Confirmation of the structure of a glucono-1,4-lactone derivative obtained from silylation of glucono-1,5-lactone

Article abstract of DOI:10.1016/S0957-4166(02)00747-4

Silylation reactions of glucono-1,5-lactone can give the persilylated glucono-1,5-lactone or the persilylated 1,4-lactone depending on the reaction conditions employed. The structure of 2,3,5,6-tetra-O-(tert-butyldimethylsilyl)-D-glucono-1,4-lactone, obta

Full text of DOI:10.1016/S0957-4166(02)00747-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 79–85
Confirmation of the structure of a glucono-1,4-lactone derivative
obtained from silylation of glucono-1,5-lactone
Paul V. Murphy,a,* Ciaran McDonnell,a Ludger Ha¨mig,b Duncan E. Patersonc and
Richard J. K. Taylorc
aDepartment of Chemistry, Centre for Synthesis and Chemical Biology,
Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland
b
8
Bruker AXS GmbH, Ostliche Rheinbru¨ckenstraße 49, D-76187 Karlsruhe, Germany
cDepartment of Chemistry, University of York, Heslington, York Y010 5DD, UK
Received 21 September 2002; accepted 8 November 2002
Abstract—Silylation reactions of glucono-1,5-lactone can give the persilylated glucono-1,5-lactone or the persilylated 1,4-lactone
depending on the reaction conditions employed. The structure of 2,3,5,6-tetra-O-(tert-butyldimethylsilyl)-D-glucono-1,4-lactone,
obtained in 84% yield from the reaction of glucono-1,5-lactone with TBSOTf and lutidine in dichloromethane, has been confirmed
by X-ray crystallography. Formation of the glucono-1,5-lactone and manno-1,5-lactone derivatives and other possible products
has also been ruled out by synthesis of possible exo-glycal derivatives of these lactones using the Ramberg–Ba¨cklund
rearrangement of the corresponding sulfones. © 2003 Elsevier Science Ltd. All rights reserved.
they obtained a product with [h]2D0 +17.2 (c 0.97,
CHCl3) and mp 99.5–100°C; Fang et al.4 have used
DMAP, 2,6-lutidine and TBSCl and they obtained a
product with [h]D25 +55 (c 5.4, CHCl3);5 the NMR
spectroscopic data for the major product isolated in
these two cases differed considerably. More recently,
Yang et al.6 suggested that the reaction of 4 with
TBSOTf in the presence of pyridine in DMF gives the
1. Introduction
We have been interested in developing routes to inter-
mediates that will be useful for the synthesis of ana-
logues of L-idose and L-iduronic acid (e.g. 3). This work
forms part of a project aimed at the synthesis and
biological evaluation of hexuronic acid conjugates; we
have recently shown that glucuronic acid-containing
glycoconjugates are inhibitors of heparin binding to
FGF and also inhibitors of endothelial cell survival
pathways.1 It would be interesting to compare the
1,5-lactone 6a, whereas
a
similar reaction in
dichloromethane gives the 1,4-lactone 5a; their assign-
ment was based on 13C NMR and IR data (for example
5a had a higher stretching frequency than 6a; 1794
versus 1769 cm−1).
biological activity of
logues in these assays.
L
-iduronic acid containing ana-
L
-Iduronic acid is the C-5 epimer
of
D-glucuronic acid and is an important structural
component of heparin and related oligosaccharides2
and synthetic routes to these derivatives are often long.
Our proposed synthesis (Scheme 1) of the C-glycosyl
We could not introduce silyl groups on to all of the
hydroxyl groups of 4 using the method described by
derivative 3 from commercially available L-glucono-1,5-
lactone 1 prompted us to investigate the silylation
reactions of 1 or alternatively its less expensive enan-
tiomer,
D
-glucono-1,5-lactone 4.
The silylation of
D
-glucono-1,5-lactone 4 has been
investigated previously. Collins and Jones3 have
described the use of TBSCl and imidazole in DMF and
* Corresponding author. Fax: +353-1-7162127; e-mail: paul.v.
murphy@ucd.ie
Scheme 1. Proposed synthesis of
L-iduronic acid analogues.
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00747-4

80
P. V. Murphy et al. / Tetrahedron: Asymmetry 14 (2003) 79–85
this is less likely), as could the formation of the seven-
membered lactone 10, possibly from 8.
A synthetic approach was adopted to provide confirma-
tion that the structure of the product obtained from
this reaction was neither that of the l-lactone 6b nor
that of 9a. In order to obtain structural clarification we
decided to convert 5a into an exo-glycal methylene
derivative such as 5b–e, and then to prepare an authen-
tic sample of 6b or 6c using Ramberg–Ba¨cklund chem-
istry.8 We were unable to prepare the exo-glycal
derivative 6b by Ramberg–Ba¨cklund reaction of 11,
which can be prepared in three steps from sodium
thioglucose (Scheme 2); this reaction gave instead the
monobromide 12 and the dibromide 13. A similar
approach using the mannose derivative 14 was also
unsuccessful and did not provide 9b.
The synthesis of 9c was instead achieved using the
Ramberg–Ba¨cklund reaction of 15 (Scheme 3), pre-
Collins and Jones but the silylation of 4 with TBSOTf
and 2,6-lutidine in dichloromethane gave a compound
(86%; mp 92–96°C; [h]D +36.1 (c 1.0, CHCl3)) which
had spectroscopic data similar to that obtained by these
workers; a minor amount of 8 was also observed in the
product mixture; support for formation of 8 was
obtained from the 13C NMR spectrum which had a
signal at l 118.0 ppm consistent with the ortho ester.7
The IR spectrum of the major product had a band at
1785 cm−1 indicating that it was the g-lactone 5a.
