PhBCl2 promoted reductive opening of 2′,4′-O-p- methoxybenzylidene: New regioselective differentiation of position 2′ and 4′ of α-L-iduronyl moieties in disaccharide building blocks

Article abstract of DOI:10.1016/j.tetlet.2004.03.046

We describe a new protocol for the challenging differentiation of the position 2^′ and 4^′ of L-iduronyl moieties located at the nonreducing end of various disaccharide building blocks. This methodology is based on the introduction of a 2^′,4 ^′-O-p-methoxybenzylidene group, followed by a totally regioselective reductive opening of this acetal by the PhBCl₂/Et ₃SiH reagent system. L-Iduronyl moieties protected by a 4 ^′-O-p-methoxybenzyl group were thus obtained regioselectively and efficiently.

Full text of DOI:10.1016/j.tetlet.2004.03.046

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3643–3645
PhBCl2 promoted reductive opening of 20,40-O-p-
methoxybenzylidene: new regioselective differentiation of position 20
and 40 of a- -iduronyl moieties in disaccharide building blocksq
L
ꢀ*
Anna Dilhas and David Bonnaffe
Laboratoire de Chimie Organique Multifonctionnelle, UMR CNRS-UPS 8614 ‘Glycochimie Molꢀeculaire’ Bat. 420,
Universitꢀe Paris Sud, 91405 Orsay Cedex, France
Received 11 February 2004; accepted 8 March 2004
Abstract—We describe a new protocol for the challenging differentiation of the position 20 and 40 of
L-iduronyl moieties located at
the nonreducing end of various disaccharide building blocks. This methodology is based on the introduction of a 20,40-O-p-meth-
oxybenzylidene group, followed by a totally regioselective reductive opening of this acetal by the PhBCl2/Et3SiH reagent system.
L
-Iduronyl moieties protected by a 40-O-p-methoxybenzyl group were thus obtained regioselectively and efficiently.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Heparan sulfate (HS) is a linear sulfated polysaccharide
in which a basic disaccharide, composed of an uronic
acid (1!4)-linked to a 2-deoxy-2-aminoglucose, is
repeated throughout the sequence. HS chains, either at
the cell surface or in the extracellular matrix, interact
and regulate the activity of numerous proteins such as
growth factors, cytokines, chemokines, viral proteins
and coagulation factors.1;2 HS is one of the most het-
erogeneous biopolymers since various epimerisation and
sulfation patterns (sulfoforms) may occur along the
chain.3–5 We have recently published efficient routes to
in such conditions, the 40-O-p-methoxybenzyl product is
obtained with total regioselectivity. This PhBCl2/Et3SiH
based procedure complements nicely the use of
NaBH3CN/Me3SiCl, which was recently described by
Martin–Lomas and his co-workers to give the regioiso-
meric 2-O-p-methoxybenzyl product with b-L-iduronyl
monosaccharide building blocks.14 To our knowledge,
this is the first time that the PhBCl2/Et3SiH system has
been used to perform regioselective reductive opening of
acetals in systems less classical than 4,6-protected hex-
ose-derivatives.6;15;16
one
D-glucuronyl and the two L-iduronyl-containing
building blocks 1 and 2 (Scheme 2) that we are currently
using for the combinatorial synthesis of HS fragments.6
One key step in the preparation of 1 and 2 is the dif-
In the course of this study, we first reinvestigated the
preparation of disaccharides 7 and 8 (Scheme 1). Our
previous approach6 was based on the condensation of
ferentiation of the positions 20 and 40 in the a-
L
-iduronyl
the easily available
L
-iduronyl bromide 317–19 with
L-iduronyl trichloroacetimidates
moiety, which is always considered as an important
challenge.7–14 Our first strategy relied on stannylene-
mediated regioselective acetylation of position 20.6 We
describe here that the differentiation of the positions 20
and 40 may also be efficiently performed using PhBCl2/
Et3SiH15;6-mediated reductive opening of a 20,40-O-p-
methoxybenzylidene moiety in Et2O as solvent.6 Indeed,
acceptors 5 or 6.6 Since
have been reported to be superior donors to fluoro- or
thio-derivatives in glycosylation reactions,8 we decided
to study the glycosylating properties of trichloroacet-
imidate 4 onto acceptors 5 and 6. Trichloroacetimidate
4 was prepared in two high yielding steps from bromide
3 (Scheme 1), and the glycosylation conditions were
optimised with acceptor 5. We found that the reaction
was more efficient when performed with two successive
additions of promotor. First 0.02 equiv of TMSOTf was
added to a solution of donor 4 (1.3 equiv) and acceptor 5
in dichloromethane, resulting in the rapid formation
(20 min) of an ortho-ester intermediate, which
rearranged smoothly into disaccharide 7 upon further
addition of 0.05 equiv of TMSOTf, giving disaccharide 7
Keywords: Oligosaccharides; Heparan sulfate; Heparin; Combinatorial
chemistry; Reductive acetal opening; Glycosylation.
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2004.03.046
* Corresponding author. Tel.: +33-01-69-15-47-19; fax: +33-01-69-15-
47-15; e-mail: david.bonnaffe@icmo.u-psud.fr
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.046

