Rapid, simple, and efficient deprotection of benzyl/benzylidene protected carbohydrates by utilization of flow chemistry

Article abstract of DOI:10.1016/j.tetlet.2010.12.109

A rapid, simple, and efficient deprotection procedure for the deprotection of benzyl- and/or benzylidene protected carbohydrates is described utilizing a continuous flow hydrogenation reactor. The method tolerates both acid- and base sensitive functional groups. The high efficiency, simple work-up, and short reaction time should make this method appealing to researchers working in the fields of carbohydrate chemistry and total synthesis.

Full text of DOI:10.1016/j.tetlet.2010.12.109

Tetrahedron Letters 52 (2011) 1839–1841
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rapid, simple, and efficient deprotection of benzyl/benzylidene protected
carbohydrates by utilization of flow chemistry
Filip S. Ekholm , István M. Mándity , Ferenc Fülöp , Reko Leino a,
a
b
b,
⇑
⇑
a
Laboratory of Organic Chemistry, Åbo Akademi University, FI-20500 Åbo, Finland
Institute of Pharmaceutical Chemistry, Univeristy of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A rapid, simple, and efficient deprotection procedure for the deprotection of benzyl- and/or benzylidene
protected carbohydrates is described utilizing a continuous flow hydrogenation reactor. The method tol-
erates both acid- and base sensitive functional groups. The high efficiency, simple work-up, and short
reaction time should make this method appealing to researchers working in the fields of carbohydrate
chemistry and total synthesis.
Received 15 December 2010
Accepted 22 December 2010
Available online 17 February 2011
Keywords:
Carbohydrates
Ó 2011 Elsevier Ltd. All rights reserved.
Protective groups
Benzyl/benzylidene
Flow chemistry
Heterogenous catalysis
Carbohydrates, defined as polyhydroxylated aldehydes or ke-
tones, are a class of naturally occurring molecules widely distrib-
uted in nature. In recent years, advances in carbohydrate
try approach is commonly applied in modern organic synthesis.7
One of the major advances within flow chemistry has been
achieved with laboratory hydrogenations. It has been applied in a
diverse set of reactions including: nitro, oxime and imine group
reduction, double and triple bond saturation, etc. In addition, the
methodology has been used for N-benzyl or N-Cbz deprotection
1
chemistry have led to the synthesis of many naturally occurring
oligosaccharides and glycoconjugates (and analogues thereof),
simultaneously providing a deeper understanding of the diverse
biological roles and functions of these biomolecules.2 Due to the
presence of multiple hydroxyl functionalities in carbohydrates,
modern carbohydrate chemistry is heavily entwined with protec-
8
of different peptides and amino acids. Here, we describe a method
for the rapid and efficient deprotection of several carbohydrate
derivatives bearing benzyl and benzylidene protective groups uti-
lizing a continuous flow (CF) hydrogenation reactor.
3
tive group chemistry. Some of the most widely used protective
groups in carbohydrate chemistry include benzyl ethers and ben-
zylidene acetals. The main reasons for their wide use are their sta-
2
A CF hydrogenation reactor consists of a H O-reservoir from
4
9
which hydrogen gas is produced by electrolytic cleavage of water.
In comparison to batch reactors, where a hydrogen bottle is man-
datory, this alternative way of releasing hydrogen can be consid-
ered as a superior option in terms of laboratory safety. Under
standard reaction conditions the sample is pumped through the
system with a HPLC pump, mixed with the hydrogen gas, filtered
through the catalyst cartridge, collected, and concentrated
(Fig. 1). Another advantage of this system is the simplicity with
bility toward a wide range of conditions and the selective and mild
removal conditions mainly featuring hydrogenolyses.5 Although
widely used, the commonly employed deprotection procedures
6
utilizing batch reactors require rather long reaction times. Fur-
thermore, the long reaction times needed lead to time consuming
optimization of reaction conditions. In order to circumvent these
drawbacks, we envisioned that a flow chemical approach to the
deprotection might provide advantages especially in the optimiza-
tion of reaction conditions and decreasing of the reaction time.
Flow chemistry offers a unique and robust way of increasing the
reaction rate and specificity, thereby improving the purity of iso-
lated products. Due to recent progress in this field, a flow chemis-
2
which reaction parameters, such as H -pressure, temperature,
flow-rate and catalysts can be varied thus enabling a rapid screen-
ing of reaction conditions.
In order to explore the possibilities of utilizing a CF reactor for
deprotections of carbohydrates, a limited set of protected carbohy-
drate derivatives were synthesized according to the literature pro-
1
0
cedures ( Fig. 2). Due to the wide utilization of orthogonal
protecting group strategies in carbohydrate chemistry, derivatives
containing acid- and base labile protecting groups were likewise
synthesized in order to ensure that the reaction conditions would
⇑
Corresponding authors. Tel.: +36 62 545 564; fax: +36 62 545 705 (F.F.); tel.:
358 2 2154132 (R.L.).
+
E-mail addresses: fulop@pharm.u-szeged.hu (F. Fülöp), reko.leino@abo.fi (R.
Leino).
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.109

