Selective Removal of Benzyl Carbonate Used as a Protecting Group in Carbohydrate Chemistry

Article abstract of DOI:10.1081/SCC-120027267

It has been demonstrated that benzyl carbonate protecting group is orthogonal with tert-butyldimethylsilyl and (4-methoxy)trityl ethers. Moreover, benzyl carbonates can be selectively cleaved using aminolysis conditions.

Full text of DOI:10.1081/SCC-120027267

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Selective Removal of Benzyl Carbonate Used as a
Protecting Group in Carbohydrate Chemistry
Fouzi Mouffouk a , Alain Morère a , Sébastien Vidal a , Alain Leydet a & Jean-Louis
Montero a
a Laboratoire de Chimie Biomoléculaire , UMR 5032 Université Montpellier II–ENSCM , 8,
rue de l'Ecole Normale, 34296, Montpellier, Cedex 05, France
Published online: 18 Oct 2011.
To cite this article: Fouzi Mouffouk , Alain Morère , Sébastien Vidal , Alain Leydet & Jean-Louis Montero (2004) Selective
Removal of Benzyl Carbonate Used as a Protecting Group in Carbohydrate Chemistry, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:2, 303-307, DOI: 10.1081/
SCC-120027267
To link to this article: http://dx.doi.org/10.1081/SCC-120027267
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 2, pp. 303–307, 2004
Selective Removal of Benzyl Carbonate
Used as a Protecting Group in
Carbohydrate Chemistry
*
Fouzi Mouffouk, Alain Morere, Sebastien Vidal,
`
Alain Leydet, and Jean-Louis Montero
´
´ ´
Laboratoire de Chimie Biomoleculaire, UMR 5032 Universite
Montpellier II–ENSCM, Montpellier, France
ABSTRACT
It has been demonstrated that benzyl carbonate protecting group is
orthogonal with tert-butyldimethylsilyl and (4-methoxy)trityl ethers.
Moreover, benzyl carbonates can be selectively cleaved using aminolysis
conditions.
Key Words: Deprotection; Benzyloxycarbonyl; Selective; Carbo-
hydrate; Carbonate.
*
` ´
Correspondence: Alain Morere, Laboratoire de Chimie Biomoleculaire, UMR 5032
´
Universite Montpellier II–ENSCM, 8, rue de l’Ecole Normale, 34296 Montpellier,
Cedex 05, France; Fax: þ33 4 67 14 43 44; E-mail: morere@univ-montp2.fr.
303
DOI: 10.1081/SCC-120027267
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Mouffouk et al.
Naturally occuring oligosaccharides need to be synthesized through
multistep organic synthesis in order to better understand and maybe cure
numerous biological disorders[1] (cancer, viruses, etc.). During the multistep
organic synthesis of oligosaccharides,[2] the efficiency of the synthetic
protocol employed often depends largely on the selectivity of protection and
deprotection steps for the various hydroxyl groups involved. Protecting
groups[3] commonly used are esters (acetates, benzoates) and ethers (benzylic
or silyl) for both primary and secondary alcohols. A selective protection of
primary alcohols is generally achieved by using a bulky silyl or trityl group.
However, there is still an important demand for other useful protecting groups.
We have demonstrated[4,5] that secondary alcohols in glycosidic series
can be protected in high yields by a benzyloxycarbonyl group (Cbz). These
carbonates offer a good alternative to the benzyl protecting groups knowing
that they can be selectively removed under mild conditions. Indeed, benzyl
carbonates are efficiently deprotected by catalytic hydrogenolysis and are
more readily cleaved under these conditions than benzyl ethers. Removal of
the Cbz group can also be achieved by electrolytic reduction.[6]
Considering these data, we decided to determine which protecting groups
commonly used in saccharidic series are orthogonal to benzyl carbonates. The
mannopyranosides 1 and 2 (Sch. 1) were chosen as substrates because of the
Scheme 1. Selective cleavage of benzyloxycarbonyl protecting group (see data in
Table 1).

