Reductive ring opening of o-nitrobenzylidene acetals of monosaccharides: synthesis and photolysis of some photolabile sugars.

Article abstract of DOI:10.1021/ol0068952

[figure: see text] A 6-O-o-nitrobenzyl methylglucoside and methylmannoside were synthesized by reacting 4,6-O-o-nitrobenzylidene acetals with triethylsilane and boron trifluoride etherate. A 2,6-di-O-o-nitrobenzyl and a 3,6-di-O-o-nitrobenzyl methylmannoside were obtained from a 2,3:4,6-di-O-o-nitrobenzylidene methylmannoside by the same method. The photolabile sugars obtained were deprotected by irradiation at 350 nm to afford methylglycosides.

Full text of DOI:10.1021/ol0068952

ORGANIC
LETTERS
2001
Vol. 3, No. 2
255-257
Reductive Ring Opening of
o-Nitrobenzylidene Acetals of
Monosaccharides: Synthesis and
Photolysis of Some Photolabile Sugars
Soichiro Watanabe, Takashi Sueyoshi, Megumi Ichihara, Chiaki Uehara, and
,†
Michiko Iwamura*
Department of Biomolecular Science, Faculty of Science, Toho UniVersity,
2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
michiko@biomol.sci.toho-u.ac.jp
Received November 20, 2000
ABSTRACT
A 6-O-o-nitrobenzyl methylglucoside and methylmannoside were synthesized by reacting 4,6-O-o-nitrobenzylidene acetals with triethylsilane
and boron trifluoride etherate. A 2,6-di-O-o-nitrobenzyl and a 3,6-di-O-o-nitrobenzyl methylmannoside were obtained from a 2,3:4,6-di-O-o-
nitrobenzylidene methylmannoside by the same method. The photolabile sugars obtained were deprotected by irradiation at 350 nm to afford
methylglycosides.
Recently, considerable attention has been paid to the biologi-
cally important functions of glycoconjugates.1 The total
synthesis of naturally occurring compounds containing sugar
units is one of the most challenging areas in organic synthetic
chemistry. Although many strategies have been developed
for the synthesis of complex oligosaccharides, further useful
protecting groups are required. Such protecting groups should
be able to be selectively removed without affecting other
protecting groups. Photolabile protecting groups are promis-
ing candidates as hydroxyl-protecting groups in sugars
because they can be removed simply by irradiation in neutral
media without any addition of chemical reagents.2 Although
several examples of sugar units protected by a photolabile
substituent have been reported, almost all of them have an
o-nitrobenzyl group at their anomeric position.3 To use an
o-nitrobenzyl group as a useful protecting group compared
to other well-established protecting groups, new methods are
needed to introduce an o-nitrobenzyl group into sugars at
other than an anomeric position.4 These photolabile sugars
(2) Binkley, R. W.; Flechtner, T. W. Synthetic Organic Photochemistry;
Horspool, W. M., Ed.; Plenum: New York, 1984; pp 375-423.
(3) (a) Zehavi, U.; Amit, B.; Patchornik, A. J. Org. Chem. 1972, 37,
2281-2285. (b) Zehavi, U.; Patchornik, A. J. Org. Chem. 1972, 37, 2285-
2288. (c) Zehavi, U. AdV. Carbohydr. Chem. Biochem. 1988, 46, 179-
204. (d) Nicolaou, K. C.; Hummel, C. W.; Nakada, M.; Shibayama, K.;
Pitsinos, E. N.; Saimoto, H.; Mizuno, Y.; Baldenius, K.-U.; Smith, A. L. J.
Am. Chem. Soc. 1993, 115, 7625-7635. (e) Watanabe, S.; Hirokawa R.;
Iwamura M. Bioorg. Med. Chem. Lett. 1998, 8, 3375-3378.
† Tel: +81-47-472-7562. Fax: +81-47-475-1855.
(1) Neoglycoconjugates: preparation and applications; Lee, Y. C., Lee,
R. T., Eds.; Academic Press: San Diego, 1994.
(4) o-Nitrobenzyl derivatized methyl glucoside, see: Corrie, J. E. T. J.
Chem. Soc., Perkin Trans. 1 1993, 2161-2166.
10.1021/ol0068952 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/09/2000