1
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F. S. Ekholm et al. / Tetrahedron Letters 52 (2011) 1839–1841
Table 1
A summary of the performed deprotections13
Entry
Substrate
Product
Yielda (%)
95
OBn
O
OH
O
BnO
HO
BnO
HO
1
2
3
4
HO
BnO
OMe
OBn
OMe
OH
TBDMSO
BnO
TBDMSO
HO
O
O
BnO
HO
95
95
90
Figure 1. Schematic representation of the CF reactor.
OMe
OMe
OAc
OAc
O
Ph
Ph
O
HO
HO
not influence other functional groups.1,2 One of the major concerns
O
O
AcO
AcO
associated with the deprotection of carbohydrate derivatives is the
extreme change in the nature of the molecules brought on by the
cleavage of protecting groups. While the protected carbohydrates
are relatively hydrophobic, the deprotected ones are hydrophilic.
Therefore, the choice of the solvent system turned out to be crucial,
in order to maintain the solubility of both the starting material and
the product but simultaneously avoiding rapid solidification of the
material, which would cause stocking of tubes and lines. A solvent
system containing MeOH:EtOAc 1:1 was found to be suitable when
the sample concentration was 1 mg/ml.
OMe
OMe
OH
OBn
O
O
HO
HO
O
O
BnO
HO
OMe
OMe
a
Isolated yield.
Because the yields were high in all cases no additional efforts to
further optimize the reaction conditions were made. It should be
noted that all experiments were carried out with a single run
and the easiest way of obtaining higher conversions, in the case
of low conversions, would be to perform additional runs. In addi-
tion, it is worth to mention that the CF reactor was a small scale
model and, therefore, a further up-scaling of the reactions to gram
or kilogram scale should be possible by using a larger version of the
Most debenzylation reactions described have been performed
by the use of acidic additives.8 Due to the presence of acid labile
protecting groups the use of additional acids was avoided. There-
fore, new reaction conditions needed to be developed and opti-
mized. Since Pd/C is commonly used as
a catalyst when
debenzylations are performed in batch reactors, it was also our ini-
tial choice of catalyst and a standard 30 mm long holder was filled
9
reactor. Future work will focus on the one-pot removal of other
types of protective groups, for example, base- and acid labile pro-
tective groups, with the subsequent hydrogenolyses of benzyl and
benzylidene groups. This extension of the methodology is expected
to find wide use as it will further decrease the amount of synthetic
steps needed to obtain fully deprotected natural products.
To conclude, a simple, rapid and efficient methodology for the
deprotection of benzyl- and benzylidene protected carbohydrates
has been developed utilizing a CF hydrogenation reactor. The
method tolerates both acid- and base sensitive functional groups
as shown by the deprotection of the derivatives containing acetyl
and silyl protective groups. The high efficiency, simple work-up,
and short reaction time should make this method appealing to a
researcher working with carbohydrate chemistry and total
synthesis.
6
,11
with it.
Compound 1 was selected as a model substrate and
-pres-
optimal reaction parameters were found utilizing 40 bar H
2
sure, a reactor temperature of 80 °C, and a flow velocity of 1 ml/
min. Another advantage of performing the reactions in a CF reactor
is that the reaction is followed by simple evaporation as opposed to
the batch reactors where filtration through celite is necessary be-
4
c,6a,12
fore evaporation.
Deprotection of 1 proceeded smoothly un-
der the mentioned conditions, thereby resulting in methyl
a-D-
mannopyranoside in almost quantitative yield. 1H NMR spectros-
copy was found to be a simple and convenient method for monitor-
ing of the reaction, especially following the disappearance of the
1
aromatic signals from the H NMR spectra.
With compounds 2 and 3, the reactions proceeded with full
conversions and the compounds could be isolated in high yields
(
Table 1). In both cases the additional protective groups remained
Acknowledgments
intact, thereby showing that these groups remain unaltered under
the employed reaction conditions. While the reactions were mainly
performed on a 20 mg scale, deprotection of compound 2 was suc-
cessfully upscaled to 200 mg scale. Deprotection of compound 4
Financial support from the Academy of Finland (Projects
#121334 and #121335) and the Finnish Glycoscience Graduate
School is gratefully acknowledged.
gave methyl
a-
D-mannopyranoside with 95% conversion. In order
to further optimize the conditions for this substrate, the H
2
-pres-
References and notes
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2