Epimerisation of the lactone to give 9a could also
explain the observations by different workers (although
pared from sodium 1-thio-D
-mannose,9 and we found
that this compound had spectroscopic data identical
with that reported previously.10 The exo-glycal deriva-
tive 6c has been prepared previously using this method-
ology and its spectroscopic data was available to us for
comparison purposes.11 Reaction of 5a, obtained from
reaction of 4 with TBSOTf/lutidine/CH2Cl2, with
Cp2TiMe2, followed by removal of the silyl groups
using TBAF and subsequent benzylation gave a
product 5c where the bulk material had spectroscopic
data different to both 6c and 9c.
Scheme 2. Reagents and conditions: (a) MeI, MeOH; (b) TBSOTf, 2,6-lutidine, CH2Cl2; (c) MCPBA, CH2Cl2; (d) KOH–Al2O3,
CF2Br2, CH2Cl2, t-BuOH.
Scheme 3. Reagents and conditions: (a) MeI, MeOH; (b) NaH, BnBr, DMF; (c) MCPBA, CH2Cl2; (d) KOH–Al2O3, CF2Br2,
CH2Cl2, t-BuOH; (e) TBSOTf, 2,6-lutidine, CH2Cl2; (f) Cp2TiMe2, then TBAF, THF, then NaH, BnBr, DMF.

P. V. Murphy et al. / Tetrahedron: Asymmetry 14 (2003) 79–85
81
We obtained single crystals of 5a and determined the
structure of the major product from this reaction by
X-ray crystallography (Fig. 1); this confirmed that the
g-lactone is the major product of the reaction obtained
from silylation of the lactone using TBSOTf in
dichloromethane. X-Ray powder diffraction techniques,
together with the synthetic work, confirmed that the
product obtained from the silylation reaction of 4 was
the same as that used for single crystal analysis. The
synthesis of 5d and 5e was also carried out from 5b
using standard reaction sequences.
are reported relative to internal tetramethylsilane in
chloroform (l 0.0), deuterium oxide (l 4.80) for H and
1
either chloroform (l 77.0), deuterium oxide (with aceto-
nitrile as reference; l 119.2), for 13C. Multiplicity (in
parentheses) in 13C NMR was determined by DEPT.
Coupling constants are reported in hertz. IR spectra
were recorded with a Mattson Galaxy Series FTIR
3000 using either thin film between NaCl plates or KBr
discs as specified. Melting points were measured on a
Gallenkamp Melting Point apparatus. Elemental analy-
sis was performed on an Exeter Analytical CE440
elemental analyser. Low and high resolution mass spec-
tra were measured on either a VG micromass 70/70H
or VG ZAB-E spectrophotometer or autospec spec-
trometers and were measured in ES positive mode
unless otherwise indicated. TLC was performed on
aluminium sheets precoated with silica gel 60 (HF254, E.
Merck) and spots visualized by UV and charring with
sulphuric acid–ethanol (1:20). Flash column chro-
matography was carried out with silica gel 60 (0.040–
0.630 mm, Merck) and employed a stepwise solvent
polarity gradient correlated with TLC mobility. Chro-
matography solvents used were EtOAc (Riedel–
deHaen) and petroleum ether (BDH laboratory
supplies) with the fraction of light petroleum ether with
boiling point 40–60°C. Toluene and dichloromethane
reaction solvents were freshly distilled from calcium
hydride.
2. Summary
Silylation reactions of glucono-1,5-lactone can afford
the protected glucono-1,4-lactone or the protected 1,5-
lactone depending on the reaction conditions employed.
The structure of 2,3,5,6-tetra-O-(tert-butyldimethylsi-
lyl)-g-D-gluconolactone, obtained from the reaction of
l-gluconolactone with TBSOTf and lutidine in
dichloromethane has been confirmed by X-ray crystal-
lography; the presence of the glucono-1,5-lactone was
ruled out by synthesis of exo-glycal derivatives using
the Ramberg–Ba¨cklund reaction. This rearrangement is
interesting and gives useful yields of the five-membered
lactone. Thus, the method should have good potential
utility in synthesis.
3.2. 2,3,5,6-Tetra-O-(tert-butyldimethysilyl)-L-glucono-
3. Experimental
1,4-lactone (enantiomer of 5a) and 1-(tert-butyl-
dimethylsilyloxy)-2,3,4-tri-O-(tert-butyldimethylsilyl)-
3.1. General methods
1,6-anhydro-
L
-glucopyranose (enantiomer of 8)
Optical rotations were determined with a Perkin–Elmer
241 model polarimeter at the sodium D line at 23°C.
