Efficient alternative for the reduction of N-trichloroacetyl groups in synthetic chondroitin oligosaccharide intermediates

Article abstract of DOI:10.1016/j.tetlet.2010.02.005

An efficient alternative for the reduction of N-trichloroacetyl groups in chondroitin oligosaccharides is reported. It involves the use of Zn-Cu couple in acetic acid, and was successfully applied to a large panel of synthetic intermediates useful for the preparation of chondroitin oligomers, a class of natural products with numerous relevant biological functions.

Full text of DOI:10.1016/j.tetlet.2010.02.005

Tetrahedron Letters 51 (2010) 1867–1869
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient alternative for the reduction of N-trichloroacetyl groups
in synthetic chondroitin oligosaccharide intermediates
*
Aude Vibert, Chrystel Lopin-Bon, Jean-Claude Jacquinet
Institut de Chimie Organique et Analytique, UMR 6005 Université d’Orléans et CNRS, UFR Sciences, Université d’Orléans, BP 6759, 45067 Orléans Cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient alternative for the reduction of N-trichloroacetyl groups in chondroitin oligosaccharides is
reported. It involves the use of Zn–Cu couple in acetic acid, and was successfully applied to a large panel
of synthetic intermediates useful for the preparation of chondroitin oligomers, a class of natural products
with numerous relevant biological functions.
Received 18 January 2010
Revised 28 January 2010
Accepted 1 February 2010
Available online 6 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Zn–Cu reduction
Oligosaccharides
N-Trichloroacetyl group
Chondroitin sulfate
Chondroitin sulfate (CS) belongs to the family of proteoglycans,
an important class of biomolecules involved in numerous relevant
biological processes.1 They are heterogenous linear polysaccha-
rides constituted of a disaccharide-repeating unit composed of
stereocontrolling auxiliary in the synthesis of 1,2-trans-2-amino-
2-deoxy sugars.4a–e This later was reduced into its N-acetyl
congener under radical conditions using toxic tributylstannane.5
However, in some cases, the radical reduction did not go to
completion and mono- or dichloroacetamide intermediates were
isolated.6 In addition, the yields are sometimes not reproducible
and difficulties in eliminating tin species are often encountered.4e
Since classical basic conditions such as the use of NaBH4/EtOH7
or KOH/EtOH8 which removed the trichloroacetyl group and gener-
ated the free amine cannot be employed when ester groups were
used in the synthetic plan, we turn out our attention toward a mild
and less toxic method using Zn–Cu couple in acetic acid, a tech-
nique still reported for trichloroacetyl dehalogenation on sugar
structures,9 but that, to the best of our knowledge, was never
D
-glucuronic acid (
D
-GlcA) and 2-acetamido-2-deoxy-D-galactose
(D
-GalNAc) arranged in the sequence [?4)-b-
D-GlcpA-(1?3)-b-D-
GalpNAc-(1?]n, and contain, on average, one sulfate group per
disaccharide unit. Up to date, two main strategies have been re-
ported for the preparation of the
cules. The first one was based on the azidonitration of
D
-GalNAc residue in such mole-
D
-galactal2
which provided a 2-azido-2-deoxy group that was further reduced
and transformed in the last steps of the synthesis into a 2-acetam-
ido-2-deoxy group.3a–d The second strategy involved the use of a
2-deoxy-2-trichloroacetamido group, which acted as a powerful
OR6
R4O
OR6
R4O
O
CO2Me
CO2Me
O
O
Zn-Cu Couple
O
O
R4'O
R3'O
R4'O
R3'O
OR1
OR1
O
AcOH, 50°C
TCANH
ACNH
R2'O
R2'O
R1 = Ac, NAP, (CH2)2NHZ
R4, R6 = Ac, Bz, H
R2', R3' = Ac, Bz
R4' = Ac, H, Lev
O
TCA =
CCl3
Scheme 1. Reduction of the N-trichloroacetyl group in various chondroitin derivatives.
* Corresponding author. Tel.: +33 238 417072; fax: +33 238 417281.
E-mail address: Jean-Claude.Jacquinet@univ-orleans.fr (J.-C. Jacquinet).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.005

