Selective oxidative debenzylation of mono- and oligosaccharides in the presence of azides

Article abstract of DOI:10.1039/c1cc13884g

When using benzyl ethers as permanent protecting groups in oligosaccharide synthesis selective oxidative debenzylation with NaBrO₃ + Na ₂S₂O₄ under biphasic conditions is efficient and compatible with anomeric a

Full text of DOI:10.1039/c1cc13884g

View Online / Journal Homepage / Table of Contents for this issue
This article is part of the
Glycochemistry & glycobiology
web themed issue
Guest Editors are Professor Peter H. Seeberger and Dr Daniel B. Werz
Please visit the website to access the other articles in this issue:-
http://www.rsc.org/chemcomm/glycochemistry

Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 10485–10487
www.rsc.org/chemcomm
COMMUNICATION
Selective oxidative debenzylation of mono- and oligosaccharides
in the presence of azideswzy
¨
Mathaus Niemietz, Lukas Perkams, Joanna Hoffman, Steffen Eller and Carlo Unverzagt*
Received 29th June 2011, Accepted 29th July 2011
DOI: 10.1039/c1cc13884g
When using benzyl ethers as permanent protecting groups in
oligosaccharide synthesis selective oxidative debenzylation with
NaBrO3 + Na2S2O4 under biphasic conditions is efficient and
compatible with anomeric azides and many other functions.
selective cleavage of benzyl ethers in complex carbohydrates
by Lewis acids and oxidative methods.12
For an initial screen on selective debenzylation methods we
selected trisaccharide 113 where the removal of the benzyl ether
using Pd–H2 in MeOH tended to be sluggish and consumed
inadequate amounts of expensive catalyst. Dimethyldioxyrane
(DMDO) was shown to cleave benzyl ethers14 and thus 1 was
reacted with DMDO (5 equiv.) in acetone.15 The desired
anomeric debenzylation was found, albeit only low conversion
occurred. The acetyl and trifluoroacetamido groups were not
affected under these conditions. Anhydrous FeCl3 in DCM16
at 0 1C was tested subsequently. It was found that 40 equi-
valents of FeCl3 were required in order to convert most
of trisaccharide 1 to the corresponding hemiacetal 2. The
addition of molecular sieves did not improve the conversion
but instead more FeCl3 was needed. By adding dry FeCl3 in
two portions an isolated yield of 85% of 2 could be obtained
(Scheme 1).
We then tested biphasic oxidative debenzylation conditions,17
which were adapted previously to carbohydrates by using
NaBrO3/Na2S2O4.18 Trisaccharide 1 was dissolved in ethyl
acetate and stirred vigorously with an aqueous solution of
NaBrO3 and Na2S2O4. High conversion occurred on a 2 g
scale and after quenching the reaction with sodium thiosulphate
the desired hemiacetal 2 was isolated in 91% yield next to only
some unreacted starting material. Under the biphasic conditions
the reaction appears to follow the proposed radical mechanism.17
No evidence was found for any oxidation of the hydroxyl group,
which may occur under certain conditions.19
Azido groups on carbohydrates1 are frequently used in the
synthesis of glycoconjugates2 by 1,3-dipolar cycloadditions3
and in amide forming reactions via Staudinger ligation,4
thioacids5 or after reduction to an amine.6 The introduction
of azido groups can be carried out with protected sugars7 but
also on free carbohydrates at the anomeric center8,9 or by
diazotransfer to amino groups.10 When using synthetic
carbohydrates carrying temporary benzyl protection, azido
groups need to be reacted prior to reductive debenzylation.
Thus, a method for the selective removal of benzyl ethers in
the presence of azides would be desirable. We found that a
biphasic system using a combination of sodium bromate and
sodium dithionite allows the selective cleavage of benzyl
groups even in the presence of anomeric azides.
The appropriate use of permanent and transient protection
groups is one of the key requirements of chemical oligo-
saccharide synthesis. Protecting groups control the overall
reactivity of the building blocks as well as the stereochemistry
during glycosylations.11 Typically a complex combination of
protecting groups is applied providing selective options for
cleavage under acidic or basic conditions in conjunction with
additional groups susceptible to reducing or oxidative environ-
ments. Benzylethers are frequently installed as permanent
protecting groups due to their high stability towards acids
and bases and are commonly removed using a variety of
reducing conditions.12 However, azides are more susceptible
to reduction than benzyl groups. In order to combine the
convenient use of stable benzyl protection during synthesis
with the option to obtain azides after deprotection, non-
reducing conditions are required. We thus investigated the
Encouraged by this outcome the compatibility of the
oxidative reagents with azides was tested. Azide 320 was
reacted with DMDO or NaBrO3/Na2S2O4. Under both
conditions azide 3 was completely stable (Scheme 2). Sub-
sequently, the regioselectivity for benzyl groups21 was probed
with the dibenzylated azide 4.22 In the case of DMDO two
products were obtained. The major product 523 (56% yield)
Bioorganische Chemie, Gebaude NWI, Universitat Bayreuth,
¨ ¨
95440 Bayreuth, Germany. E-mail: carlo.unverzagt@uni-bayreuth.de;
Fax: +49-921-555365; Tel: +49-921-552670
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc13884g
z This work is dedicated to Prof. Gerhard Bringmann on the occasion
Scheme 1 (a) DMDO, acetone 0–22 1C (yield not determined);
(b) FeCl3, DCM, 0 1C (85%); (c) Na2S2O4, NaBrO3, H2O, EtOAc,
22 1C (91%).
of his 60th birthday.
y This article is part of the ChemComm ‘Glycochemistry and glyco-
biology’ web themed issue.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10485–10487 10485

