A new entry to 4,6-O-benzylidene glucal from phenyl 1-seleno-α-d- mannopyranoside

Article abstract of DOI:10.1016/j.tetasy.2005.05.004

The two-step synthesis of 4,6-O-benzylidene glucal, in 59% overall yield, from phenyl 1-seleno-α-d-mannopyranoside is described.

Full text of DOI:10.1016/j.tetasy.2005.05.004

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 1935–1937
A new entry to 4,6-O-benzylidene glucal from phenyl
1-seleno-a-D-mannopyranoside
a
a
Helen M. I. Osborn,a,b, Paul Meo and Rajdeep K. Nijjar
*
aSchool of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK
bSchool of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AJ, UK
Received 1 February 2005; accepted 3 May 2005
Abstract—The two-step synthesis of 4,6-O-benzylidene glucal, in 59% overall yield, from phenyl 1-seleno-a-D-mannopyranoside is
described.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
ysis of target glycal 1 (Fig. 1) suggested that 4,6-O-benz-
ylidene glucal 3 would be a suitable precursor and the
opportunity arose for developing a new entry to this
generally useful intermediate.
Glycals (1,2-anhydro sugars) have found widespread use
and application within synthetic carbohydrate pro-
grammes. In particular, they have been exploited within
DanishefskyÕs solution1 and solid phase2 glycal assembly
approaches to complex oligosaccharides and within the
synthetically useful Ferrier rearrangement method-
ology.3 3,4,6-Per-O-acetylated glycals are generally
prepared in excellent yields from per-O-acetylated
bromopyranosides, via zinc catalysed reductive elimina-
tion.4 4,6-O-Benzylidene glucal was originally prepared
in low yield by benzylidene protection of the C-4, C-6
hydroxyl pair within the acid sensitive free glucal.5 How-
ever, improved methods for entry to this target, from
methyl, thiophenyl or sulfone glycosides, have subse-
quently been reported.6 We herein report a complemen-
tary two-step protocol that allows access to 4,6-O-
benzylidene glucal from phenyl 1-seleno-a-D-mannopyr-
anoside. This approach is expected to be particularly
attractive to researchers who utilise phenyl 1-seleno gly-
cosides as intermediates for carbohydrate assembly
within their laboratories.
Our approach develops a method described by Horton
and Weckerle8 for the synthesis of methyl-2-deoxy-3-
ulose mannopyranoside from methyl 2,3;4,6-di-O-ben-
zylidene mannopyranoside. This reaction proceeds via
elimination of benzaldehyde after abstraction of the
more sterically accessible axial proton at C-3. We
rationalised that if an anomeric substituent could be
incorporated, which both assisted removal of the C-1
anomeric proton, thus initiating eliminative loss of benz-
aldehyde from the 2,3-O-benzylidene acetal, and that it-
self could be readily removed under basic conditions,
then direct entry to 4,6-O-benzylidene protected glycals
could be developed. Since phenyl 1-selenopyranosides are
common intermediates for oligosaccharide synthesis,9
Ph
O
Ph
O
O
O
O
O
O
2
1
2. Results and discussion
As part of a programme directed towards the synthesis
of C-linked glycosides using a carbon-Ferrier reaction,7
we wished to access allylic glycal 1. Retrosynthetic anal-
Ph
O
O
O
HO
3
*
Corresponding author. Fax: +44 (0) 118 931 6331; e-mail:
h.m.i.osborn@rdg.ac.uk
Figure 1.
