), 5.02 (1H, t, J¼10, 9 Hz), 5.08 (1H, t,
J¼9 Hz), 5.12 (1H, t, J¼10 Hz), 5.36 (1H, t, J¼10 Hz),
6.26 (1H, d, J¼9 Hz), 7.32–7.36 (2H), 8.24–8.27 (2H);
dC(CDCl3); 20.4, 20.5, 61.5, 67.9, 70.2, 72.5, 73.5, 80.8,
121.9, 125.2, 145.2, 152.5, 155.1, 169.6, 169.9, 170.6, 170.9.
Scheme 11. Synthesis of urea-tethered cluster of glucoside with a-
anomeric stereochemistry.
3. Conclusion
We have demonstrated that glucopyranosyl carbamates are
valuable synthons for the preparation of urea-tethered
neoglycoconjugates. The present method is especially
useful for the synthesis of urea glycosides with a-
stereochemistry. Studies to prepare mannopyranosyl and
galactopyranosyl isocyanates and their use for the neogly-
coconjugate synthesis is now in progress.
4. Experimental
4.1. General procedures
Melting points were recorded with a micro melting point
apparatus and are not corrected. Optical rotations were
measured on a JASCO DIP-370 digital polarimeter. Infrared
spectra were recorded with a JASCO FT/IR-8300 spectro-
photometer and are reported in wavenumbers (cm21).
Proton nuclear magnetic resonance (1H NMR) and carbon
nuclear magnetic resonance (13C NMR) spectra were
recorded with Varian Gemini-2000 spectrometers. 1H
NMR chemical shifts (d) are reported in parts per million
(ppm) relative to tetramethylsilane (TMS, d¼0.00 in
CDCl3), CHD2OH (d¼3.31 in CD3OH), and t-BuOH
(d¼1.24 in D2O) as internal standards. Data are reported
as follows; chemical shift, integration, multiplicity (s¼
singlet, d¼doublet, t¼triplet, q¼quartet, qn¼quintet, sext¼
sextet, br¼broadened, m¼multiplet), coupling constants (J,
given in Hz). 13C NMR chemical shifts (d) are recorded in
parts per million (ppm) relative to CDCl3 (d¼77.0), CD3OD
(d¼49.0), t-BuOH (d¼30.29, in D2O) as internal standards.
High-resolution mass spectra (HRMS) are reported in m/z.
To a solution of p-nitrophenyl glucopyranosyl carbamate 12
(100 mg, 0.20 mmol) dissolved in 1,2-dichloroethane
(10.0 mL) was added diisopropylethylamine (175 mL,
0.98 mmol) at room temperature. The starting material
disappeared immediately (TLC check), and the resulting
yellow solution was treated with cyclohexylamine (30 mL,
0.26 mmol). After stirring for 10 min, the solution was
poured into aqueous saturated ammonium chloride solution,
and the aqueous layer was extracted with AcOEt. The
combined organic layer was washed with brine, dried
(Na2SO4), and then concentrated under reduced pressure.
Purification of the resulting residue by silica-gel column
chromatography (AcOEt–hexane, 2:1) gave b-urea 4
(79 mg, 87%).
4.1.2. Methyl-2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl
carbamate 14. A solution of 1 (500 mg, 1.34 mmol), Et3N
(0.19 mL, 1.40 mmol) and palladium on activated carbon

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Y. Ichikawa et al. / Tetrahedron 60 (2004) 2621–2627
(2%, 0.20 g) in THF (20 mL) was stirred vigorously under
hydrogen atmosphere for 90 min. The resulting solution was
then filtered on Super Cell, and the filtrate was concentrated
under reduced pressure until half volume. The resulting
solution containing amine 2 was diluted with CH2Cl2
(10 mL), and then treated with pyridine (0.54 mL,
6.70 mmol) and methyl chloroformate (0.26 mL,
3.35 mmol) at room temperature. After stirring for 15 min,
the mixture was poured into aqueous saturated sodium
hydrogencarbonate solution, and aqueous layer was
extracted with AcOEt. The combined organic layer was
washed with brine, dried (Na2SO4), and then concentrated
under reduced pressure. Purification of the resulting residue
by silica-gel column chromatography (AcOEt–hexane, 1:1)
afforded b-methyl carbamate 14 (535 mg, 98%); mp
104 8C; [a]2D2¼þ3.84 (c 1.00, CHCl3); IR (KBr)
nmax¼1753, 1541, 1370, 1237; dH(CDCl3); 2.02 (3H, s),
2.04 (3H, s), 2.06 (3H, s), 2.09 (3H, s), 3.71 (3H, s), 3.76–
3.84 (1H, m), 4.10 (1H, dd, J¼12.5, 2 Hz), 4.31 (1H, dd,
J¼12.5, 4.5 Hz), 4.92 (1H, t, J¼9.5 Hz), 5.03 (1H, bdt,
J¼9.5 Hz), 5.07 (1H, t, J¼9.5 Hz), 5.30 (1H, t, J¼9.5 Hz),
5.53 (1H, bd, J¼9.5 Hz); dC(CDCl3); 20.4, 20.5, 20.6, 52.6,
61.6, 68.1, 70.2, 72.8, 73.2, 80.8, 156.1, 169.6, 170.0, 170.7.