complex substrate (9), in particular the subsequent oxidation19
of the liberated OH groups, we extended the reaction time to
several days. To our delight only traces of a heptasaccharide,
where the azido group was hydrolysed, were detectable by
LC-MS. Presumably the acidic reaction conditions (pH 1) in
the aqueous phase led to slow hydrolysis at the reducing9,10
end (Scheme 3).
In contrast the reaction of DMDO with the tetrabenzylated
compound 8 gave only a complex mixture of mono debenzyl-
ated heptasaccharides with no apparent selectivity.
Compound 9 was further deprotected by global deacylation
with ethylene diamine followed by a selective N-acetylation.
The free heptasaccharide azide 10 was purified by solid phase
extraction followed by gel filtration. Thus traces of remaining
benzylated intermediates were removed efficiently. Compound
10 was obtained in 73% yield and represents a suitable starting
material for the convergent synthesis of glycopeptides25 as well
as click couplings.
Scheme 2 Different selectivity of oxidative cleavage reagents for
benzyl groups.
resulted from debenzylation only at the primary O-6 position
whereas the minor product 624 (20%) was completely
debenzylated. A corresponding compound with a single
debenzylation at O-3 was not detected after flash chromato-
graphy. The reaction of 4 with NaBrO3/Na2S2O4 gave
complete conversion to the fully debenzylated product 6 as
judged by TLC. Due to its high water solubility compound 6
migrated to the aqueous phase and was difficult to isolate.
It was then investigated if non-anomeric azides are also
compatible. When submitting peracetylated 2-azidoglucose
to NaBrO3/Na2S2O4 no conversion occurred according to
TLC and LC-MS, which indicated that the most common
types of sugar azides are well tolerated.
The selective oxidative debenzylation of protected mono-
and oligosaccharides can be carried out in high conversion
using NaBrO3/Na2S2O4 in a biphasic water/ethyl acetate
system. Under these conditions protecting groups of the ester
and amide type as well as azides remained intact. The robust
protocol appears to be unaffected by trace impurities causing
deactivation of hydrogenation catalysts. Oxidation of the
liberated hydroxyl groups was not found under the biphasic
conditions.
We are grateful for the support by the Deutsche For-
schungsgemeinschaft, the Fonds der Deutschen Chemischen
For oxidative debenzylations the biphasic NaBrO3/Na2S2O4
system showed reliable and high conversions. The debenzyl-
ation of the biantennary N-glycan azide 8 was tested under
these conditions. Heptasaccharide 8 was obtained from 725,26
by acetylation. After stirring for 3.5 h at room temperature the
reaction was complete and the debenzylated heptasaccharide
azide 9 was obtained in 97% yield after flash chromatography.
In order to probe the occurrence of side reactions with this
Industrie and the European Union. Mathaus Niemietz
¨
acknowledges support by the Bavaria California Technology
Center (BaCaTeC) and the Elite Network of Bavaria.
Notes and references
1 H. S. G. Beckmann and V. Wittmann, in Org. Azides: Syntheses
and Applications, ed. S. Brase and K. Banert, John Wiley & Sons,
¨
Chichester, 2010, pp. 469–490.
2 D. P. Gamblin, E. M. Scanlan and B. G. Davis, Chem. Rev., 2009,
109, 131–163.
3 (a) C. W. Tornoe, C. Christensen and M. Meldal, J. Org. Chem.,
2002, 67, 3057–3064; (b) W. G. Lewis, L. G. Green, F. Grynszpan,
Z. Radic, P. R. Carlier, P. Taylor, M. G. Finn and K. B. Sharpless,
Angew. Chem. Int. Ed., 2002, 41, 1053–1057; (c) W. Broder and
¨
H. Kunz, Carbohydr. Res., 1993, 249, 221–241.
4 Y. He, R. J. Hinklin, J. Chang and L. L. Kiessling, Org. Lett.,
2004, 6, 4479–4482.
5 F. Fazio and C.-H. Wong, Tetrahedron Lett., 2003, 44, 9083–9085.
6 H. Herzner, T. Reipen, M. Schultz and H. Kunz, Chem. Rev., 2000,
100, 4495–4538.
7 (a) F. Micheel and A. Klemer, Adv. Carbohydr. Chem. Biochem.,
1961, 16, 85–103; (b) Z. Gyorgydeak, L. Szilagyi and H. Paulsen,
J. Carbohydr. Chem., 1993, 12, 139–163.
8 (a) T. Tanaka, H. Nagai, M. Noguchi, A. Kobayashi and S. Shoda,
Chem. Commun., 2009, 3378–3379; (b) S. G. Gouin and
J. Kovensky, Tetrahedron Lett., 2007, 48, 2875–2879; (c) M.-L.
Larabi, C. Frechou and G. Demailly, Tetrahedron Lett., 1994, 35,
2175–2178.
9 A. V. Gudmundsdottir and M. Nitz, Org. Lett., 2008, 10, 3461–3463.
10 A. Vasella, C. Witzig, J. L. Chiara and M. Martin-Lomas, Helv.
Chim. Acta, 1991, 74, 2073–2077.
11 H. Paulsen, Angew. Chem., Int. Ed. Engl., 1982, 21, 155–173.
12 P. G. M. Wuts and T. W. Greene, Greene’s Protective Groups in
Organic Synthesis, Wiley-Interscience, 2006.
13 (a) C. Unverzagt, G. Gundel, S. Eller, R. Schuberth, J. Seifert,
H. Weiss, M. Niemietz, M. Pischl and C. Raps, Chem.–Eur. J.,
Scheme 3 Oxidative cleavage of multiple benzyl groups in a tetra
benzylated complex N-glycan: (a) Ac2O, pyridine; (b) Na2S2O4,
NaBrO3, H2O, EtOAc, 22 1C (97%); (c) 1. ethylene diamine, nBuOH,
90 1C; 2. Ac2O, MeOH, H2O (1.-2. 73%).
c
10486 Chem. Commun., 2011, 47, 10485–10487
This journal is The Royal Society of Chemistry 2011

