Convenient stereoselective synthesis of substituted ureido glycosides using stable 4-chlorophenylcarbamates without the requirement of Lewis acids

Article abstract of DOI:10.1055/s-0033-1340220

A modification of the synthesis of substituted ureido glycosides in a stereospecific fashion is described, in which commercially available azido glycosides are reduced to the amines, which are then reacted with 4-chlorophenyl chloroformate to the corresponding 4-chlorophenyl carbamate of the glycosides. These synthetic intermediates are stable at room temperature and have a long shelf life, and can transiently form the 1-isocyanato glycosides under mildly basic conditions, which subsequently can react with amines to form substituted ureido glycosides Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340220

LETTER
▌205
lCettoernvenient Stereoselective Synthesis of Substituted Ureido Glycosides Using
Stable 4-Chlorophenylcarbamates without the Requirement of Lewis Acids
Stereoselective Synthesis of Substituted Ureido Glycosides
Steffen van der Wal,a Ou Fu,a Stamatia Rontogianni,a Roland J. Pieters,a Rob M. J. Liskamp*a,b
a
Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht
University, PO Box 80082, 3508 TB Utrecht, The Netherlands
b
Chemical Biology and Medicinal Chemistry, School of Chemistry, University of Glasgow, Glasgow G12 8QQ, Glasgow, UK
Fax +44(141)3306867; E-mail: robert.liskamp@glasgow.ac.uk
Received: 16.09.2013; Accepted after revision: 14.10.2013
Although several methods for generating these urea con-
Abstract: A modification of the synthesis of substituted ureido gly-
jugates have been described in the literature most of the
cosides in a stereospecific fashion is described, in which commer-
older literature deals with anomeric mixtures or contain
cially available azido glycosides are reduced to the amines, which
are then reacted with 4-chlorophenyl chloroformate to the corre-
the more stable β-type urea glycosidic linkage.7 It was
sponding 4-chlorophenyl carbamate of the glycosides. These syn- only recently that synthetic procedures have appeared that
thetic intermediates are stable at room temperature and have a long
shelf life, and can transiently form the 1-isocyanato glycosides un-
der mildly basic conditions, which subsequently can react with
egies are available for selective formation of α-ureido gly-
amines to form substituted ureido glycosides
exert full control over the stereochemistry of the anomeric
center in ureido glycosides.8 Currently, a number of strat-
cosides.5 Many of these methods rely on the condensation
of an isocyanato glycoside with an amine or condensation
of an amino glycoside with an isocyanate. The inherent re-
Key words: carbohydrates, stereoselective synthesis, azides, urea,
carbamates
activity of isocyanato glycosides, however, poses a chal-
lenge for the preparation and isolation of these
Carbohydrates can be tethered in various ways to other
compounds. Moreover, although the isolation of amino
(bio)molecules, mostly via glycoside bonds. In glycopro-
glycosides is feasible for the β-amino glycosides, the α-
teins common glycosidic linkages include those to threo-
amino glycosides rapidly interconvert to the more stable
nine and serine residues. Recently, thioglycosidic
β-isomer and cannot be stored for a prolonged period of
linkages to cysteine residues were found in nature,1 al-
though with the exception of glucosinolates,2 most thio-
glycosides are synthetically produced.3 The last important
type comprises the glycoside–carboxamide linkage, as
found in asparagine and glutamine glycoconjugates. Con-
jugates of carbohydrates to (substituted) urea moieties,
which are chemically similar to those of the carboxamide
linkages, are a characteristic of a natural class of antibiot-
ics; the glycocinnamoylspermidines,4 and have recently
received increasing attention as potential urea-based in-
hibitors of many enzymes were found.5 Additionally, the
formation of an α-ureido glycoside was a key step in the
synthesis of trehazolin, a trehalase inhibitor.6
time.8 This can be circumvented to some extent by forma-
tion of the amino glycoside from the azido glycoside fol-
lowed by direct conversion by a suitable reagent. Many
currently used synthetic strategies employ a crystalline
and stable azido glycoside as a masked amino glycoside.