3644
A. Dilhas, D. Bonnaffꢀe / Tetrahedron Letters 45 (2004) 3643–3645
Br
OR
OBn
O
OBn
O
O
O
CCl
3
a
HO
BnO
MeOOC
OAc
MeOOC
OAc
+
NH
N3
O
OAc
OAc
3
4
5 (R = Bn)
6 (R = Ac)
OR
O
O
BnO
b
OBn
O
N
3O
MeOOC
OAc
OAc
7 (R = Bn)
8 (R = Ac)
Scheme 1. Reagents and conditions: (a) (i) HgO, HgCl2, acetone/H2O, 88%. (ii) CCl3CN, K2CO3, CH2Cl2, 86%. (b) TMSOTf, CH2Cl2, 0 ꢁC, 91% (7)
and 92% (8), see supplementary material for details.
OR
OR
O
O
O
O
BnO
BnO
OBn
O
OBn
O
c
a
7
8
N
N
3
MeOOC
3
MeOOC
OH
O
O
9
(R = Bn)
10 (R = H)
11 (R = Ac)
O
O
12 (R = Bn)
13 (R = H)
14 (R = Ac)
OH
b
pMeOPh
OR
O
OR
O
O
O
BnO
BnO
OBn
O
OBn
O
d
e
N
3
N
MeOOC
pMBnO
3
MeOOC
pMBnO
O
O
OAc
OH
1 (R = Bn)
2 (R = Ac)
17 (R = Bn)
18 (R = H)
19 (R = Ac)
Scheme 2. Reagents and conditions: (a) K2CO3, MeOH, quant. (b) PPh3, DIAD, AcOH, THF, 85%. (c) p-MeOPh(OMe)2, camphorsulfonic acid,
ꢁ
CH2Cl2, 90% (12), 62% (13, after methanolysis of 15 and 16), 83% (14), see supplementary material for details. (d) PhBCl2, Et3SiH, 4 A, Et2O, )78 to
)40 ꢁC, 90% (17), 71% (18), 84% (19). (e) Ac2O, pyridine, quant.
in 91% isolated yield. Under the same conditions, the
condensation with acceptor 6 gave disaccharide 8 in 92%
yield. Using this procedure, we were able to prepare up
to 9 g of disaccharide in a single batch without affecting
the isolated yields.
the expected disaccharide 13 we obtained the mixed
acetals 15 and 16 (Fig. 1). Unfortunately selective
methanolysis of the unwanted acetals lead also to partial
cleavage of the 20,40-O-p-methoxybenzylidene moiety
and thus disaccharide 13 was only isolated in 62% after
the two steps. In order to avoid the formation of the side
products 15 and 16 and to prepare a precursor of
disaccharide 2, we treated disaccharide 10 with acetyl
chloride in pyridine at 0 ꢁC, but the regioselectivity was
low and we obtained a mixture of products. We thus
turned to a Mitsunobu reaction (Scheme 2), which gave
regioselectively the mono-acetylated compound 11 in
85% yield. As expected, this 6-OH protected derivative
11 was more efficiently converted (84%) than 10 to its
20,40-O-p-methoxybenzylidene protected derivative.
Disaccharides 7 and 8 were then deacetylated, using
standard conditions, giving disaccharides 9 and 10 in
quantitative yields (Scheme 2). The introduction of
the 20,40-O-p-methoxybenzylidene moiety on 9, using
p-anisaldehyde dimethyl acetal and acid catalysis
(Scheme 2), proved to be more difficult than anticipated.
We found that prolonged heating at high temperature
should be avoided in order to preclude the formation of
side products, arising probably from a cycloaddition
between the azide and allyl moieties.20 We thus per-
formed the reaction in methylene chloride, which
allowed the removal of the methanol formed, and
afforded disaccharide 12 in 90% yield. We then used
these optimised conditions with triol 10, but along with
The three disaccharides 12–14 were then subjected to
PhBCl2/Et3SiH in Et2O as described (Scheme 2).6 In all
cases we obtained a single regioisomer in good to
excellent yields: 17 (90%), 18 (71%) or 19 (84%). The
PhOMe
O
OMe
O
PhOMe
O
O
O
2
BnO
OBn
O
O
BnO
OBn
N
3O
MeOOC
N
3O
MeOOC
O
16
O
O
15
O
O
pMeOPhO
OpMeOPh
Figure 1. Side products formed in the preparation of disaccharide 13.