may also provide a new method for controlling the function
of biologically important glycoconjugates by irradiation.5 In
this Letter, we report the synthesis and photoinduced
deprotection of sugars with an o-nitrobenzyl group at a
nonanomeric position.
obtained, and their structures were confirmed by NMR
spectroscopy. A doublet at 5.57 and 5.42 ppm in the 1H NMR
spectra of 2a and 2b (DMSO-d6) suggested that there were
free secondary alcohols at C4 in both compounds.9 These
compounds were deacetylated using sodium methoxide in
methanol to afford 6-O-o-nitrobenzyl derivatives 3a and
3b.10
We used a methylglucoside, a methylmannoside, and a
methylgalactoside as model compounds. 4,6-O-o-Nitro-
benzylidene acetals were prepared by a modified procedure
reported previously.6 An o-nitrobenzyl ether at C6 was
obtained by the reductive ring-opening of 4,6-O-o-nitro-
benzylidene acetals, as shown in Scheme 1 and Table 1.
Both endo- and exo-2,3:4,6-di-O-o-nitrobenzylidene meth-
ylmannoside, 4 and 5,6 were treated with Et3SiH/BF3‚Et2O
to afford two products with two o-nitrobenzyl groups per
molecule, 2,6-di-O-o-nitrobenzyl and 3,6-di-O-o-nitrobenzyl
methylmannoside, 6 and 7 (Scheme 2). The structures of
Scheme 1. Synthesis of 6-O-o-Nitrobenzyl Methylglycosides
2
Scheme 2. Synthesis of Di-O-o-nitrobenzyl Derivatives 6 and
7
Reductive single-bond cleavage of the benzylidene acetal
moiety of methylglucoside 1a and methylmannoside 1b
proceeded smoothly by the treatment of acetal with tri-
ethylsilane (12 equiv) and boron trifluoride etherate (6
equiv).7 A 4,6-O-o-nitrobenzylidene methylgalactoside gave
a complex mixture under the same conditions. When we used
NaBH4CN/TiCl4 or NaBH4CN/TMSCl instead of Et3SiH/
BF3‚Et2O, the yield of the target material was lower.
a The exo-isomer 5 contains 17% of the endo-isomer 4.
these products were determined by H-H COSY, C-H
COSY, and differential NOE spectra after the acetylation of
free hydroxyl groups.11
The exo-2,3:4,6-di-O-o-nitrobenzylidene methylmannoside
5 used here contained about 17% of the endo-isomer 4 due
to the difficulty of separation. Therefore, the 2,6-di-O-o-
nitrobenzyl methylmannoside 6 obtained in the present
experiment was considered to have been derived exclusively
from 4. This result means that exo-2,3:4,6-di-O-o-nitro-
benzylidene methylmannoside 5 gives 3,6-di-O-o-nitrobenzyl
methylmannoside 7 selectively in about 50% yield.
Table 1. Yields of 6-O-o-Nitrobenzyl Methylglycosides 2
1
conditionsb
2
recovery of 1
1a a
1a
1a
A
B
C
C
17%
47%
88%
73%
29%
43%
Although the origin of the regioselectivity of the ring
opening has not yet been fully explained, steric congestion
may affect this reaction. A nitro group also plays a role in
this reaction, since the selectivity is somewhat different from
that for other O-benzylidene acetals.8
1b
a o-Nitrobenzyl alcohol was also obtained in 39% yield. b Condition A:
NaBH4CN/TiCl4/CH3CN, -30 to 10 °C, 5 h. Condition B: NaBH4CN/
TMSCl/CH3CN, rt, 3 d. Condition C: Et3SiH/BF3‚Et2O/CH2Cl2, rt, 3 h.
To examine their availability as photolabile synthetic
building units as well as caged sugars, solutions of 3a, 3b,
