Regioselective reduction of 4,6-O-benzylidenes using triethylsilane and BF3.Et2O

Article abstract of DOI:10.1016/S0957-4166(99)00584-4

The 4,6-di-O-benzylidene acetals of glucose, mannose, glucosamine, and galactose were regioselectively reduced by triethylsilane in the presence of BF₃.Et₂O to yield the 6-O-benzyl ethers in good to excellent yields. Copyright (C) 20

Full text of DOI:10.1016/S0957-4166(99)00584-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 385–387
Regioselective reduction of 4,6-O-benzylidenes using
triethylsilane and BF3·Et2O
Sheryl D. Debenham and Eric J. Toone ∗
Department of Chemistry, Duke University, Durham, NC 27708, USA
Received 24 November 1999; accepted 13 December 1999
Abstract
The 4,6-di-O-benzylidene acetals of glucose, mannose, glucosamine, and galactose were regioselectively re-
duced by triethylsilane in the presence of BF3·Et2O to yield the 6-O-benzyl ethers in good to excellent yields.
© 2000 Elsevier Science Ltd. All rights reserved.
Carbohydrates are by now well recognized as important participants in cellular communication events
such as chemotaxis, neutrophil recruitment, fertilization, host-pathogen recognition, and both random
and non-random metastasic distributions of malignancies.1 With this understanding of the vital roles
played by carbohydrate recognition elements has come an increased need for efficient synthetic strategies
for the preparation of carbohydrate-based materials. Successful oligosaccharide synthesis relies heavily
on efficient methodology for the selective protection/deprotection of carbohydrate hydroxyl groups. A
commonly utilized protecting group in this regard is the benzylidene acetal, which provides selective
protection of the 4- and 6-hydroxyl moieties of, among other species, the pyranoses of glucose, galactose,
and mannose.2,3 Adding greatly to the utility of this group are methodologies for the regioselective
reductive cleavage of the benzylidene acetal, allowing selective formation of a benzyl ether at either
the C4 or C6 hydroxyl groups.
Methodology for the regioselective reduction of 4,6-O-benzylidene acetals to the corresponding 4-
hydroxyl-6-O-benzyl ether has been in place since 1981.4 The most commonly used protocol for this
transformation uses NaCNBH3 in the presence of hydrogen chloride gas. The procedure suffers from
low yields and requires scrupulously dry conditions. Other reported conditions for the reduction of
benzylidene acetals make use of stronger hydride sources, such as LiAlH4–AlCl3 or DIBAL, reagents
incompatible with many other protecting groups.3
In the course of our studies towards C-glycosyl serine derivatives, we carried out the deoxygenation of
disaccharide 1 with triethylsilane and BF3·Et2O. These conditions effected the simultaneous reduction
of the benzylidene, providing the fully reduced disaccharide 2 in 73% yield (Scheme 1).5 The reduction
showed complete regiospecificity, producing only the 60-O-benzyl disaccharide.
∗
Corresponding author: Tel: (919) 681-3484; e-mail: toone@chem.duke.edu
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00584-4
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S. D. Debenham, E. J. Toone / Tetrahedron: Asymmetry 11 (2000) 385–387
Scheme 1. Reduction of galactose-derived benzylidene and anomeric hydroxyl using TES/BF3·Et2O
A survey of the literature yielded only one other example of the use of triethylsilane for the reduction
of benzylidene acetals. In this case the reaction was promoted only by a large excess (5.4 equivalents) of
trifluoroacetic acid, conditions incompatible with many functional groups.6 Additionally, the transforma-
tion was successful only for glucose-derived benzylidenes; galactose derivatives were either unreactive
or decomposed.
To examine the generality of benzylidene reduction with TES/BF3·Et2O, the 4,6-di-O-benzylidenes of
glucose 3, mannose 5, and glucosamine 7 were subjected to the reduction conditions.7 In each instance
the benzylidene was smoothly reduced to the 6-O-benzyl ether in unoptimized yields ranging from 59%
to 85% (Scheme 2). No 4-O-benzyl products were detectable by NMR, demonstrating the complete
regioselectivity of the reaction. Gray and co-workers have previously reported the use of a large excess
of TES/BF3·Et2O/TFA for the reductive cleavage of a variety of glycosides.8 Here, no glycosidic bond
cleavage was detectable in any of the reactions.
Scheme 2. Reduction of glucose-, mannose-, and glucosamine-derived monosaccharides
In
a
typical procedure, methyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-phthalimido-β-D-
glucopyranoside 7 (49.5 mg, 0.098 mmol) was dried under high vacuum for 15 hours prior to
use. To a solution of 7 in CH2Cl2 (0.1 M, 1.0 mL) at 0°C was added Et3SiH (12 equiv., 0.188 mL) and
BF3·Et2O (2 equiv., 25 µL). The reaction was warmed to 25°C over 4 hours. The mixture was diluted
with CH2Cl2 (30 mL), washed with satd NaHCO3 (1×40 mL), dried, and concentrated. Purification via
flash chromatography eluting with a gradient of 2:1 to 1:1 petroleum ether:EtOAc provided 8 (42.2 mg,
85%) as a film.9
In conclusion, we have reported a robust facile procedure for the regioselective reductive cleavage
of the 4,6-di-O-benzylidene group to the corresponding 6-O-benzyl ether. The methodology is experi-
mentally straightforward and utilizes reaction conditions compatible with most common carbohydrate
protecting groups.

S. D. Debenham, E. J. Toone / Tetrahedron: Asymmetry 11 (2000) 385–387
387
Acknowledgements
This work was supported by a grant from the NIH (GM57179).
References
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