This can then be transformed into its corresponding isocy-
anate and subsequently into the ureido glycoside (Scheme
1).
The tetraacetyl azido glycosides themselves are easily
synthesized as either the α- or the β-anomer from the cor-
responding 1,2-trans-peracetyl sugars9–12 and are also
commercially available. To circumvent the handling of
phosgene derivatives leading to the isocyanato glyco-
O
O
R2NH2
O
H
N
R1O
R1O
R1O
H
N3
N
N
C
R2
O
O
R2NH2
O
O
O
R1O
R1O
R1O
N
HN
O
N3
C
O
HN
R2
Scheme 1 Common synthesis route in the synthesis of ureido glycosides via isocyanate intermediates
SYNLETT 2014, 25, 0205–0208
Advanced online publication: 02.12.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340220; Art ID: ST-2013-B0885-L
© Georg Thieme Verlag Stuttgart · New York

206
S. van der Wal et al.
LETTER
sides, much effort has been put into producing a masked tetraacetyl α-amino galactoside was easily synthesized
version of these glycosides. Especially Ichikawa and co- and it proved easy to crystallize the intermediate to high
workers have described two attractive strategies that pro- purity. The elimination of the phenyl carbamate, however,
duce stable masked isocyanates with a long shelf life, such required refluxing with silyl chlorides under basic condi-
as glycoside isocyanides13 and carbamates14 (Scheme 2), tions to form the isocyanate intermediate. While success-
which are crystalline and easy to purify.
ful, we surmised the possibility of performing the reaction
under milder conditions. Indeed, the synthesis of the 4-ni-
trophenyl carbamate,15,14 amongst other carbamates,16 has
been described in literature. The pKa of the nitrophenol is
3 units lower than the pKa of phenol itself (Scheme 2),
thus a far greater reactivity was observed in the base-
mediated elimination, to such an extent that the com-
pounds decomposed even without a strong base present.
As a result, the 4-nitrophenyl carbamate was not stable to
chromatography conditions nor suitable for storage at
room temperature.
O
O
R1O
R1O
– OR2
N
O
N
H
C
O
base
O
R2
R2
pKa HOR2
115.5
Me
CH2CCl3
Ph
112.0
110.0
4-O2NC6H4
17.2
Thus, we turned our attention to carbamates containing a
Scheme 2 Base-mediated elimination of sugar carbamates,17 here leaving group with a character between that of phenol and
depicted for an α-glycoside
4-nitrophenol. We turned to 4-chlorophenol with a pKa of
around 9 and investigated the corresponding 4-chloro-
phenyl carbamate in its ability to function as a stable pre-
cursor of an isocyanate using milder conditions than silyl
chlorides in the presence of base at reflux.14 The synthesis
of the carbamate was analogous to those described earlier
by Ichikawa et al.15 The resulting chlorophenyl carbamate
In our work on glycopeptides we required an efficient
synthesis of substituted ureido α-galactosides, and the
strategy of Ichikawa et al. using an amine and a phenyl-
carbamido glycoside seemed very promising.14 Indeed,
under the conditions described, the phenyl carbamate of
Table 1 Synthesis of 4-Chlorophenylcarbamates 5–8 and Ureas 9–12
Entry
Starting azide
4-Chlorophenylcarbamate
Yield (%)a Urea
Yield (%)
67d
OAc
OAc
O
O
H
OAc
AcO
AcO
H
N
H
AcO
O
N
O
N
AcO
AcO
AcO
AcO
1
N3
68
AcO
AcO
O
O
Cl
9
1
5
OAc
O
OAc
O
AcO
AcO
AcO
AcO
OAc
O
AcO
HN
AcO
AcO
AcO
HN
H
N
2
3
69b
68
O
AcO
N3
O
O
Cl
2
10
6
OAc
OAc
OAc
OAc
O
OAc
OAc
OAc
H
O
H
H
N
O
O
AcO
N
N
AcO
60
89d
N3
AcO
AcO
AcO
AcO
O
O
Cl
11
3
7
OAc
OAc
O
OAc
O
OAc
OAc
O
AcO
AcO
AcO
HN
4
72c
81
AcO
HN
H
N
O
AcO
AcO
N3
O
O
Cl
4
12
8
a Isolated yield after crystallization.
b A small amount (<5%) of the β-anomer was present after the first crystallization.
c This compound was obtained as crystals co-crystallized with ca. 1 equiv of Et2O.
d DBU was used as a base instead of DIPEA in the synthesis.
