Fast synthesis of uronamides by non-catalyzed opening of glucopyranurono-6,1-lactone with amines, amino acids, and aminosugars

Article abstract of DOI:10.1016/j.tetlet.2010.03.019

A series of glucuronamides have been easily prepared by reaction of glucopyranurono-6,1-lactone with a wide variety of amines. Primary and secondary amines gave the corresponding amides in short times, high yields. Diamines led to diuronamide compounds, whereas glucuronic acid conjugates were obtained with amino acids. The reaction with aminosugars afforded disaccharide analogues. In all products, the anomeric position is free for further conversion.

Full text of DOI:10.1016/j.tetlet.2010.03.019

Tetrahedron Letters 51 (2010) 2553–2556
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Fast synthesis of uronamides by non-catalyzed opening
of glucopyranurono-6,1-lactone with amines, amino acids, and aminosugars
*
Michaël Bosco, Stéphanie Rat, José Kovensky, Anne Wadouachi
Laboratoire des Glucides UMR 6219, Université de Picardie Jules Verne, 33 Rue Saint-Leu, F-80039 Amiens, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of glucuronamides have been easily prepared by reaction of glucopyranurono-6,1-lactone with a
wide variety of amines. Primary and secondary amines gave the corresponding amides in short times,
high yields. Diamines led to diuronamide compounds, whereas glucuronic acid conjugates were obtained
with amino acids. The reaction with aminosugars afforded disaccharide analogues. In all products, the
anomeric position is free for further conversion.
Received 14 January 2010
Revised 1 March 2010
Accepted 5 March 2010
Available online 11 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
6,3-Lactone
Glucuronamide
Amino acid
Aminosugar
Phosphodiester
The formation of amide bond has a real importance in the or-
ganic synthesis because it is found in many structures like proteins,
polyamides, and complex carbohydrates compounds such as
meonomycin,1 capuramycin2, and glycyrrhizic acid conjugates.3
Generally, the preparation of glucuronamide involves carboxylic
acid activation as a chloride,4 or by using a method derived from
peptide synthesis.5,6 To obtain glucofuranuronamide derivatives,
a glucofuranurono-6,3-lactone intermediate has been used, for
example, in the synthesis of bolaamphiphiles7 or as a key-step
for the preparation of glycosylated ortho-carboranyl amino acid
or mono- and bis-glucuronylated carboranes.8
All compounds were isolated as a mixture of
were characterized by NMR spectroscopy and ESI-MS spectrome-
try. Thus, for the major products, uronamide C-6 resonances
were observed at d 168.6 (3a and 3b), 168.3 (3c), 167.8 (3d), and
168.5 (3e). NH protons appear at d 6.60 (3a) 6.59 (3b), 6.73 (3c),
6.39 (3d), and 6.62 (3e).
a,b anomers and
a
For secondary amines (Table 1, entries 6 and 7), piperidine re-
acted as quickly as primary amines in 95% yield. In the case of
di-n-octylamine, the reaction was really slow. To increase the reac-
tion rate, the mixture was heated at 40 °C and after 30 min the cor-
responding amide 3f was obtained in 73% yield. On the other hand,
the reaction with di-n-isopropylamine failed, in spite of several at-
tempts using longer reaction times or heating, probably because of
the hindered character of this secondary amine. C-6 resonances of
disubstituted amines were observed at d 166.0 and 165.0 for 3f10
and 3g, respectively.
The reactivity with diamines was then studied. The yield of the
reaction with ethylenediamine (Table 1, entry 8, 94%) was higher
than 1,6-hexanediamine (Table 1, entry 9, 59%), certainly due to
the lower solubility of the latter in the reaction mixture. When
the reaction was conducted in DMF, the yield increased to 92% in
5 min. In both cases, the main product resulted from di-N-substitu-
tion, as shown by mass spectrometry: [MNa]+ peaks appear at m/z
687.2 (3h, 94% yield) and 743.2 (3i, 59% yield) corresponding to
interesting dimeric molecules.
Previously, we have developed a one-pot synthesis of acetylated
glucopyranurono-6,1-lactone from glucuronic acid (GlcA) under
microwave irradiation, and this lactone was used to prepare alkyl
(alkyl-D
-glucopyranoside)uronate derivatives.9
Herein, we examined the reaction between the 6,1-lactone 1
and various amines.
Firstly, we examined the reactivity of the 6,1-lactone 1 with
various aliphatic amines at room temperature (Table 1). The reac-
tion needs only a small amount of dichloromethane as a solvent
and 1.2 equiv of the amine. For primary amines, the reaction was
followed by TLC and furnished quickly (ca. 5 min) the correspond-
ing amides 3a–e in good to excellent yields (81À96%) after purifi-
cation (Table 1, entries 1–5).
In addition, we tested the reaction with amines containing dif-
ferent chemical functions. Coupling to amino acids was first as-
sayed, as amino acids are only available in the hydrochloride
form, 1 equiv of triethylamine was added in the reaction mixture.
* Corresponding author. Tel.: +33 3 22 82 75 27; fax: +33 3 22 82 75 60.
E-mail addresses: anne.wadouachi@u-picardie.fr, anne.wadouachi@sc.u-picardie.
fr (A. Wadouachi).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.019