Table 1
N-Acetylated chondroitin derivatives produced via Scheme 1
Entry
Starting material
Product
Conditions
Yield (%)
95
AcO
O
AcO
OAc
O
OAc
O
CO2Me
CO2Me
O
O
AcO
AcO
AcO
AcO
1
O
24 h at 50 °C
AcHN
TCANH
OAc
OAc
OAc
OAc
1
8
OAc
OAc
AcO
AcO
CO2Me
CO2Me
O
O
O
O
ONAP
ONAP
AcO
AcO
AcO
AcO
O
O
2
3
24 h at 50 °C
24 h at 50 °C
24 h at 50 °C
77
92
98
TCANH
AcNH
OAc
OAc
9
2
OAc
O
OAc
O
AcO
AcO
CO2Me
CO2Me
O
O
AcO
AcO
AcO
AcO
O
O
TCANH
AcNH
OAc
OAc
ONAP
ONAP
10
3
OBz
OBz
BzO
BzO
CO2Me
CO2Me
O
O
O
O
HO
BzO
HO
BzO
O
O
O
O
4
5
6
NHZ
NHZ
AcNH
TCANH
OBz
OBz
11
4
HO
48a
71
HO
24 h at 50 °C
5 h at 50 °C
OBz
O
OBz
O
CO2Me
CO2Me
O
O
ONAP
LevO
BzO
ONAP
ONAP
LevO
O
O
BzO
TCANH
OBz
AcNH
OBz
12
5
BzO
BzO
OH
O
OH
CO2Me
CO2Me
O
O
O
ONAP
LevO
BzO
LevO
BzO
O
O
7 h 30 min at 50 °C
85
93
AcNH
TCANH
TCANH
OBz
OBz
13
6
OBz
OBz
BzO
O
BzO
O
OAc
OAc
AcNH
CO2Me
CO2Me
O
O
O
AcO
AcO
O
AcO
AcO
O
ONAP
O
ONAP
O
O
BzO
7
24 h at 50 °C
BzO
O
O
O
O
CO2Me
AcNH
OBz
CO2Me
TCANH
OBz
AcO
OAc
AcO
14
OAc
7
a
Mixture of products with 22% yield of furanoside 15 side-product.
CO2Me
ONAP
O
O
O
LevO
BzO
BzO
OH
NHAc
15
OBz

A. Vibert et al. / Tetrahedron Letters 51 (2010) 1867–1869
1869
applied to complex molecules such as CS oligomers. Classical
reduction conditions10 were tested on several chondroitin oligo-
saccharides which have been used as key intermediates during
CS oligomer syntheses.4a–c,11 These molecules are equipped with
different protective groups at the anomeric center, and bear di-
verse ester (acetate, benzoate, and levulinate) or hydroxy groups
on the other positions (Scheme 1).
The results of these studies are reported in Table 1. The reduc-
tion reaction was first attempted on peracetylated disaccharide
derivative 1 (entry 1). The reaction proceeded smoothly and was
complete within 24 h at 50 °C giving the acetamide 8 in 95% yield.
Next were tested glycosides 2 and 3 (entries 2 and 3), which differ
only by the chirality at the anomeric center with a bulky 2-naph-
thylmethyl group in the vicinity of the trichloroacetyl group. Both
reductions proceeded well and the acetamides 9 and 10, respec-
tively, were isolated in good yields. More interesting is the reduc-
tion of 4 (entry 4) which possesses a benzyl carbamate and a free
hydroxy group. In that case, neither cleavage of the carbamate nor
acetylation of the hydroxyl was observed. When these conditions
were applied to disaccharide derivative 5 (entry 5) having a free
thetic intermediates bearing
group in the synthesis of other members of the biologically rele-
vant GAG’s family such as hyaluronic acid and dermatan sulfate.
a
2-deoxy-2-trichloroacetamido
Acknowledgments
This research was supported by the Program ANR-08-PCVI-
0023-02 ‘GAGNetwork’. We are grateful for the support by the
Ministère de l’Enseignement Supérieur et de la Recherche through
a studentship to A.V.
Supplementary data
Supplementary data (Protocols for each reaction and 1H and 13
NMR data for reduced products) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.02.005.
C
References and notes
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Karst, N.; Jacquinet, J.-C. Eur. J. Org. Chem. 2002, 815–825; (e) Bélot, F.;
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10. General procedure for the reduction reaction: Zn–Cu couple (Acros Organics,
100 mg, 1.5 mmol) was added portionwise to a solution of the starting material
(0.1 mmol) in pure acetic acid (1.5 mL) at 50 °C under Ar, and the mixture was
stirred for the allotted time (see Table 1), cooled, filtered through a pad of
CeliteÒ, and concentrated. The resulting residues were directly purified by
flash-silica chromatography.
hydroxyl group at C-4 of the D-galactosamine unit, a mixture of
products was obtained in which the desired acetamide 12 could
be isolated in only 48% yield. A major side-product was formed
and unambiguously identified through 1H and 13C NMR as the
furanoside 15.12 Such a modification of structure resulting from
ring contraction at the D-galactosamine unit was already observed
on the parent molecules under acidic conditions.4d We assumed
that the zinc salts slowly released during the reaction acted as a Le-
wis acid which led to transient open-chain oxonium ion which re-
acted further with the free 4-OH group to provide the furanoside
15. However, shortening the reaction time to 5 h allowed the isola-
tion of acetamide 12 in an improved 71% yield. Starting from disac-
charide 6 having a free hydroxy group at C-6 and a benzoate ester
at C-4, no side-product was formed, and acetamide 13 was isolated
in 85% yield. Both compounds 12 and 13 were now ready for sub-
sequent O-sulfonation. More relevant is the reduction of tetrasac-
charide 7 (entry 7) bearing two trichloroacetyl groups, which
gave diacetamide 14 in 93% yield, whereas the radical-mediated
reductive dehalogenation allowed the isolation of 14 in only 62%
yield. As a general rule, the yields of the reactions are 20–30% supe-
rior to those obtained by the tin procedure.
In conclusion, these mild conditions using an operationally sim-
ple procedure worked well on a large panel of chondroitin deriva-
tives with one or more trichloroacetyl group(s) and compared well
with those previously reported,5 and could be applied to other syn-
11. Vibert, A. PhD Thesis, University of Orléans (France), November 2009.
12. See Supplementary data.