Synthesis of urea and carbamate glycosides employing unprotected carbohydrates

Article abstract of DOI:10.1055/s-0030-1260587

A study of methods for the synthesis of urea and carbamate glycosides, starting with unprotective carbohydrates, led to the preparation of amino acid-carbohydrate conjugates in aqueous media. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260587

1462
LETTER
Synthesis of Urea and Carbamate Glycosides Employing Unprotected
Carbohydrates
Synthesis of
Urea
o
and Carbama
s
te
G
lycos
h
ides
E
mploy
i
ing U
n
y
protected Ca
a
rbohydratessu Ichikawa,* Shohei Kusaba, Takahiro Minami, Yumiko Tomita, Keiji Nakano, Hiyoshizo Kotsuki
Faculty of Science, Kochi University, Akebono-cho Kochi, 780-8520, Japan
Fax +81(88)8448359; E-mail: ichikawa@kochi-u.ac.jp
Received 9 March 2011
OH
O
OH
O
Abstract: A study of methods for the synthesis of urea and carbam-
O
ate glycosides, starting with unprotective carbohydrates, led to the
preparation of amino acid–carbohydrate conjugates in aqueous
media.
HO
HO
HO
HO
H2N
NH2
O
aq H2SO4
OH
N
NH2
H
Key words: neoglycoconjugates, urea, carbamate, glucose, glu-
cosamine
OH
OH
1
2
O
OH
O
OH
O
R1
H2N
N
R2
HO
HO
The fundamental importance of glycoconjugates in a wide
range of biological processes has promoted a great deal of
interest in neoglycoconjugates as tools for glycobiology
as well as potential therapeutic agents.1 Our efforts in this
area have focused on the synthesis of neoglycoconjugates,
in which the O- and N-glycosyl linkages are replaced with
urea–glycosyl bonds.2 Our specific interest in urea-teth-
ered neoglycoconjugates arose during the synthetic works
of the amino sugar antibiotic, glycocinnasperimicin D,
which possesses a urea glycoside as a key structural unit.3
HO
HO
O
R1
OH
this work
N
N
R2
H
OH
OH
1
3
Scheme 1 Urea glycoside synthesis plan
products were characterized only by melting points, ele-
mental analyses and optical rotations. Importantly, the
structures of the products of these processes have never
Although a number of new synthetic methods to access been elucidated completely. In addition, the yields are
urea glycosides have been developed by us4 and others5 quite low, and the stereochemistry of the products (a/b se-
the existing procedures have the drawback in their low ef- lectivity) has not been determined.
ficiency, particularly due to the length of the synthetic
routes arising from extensive use of protection/deprotec-
tion sequences. In this context, we became intrigued by a
classical method for the synthesis of urea glucoside 2,
which involves acid-catalyzed condensation of D-glucose
(1) with urea6 (Scheme 1). This simple process is remark-
able, because urea glucoside 2 is formed from protecting-
group-free D-glucose. Stimulated by the synthetic poten-
tial of this reaction as a method for urea-tethered neogly-
coconjugate synthesis, we launched an investigation to
extend this process to the synthesis of N-substituted urea
glycosides 3.
1) methyl-harnstoff,
6.5 M aq HCl
50 °C, 16 d
glucose
d-glucose-monomethylureid
2) MeOH (32%)
Scheme 2 Classical synthesis of d-glucose-monomethylureid by
Helferich
Our initial efforts focused on identifying the structure of
d-glucose-monomethylureid reported by Helferich. Ac-
cordingly, we synthesized an anomeric pair of 1-methyl-
3-glucosylureas by employing a method we developed
previously (Scheme 3). b-Glucosyl isonitrile 5, prepared
from acetyl glucoside 4 in four steps, was oxidized with
pyridine N-oxide and a catalytic amount of iodine in the
presence of MS 3A (anhydrous conditions) to generate the
glucosyl isocyanate 6.2 Successive treatment of 6 with
methylamine provided the b-1-methyl-3-glucosylurea 7
in 88% yield. A similar transformation employing a-glu-
cosyl isonitrile 8, prepared from 4 in five steps, afforded
a-1-methyl-3-glucosylurea 9 in 74% yield. With these
two authentic samples in hand, we carried out the experi-
ments of Helferich. After acetylation of d-glucose-
monomethylureid we found the product is identical to 7,
synthesized from b-glucosyl isonitrile 5.