Anal. Calcd for C16H23NO11: C, 47.41; H, 5.72; N, 3.46.
Found: C, 47.40; H, 5.54; N, 3.43.
(143 mg, 93%). Mp 144 8C; [a]2D1¼þ112.3 (c 1.43, CHCl3);
IR (KBr) nmax¼3386, 1752, 1654, 1559, 1228; dH(CDCl3);
2.01 (6H, s), 2.04 (3H, s), 2.06 (3H, s), 3.06 (1H, dd, J¼14,
6.5 Hz), 3.26 (1H, dd, J¼14, 6.5 Hz), 3.64 (1H, brdd,
J¼12.5, 1.5 Hz), 3.76 (3H, s), 3.93 (1H, dt, J¼10, 1.5 Hz),
4.20 (1H, dd, J¼12.5, 3.5 Hz), 4.77 (1H, q, J¼6.5 Hz), 5.07
(1H, t, J¼10 Hz), 5.10 (1H, dd, J¼10, 5 Hz), 5.32 (1H, t,
J¼10 Hz), 5.50 (1H, t, J¼5 Hz), 5.57 (1H, d, J¼4 Hz), 5.73
(1H, d, J¼7 Hz), 7.10–7.34 (5H); dC(CDCl3); 20.37, 20.40,
20.43, 20.5, 37.8, 52.3, 53.8, 61.2, 67.1, 67.8, 68.6, 69.9,
76.7, 127.2, 128.6, 129.2, 135.9, 156.6, 169.2, 169.4, 170.3,
170.7, 172.7. Anal. Calcd for C25H32N2O12: C, 54.34; H,
5.84; N, 5.07. Found: C, 54.35; H, 5.85; N, 5.11.
4.2.3. Tris[2-(2,3,4,6-tetra-O-acetyl-a-D-glucopyrano-
syl)urea-ethyl]amine (23). A solution of 17 (200 mg,
0.43 mmol), trichloromethylsilane (75 mL, 0.64 mmol)
and diisopropylethylamine (260 mL, 1.46 mmol) dissolved
in 1,2-dichloroethane (10.0 mL) was heated at 75 8C for 5 h.
The resulting solution was diluted with CH2Cl2 (40 mL) and
then carefully poured into water containing cracked ice. The
resulting precipitate was quickly filtered on glass filter, and
the aqueous layer was extracted with CH2Cl2. The
combined organic extracts were dried (Na2SO4) and
concentrated. The resulting residue was immediately
dissolved in 1,2-dichloroethane (10.0 mL) and then treated
4.2. General procedure for the preparation of
glucopyranosyl urea
with a solution of tris(2-aminoethyl)amine (12 mg,
0.082 mmol) in 1,2-dichloroethane (1.5 mL). After stirring
at room for 30 min, usual work-up and purification by silica-
gel chromatography (AcOEt–2–PrOH, 10:1) afforded
the multivalent glucoside 23 (92 mg, 89%); mp 134 8C;
[a]2D1¼þ128.7 (c 1.00, CHCl3); IR (KBr) nmax¼3377, 1752,
1663, 1236; dH(CD3OD); 1.99 (9H, s), 2.01 (9H, s), 2.02
(9H, s), 2.05 (9H, s), 2.48–2.68 (6H), 3.12–3.28 (6H),
3.93–4.04 (6H), 4.26 (3H, dd, J¼12, 5 Hz), 5.03 (3H, t,
J¼10 Hz), 5.09 (3H, dd, J¼10, 5.5 Hz), 5.52 (3H, t,
J¼10 Hz), 5.80 (3H, d, J¼5.5 Hz); dC(CDCl3); 20.47,
20.56, 20.69, 20.7, 39.6, 55.5, 63.7, 68.3, 70.2, 70.4, 71.8,
76.8, 156.0, 171.4, 171.6, 171.8, 172.5. Anal. Calcd for
C51H75N7O30: C, 48.38; H, 5.97; N, 7.74. Found: C, 48.38;
H, 5.65; N, 7.45. HRMS (FAB) calcd for C51H76N7O30
[MþH]þ 1266.4637, found 1266.4659.