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.05.004

1936
H. M. I. Osborn et al. / Tetrahedron: Asymmetry 16 (2005) 1935–1937
apparatus. All melting points are uncorrected. Infrared
Ph
OH
OH
O
spectra were recorded on a Perkin–Elmer Paragon
1000 FT-IR spectrometer. Frequencies of absorption
maxima are reported in wave numbers (cmꢀ1). 1H
NMR spectra were recorded at 250 MHz on a Bruker
DPX-250 FT-NMR spectrometer, using CDCl3 as an
internal standard unless stated otherwise. Correlations
between protons were determined using correlation
spectroscopy (COSY) while proton–carbon correlations
were determined using heteronuclear correlation spec-
troscopy (HETCOR). Multiplicities of carbon atoms
(methyl, methylene, methine or quaternary) were deter-
mined using broadband decoupled carbon spectra and
distortionless enhancement by polarisation transfer
(DEPT) carbon spectra. All chemical shifts (dH values)
are quoted in units of parts per million (ppm). The fol-
lowing abbreviations are used: s (singlet), d (doublet), t
(triplet), dd (double doublet), m (multiplet). All cou-
pling constants (J values) are expressed in hertz to the
nearest 0.5 Hz. 13C NMR spectra were recorded on
the spectrometer described above at 62.5 MHz and the
external reference provided by the CDCl3 solvent. The
chemical shifts (dC values) are quoted in units of ppm.
Low- and high-resolution mass spectrometry data were
recorded by the School of ChemistryÕs mass spectrome-
try service using a Fisons VG Autospec. Low resolution
mass spectra were also recorded at the School of Chem-
istry using a Micromass Platform LC/MS. In addition,
high-resolution mass spectra were recorded by the
EPSRC National Mass Spectrometry Service, Swansea,
using a Finnigan MAT900XLT. Molecular ions and
fractions from molecular ions are reported as mass/
charge (m/z) ratios. Optical activities were determined
using a Perkin–Elmer 341 polarimeter at a wavelength
O
Ph
O
O
i)
HO
HO
O
O
SePh
4
SePh
5
ii)
Ph
O
O
Ph
+
O
O
O
HO
O
SePh
HO
6
3
Scheme 1. Reagents and conditions: (i) PhCH(OMe)2, p-TsOH, DMF,
50 ꢁC, 69%; (ii) 2 equiv n-BuLi, THF, ꢀ40 ꢁC.
we considered phenyl 1-seleno-a-D-mannopyr- anoside
to be a useful starting material for this strategy. To
test this hypothesis, phenyl 1-seleno-2,3;4,6-di-O-benzyl-
idene pyranoside 5 was prepared from tetrol 410 using
benzaldehyde dimethyl acetal and p-TsOH at 50 ꢁC
under reduced pressure (Scheme 1). The fully protected
di-O-benzylidene acetal 5 was produced as a 1:1 mixture
of benzylidene diastereoisomers at O-2 and O-3 in 69%
yield. In our initial studies, the mixture of diastereoiso-
mers was subsequently treated with 2 equiv of n-BuLi
at ꢀ40 ꢁC to facilitate removal of the C-1 anomeric
proton and potentially initiate elimination of benzalde-
hyde. This allowed access to a separable mixture of
the desired product 3 and the intermediate glycal 6 in
a 1:1 ratio, with a total yield of 60%. Formation of
the intermediate glycal 6 suggested that there was insuf-
ficient base present to effect complete conversion as the
reaction of the second equivalent of n-BuLi with the
liberated benzaldehyde competes with the desired
transformation.
of 589 nm and are quoted in units of 10ꢀ1 deg cm2 gꢀ1
.
Flash chromatography was performed using silica gel
60 (Merck) using head pressure by means of bellows.
TLC analysis was performed using Merck aluminium
backed plates, coated with 0.2 mm silica 60 F254. Visual-
isation of the compounds on TLC plates was achieved
using 254 nm UV light or by using an acid dip (EtOH/
H2SO4, 25:1). All chemicals were obtained from Sig-
ma–Aldrich, BDH, Fluka or Lancaster chemical suppli-
ers and were used as received, unless stated otherwise.
For reactions requiring anhydrous conditions, anhy-
drous solvents were used, with glassware oven-dried
prior to use and the procedures carried out under a
nitrogen atmosphere.