After extensive literature browsing, we found that few
precedents exist for the reaction of N-substituted urea de-
rivatives with carbohydrates. In 1926, Helferich reported
the reaction of glucose with methyl-harnstoff (1-methyl-
urea) in aqueous HCl at 50 °C for 16 days leading to the
production of D-methylurea glucoside (d-glucose-
monomethylurid)7 (Scheme 2). Following this work,
Erickson investigated the reaction of long-chain octade-
cylurea with D-glucose.8 Although these two early reports
described the synthesis of N-substituted urea glucosides,
SYNLETT 2011, No. 10, pp 1462–1466
x
x
.x
x
.2
0
1
1
Advanced online publication: 26.05.2011
DOI: 10.1055/s-0030-1260587; Art ID: U02511ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Urea and Carbamate Glycosides Employing Unprotected Carbohydrates
1463
OAc
O
OAc
O
Table 1 Urea Glucosylation in 6 M HCl
1) pyridine N-oxide
cat. I2, MS 3 Å
O
AcO
AcO
AcO
1)
6 M HCl
4 steps
OH
O
(10 equiv)
r.t.
H2N
R
3 d
HO
HO
AcO
AcO
OAc
N
C
workup A: neutralization, concentration
2) Ac2O, pyridine
AcO
4
5
OH
OAc
O
OAc
OH
OAc
OAc
O
AcO
AcO
AcO
2) MeNH2
(88%)
O
O
AcO
AcO
O
C
AcO
AcO
Me
O
O
O
+
AcO
N
N
H
N
H
AcO
N
H
R
AcO
N
R
6
7
H
OR
OAc
Entrya
1
Urea glucoside (R)
Yield (%)
67
a/b
OAc
O
AcO
AcO
1) pyridine N-oxide
cat. I2, MS 3 Å
2) MeNH2
AcO
O
N
H
O
5 steps
93:7
4
(74%)
Me
AcO
N
N
H
12
AcO
N
H
C
AcO
AcO
9
8
2
3
56
26
93:7
N
H
Scheme 3 Synthesis of b- and a-1-methyl-3-glucosylureas from
glucosyl isonitriles
13
O
1)
92:8
OH
O
6 M HCl
r.t.
3 d
N
H
Me
H2N
N
(10 equiv)
H
HO
HO
14
workup A: neutralization; concentration
workup B: addition of Et2O; filtration
Me
OH
2) Ac2O, pyridine
4
N
H
24
>98:2
OH
1
OR
O
OR
O
15
RO
RO
RO
RO
O
O
+
N
5
6
10
6
97:3
97:3
Me
Me
N
N
N
N
H
H
H
H
16
OR
OR
10: R = H
7: R = Ac
11: R = H
9: R = Ac
Me
N
Me
workup A: 68% (β/α= 94:6)
workup B: 71% (only β-isomer 7)
17
a The reaction was carried out on 300-mg scale of D-glucose.