NMR spectra were recorded with JEOL JNM-GX270
and Varian Inova 300 spectrometers. Chemical shifts
To -gluconolactone 1
L
(0.25 g, 1.40 mmol) in
dichloromethane (10 mL) at 0°C under N2, 2,6-lutidine
(1.30 mL, 11.2 mmol) and tert-butyldimethylsilyl trifl-
ate (1.93 mL, 8.43 mmol) were added. The solution was
allowed to stir at 0°C for 2 h, then warmed to room
temperature. The reaction was quenched with the addi-
tion of water (10 mL). The organic layer was further
washed with 5% aqueous CuSO4 solution (3×10 mL)
and water (3×10 mL), dried with Na2SO4, filtered and
the dichloromethane was removed in vacuo. Chro-
matography (20:1 petroleum spirits–diethyl ether) gave
2,3,5,6-tetra-O-(tert-butyldimethysilyl)-L-glucono-1,4-
lactone as a white solid (0.77 g, 86%) and 1-(tert-
butyldimethylsilyloxy)-2,3,4-tri-O-(tert-butyldimethylsily
l)-1,6-anhydro-L-glucopyranose, as a clear oil, that was
crystallised from ethanol to give clear crystals (0.06 g,
6%).
3.2.1. Analytical data for 2,3,5,6-tetra-O-(tert-butyl-
dimethysilyl)-
L
-glucono-1,4-lactone.
Rf
0.56
(9:1
petroleum spirits–diethyl ether); mp 92–96°C; [h]D
−
1
36.1 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3): l
4.58 (d, 1H, J 6.8 H-2), 4.58 (apt t, 1H, J 7.0 H-4), 4.43
(apt t, 1H, J 6.8, H-3), 4.03 (ddd, 1H, J 5.5, 3.0, H-5),
3.94 (dd, 1H, J 6.6, 10.1, H-6a), 3.34 (dd, 1H, H-6b),
0.92, 0.92, 0.90, 0.89 (4s, 36H, 4×Si(CH3)2C(CH3)3),
0.19, 0.14, 0.12, 0.11, 0.06, 0.05 (6s, 24H, 4×
Si(CH3)2C(CH3)3); 13C NMR (CDCl3) l 174.6 (s, C-1),
Figure
butyldimethysilyl)-
shown).
1. X-Ray
structure
of
2,3,5,6-tetra-O-(tert-
D-glucono-1,4-lactone 5a (H atoms not
––
80.8, 76.3, 74.4, 73.5 (4d, C-2 5), 63.8, 25.9, 25.8, 25.7,

82
P. V. Murphy et al. / Tetrahedron: Asymmetry 14 (2003) 79–85
3.4. 2,5-Anhydro-3,4,6,7-tetra-O-(tert-butyldimethylsi-
lyl)-1-deoxy- -gluco-hept-1-enitol, 5b
25.5 (each q, Si(CH3)2C(CH3)3), 18.2, 18.1, 18.0, 17.9
(4s, 4×Si(CH3)2C(CH3)3), −4.11, −4.4, −4.5, −4.5, −4.8,
−5.1, −5.1, −5.7, −5.8 (each q, Si(CH3)2C(CH3)3); IR
(KBr): 2961, 1786 (CꢀO), 1463, 1258, 1119, 1003, 835,
773 cm−1. Anal. calcd for C30H66O6Si4: C, 56.73; H,
10.47. Found: C, 56.45; H, 10.42%. CI-HRMS: Found
635.4007, required 635.4015 [M+H]+.
D
To a stirred solution of 5a (1.80 g, 2.84 mmol) in dry
toluene (50 mL), dimethyl-bis-cyclopentadiene titanium
(1.40 g, 7.62 mmol) was added. The resulting solution
was stirred for 20 h at 70°C, cooled and toluene
removed in vacuo. Chromatography of the resulting
residue (petroleum spirits as eluant; silica prewashed
with 1% triethylamine in petroleum spirits) gave the
title compound as a clear oil (1.25 g, 87%); Rf 0.66 (20:1
petroleum spirits–EtOAc); [h]D +14.3 (c 1.5, CHCl3);
1H NMR (270 MHz, CDCl3) l 4.30–4.34 (m, 2H, H-4,
H-3), 4.24 (d, 1H, J 1.8, H-1a), 4.02–4.08 (m, 2H, H-5,
H-6), 3.98 (d, 1H, J 1.8, H-1b), 3.87, 3.73 (2H, J7a,7b
11.0, J7,6 5.5 and 2.6 H-7a, H-7b), 0.89, 0.88, 0.88, 0.87
(each s, 36H, Si(CH3)2C(CH3)3), 0.12, 0.11, 0.10, 0.10,
0.09, 0.08, 0.07, 0.06 (each s, 24H, Si(CH3)2C(CH3)3);
13C NMR (CDCl3), l: 163.1 (s, C2), 89.7 (t, C1), 83.6
(d, C3), 77.2, 76.7, 71.8 (3d, C-4–6), 65.0 (t, C-7), 26.0,
25.9, 25.8, 25.7, 25.6, 25.5, 25.4 (each q,
Si(CH3)2C(CH3)3), 18.4, 18.3, 18.0, 18.0, 17.9 (each s,
Si(CH3)2C(CH3)3), −3.6, −3.8, −4.0, −4.1, −4.2, −4.3,
−4.5, −4.6, −4.8, 4.9 (each q, Si(CH3)2C(CH3)3); IR
(film): w 2957, 2887, 2860, 1682 (CꢀC), 1473, 1255,
1096, 835, 777 cm−1; CI-HRMS. Found 633.4218,
required 633.4222 [M+H]+.