2554
M. Bosco et al. / Tetrahedron Letters 51 (2010) 2553–2556
Table 1
Reactions with aliphatic amines, amino acids, caprolactam
Entry
1
Amine
Temperature
Time
Products
Yield
81%
H
N
O
n-Hexylamine
rt
rt
5 min
O
3a
3b
AcO
AcO
OH
AcO
H
N
O
2
3
n-Dodecylamine
5 min
5 min
87%
96%
O
AcO
AcO
OH
AcO
H
N
O
O
O
Benzylamine14
rt
3c
O
AcO
AcO
OH
OH
AcO
H
N
4
5
Cyclohexylamine
Tryptamine
rt
rt
5 min
3d
3e
89%
92%
O
AcO
AcO
AcO
H
N
10 min
O
AcO
AcO
N
OH H
AcO
O
O
O
N
O
rt
40 °C
30 min
30 min
Traces
73%
6
Di-n-octylamine
3f
AcO
AcO
OH
OH
AcO
N
O
7
8
9
Piperidine
rt
rt
5 min
5 min
3g
3h
3i
95%
94%
AcO
AcO
AcO
H
N
O
N
c
O
H
Ethylenediamine
O
AcO
AcO
AcO
AcO
OH
O
AcO
OH
AcO
H
N
O
O
N
H
40°C
rt
5 min
5 min
59%a
92%b
c
O
1,6-Hexanediamine
AcO
AcO
AcO
AcO
OH
AcO
OH
AcO
O
O
NH3+Cl-
H2N
NH2
OH
10
11
rt
rt
20 min
3j
88%a
O
NH
O
AcO
AcO
AcO
NH3+Cl-
NH
5 min
16 h
29%a
91%b
O
N
O
H
3k
O
NH
O
AcO
AcO
OH
AcO
NH3+Cl-
O
O
HS
OMe
MeO
SH
O
NH
O
12
13
rt
rt
5 min
3l
92%
95%
O
AcO
AcO
OH
AcO
O
OMe
MeO
O
NH3+Cl-
NH
O
60 min
3m
N
H
AcO
AcO
N
H
OH
AcO
a
b
c
The reaction was carried out in dichloromethane and methanol (1:1 v/v) to increase the amide solubility.
The reaction was performed in DMF.
The reaction was carried out with 1.9 equiv of lactone 1 for 1 equiv of diamine reagent.