However, further studies illustrated that glycal 6 could
be converted to the desired glycal product 3 in 89% yield
upon exposure to two further equivalents of n-BuLi, at
ꢀ40 ꢁC. In subsequent reactions, deprotonation, elimi-
nation and removal of the phenyl selenide substituent
were effected in one pot by simply treating the di-O-benz-
ylidene acetal 5 with four equivalents of n-BuLi at
ꢀ40 ꢁC. The desired glycal 3 was then obtained in an
excellent 85% yield.
4.1. Phenyl 2,3:4,6-O-benzylidene-1-seleno-a-D-
mannopyranoside 5
3. Conclusion
In summary, we have developed an efficient, high yield-
ing, two-step strategy for entry to the synthetically
useful 4,6-O-benzylidene glucal, from a common carbo-
hydrate intermediate. The incorporation of this glycal
within our carbon-Ferrier protocol is currently under
investigation.
Phenyl 1-seleno-a-D-mannopyranoside 410 (1.073 g,
3.5 mmol) was dissolved in anhydrous DMF (40 ml).
To this were added benzaldehyde dimethyl acetal
(1.3 ml, 8.75 mmol) and p-toluene sulfonic acid
(40 mg), and the reaction mixture placed on a rotary
evaporator at 50 ꢁC. After 3 h, TLC analysis showed
the reaction to be complete. The reaction mixture was
quenched by the addition of satd NaHCO3 (50 ml), ex-
tracted with DCM (2 · 50 ml) and washed with brine
(50 ml). The organic fractions were collected, dried over
MgSO4, filtered and concentrated in vacuo to afford a
4. Experimental
The melting points of all solid products were determined
using an Electrothermal digital heated metal block

H. M. I. Osborn et al. / Tetrahedron: Asymmetry 16 (2005) 1935–1937
1937
white solid. This was suspended in a minimum amount
of hexane and the ensuing white solid filtered off to af-
ford 5 (1.191 g, 69%) as a mixture of diastereoisomers.
Mp 174–178 ꢁC; mmax/cmꢀ1 2929 (C–H stretch), 2878
(CH3 stretch), 1461 (CH3, C–C ring stretch), 1406 (C–
C ring stretch), 746 (C–H aromatic bend), 694 (C–H
aromatic bend); dH (250 MHz; CDCl3) 7.63–7.56 (4H,
m, ArH), 7.47–7.33 (11H, m, ArH), 6.34 (1H, s, PhCH),
6.18 (1H, s, H-1), 5.67 (1H, s, PhCH), 4.71 (1H, dd, J
5.0, 8.0, H-4), 4.50 (1H, d, J 5.0, H-3), 4.30–4.21 (2H,
m, H-2, H-6), 4.28 (1H, dd, J 8.0, 9.5, H-5), 3.83 (1H,
t, J 11.5, H-6); dC (62.5 MHz; CDCl3) 138.87 (ArC),
137.41 (ArC), 135.10 (ArCH), 129.74 (ArCH), 129.63
(ArCH), 128.86 (ArCH), 128.76 (ArCH), 128.694
(ArCH), 128.48 (ArC), 126.71 (ArCH), 126.43 (ArCH),
103.56 (PhCH), 102.43 (PhCH), 81.67 (C-1), 78.09 (C-5),
77.08 (C-3), 75.58 (C4), 68.81 (C-6), 63.75 (C-2); m/z (CI)
497 (M+H+, 19%), 390 (25), 339 (49), 233 (44), 105
(100). Found 497.0855. C26H25O5Se requires 497.0867.
3.70 (2H, m, H-4, H-6); 13C NMR (62.5 MHz; CDCl3)
147.31 (C-1), 137.24 (ArC), 133.66 (ArCH), 129.82
(ArCH), 129.79 (ArCH), 128.80 (ArCH), 128.45
(ArCH), 126.64 (ArCH), 109.68 (C-2), 102.23 (PhCH),
80.51 (C-4), 70.74 (C-5), 68.47 (C-6), 68.45 (C-3); m/z
(CI) 390 (M+, 2 %), 338 (2), 316 (51), 85 (25). Found
M+ 390.0352. C19H18O4Se requires 390.0370.