2009, 15, 12292–12302; (b) A. Makino, K. Kurosaki, M. Ohmae
and S. Kobayashi, Biomacromolecules, 2006, 7, 950–957.
14 B. A. Marples, J. P. Muxworthy and K. H. Baggaley, Synlett, 1992,
646; R. Csuk and P. Dorr, Tetrahedron, 1994, 50, 9983–9988.
15 W. Adam, J. Bialas and L. Hadjiarapoglou, Chem. Ber., 1991,
124, 2377.
16 R. Rodebaugh, J. S. Debenham and B. Fraser-Reid, Tetrahedron
Lett., 1996, 37, 5477–5478.
17 D. Kikuchi, S. Sakaguchi and Y. Ishii, J. Org. Chem., 1998, 63,
6023–6026.
2, 3797–3800; (d) M. Adinolfi, G. Barone, A. Iadonisi and
M. Schiattarella, Tetrahedron Lett., 2001, 42, 5971–5972.
19 S. Sakaguchi, D. Kikuchi and Y. Ishii, Bull. Chem. Soc. Jpn., 1997,
70, 2561–2566.
20 C. Unverzagt and H. Kunz, J. Prakt. Chem., 1992, 334, 570–578.
21 E. Cabianca, A. Tatibouet and P. Rollin, Pol. J. Chem., 2005, 79,
317–322.
22 C. Unverzagt, Chem.–Eur. J., 2003, 9, 1369–1376.
23 A. Dan, M. Lergenmuller, M. Amano, Y. Nakahara, T. Ogawa
and Y. Ito, Chem.–Eur. J., 1998, 4, 2182–2190.
18 (a) M. Adinolfi, G. Barone, L. Guariniello and A. Iadonisi,
Tetrahedron Lett., 1999, 40, 8439–8441; (b) M. Adinolfi,
L. Guariniello, A. Iadonisi and L. Mangoni, Synlett, 2000,
1277–1278; (c) Y. Du, M. Zhang and F. Kong, Org. Lett., 2000,
24 L. Szilagyi and Z. Gyorgydeak, Carbohydr. Res., 1985, 143, 21–41.
25 C. Unverzagt, Angew. Chem., Int. Ed. Engl., 1996, 35, 2350–2353.
26 C. Unverzagt, S. Eller, S. Mezzato and R. Schuberth, Chem.–Eur. J.,
2008, 14, 1304–1311.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10485–10487 10487