Scheme 4 Improved synthesis of 1-methyl-3-glucosylurea
We next examined conditions varying amounts of 1-
methylurea, acid catalysts (HCl, H2SO4, acidic resins),
temperature and time in order to optimize yields. This ef-
fort led to the observation that the use of excess 1-methy-
lurea resulted in a considerable improvement in the yields
of the reactions (Scheme 4). Stirring a solution of D-glu-
cose and 1-methylurea (10 equiv) in aqueous 6 M HCl at
room temperature for three days, followed by neutraliza-
tion with sodium bicarbonate and concentration (workup
A) afforded a solid, which was acetylated utilizing stan-
dard conditions (Ac2O, pyridine). After chromatographic
purification, a mixture of acetyl b-1-methyl-3-glucosyl-
urea and acetyl a-1-methyl-3-glucosylurea (7 and 9) was
obtained in 68% yield (b/a = 95:5). Although separation
of this anomeric mixture was quite difficult, addition of
diethyl ether after the reaction (workup B) resulted in ef-
ficient crystallization of the b-anomer 10 to result in the
isolation of acetyl-b-1-methyl-3-glucosylurea 7 in 71%
yield after acetylation. Because the urea group displays
only a small anomeric effect, the product distribution
dominating the formation of b-anomer 10 over a-isomer
11 seems to reflect the sterically driven preference for the
bulky urea substituent at the pyranose anomeric position
to occupy the equatorial disposition under thermodynam-
ically controlled conditons.9
A range of substituted ureas was found to participate in
the protective-group-free urea glucosylation using similar
conditions described in Scheme 4 (Table 1). For example,
simple n-butylurea and b-phenethylurea reacted to give
products in moderate yields (entries 1 and 2; 67% and
56%, respectively). Branching at the a-position of amine
moiety in the urea [entries 3 and 4; cyclohexylamine and
(R)-a-methylbenzylamine] reduced the yield considerably
(26% and 24%). Ureas derived from secondary amines
(entries 5 and 6; pyrrolidine and dimethylamine) gave the
Synlett 2011, No. 10, 1462–1466 © Thieme Stuttgart · New York

1464
Y. Ichikawa et al.
LETTER
Table 2 Improved Urea Glucosylation
O
OAc
O
OAc
O
OH
H2N
(2.0 equiv)
2) Ac2O, pyridine
R
1)
AcO
AcO
2.4 M HCl, solvent
50 °C, 24 h
AcO
AcO
HO
HO
O
O
+
O
N
R
N
R
OH
H
H
OR
OAc
OH
Entrya
1
Urea glucoside (R)
2.4 M HCl–solvent (ratio)
2.4 M HCl–MeCN (1:4)
Yieldb (%)
68 (75)
a/b
N
H
92:8
12
2
3
2.4 M HCl–MeCN (1:6)
2.4 M HCl–EtOAc (1:6)
63 (70)
68 (77)
90:10
>98:2
N
H
13
N
H
14
Me
4
N
H
2.4 M HCl–MeCN (1:6)
69 (72)
>98:2
15
2.4 M HCl–EtOAc (1:6)
2.4 M HCl–EtOAc (1:1)
27 (29)
40c (42)
97:3
95:5
N
5
6
16
Me
N
2.4 M HCl–EtOAc (1:2)
2.4 M HCl–EtOAc (1:1)
30 (38)
49c (50)
97:3
93:7
Me
17
a The reaction was carried out on 300-mg scale of D-glucose.
b Yields in parentheses are calculated based on the consumed amount of ureas.
c Yields obtained employing 10 equiv of ureas.
urea glucosides albeit in low yields (10% and 6%). Al- products in acceptable yields (entries 3 and 4; 68% and
though the yields of these reactions are unsatisfactory, the 69%). Although yields in the case of ureas derived from
facts that urea glucosides are generated in a single step secondary amines were still low (entries 5 and 6, 27% and
from unprotected D-glucose (compare with the examples 27%), loading increased amounts of ureas (10 equiv) led
in Scheme 3) and that the process is carried out in water to modest levels of efficiency (40% and 49%).
are noteworthy.