A. Dilhas, D. Bonnaffꢀe / Tetrahedron Letters 45 (2004) 3643–3645
3645
H
OR
H
O
OR
H
H
H
H
H
H
O
O
MeO
C
MeO
C
Less hindered
oxygen
O
2'
O
O
2'
Me Si
4'
4'
3
O
O
B
Ph
B
Ph
H
Et Si
Ar
Ar
3
H
Cl
Cl
Cl
Cl
Figure 2. Model for the regioselective complexation of PhBCl2.
regioselectivity of the reaction, that is, the liberation of
position 20, was ascertained by performing an acetyla-
tion of these three compounds. Compound 17 lead to
the known disaccharide 1,6 while disaccharides 18 and
19 gave 2, whose structure has already been established
unambiguously.6 Moreover, respective 1.21 and
1.34 ppm downfield shifts of the H-20 chemical shifts of
17 and 19 were observed upon acetylation, confirming
the regioselectivity. PhBCl2 has been reported to act as a
bulky Lewis acid, which allows regioselective complex-
ation of the less hindered oxygen in cyclic 4,6-acetals.6;15
This trend is confirmed in this work where, in all the
substrates, the 2-azidoglucose moiety is in an axial
Contre le SIDA (ECS) and the Agence Nationale de
Recherche sur le SIDA (ANRS) for funding as well as
ꢂ
the Ministere de l’Education Nationale et de la
Recherche for a Ph.D. grant (A.D.).
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conformation by the p-methoxybenzylidene ring (Fig.
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gauche interaction with the C-50 carboxymethyl group,
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occurs with O-20.
We have thus shown that a 20,40-O-p-methoxybenzylid-
ene group may be efficiently introduced in various
disaccharides containing an L-iduronyl moiety at the
nonreducing end. These acetals were reductively opened,
using the PhBCl2/Et3SiH system, with total regioselec-
tivity to give the 40-O-p-methoxybenzylidene-protected
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1
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ꢀ
Acknowledgements
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We thank Prof. A. Lubineau for helpful discussions. We
ꢀ
thank the Universite Paris Sud, the CNRS, Ensemble