Synlett 2014, 25, 205–208
© Georg Thieme Verlag Stuttgart · New York

LETTER
Stereoselective Synthesis of Substituted Ureido Glycosides
207
General Procedure for the Synthesis of 4-Chlorophenylcarba-
mates of Glucose and Galactose
was then reacted with a set of primary amines at room
temperature in THF in the presence of i-Pr2EtN (DIPEA;
Scheme 3). To our delight, the tested amines (cyclohexyl-
amine as well as a small peptide with a free ornithine side
chain) reacted cleanly with the carbamate in a few hours.
A solution of azidotetraacetyl glycosides 1–4 (500 mg, 1.3 mmol)
and Et3N (90 μL, 0.6 mmol) in Et2O (30 mL) was added to a suspen-
sion of Pd/C (10% Pd on matrix activated carbon support, Sigma
Aldrich, 175 mg) in n-hexane (25 mL). The reaction mixture was
placed under a hydrogen atmosphere (3 bar, Parr apparatus) and
shaken for 45 min. The reaction mixture was then diluted with THF
(50 mL) and filtered over Celite. To the resulting filtrate pyridine
was added (0.5 mL, 6.5 mmol), followed by 4-chlorophenyl chloro-
formate (370 μL, 2.6 mmol). After stirring for 45 min, the reaction
mixture was diluted with EtOAc and washed with KHSO4 (aq 1 M)
twice and subsequently dried over Na2SO4. The crude products
were purified over a plug of silica (2:1 hexanes–EtOAc) and recrys-
tallized from Et2O–hexanes to yield the 4-chlorophenylcarbamates
as white microcrystalline solids. Rf = 0.32 (EtOAc–hexanes = 1:1,
v/v) for all four compounds.
OAc
OAc
OAc
O
OAc
O
4-ClC6H4OC(O)Cl
pyridine, THF
H2, Pd/C, Et3N
Et2O–hexanes
AcO
AcO
AcO
AcO
AcO
N3
NH2
OAc
OAc
OAc
O
OAc
O
AcO
RNH2, i-Pr2EtN
AcO
AcO
Compound 5: 1H NMR (300 MHz, CDCl3): δ = 7.31 (d, J = 8.8 Hz,
2 H), 7.06 (d, J = 8.8 Hz, 2 H), 5.96 (d, J = 9.1 Hz, 1 H), 5.32 (t, J
= 9.3 Hz, 1 H), 5.15–4.92 (m, 3 H), 4.33 (m, 1 H), 4.11 (m, 1 H),
3.83 (m, 1 H), 2.10 (s, 3 H), 2.09 (s, 3 H), 2.03 (s, 3 H), 2.03 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.85, 170.61, 169.89,
169.52, 153.41, 148.87, 131.14, 129.39, 122.68, 80.86, 73.37,
72.64, 70.26, 67.98, 61.53, 20.73, 20.70, 20.57 (2 C) ppm.
HN
O
HN
O
THF
O
NH
R
R = cyclohexylamine, 71%
R =
NH2 , 82%.
Cl
72% from azide
N
Compound 6: 1H NMR (300 MHz, CDCl3): δ = 7.32 (d, J = 8.8 Hz,
2 H), 7.10 (d, J = 8.8 Hz, 1 H), 6.12 (d, J = 7.3 Hz, 1 H), 5.75 (m, 1
H), 5.37 (m, 1 H), 5.19 (m, 1 H), 5.09 (m, 1 H), 4.33 (m, 1 H), 4.08
(m, 2 H), 2.09 (s, 3 H), 2.08 (s, 3 H), 2.06 (s, 3 H), 2.04 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 170.70, 170.41, 169.36, 169.13,
153.27, 148.86, 131.23, 129.46, 122.65, 76.70, 69.89, 68.48, 68.08,
68.00, 61.67, 20.71, 20.61, 20.59, 20.57 ppm.