3.2.2. Analytical data for 1-(tert-butyldimethylsilyloxy)-
2,3,4-tri-O-(tert-butyldimethylsilyl)-1,6-anhydro-L-gluco-
pyranose. Rf 0.64 (9:1 petroleum spirits–EtOAc); mp
78–81°C; [h]D +15.4 (c 0.9 CHCl3); 1H NMR (270
MHz, CDCl3): l 4.40–4.42 (m, 1H), 3.89–3.92 (m, 1H),
3.76–3.81 (m, 3H), 3.44–3.46 (m, 2H), 0.92, 0.92, 0.91,
0.90 (4s, 36H, 4×Si(CH3)2C(CH3)3), 0.19, 0.14, 0.13,
0.11, 0.10, 0.10, 0.09, 0.09 (each s, 24H, 4×
Si(CH3)2C(CH3)3); 13C NMR (CDCl3) l 118.0 (s, C-1),
––
78.9, 78.4, 74.6, 73.0 (each d, C-2 5), 63.8 (t, C-6),
26.3, 26.0, 26.0, 25.8, 25.7, 25.6, 25.4 (each q, 4×
Si(CH3)2C(CH3)3), 18.4, 18.1, 18.1, 17.8 (each s, 4×
Si(CH3)2C(CH3)3), −2.9, −2.9, −3.2, −3.5, −4.4, −4.7,
−4.7 (each q, 4×Si(CH3)2C(CH3)3); IR (film): w 2928,
1463, 1257, 1003 cm−1; CI-HRMS. Found 635.4009,
required 635.4015 [M+H]+.
3.3. 2,3,5,6-Tetra-O-(tert-butyldimethysilyl)-D-glucono-
1,4-lactone 5a
3.5. 2,5-Anhydro-1-deoxy-D-gluco-hept-1-enitol
An identical procedure for
D
-gluconolactone 4 as
described above for -gluconolactone gave 5a: [h]D
L
To 5b (0.59 g, 0.93 mmol) in THF (10 mL), TBAF
(3.72 mL, 1 M in THF) was added and the resulting
solution was stirred for 2 h. THF was removed in
vacuo. Chromatography (12:1 EtOAc–MeOH as elu-
ant, silica prewashed with 1% triethylamine in MeOH)
gave the title compound as a clear oil (0.15 g, 95%); Rf
+36.1 (c 1.0, CHCl3); the spectroscopic data for 5a was
identical to that of its enantiomer. Crystals of 5a were
obtained (from ethanol, crystals were twinned) and the
structure confirmed by X-ray crystallography. Crystal-
lographic data (excluding structure factors) for 5a have
been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication numbers
CCDC 196326. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road,
Cambridge, CB2 1EZ, UK [fax: +44(0)-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk]. Crystal data and
structure refinement for 5a: empirical formula
C30H66O6Si4; formula weight 635.19; temperature
363(2) K; wavelength 71.073 pm; crystal system mono-
clinic; space group P2(1); unit cell dimensions a=
1
0.51 (3:1 EtOAc–MeOH); H NMR (300 MHz D2O) l
4.61 (dd, 1H, J 1.5, 0.7), 4.37 (br s, 1H), 4.31 (d, 1H, J
2.2), 4.22–4.26 (m, 2H), 3.90 (apt ddd, 1H, J 5.7, 3.1,
2.9), 3.80 (dd, 1H, J 12.1, 2.9), 3.65 (dd, 1H, J 12.1,
5.7).
3.6. 2,5-Anhydro-3,4,6,7-tetra-O-benzyl-1-deoxy-D-
gluco-hept-1-enitol, 5c
A solution of 2,5-anhydro-1-deoxy-D-gluco-hept-1-eni-
tol (0.14 g, 0.80 mmol), sodium hydride (0.13 g, 3.20
mmol) in dry DMF (5 mL) and benzyl bromide (0.38
mL, 3.20 mmol) under N2 at room temperature was
stirred for 2 h. Methanol (10 mL) was added and water
(5 mL) and the mixture was extracted with EtOAc
(3×20 mL). The combined organic extracts were dried
(Na2SO4) filtered and the solvent was removed in vacuo
to give the title compound as a yellow oil (0.35 g, 82%);
Rf 0.75 (10:1 petroleum spirits–EtOAc); [h]D +17.0 (c
1263.45(18)
pm,
h=90°,
b=2112.3(3)
pm,
i=96.096(4)°, c=1487.1(2) pm, k=90°, volume
3.9463(10) nm3, Z=4; density (calculated 1.069 Mg/m3;
absorption coefficient 0.185 mm−1; F(000) 1400; crystal
size 0.32×0.16×0.08 mm3; theta range for data collec-
tion 1.38–8.55°; index ranges −165h516, −285k528,
05l519; reflections collected 21639; independent
reflections 21639 [R(int)=0.0000]; completeness to
theta=28.55°, 91.5%; absorption correction none; max.
and min. transmission 0.9854 and 0.9433; refinement
method full-matrix least-squares on F2; data/restraints/
parameters 21639/1/762; goodness-of-fit on F2 0.965;
final R indices [I>2|(I)], R1=0.0758, wR2=0.1807; R
indices (all data) R1=0.1242, wR2=0.2176; absolute
1
1.0, CHCl3); H NMR (300 MHz, CDCl3): l 7.20–7.37
(m, 20H, aromatic H), 4.78 (d, 2H, J 12.0, OCH2Ph),
4.67 (d, 1H, J 12.0, OCH2Ph), 4.08 (ddd, 1H, J 8.8, 5.5,
2.0), 3.91 (dd, 1H, J 10.8), 3.72 (dd, 1H, J 5.5); 13C
NMR (CDCl3): l 159.6 (s, C-2), 138.8, 138.6, 137.7,
137.6 (each s, each ipso C), 128.5, 128.4, 128.3, 128.2,
128.0, 127.8, 127.8, 127.7, 127.6, 127.6, 127.5, 127.4
(each d, each aromatic C), 87.0 (t, C-1), 81.9, 80.9, 79.8,
structure parameter, −0.01(15); largest diff. peak and
−3.