In the case of a 4,6-O-benzylidene acetal of sugar
derivatives, a 6-O-benzyl and a 4-O-benzyl derivative were
generated in a selective manner by the careful selection of
reagents.8 In the present case, 6-O-o-nitrobenzyl derivatives
with a free hydroxyl group at the C4 were exclusively
(9) The intensity of these signals was weakened by adding D2O to the
NMR sample, see: Chapman, O. L.; King, R. W. J. Am. Chem. Soc. 1964,
86, 1256-1258.
(10) Methyl 6-O-(2-nitrobenzyl)-R-D-glucopyranoside 3a: 1H NMR
(CD3OD) δ 3.25-3.33 (m, 2H), 3.45 (s, 3H), 3.58-3.85 (m, 4H), 4.69 (d,
J ) 4.0 Hz, 1H), 4.98 (s, 2H), 7.50 (t, J ) 7.6 Hz, 1H), 7.69 (t, J ) 7.6
Hz, 1H), 7.87 (d, J ) 7.6 Hz, 1H), 7.93 (d, J ) 7.6 Hz, 1H); 13C NMR
(CD3OD) δ 55.6 (q), 70.9 (t), 71.4 (t), 71.6 (d), 72.5 (d), 73.4 (d), 75.1 (d),
101.1 (d), 125.5 (d), 129.2 (d), 129.9 (d), 134.6 (d), 135.9 (s), 148.8 (s).
Methyl 6-O-(2-nitrobenzyl)-R-D-mannopyranoside 3b: 1H NMR (CDCl3)
δ 3.29 (s, 3H), 3.35-3.84 (m, 5H), 4.66 (s, 2H), 4.88 (s, 2H), 7.36 (dd, J
) 7.3, 7.8 Hz, 1H), 7.56 (dd, J ) 7.3, 7.6 Hz, 1H), 7.67 (d, J ) 7.6 Hz,
1H), 7.94 (d, J ) 7.8 Hz, 1H); 13C NMR (CDCl3) δ 55.1 (q), 68.3 (d), 70.4
(t), 70.6 (t), 70.7 (d), 71.8 (d), 77.0 (d), 100.8 (d), 124.6 (d), 128.1 (d),
128.9 (d), 133.5 (d), 134.3 (s), 147.4 (s).
(5) Caged glycosphingolipids with an o-nitrobenzyl group at their
aglycone moiety were reported, see: (a) Zehavi, U. Chem. Phys. Lipids
1997, 90, 55-61. (b) Tuchinsky, A.; Zehavi, U. Chem. Phys. Lipids 1998,
92, 91-97.
(6) Collins, P. M.; Oparaeche, N. N. Carbohydr. Res. 1974, 33, 35-
46.
(7) Debenham, S. D.; Toone, E. J. Tetrahedron: Asymmetry 2000, 11,
385-387.
(8) Garegg, P. J. PreparatiVe carbohydrate chemistry; Hanessian, S., Ed.;
Marcel Dekker: New York, 1997; pp 53-67.
(11) See Supporting Information.
256
Org. Lett., Vol. 3, No. 2, 2001

in 60-87% isolated yield, indicating that these photolabile
sugars are useful building blocks for oligosaccharide syn-
thesis (Scheme 3).
Scheme 3. Deprotection of o-Nitrobenzyl Groups by
Irradiation (350 nm) of Photolabile Sugars 3a, 3b, 6, and 7
In this Letter, we report a new method for preparing
photolabile monosaccharides with o-nitrobenzyl groups at
nonanomeric positions. While the photolabile protecting
group tolerates reaction conditions that would remove other
well-known protecting groups, it can be readily removed
under mild conditions such as irradiation. The present facile
synthetic method may provide a new tool for the synthesis
of complex oligosaccharides.
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research (Grant 11121231) from
the Ministry of Education, Science, and Culture, Japan.
Supporting Information Available: Experimental pro-
cedures for the synthesis of photolabile sugars and their
spectral data. This material is available free of charge via
the Internet at http://www.pubs.acs.org.
6, and 7 in methanol were irradiated by a Rayonet photo-
chemical reactor (3500 Å × 12) with light at 350 nm. After
exhaustive irradiation (15 h), methylglycosides were obtained
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