Compound 7: 1H NMR (300 MHz, CDCl3): δ = 7.32 (d, J = 8.8 Hz,
2 H), 7.07 (d, J = 8.8 Hz, 2 H), 5.95 (d, J = 9.4 Hz, 1 H), 5.45 (s, 1
H), 5.21–5.10 (m, 2 H), 5.04 (m, 1 H), 4.15 (m, 2 H), 4.05 (m, 1 H),
2.16 (s, 3 H), 2.11 (s, 3 H), 2.04 (s, 3 H), 2.00 (s, 3 H) ppm.13C NMR
(75 MHz, CDCl3): δ = 171.11, 170.37, 170.02, 169.78, 153.39,
148.93, 131.12, 129.38, 122.70, 81.17, 72.28, 70.78, 68.02, 67.06,
61.10, 20.77, 20.66, 20.60, 20.52 ppm.
Compound 8: 1H NMR (300 MHz, CDCl3): δ = 7.33 (d, J = 8.8 Hz,
2 H), 7.10 (d, J = 8.8 Hz, 2 H), 6.19 (d, J = 7.5 Hz, 1 H), 5.80 (m, 1
H), 5.46–5.36 (m, 2 H), 5.28 (m, 1 H), 4.25 (m, 1 H), 4.14 (m, 2 H),
2.16 (s, 3 H), 2.10 (s, 3 H), 2.04 (s, 3 H), 2.03 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 170.84, 170.56, 170.21, 169.44,
153.65, 148.96, 131.13, 129.41, 122.73, 77.11, 67.47 (2 C), 67.14,
66.08, 61.60, 20.64 (2 C), 20.62, 20.58 ppm.
H
O
Scheme 3 Synthesis of 4-chlorophenylcarmabido α-galactoside
To establish the general applicability of this new carba-
mate synthon, we synthesized a small series of propar-
gylureido glycosides (Table 1). Both anomeric forms of
tetraacetyl-glucose and -galactose were synthesized, two
of the most commonly used carbohydrates in carbo-
hydrate chemistry.
As expected, the α-gluco-derived carbamate 6 reacted
cleanly, under identical conditions as described for the α-
galacto derivative 8, to give 10. The β-glucoside carba-
mates 5 and 7, however, reacted very sluggish under these
conditions and completion of the reaction was not
achieved. Addition of the stronger neutral base 1,8-diaz-
abicyclo[5.4.0]undec-7-ene (DBU) caused the reaction to
proceed to completion within an hour. The thus obtained
ureido glycosides were found to be stable to these basic
conditions, that is, they did not anomerize. They did need
to be kept dry to prevent acetyl deprotection. However,
we noticed that exposure to strong acids such as trifluoro-
acetic acid causes appreciable anomerization, especially
of the α-urea glycosides.
General Procedure for the Synthesis of N′-Alkyl Ureido Glyco-
sides of Glucose and Galactose
Tetraacetyl-4-chlorophenyl carbamido glycoside 5–8 (100 mg,
0.2 mmol) was dissolved in THF (10 mL). Propargyl amine (25 μL,
0.4 mmol) was added, followed by i-Pr2EtN (DIPEA, 100 μL,
0.5 mmol, 2.5 equiv) and in case of the less reactive β-glycosides,
DBU (75 μL 0.5 mmol) was added instead of DIPEA. The reaction
The stability of the chlorophenyl carbamate 8 was mixture was stirred for 1–3 h, based on completion as assayed by
TLC, after which it was diluted with EtOAc, washed twice with
KHSO4 (1 M), and dried over Na2SO4. The urea products 9–12 were
purified by column chromatography (EtOAc–hexanes = 3:2, v/v)
and were obtained as white crystalline solids; Rf = ca. 0.30 (EtOAc–
hexanes = 2:1, v/v) for all four compounds.