With a good method for the synthesis of urea glycosides
In order to increase the yields and reduce the amounts of starting with unprotected carbohydrates in hand, we next
ureas, several variations in the concentration of HCl, co- focused our attention on the preparation of urea-tethered
solvent and reaction temperature were explored. Consid- amino acid–carbohydrate conjugates (Scheme 5). Con-
erable experimentation led to the finding that by employ- densation of the lysine derivative 18 with dimethylamine
ing 2.4 M HCl with co-solvents, such as ethyl acetate or using EDC in the presence of HOBt followed by removal
acetonitrile, and two equivalents of ureas promote reac- of the N-Boc group with TFA gave the amine 19. Trans-
tions that generate the corresponding urea glucosides in carbamoylation of phenyl carbamate with 19 in the pres-
much higher yields10 (Table 2). In the case of n-butylurea ence of tin catalyst furnished urea 20.11 Conjugation of
and phenethylurea (entries 1 and 2; 68% and 63%), two urea 20 with D-glucose in a mixture of 2.4 M HCl–EtOAc
equivalents of urea were enough to obtain the comparable (1:6) followed by acetylation furnished the amino acid–
yields in Table 1, where ten equivalents of urea were em- glucose conjugate 21 in 52% yield with a high b-selectiv-
ployed. Glucosylation of cyclohexylurea and (R)-a-meth- ity (b/a = 95:5).
ylbenzylurea, using the improved conditions, afforded the
Synlett 2011, No. 10, 1462–1466 © Thieme Stuttgart · New York

LETTER
Synthesis of Urea and Carbamate Glycosides Employing Unprotected Carbohydrates
1465
1) Me2NH, EDC
HOBt, DMF
(87%)
similar conditions as in Table 2 (Scheme 8) proceeded
smoothly to furnish a mixture of glucosyl carbamates 24
and 25 in 67% yield (b/a = 90:10). Further studies of this
novel carbamate glycosylation reaction are under way.
O
Boc
N
O
H2N
HN
Cbz NMe2
HN
Cbz OH
2) TFA, CH2Cl2
(74%)
H
19
18
PhOCONH2
dibutyltin maleate
O
O
1) D-glucose
OH
2.4 M HCl–EtOAc (1:1)
NMe2
1)
H2N
O
toluene, 90 °C
(80%)
2.4 M HCl–EtOAc (1:6)
50 °C, 24 h
H2N
N
H
HN
Cbz
50 °C, 24 h
(5.0 equiv)
2) Ac2O, pyridine
(67%, β/α = 90:10)
OAc
HO
HO
O
O
20
OAc
OH
OH
OAc
1
2) Ac2O, pyridine
AcO
AcO
O
O
AcO
AcO
AcO
AcO
52%, β/α = 95:5
NMe2
O
O
O
O
N
N
HN
Cbz
+
H
OAc
H
O
N
H
O
N
H
O
21
OAc
OAc
25
Scheme 5 Synthesis of urea-tethered amino acid–carbohydrate con-
24
jugate
Scheme 8 Synthesis of glucosyl carbamates
We explored the possibility that the new methodology is
not limited to D-glucose and can be expanded to the case
of N-acetyl-D-glucosamine to demonstrate the potential
generality of the reaction (Scheme 6). Cyclohexylurea
was selected as a reactant due to the high yield and selec-
tivity as observed in Table 2. In the event, a solution of N-
acetyl-D-glucosamine 22 and cyclohexylurea (10 equiv)
in a 1:1 mixture of 2.4 M HCl–EtOAc was stirred at 50 °C
for 24 hours. After workup and acetylation of the product,
the b-urea glucosamide 23 was obtained predominantly in
61% yield. The structure of 23 was unambiguously con-
firmed by comparison with an authentic sample prepared
in six steps from 22.12
The studies described above have led to the development
of a new synthetic method for the preparation of urea and
carbamate glycosides. The most noteworthy features are
the short-step synthesis of urea and carbamate glycosides
in aqueous media starting from unprotected carbohy-
drates.
Acknowledgment
Financial support from the Kochi University President’s Discretio-
nary Grant is greatly appreciated. Chiharu Hidaka is acknowledged
for her contributions to a part of experimental work in carbamate
glycosylation.