,
hole, 0.615 and −0.629 e A

P. V. Murphy et al. / Tetrahedron: Asymmetry 14 (2003) 79–85
83
76.6 (each d, C-3–6), 73.5, 72.5, 72.1, 70.7, 69.9 (each t,
C-6 and OCH2Ph); IR (film) 3029, 2864, 1676 (CꢀC),
1453, 1067, 739, 713 cm−1; LR-ESMS: 559.4 [M+Na]+.
Anal. calcd for C35H36O5: C, 78.33; H, 6.76. Found: C,
78.16; H, 6.72%.
3.9. Methyl 1-thio-b-
D
-glucopyranoside
-glucose (10 g, 45.8
A suspension of sodium 1-thio-
D
mmol), iodomethane (2.85 mL, 45.8 mmol) and MeOH
(100 mL) was stirred until a clear solution resulted. The
MeOH was then removed in vacuo and chromatogra-
phy gave the title compound as a yellow solid (8.75 g,
91%); Rf 0.49 (3:1 EtOAc–MeOH); 1H NMR (300
MHz, D2O): l 4.42 (d, 1H, J 9.7, H-1), 3.87 (dd, J 12.3,
2.1, H-6a), 3.68 (dd, J 12.3, H-6b), 3.48 (dd, J 0.9, 15.5,
H-3), 3.45 (m, H5), 3.35 (dd, 1H, J 15.5, 0.9, H-4) 3.33
(apt. t, J 9.7, H-2), 2.20 (s, 3H, SCH3); 13C NMR
3.7. 3,4,6,7-Tetra-O-acetyl-2,5-anhydro-1-deoxy-D-
gluco-hept-1-enitol, 5d
To 2,5-anhydro-1-deoxy-D-gluco-hept-1-enitol (0.18 g,
1.02 mmol) in pyridine (4 mL), acetic anhydride (4 mL)
and DMAP (cat.) were added at room temperature for
24 h. Water (4 mL) was added and the mixture was
extracted with EtOAc (2×10 mL), dried (Na2SO4)
filtered and the solvents was removed in vacuo. Chro-
matography (4:1 petroleum spirits–EtOAc) gave the
title compound as an oil (0.17 g, 49%); Rf 0.22 (4:1
petroleum spirits–EtOAc); 1H NMR (300 MHz,
CDCl3): l 5.30 (s, 1H), 5.39 (d, 1H, J 3.4, H-1a), 5.26
(ddd, 1H, J6,5 9.3, J6,7a 4.9, J6,7b 2.4, H-6), 4.57–4.64 (m,
3H, H-3, H-4, H-7a), 4.43 (d, 1H, J 2.2, H-1b), 4.17
(dd, 1H, J7a,7b 12.4, J7a,6 4.9, H-7b), 2.11, 2.10, 2.08,
2.02 (each s, 12H, C(O)CH3); 13C NMR (CDCl3): l
170.6, 169.6, 169.3, 169.1 (s, 4×C(O)CH3), 158.2 (s,
C-2), 89.3 (t, C-1), 79.0, 74.9, 73.3, 67.3 (d, C-3–6), 63.0
(C-7), 20.9, 20.8, 20.6 (each q, C(O)CH3); IR (film)
2937, 1751 (CꢀO), 1671 (CꢀC), 1437, 1371, 1225, 1050,
931; HRMS-CI. Found 345.1185; required 345.1182
[M+H]+.
–
(CDCl3), 85.8 (d, C-1), 80.1, 77.4, 71.9, 69.8 (d, C-2– 5),
61.2 (t, C-6), 11.7 (q, SCH3); IR (KBr): w 3441 (O-H),
2928, 1633, 1021 cm−1.
3.10. Methyl 2,3,5,6-tetra-O-(tert-butyldimethylsilyl)-
1-thio-b-D-glucopyranoside
To a solution of methyl 1-thio-b-D-glucopyranoside
(4.0 g, 19.0 mmol), CH2Cl2 (50 mL) and 2,6-lutidine
(17.7 mL, 152.2 mmol) at 0°C, under a N2 atmosphere,
tert-butyldimethylsilyl triflate (26.2 mL, 114.2 mmol)
was added dropwise over 10 min and the mixture then
was stirred for 3 h. Water was added (20 mL) and
stirring continued for 10 min. The product was then
diluted with CH2Cl2 (20 mL), washed with 5% aq.