Compound 9: 1H NMR (300 MHz, CDCl3): δ = 5.90 (d, J = 9.5 Hz,
1 H), 5.63 (t, J = 5.3 Hz, 1 H), 5.27 (m, 1 H), 5.12 (m, 1 H), 5.02 (m,
checked after 15 months of storage at room temperature.
No decomposition was observed by TLC, and complete
retention of the stereochemistry was observed by NMR
spectroscopy, in contrast to what is described about the ni-
trophenyl carbamate analogue, which decomposed even
when stored cold.14
1 H), 4.87 (t, J = 9.5 Hz, 1 H), 4.24 (m, 1 H), 4.02 (m, 1 H), 3.90 (m,
The reactivity of the 4-chlorophenyl carbamate synthon in
the presence of amines at room temperature, paired with
its high stability in the absence of base, suggests it might
be one of the more stable reactive masked isocyanates,
and its use greatly facilitates the synthesis of ureido teth-
ered glycopeptides and derivatives.
2 H), 3.80 (m, 1 H), 2.24 (t, J = 2.4 Hz, 1 H), 2.02 (s, 3 H), 2.00 (s,
3 H), 1.97 (s, 3 H), 1.95 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 170.98, 170.79, 169.96, 169.73, 156.32, 80.25, 79.95, 73.10,
72.99, 71.61, 70.48, 68.30, 61.89, 29.88, 20.75, 20.74, 20.58, 20.56
ppm.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 205–208

208
S. van der Wal et al.
LETTER
Compound 10: 1H NMR (300 MHz, CDCl3): δ = 6.11 (d, J = 4.4 Hz,
1 H), 5.78 (t, J = 5.2 Hz, 1 H), 5.56 (t, J = 5.1 Hz, 1 H), 5.40 (t, J =
9.8 Hz, 1 H), 5.14–4.95 (m, 2 H), 4.26 (m, 1 H), 4.14–3.96 (m, 4 H),
2.26 (t, J = 2.3 Hz, 1 H), 2.07 (s, 3 H), 2.03 (s, 3 H), 2.01 (s, 3 H),
2.00 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 170.66, 170.24,
169.43, 169.24, 157.20, 80.11, 76.77, 71.63, 69.91, 68.83, 68.27,
67.20, 61.82, 29.96, 20.71, 20.58, 20.55 (2 C) ppm.
Compound 11: 1H NMR (300 MHz, CDCl3): δ = 5.65 (d, J = 8.8 Hz,
1 H), 5.44 (d, J = 1.4 Hz, 1 H), 5.26–5.00 (m, 4 H), 4.13 (m, 2 H),
4.09–3.84 (m, 3 H), 2.24 (t, J = 2.4 Hz, 1 H), 2.15 (s, 3 H), 2.06 (s,
3 H), 2.05 (s, 3 H), 1.99 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 171.25, 170.59, 170.16, 169.79, 156.07, 80.43, 80.12, 72.23,
71.53, 71.08, 68.23, 67.35, 61.46, 29.93, 20.84, 20.75, 20.58, 20.51
ppm.
(2) Fahey, J. W.; Zalcmann, A. T.; Talalay, P. Phytochemistry
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(5) For an excellent review of ureido glycosides: Spanu, P.;
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Compound 12: 1H NMR (300 MHz, CDCl3): δ = 6.12 (d, J = 4.1 Hz,
1 H), 5.76 (t, J = 5.3 Hz, 1 H), 5.60 (s, 1 H), 5.40 (s, 1 H), 5.30 (m,
2 H), 4.28 (m, 1 H), 4.20–4.04 (m, 2 H), 4.00 (m, 2 H), 2.24 (t, J =
2.4 Hz, 1 H), 2.14 (s, 3 H), 2.06 (s, 3 H), 2.05 (s, 3 H), 1.98 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 170.47, 170.20, 170.12,
169.61, 157.59, 80.15, 77.34, 71.50, 67.73, 67.27, 66.44, 66.19,
61.96, 29.94, 20.71, 20.67, 20.60, 20.55 ppm.
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