O
References and Notes
1)
H2N
OH
O
OAc
O
N
(10 equiv)
H
(1) (a) Davis, B. G. J. Chem. Soc., Perkin Trans. 1 1999, 3215.
(b) Gamblin, D. P.; Scanlan, E. M.; Davis, B. G. Chem. Rev.
2009, 109, 131.
HO
HO
2.4 M HCl–EtOAc
(1:1), 50 °C, 24 h
AcO
AcO
O
2) Ac2O, pyridine
(61%)
(2) (a) Ichikawa, Y.; Nishiyama, T.; Isobe, M. Synlett 2000,
1256. (b) Ichikawa, Y.; Nishiyama, T.; Isobe, M. J. Org.
Chem. 2001, 66, 4200. (c) Nishiyama, T.; Ichikawa, Y.;
Isobe, M. Synlett 2003, 47. (d) Ichikawa, Y.; Matsukawa,
Y.; Nishiyama, T.; Isobe, M. Eur. J. Org. Chem. 2004, 586.
(e) Ichikawa, Y.; Nishiyama, T.; Isobe, M. Tetrahedron
2004, 60, 2621. (f) Ichikawa, Y.; Ohara, F.; Kotsuki, H.;
Nakano, K. Org. Lett. 2006, 8, 5009.
(3) (a) Dobashi, K.; Nagaoka, K.; Watanabe, Y.; Nishida, M.;
Hamada, M.; Takeuchi, T.; Umezawa, H. J. Antibiot. 1985,
1166. (b) Ellestad, G. A.; Cosulich, D. B.; Broschard, R. W.;
Martin, J. H.; Kunstmann, M. P.; Morton, G. O.; Lancaster,
J. E.; Fulmor, W.; Lovell, F. M. J. Am. Chem. Soc. 1978,
100, 2515. For synthetic works, see: (c) Nishiyama, T.;
Isobe, M.; Ichikawa, Y. Angew. Chem. Int. Ed. 2005, 44,
4372. (d) Nishiyama, T.; Kusumoto, Y.; Okumura, K.; Hara,
K.; Kusaba, S.; Hirata, K.; Kamiya, Y.; Isobe, M.; Nakano,
K.; Ichikawa, Y. Chem. Eur. J. 2010, 16, 600.
OH
N
N
H
H
NHAc
NHAc
23
22
Scheme 6 Synthesis of b-urea glucosamide starting from N-acetyl-
D-glucosamine
Finally, we attempted to extend this unique urea glycosy-
lation procedure to the preparation of analogous glycosyl
carbamate (Scheme 7), a process that, to the best of our
knowledge, has not been reported previously.13
O
O
O
O
+
R
+
R
H2N
urea
N
H2N
O
OH
H
OH
analogy
carbamate
O
O
O
O
R
(4) (a) Ichikawa, Y.; Matsukawa, Y.; Isobe, M. Synlett 2004,
1019. (b) Ichikawa, Y.; Matsukawa, Y.; Isobe, M. J. Am.
Chem. Soc. 2006, 128, 3934. (c) Ichikawa, Y.; Matsukawa,
Y.; Tamura, M.; Ohara, F.; Isobe, M.; Kotsuki, H. Chem.
Asian J. 2006, 1, 717.
N
NH2
N
O
H
H
Scheme 7 Synthesis plan of glycosyl carbamate
Interestingly, reaction of D-glucose with five equivalents
of commercially available n-butyl carbamate under the
Synlett 2011, No. 10, 1462–1466 © Thieme Stuttgart · New York

1466
Y. Ichikawa et al.
LETTER
(5) (a) Fisher, E. Ber. 1914, 47, 1377. (b) Bannister, B.
J. Antibiot. 1972, 377. (c) Pinter, I.; Kovacs, J.; Toth, G.
Carbohydr. Res. 1995, 273, 99. (d) Bottcher, C.; Burger, K.