4.3. Direct entry to 4,6-O-Benzylidene-1,2-dideoxy-
D-arabino-hex-1-enitol 3
Phenyl 2,3:4,6-O-benzylidene-1-seleno-a-D-mannopyr-
anoside 5 (500 mg, 1 mmol) was dissolved in anhydrous
THF (25 ml) and cooled to ꢀ40 ꢁC. n-BuLi (1.6 ml,
4 mmol, 2.5 M) was added to the reaction mixture, with
the temperature maintained at ꢀ40ꢁC. After TLC anal-
ysis confirmed the reaction to be complete, satd ammo-
nium chloride (20 ml) was added and the mixture
extracted with ethyl acetate (3 · 20 ml) and washed with
brine (2 · 40 ml). The organic fractions were collected
and dried over MgSO4, filtered and the solvent removed
in vacuo. The crude product was subjected to column
chromatography using silica gel (hexane/ethyl acetate
[1:1]) to afford 3 (199 mg, 85 %) as a white solid with
spectroscopic data identical to that reported above.
4.2. 4,6-O-Benzylidene-1,2-dideoxy-D-arabino-hex-1-
enitol 3 and phenyl 4,6-O-benzylidene-1,2-dideoxy-1-
seleno-D-arabino-hex-1-enitol 6
Phenyl 2,3:4,6-O-benzylidene-1-seleno-a-D-mannopyr-
anoside 5 (500 mg, 1 mmol) was dissolved in anhydrous
THF (25 ml) and cooled to ꢀ40 ꢁC. n-BuLi (0.8 ml,
2 mmol, 2.5 M) was added to the reaction mixture with
the temperature maintained at ꢀ40 ꢁC. After TLC anal-
ysis confirmed complete consumption of starting mate-
rial satd ammonium chloride (20 ml) was added and
the mixture extracted with ethyl acetate (3 · 20 ml)
and washed with brine (2 · 40 ml). The organic fractions
were collected and dried over MgSO4, filtered and the
solvent removed in vacuo. The crude product was
subjected to column chromatography using silica gel
(hexane/ethyl acetate [1:1]) to afford 3 (70 mg, 30%) as
a white solid and 6 (117 mg, 30%) as a yellow oil.
Acknowledgements
We gratefully acknowledge the EPSRC and the Univer-
sity of ReadingÕs Research Endowment Trust Fund for
their financial support of this work.
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22
½aꢁ ¼ ꢀ15.8 (c 0.83, CHCl3), {lit.5a ½aꢁ ¼ ꢀ19 (c 0.6,
D
D
CHCl3)}; mmax/cmꢀ1 (nujol) 3166 (O–H stretch) 2715
(ArCH stretch), 1635 (C@C stretch), 1406 (C–C ring
stretch), 746 (C–H aromatic bend), 694 (C–H aromatic
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CDCl3) 144.58 (C-1), 137.41 (ArC), 129.73 (ArCH),
128.79 (ArCH), 126.62 (ArCH), 103.93 (C-2), 102.25
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20
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D
(nujol) 3411 (O–H stretch), 3061, 2955, 2930, 2859
(ArCH stretch), 1734, 1575, 1494, 1474, 1455, 1437,
1380, 1297, 1176, 1077, 1020, 915, 736, 699, 688; H
1
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7.30–7.22 (6H, m, ArH), 5.49 (1H, s, PhCH), 5.05 (1H,
d, J 2.5, H-2), 4.45–4.41 (1H, m, H-3), 4.26 (1H, dd,
J 5.0, 10.5, H-6), 3.90 (1H, dd, J 5.0, 10.0, H-5), 3.79–