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Selective Removal of Benzyl Carbonate
305
interest we have in the biological applications of mannose 6-phosphate and its
analogs.[7,8]
Products obtained under deprotective conditions are shown in Sch. 1 and
the results obtained are summarized in Table 1. Reactions of deprotection
were monitored by thin layer chromatography (TLC) and products obtained
1
were compared with pure standard using H NMR and mass spectrometry.
Under detritylation or desilylation conditions only product 3 was
quantitatively obtained (entries 1 to 4, Table 1). However, when strong acidic
conditions were used (entry 5) all protecting groups were removed providing
6. The stability of the benzyl carbonate group under basic conditions
(deacetylation conditions) has also been studied. Surprisingly, we observed
the complete deprotection of secondary alcohols (entries 6 and 7) under
methanol/ammonia conditions. Moreover, the fact that benzyl ethers are
stable under methanol/ammonia conditions makes this result particularly
Table 1. Conditions used for the selective cleavage of benzyloxycarbo-
nyl protecting group.
Entry
Reactant
Conditionsa
Product (yieldb)
1
2
1
2
1
1
1
1
2
1
1
1
1
CAN
TBAF
TFA
3 (90%)
3 (75%)
3 (78%)
3 (81%)
6 (80%)
4 (90%)
5 (86%)
NR
3
4
HCl
5
HBr
6
NH3/MeOHc
NH3/MeOHc
MeONa/MeOH
Et3N/MeOH
K2CO3/MeOH
H2/Pd-Cd
7
8
9
NR
NR
10
11
4 (85%)
Notes: CAN: ceric ammonium nitrate; TBAF: tetra-butyl ammonium
fluoride. NR: No reaction.
aAll deprotective conditions used are given in reference[9] except for the
entry 1 see Ref.[10]
.
bYields were determined after standard silica gel column chromatography.
cTypical procedure: 1 mmol of protected saccharide was dissolved into a
methanol solution saturated with ammonia (10 mL) and stirred at 08C for
4 h.
dTypical procedure: 1 mmol of protected saccharide was dissolved into
EtOH/H2O (1 : 1; 20 mL) and Pd/C 10% (100 mg) was added. The result-
ing suspension was stirred vigorously under an hydrogen atmosphere for
16 h.

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Mouffouk et al.
interesting because, under these conditions, the Cbz group could be removed
without cleavage of the benzyl ethers. We have also shown that the Cbz group
is stable under NaOMe/MeOH, Et3N/MeOH or K2CO3/MeOH (entries 8 to
10 respectively) which are conditions commonly used for the removal of ester
protecting groups (e.g., acetates or benzoates).
In conclusion, the benzyloxycarbonyl protecting group is orthogonal to
silyl ethers (e.g., TBDMS) and to trityl groups (e.g., MMTr). Indeed, under
aminolysis conditions, the benzyloxycarbonyl group can be selectively
removed without effect on ethers. These results are particularly relevant to
expand the utilisation of benzyloxycarbonyl as a protecting group in
oligosaccharide synthesis.
REFERENCES
1. Varki, A.; Cummings, R.; Esko, J.; Freeze, H.; Hart, G.; Marth, J.
Essentials of Glycobiology; Varki, A., Cummings, R., Esko, J., Freeze, H.,
Hart, G., Marth, J., Eds.; Cold Spring Harbor Laboratory Press: New York;
1999.
2. Davis, B.G. Recent developments in oligosaccharide synthesis. J. Chem.
Soc. Perkin Trans. 1 2000, 2137–2160.
3. Kocienski, J.; Kocienski, P. Protecting groups. J. Chem. Soc. Perkin
Trans. 1 2000, 2495–2527.
`
4. Morere, A.; Mouffouk, F.; Chavis, C.; Montero, J.-L. The benzylox-
ycarbonyl protective group: a good alternative to the benzyl protective
group in the glycopyranoside and glycofuranoside series. Tetrahedron
Lett. 1997, 38 (43), 7519–7522.
`
5. Morere, A.; Menut, C.; Vidil, C.; Skaanderup, P.; Thorsen, J.;
Roque, J.-P.; Montero, J.-L. The benzyloxycarbonyl group: an alternative
protective group in the mannose series. Carbohydr. Res. 1997, 300 (2),
175–178.
6. Mairanovsky, V.G. Electro-deprotection: electrochemical removal of
protecting groups. Angew. Chem. Int. Ed. Engl. 1976, 15, 281–291.
`
7. Barragan, V.; Menger, F.; Caran, K.L.; Vidil, C.; Morere, A.;
Montero, J.-L. Synthesis of a mannose 6-phosphonate/cholesterylamine
conjugate as a specific molecular adhesive linking cancer cells with
vesicles. Chem. Commun. 2001, 85–86.
`
8. Vidal, S.; Garcia, M.; Montero, J.-L.; Morere, A. Synthesis and biological
evaluation of new mannose 6-phosphate analogs. Bioorg. Med. Chem.
2002, 10, 4051–4056.
9. Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis,
3rd Ed.; John Wiley & Sons: New York; 1999.

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307
10. Hwu, J.R.; Jain, M.L.; Tsay, S.-C.; Hakimelahi, G.H. New detritylation
method for nucleosides and nucleotides by ceric ammonium nitrate.
Chem. Commun. 1996, 545–546.
Received in the UK February 27, 2003

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