Tetrahedron Lett. 2003, 44, 4223. (e) Prosperi, D.; Ronchi,
S.; Lay, L.; Rencurosi, A.; Russo, G. Eur. J. Org. Chem.
2004, 395. (f) Prosperi, D.; Ronchi, S.; Panza, L.; Rencurosi,
A.; Russo, G. Synlett 2004, 1529. (g) Bianchi, A.; Ferrario,
D.; Bernardi, A. Carbohydr. Res. 2006, 341, 1438.
(h) Sawada, D.; Sasayama, S.; Takahashi, H.; Ikegami, S.
Tetrahedron Lett. 2006, 47, 7219. (i) Yang, J.; Mercer, G.
J.; Nguyen, H. M. Org. Lett. 2007, 9, 4231. (j) Sawada, D.;
Sasayama, S.; Takahashi, H.; Ikegami, S. Tetrahedron 2008,
64, 8780. (k) Mercer, G. J.; Yang, J.; McKay, M. J.; Nguyen,
H. M. J. Am. Chem. Soc. 2008, 130, 11210. (l) For a
review, see: Spanu, P.; Ulgheri, F. Curr. Org. Chem. 2008,
12, 1071.
urea, which was treated with a mixture of acetic anhydride
(5.0 mL) and pyridine (10 mL) at 50 °C for 3 h. After
standard workup followed by chromatographic purification,
a mixture of acetyl b-1-n-butyl-3-glucosylurea and acetyl
a-1-n-butyl-3-glucosylurea 12 (507 mg, b/a = 92:8) was
obtained in 68% yield. Concentration of CH2Cl2 extracts and
purification by chromatography provided the recovered 1-n-
butylurea (210 mg). The yield of 1-n-butyl-3-glucosylureas
12 based on the consumed 1-n-butylurea was calculated to
be 75%.
(11) Ichikawa, Y.; Morishita, Y.; Kusaba, S.; Sakiyama, N.;
Matsuda, Y.; Nakano, K.; Kotsuki, H. Synlett 2010, 1815.
(12) Urea glucosamide 23 was reported to be synthesized from
isonitrile 26 prepared from N-acetyl-D-glucosamine 22 in
five steps (Scheme 9). See reference 2f.
AcO
(6) (a) Schoorl, M. N. Recl. Trav. Chim. Pays-Bas 1903, 22, 31.
(b) Benn, M. H.; Jones, A. S. J. Chem. Soc. 1960, 3837.
(7) Helferich, B.; Kosche, W. Ber. 1926, 59, 69.
(8) Ercikson, J. G.; Keps, J. S. J. Am. Chem. Soc. 1953, 75,
4339.
1) pyridine N-oxide
cat. I2, MS 3 Å
2) cyclohexylamine
AcO
O
5 steps
23
22
AcO
NC
(9) Ichikawa, Y.; Watanabe, H.; Kotsuki, H.; Nakano, K. Eur. J.
Org. Chem. 2010, 6331.
NHAc
26
(10) A solution of D-glucose (300 mg, 1.67 mmol) and 1-n-
butylurea (387 mg, 3.33 mmol) in a mixture of 2.4 M HCl
(0.25 mL) and MeCN (1.0 mL) was stirred at 50 °C for 24 h.
The mixture was neutralized by the addition of NaHCO3 and
washed with CH2Cl2 to remove excess 1-n-butylurea. The
resulting aqueous layer was extracted with n-butanol. The
combined n-butanol extracts were concentrated under
reduced pressure to afford the crude 1-n-butyl-3-glucosyl-
Scheme 9
(13) These types of N-glycosyl carbamates were synthesized by
the reaction of glycosyl isocyanates with alcohols. Authentic
samples of 24 and 25 were prepared by the reaction of n-
butyl alcohol with glucosyl isocyanates, generated from
glucosyl isonitriles 5 and 8. See reference 2d.
Synlett 2011, No. 10, 1462–1466 © Thieme Stuttgart · New York