CuSO4 (3×60 mL), dried (Na2SO4) filtered and the
solvent was removed. Chromatography (75:1 petroleum
spirits:EtOAc) gave the title compound as a clear oil
(10.58 g, 83.4%); Rf 0.81 (24:1 petroleum spirits–
EtOAc); [h]D −18.5 (c 1.0, CHCl3); 1H NMR (300
MHz, CDCl3): l 4.58 (d, 1H, J 8.0, H-1), 3.96 (dt, 1H,
J 3.1, 1.2), 3.81 (dd, 1H, J 8.0, 3.1), 3.70–3.79 (m, 3H),
3.64 (dt, 1H, J 1.0, 7.8), 2.16 (s, 3H, CH3), 0.90, 0.89,
0.89 (each s, 36H, Si(CH3)2C(CH3)3), 0.14, 0.11, 0.10,
0.08, 0.05, 0.02 (each s, 24H, Si(CH3)2C(CH3)3); 13C
NMR (CDCl3): l 84.3, 83.4, 78.0, 76.3, 70.0 (each d,
C-1–5), 64.3 (t, C-6), 26.1, 26.0, 25.9 (each q,
Si(CH3)2C(CH3)3), 18.4, 18.1, 18.0, 17.9 (each s,
Si(CH3)2C(CH3)3), 12.9 (q, SCH3), −4.1, −4.2, −4.3,
−4.4, −4.7, −5.2 (each q, Si(CH3)2C(CH3)3); IR (film) w
2964, 1462, 1250, 923, 777, 642 cm−1; LRMS-ES: 689.4
[M+Na]+. Anal. calcd for C31H70O5Si4S: C, 55.80; H,
10.57; S, 4.80. Found: C, 55.80; H, 10.71; S, 5.21%.
3.8. 2,5-Anhydro-3,4,6,7-tetra-O-benzoyl-1-deoxy-D-
gluco-hept-1-enitol, 5e
To a stirred solution of 2,5-anhydro-1-deoxy-D-gluco-
hept-1-enitol (0.15 g, 0.85 mmol) in dry pyridine (8 mL)
at 0°C under N2, benzoyl chloride (0.59 mL, 5.11
mmol) was added. The resulting solution was stirred at
0°C for 3 h and warmed up to room temperature and
water was added (10 mL). The mixture was extracted
with EtOAc (3×20 mL) and the combined organic
layers were washed with 5% aqueous CuSO4 (2×40 mL)
and water (2×40 mL), dried with Na2SO4, filtered and
the solvent was removed in vacuo. Chromatography
(silica prewashed and with 1% triethyamine in 6:1
petroleum spirits–EtOAc which was also eluant) gave
5e as a white solid (0.26 g, 52%); Rf 0.42 (4:1 petroleum
spirits–EtOAc); mp 52–56°C; 1H NMR (300 MHz,
CDCl3): l 7.84–8.10 (m, 8H, aromatic H), 7.24–7.63
(m, 12H, aromatic H), 5.92 (d, 1H, J 1.0, H-3), 5.87
(ddd, 1H, J6,5 9.1, J6,7a 5.5 J6,7b 2.8, H-6), 5.83 (dd, 1H,
J4,5 3.8, J4,3 1.0), 5.09 (dd, 1H, J5,4 3.6, J5,6 9.1, H-5),
5.00 (dd, 1H, J7b,7a 12.3, J7b,6 2.8, H-7b), 4.72 (dd, 1H,
J7a,7b 12.3, J7a,6 5.5), 4.71 (d, J1a,1b 2.2, H-1a), 4.56 (d,
1H, J1b,1a 2.2); 13C NMR (CDCl3): l 166.4, 165.3,
165.2, 165.1 (each s, C(O)Ph), 158.2 (s, C-2), 133.9,
133.8, 133.5, 133.4, 130.2, 130.0, 130.0, 129.9, 129.5,
128.8, 128.7, 128.7, 128.6 (aromatic C), 89.8 (t, C-1),
79.7, 75.7, 74.9, 68.9 (each d, C-3–6), 64.0 (t, C-7); IR
(KBr): w 3069, 1725 (CꢀO), 1451, 1281 (CꢀC), 1106
cm−1.
3.11. 2,3,5,6-Tetra-O-(tert-butyldimethylsilyl)-1-b-D-
glucopyranosyl methyl sulfone, 11
A solution of methyl 2,3,5,6-tetra-O-(tert-butyldime-
thylsilyl)-1-thio-b- -glucopyranoside (3.88 g, 5.8
D
mmol), MCPBA (6.05 g, 17.5 mmol) and CH2Cl2 (50
mL), were stirred at 0°C, under a N2 atmosphere for 4
h. The mixture was washed with 10% aqueous sodium
thiosulphate (3×50 mL), saturated NaHCO3 solution
(2×50 mL), dried (MgSO4), filtered and the solvent was
removed in vacuo. Chromatography (40:1 petroleum
spirits–EtOAc) gave the title compound as a white
crystalline solid (2.37 g, 58.6%); Rf 0.51 (10:1 petroleum
spirits–EtOAc); mp 38–42°C; 1H NMR (300 MHz,
CDCl3): l 4.55 (d, 1H, J 5.3, H-1), 4.28 (dt, 1H, J 5.0,
1.5), 3.98 (br m, 1H), 3.88 (apt t, 1H, J 1.8), 3.74–3.80
(m, 3H), 2.88 (s, 3H, SCH3), 0.91, 0.90, 0.89, 0.88 (each

84
P. V. Murphy et al. / Tetrahedron: Asymmetry 14 (2003) 79–85
s, 36H, Si(CH3)2C(CH3)3), 0.17, 0.16, 0.14, 0.13, 0.11,
0.10, 0.07, 0.01 (each s, 24H, Si(CH3)2C(CH3)3), 13C
NMR (CDCl3): l 94.7 (d, C1), 82.5, 75.5, 70.6, 69.9
(each d, C-2–5), 63.4 (t, C-6), 37.3 (q, S(O)2CH3, 25.9,
25.8 (each q, Si(CH3)2C(CH3)3), 18.3, 18.0, 18.0, 17.9
(each s, Si(CH3)2C(CH3)3), −5.3, −5.0, −4.8, −4.3, −4.3,
−4.1, −3.9 (each q, 4×Si(CH3)2C(CH3)3); IR (KBr): w
2957, 2658, 1453, 1255, 1101, 938, 811, 756 cm−1;
LRMS-ES: 721.3 [M+Na]+. Anal. calcd for
C31H70O7Si4S: C, 53.24; H, 10.09; S, 4.60. Found: C,
52.99; H, 10.00; S, 4.73%.