To a solution of 16 (120 mg, 0.26 mmol) and diisopropyl-
ethylamine (220 mL, 1.28 mmol) dissolved in 1,2-dichloro-
ethane (6.0 mL) was added trichloromethylsilane (45 mL,
0.39 mmol). The reaction flask was sealed under nitrogen
and then heated at 75 8C for 5 h. The resulting brown
solution was treated with cyclohexylamine (58 mL,
0.51 mmol) at room temperature for 20 min. Usual work-
up and purification by silica-gel chromatography (AcOEt–
hexane, 2:3) afforded urea 4 (99 mg, 82%).
4.2.1. 2,3,4,6-Tetra-O-acetyl-N-(benzenaminocarbonyl)-
a-D-glucopyranosylamine 18d. Mp 87 8C; [a]2D4¼þ135.2
(c 1.06, CHCl3); IR (KBr) nmax¼3368, 1753, 1671, 1559,
1232,; dH(CDCl3); 1.99 (3H, s), 2.03 (3H, s), 2.04 (3H, s),
2.07 (3H, s), 4.10–4.20 (2H), 4.24 (1H, dd, J¼12, 5.5 Hz),
5.08 (1H, t, J¼10 Hz), 5.17 (1H, dd, J¼10, 5 Hz), 5.48 (1H,
t, J¼10 Hz), 5.76 (1H, t, J¼5 Hz), 6.29 (1H, brd, J¼4 Hz),
7.00–7.50 (5H); dC(CDCl3); 20.43, 20.48, 61.8, 67.4, 68.3,
68.8, 69.9 76.7, 120.1, 123.9, 129.1, 137.9, 155.3, 169.3,
169.5, 170.3, 170.8. Anal. Calcd for C21H26N2O10: C,
54.07; H, 5.62; N, 6.01. Found: C, 54.31; H, 5.55; N, 5.99.
4.2.4. Tris[2-(a-D-glucopyranosyl)urea-ethyl]amine 24.
A solution of 23 (253 mg, 0.20 mmol) and Et3N (2.0 mL) in
methanol (12.0 mL) was stirred at room temperature
overnight, and the reaction mixture was concentrated
under reduced pressure. The resulting residue was washed
with methanol to give 24 (151 mg, quantitatively) as a white
amorphous solid; [a]D23¼þ106.0 (c 0.57, H2O); IR (KBr)
nmax¼3352, 1652, 1560; dH(D2O); 2.66 (6H, brt, J¼6 Hz),
3.23 (6H, brt, J¼6 Hz), 3.41 (3H, t, J¼10 Hz), 3.53 (3H,
ddd, J¼10, 4, 2 Hz), 3.62 (3H, t, J¼10 Hz), 3.68–3.84 (9H),
5.46 (3H, d, J¼5.5 Hz); dC(D2O); 38.4, 49.6, 54.3, 61.3,
70.2, 72.5, 73.9, 78.7 160.7. HRMS (FAB) calcd for
C27H52N7O18 [MþH]þ 762.3369, found 726.3339.
4.2.2. Methyl N-(2,3,4,6-tetra-O-acetyl-a-D-glucopyra-
nosyl-aminocarbonyl)-2(S)-phenylalanine 18e. A sol-
ution of 17 (200 mg, 0.43 mmol), trichloromethylsilane
(75 mL, 0.64 mmol) and diisopropylethylamine (225 mL,
1.28 mmol) dissolved in 1,2-dichloroethane (10.0 mL) was
sealed under nitrogen and then heated at 75 8C for 6.5 h. The
resulting brown solution was treated with a solution of
L-phenylalanine methyl ester hydrochloride (64 mg,
0.28 mmol) and diisopropylethylamine (65 mL, 0.36 mmol)
in 1,2-dichloroethane (2.0 mL) at room temperature for
30 min. Usual work-up and purification by silica-gel
chromatography (AcOEt–hexane, 1:3) afforded urea 18e
Acknowledgements
This research was financially supported by a Grant-In-Aid
for Scientific Research from the Ministry of Education,
Science, Sports and Culture.

Y. Ichikawa et al. / Tetrahedron 60 (2004) 2621–2627
2627
reference: Ichikawa, Y.; Matsukawa, Y.; Nishiyama, T.; Isobe,
M. Eur. J. Org. Chem. 2004, 586.
References and notes
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1
line broadening of the H NMR peaks measured in CDCl3,
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13. Recently, we have succeded in establishing a simple procedure
for isolating glucopyranosyl isocyanate 1 as crystals. See the