M. Bosco et al. / Tetrahedron Letters 51 (2010) 2553–2556
2555
R1
N
O
O
O
AcO
O
R2
H
N
+
O
AcO
AcO
R1
R2
OH
AcO
3a-p
OAc
OAc
2a-p
1
Scheme 1. Reaction between the 6,1-lactone 1 and amines 2a–p.
O
H
O
P
H
H
N
H
O
N
1)
O
N
O
C
O
H
O
N
12 25
O
C
H
C
H
Cl
1) pivaloyl chloride
pyr, dodecanol
12 25
12 25
C
H
12 25
O
O
CH3CN / pyr
AcO
AcO
O
NaOH/H O/THF
2
AcO
AcO
HO
HO
AcO
AcO
OH
AcO
3b
AcO
HO
2) H2O
69%
AcO
O
O
O
O
2) I2
O
O
P
P
O
P
O
3) Na2S2O3
62%
4b
5b
6b
70%
O
O C H
12 25
O
C
H
12 25
H
Et NH
3
Et NH
3
Et NH
3
Scheme 2. Phosphorylation of the anomeric position of N-dodecylglucuronamide 3b.
Table 2
Reactions with amino sugars
Entry
Sugars
H2N
Temperature
rt
Time
Products
Yield (%)
H
N
O
O
BnO
BnO
O
O
1
5 min
3n
91
95
BnO
BnO
AcO
BnO
AcO
OH
BnO
AcO
OMe
OMe
NH2
O
H
N
O
O
O
O
O
O
O
AcO
AcO
2
3
rt
rt
5 min
3o
3p
O
O
O
OH
AcO
O
O
O
O
O
O
O
O
O
O
O
10 min
82
NH
O
H2N
O
AcO
AcO
OH
AcO
In the absence of triethylamine no amide formation was observed.
As shown in Table 1 (entries 10, 12, and 13), the reaction led to the
coupled products in high yields with glycine, cysteine, and trypto-
phan (88%, 92%, and 95%, respectively) making this approach suit-
able for the synthesis of glycopeptides. On the other hand, the poor
yield obtained with the caprolactame derivative may be assigned
to its low solubility in DCM. Accordingly, when the reaction was
performed in DMF, compound 3k was obtained in 91% yield (Table
1, footnote a).
As shown in Scheme 1, the caprolactam glucuronamide derived
is formed and the anomeric position is free. The scaffold 3 can be
used as a starting material for the preparation of glycosyl donors
such as trichloroacetamidates6a or phosphates.11 We have phos-
phorylated the anomeric hydroxyl using the procedure developed
by van Boom and co-workers (Scheme 2).12 The glucuronamide
3b was treated by salicylchlorophosphite, the hydrogen phospho-
nate intermediate 5b was then transformed into a mixed anhy-
methodology is based on peptide synthesis.15 Recently, Crich
and Sasaki16 developed a new two-step strategy based on the
reaction of a thiocarboxylate with an electrondeficient isocyanate
to give the corresponding amide. Our approach involves the reac-
tion of the 6,1-lactone with an amine derived from a sugar. As
shown in Table 2, the 6?6 (entries 1 and 2) or 3?6 (entry 3)
disaccharide analogues were obtained in short times and in high
yields (82–95%).
In conclusion, we have developed an efficient and fast reaction
to prepare glucuronamides from glucopyranurono-6,1-lactone and
different amine-containing compounds. Moreover, the formed
products can be used as scaffolds or key intermediates for the syn-
thesis of more complex molecules. A new phosphodiester amphi-
phile derived from
D-glucopyranuron-N-dodecylamide has been
prepared; other derivatives with different alkyl chains are cur-
rently synthesized.
dride with pivaloyl chloride followed by
a coupling with
Acknowledgment
dodecanol and an oxidation with iodine in the presence of water
to give the corresponding phosphate 6b.13
The authors acknowledge the ‘Conseil Régional de Picardie’ for
financial support.
Several research groups are interested in the preparation of
amide bond containing disaccharide analogues. The current

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M. Bosco et al. / Tetrahedron Letters 51 (2010) 2553–2556
8. (a) Thimon, C.; Panza, L.; Morin, C. Synlett 2003, 1399–1402; (b) Ronchi, S.;
Supplementary data
Prosperi, D.; Timon, C.; Morin, C.; Panza, L. Tetrahedron: Asymmetry 2005, 16,
39–44.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.03.019.
9. Rat, S.; Mathiron, D.; Michaud, P.; Kovensky, J.; Wadouachi, A. Tetrahedron
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10. Typical experimental procedure for the preparation of glucuronamide 3f: To a
solution of 6,1-lactone 1 (100 mg, 331 lmol) in dichloromethane (1 mL) was
References and notes
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O
H
O
O
N
AcO
O
SnCl4
O
PhCH2NH2
AcO
AcO
+
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H
MW 60°C
15W, 5 min
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4c
OAc
OAc
1
2c
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