3.13. Methyl 1-thio-b-
D
-mannopyranoside12
-mannose9 (3.25 g,
To a suspension of sodium 1-thio-
D
14.9 mmol) in MeOH (40 mL), iodomethane (1.38 mL,
22.3 mmol) was added. The suspension was stirred until
a clear solution was observed. The MeOH was removed
in vacuo and residue applied to a column packed and
eluted with 3:1 EtOAc–MeOH to give the product as a
yellow solid (2.99 g, 95%); Rf 0.39 3:1 EtOAc–MeOH;
[h]D −115° (c 1.0 MeOH) [h]D −129.2 (c 1.1, MeOH);
1H NMR (300 MHz, D2O): l 4.78 (d, 1H, J 0.9, H-1),
4.04 (dd, 1H, J 3.5, H-2), 3.92 (dd, 1H, J 2.4, 12.3,
H-6a), 3.73 (dd, 1H, J 6.2, H-6b), 3.66 (dd, 1H, J 3.5,
H-3), 3.60 (t, 1H, J 9.7, H-4), 3.41 (ddd, 1H, J 6.2,
H-5), 2.27 (s, 3H, OMe); 13C NMR (D2O): l 86.9 (d,
C-1), 81.4, 75.1, 72.8, 67.5 (d,C-2–5) 62.4 (t, C-6).
3.12. 2,6-Anhydro-3,4,6,7-tetra-O-(tert-butyldimethyl-
silyl)-1-deoxy-1-bromo-D-gluco-1-enitol, 12 and 2,6-
anhydro-3,4,6,7-tetra-O-(tert-butyldimethylsilyl)-1-
deoxy-1,1-dibromo- -gluco-1-enitol, 13
D
To a stirred solution of 11 (0.23 g, 0.33 mmol), KOH
supported on neutral alumina (0.75 g) and tert-butanol
(10 mL) at 5–10°C, dibromodifluromethane (0.32 g,
1.32 mmol) from a pre-cooled syringe was added drop-
wise over 10 min. The solution was stirred for 30 min
and then filtered through a pad of Celite, washing with
dichloromethane (15 mL). The combined organic
extracts were washed with brine (1×20 mL) and water
(1×20 mL) successively, dried (MgSO4) filtered and the
solvent was removed in vacuo. Chromatography (silica
prewashed with 1% triethylamine in petroleum spirits;
eluted with same mixture), gave 12 (0.025 g, 11%) and
13 (0.05 g, 19%).
3.14. Methyl 2,3,5,6-tetra-O-benzyl-1-thio-b-D-
mannopyranoside
To a stirred solution of methyl 1-thio-b-D-mannopyran-
oside (2.10 g, 10.0 mmol) and sodium hydride (1.6 g,
40.0 mmol) in dry DMF (40 mL) under N2 at room
temperature, benzyl bromide was added. The mixture
was stirred for 4 h and MeOH (45 mL) was then added
followed by water (45 mL). The mixture was extracted
with EtOAc (3×50 mL), dried (Na2SO4), filtered, and
the solvent was removed in vacuo. Chromatography
(4:1 petroleum spirits–EtOAc) gave the title compound
as a yellow oil (3.86 g, 67%); Rf 0.54 (4:1 petroleum
1
spirits:EtOAc); H NMR (300 MHz, CDCl3): l 7.18–
3.12.1. Analytical data for 12. Rf 0.94 (10:1 petroleum
spirits–EtOAc); mp 82–84°C; 1H NMR (300 MHz,
CDCl3) l 5.02 (s, 1H, H-1), 4.19 (ddd, 1H, J6,7a 1.9,
J6,7b 2.9, J6,5 9.1, H-6), 4.04 (dd, 1H, J 3.4, 1.0, H-3),
4.01 (dd, 1H, J5,6 9.1, J5,4 0.7, H-4), 3.93 (dd, 1H, J7a,7b
12.0, J7a,6 1.9, H-7a), 3.82 (dd, 1H, J7b,7a 12.0, J7b,6 2.9,
H-7b), 3.78 (overlapping dd, 1H, J4,5 0.7, J4,3 3.4), 0.91,
0.90, 0.89, 0.89, 0.88, 0.88, 0.87, 0.86, 0.85, 0.84 (each s,
Si(CH3)2C(CH3)3), 0.13, 0.13, 0.11, 0.10, 0.09, 0.07, 0.06
(each s, Si(CH3)2C(CH3)3); 13C NMR (CDCl3): l 153.2
(s, C-2), 81.3, 78.1, 76.7, 72.6, 72.0 (all d, C-1, C3–6),
61.6 (t, C-7), 25.9, 25.8, 25.6 (each q, Si(CH3)2-
C(CH3)3), 18.3, 18.0, 17.8 (each s, Si(CH3)2C(CH3)3),
−0.0, −4.0, −4.1, −4.6, −4.6, −4.8, −5.0, −5.0, −5.4 (each
q, Si(CH3)2C(CH3)3); IR (KBr): w 2957, 2856, 1259,
1098, 1020, 836 cm−1; HRMS-ES. Found 733.3147,
required 733.3147 [M+Na]+.
7.46 (m, 20H, 4×OCH2C6H5), 4.95 (d, 1H, J 11.6
OCH2Ph), 4.87 (d, 1H, J 10.7, OCH2Ph), 4.82 (d, 1H, J
11.8, OCH2Ph), 4.70 (d, 1H, J 11.6, OCH2Ph), 4.65 (d,
1H, J 11.6, OCH2Ph), 4.58 (m, 2H, OCH2Ph), 4.45 (s,
1H, H-1), 3.97 (d, J2,3 2.9, H-2), 3.93 (apt t, 1H, J3,4 9.5,
H-4), 3.81 (dd, 1H, J6a,5 1.8, J6a,6b 11.0, H-6a), 3.72 (dd,
1H, J6b,5 5.9, J6b,6a 11.0, H-6b), 3.60 (dd, 1H, J3,2 2.9
J3,4 9.5, H-3), 3.48 (ddd, 1H, J5,6a 1.8, J5,6b 5.9, J5,4 9.5,
H-5), 2.24 (s, 3H, SCH3); 13C NMR (CDCl3) l 139.6,
138.7, 138.4, 137.6 (each s, ipso C), 128.7, 128.6, 128.5,
128.5, 128.4, 128.0, 127.9, 127.8, 127.7 (each d, aro-
matic C), 86.0, 84.7, 80.6, 77.1, 75.3 (each d, C-1–5),
75.5, 75.1, 73.7, 72.7, 70.1 (each t, C-6 and CH2Ph),
14.9 (q, SCH3); LRMS-ES: 593.4 [M+Na]+.
3.15. 2,3,4,6-Tetra-O-benzyl-b-D-mannopyranosyl methyl
sulfone, 15
3.12.2. Analytical data for 13. Rf 0.86 (10:1 petroleum
spirits–EtOAc); mp 68–70°C; 1H NMR (300 MHz,
CDCl3) l 4.72 (dd, 1H, J 3.5, 1.0, H-5), 4.23 (ddd, 1H,
J 9.1, 2.6, 1.9, H-4), 4.05 (d, 1H, J 9.1, H-3), 3.92 (dd,
1H, J 12.1, 1.7 H-7a), 3.79–3.84 (m, 2H, H-6, H-7b),
0.82, 0.89, 0.89, 0.88 0.87, 0.86, 0.85 (each s, 36H) (each
s, Si(CH3)2C(CH3)3), 0.17, 0.16, 0.16, 0.13, 0.11, 0.11,
0.10 (each s, 24H, Si(CH3)2C(CH3)3); 13C NMR
(CDCl3): l 152.2 (s, C-2), 78.8, 76.5 71.6, 71.0 (each d,
To a solution of methyl 2,3,5,6-tetra-O-benzyl-1-thio-b-
-mannopyranoside (1.50 g, 2.63 mmol) in CH2Cl2 (20
D
mL), MCPBA (1.36 g, 7.88 mmol) added and stirring
was continued until all the starting material was con-
sumed. The reaction mixture was then diluted with
CH2Cl2 (20 mL), washed with 5% aqueous sodium
thiosulphate (2×50 mL) and a saturated NaHCO3 solu-
tion (3×50 mL), dried (Na2SO4), filtered and the solvent
was removed. This gave the title compound as a clear
oil (1.26 g, 80%); Rf 0.88 (10:1 petroleum spirits–
–
C-3 6), 70.1 (s, C-1), 61.6 (t, C-7), 25.9, 25.7, 25.6 (each
q, Si(CH3)2C(CH3)3), 18.3, 18.0, 17.8 (each s,
Si(CH3)2C(CH3)3), −4.0, −4.0, −4.3, −4.6, −4.7, −4.9,
−5.0, −5.4 (each q, Si(CH3)2C(CH3)3); IR (KBr): w
2928, 2858, 1257, 1089, 837 cm−1; HRMS-ES. Found
811.2252; required 811.2252 [M+Na]+.
1
EtOAc); H NMR (300 MHz, CDCl3): l 7.20–7.41 (m,
20H, 4×OCH2C6H5), 5.13 (d, 1H J 10.3, OCH2Ph), 4.88
(d, 1H J 10.8, OCH2Ph), 4.81 (d, 1H J 11.6, OCH2Ph),
4.74 (d, 1H J 11.6, OCH2Ph), 4.67 (d, 1H J 9.9,

P. V. Murphy et al. / Tetrahedron: Asymmetry 14 (2003) 79–85
85
OCH2Ph), 4.64 (d, 1H J 10.8, OCH2Ph), 4.61 (d, 1H J
11.8, OCH2Ph), 4.50 (d, 1H J 11.8, OCH2Ph), 4.50 (apt
t, 1H, J2,3 2.6 H-2), 4.25 (s, 1H, H-1), 4.16 (apt t, J4,3
9.7 H-4), 3.84 (dd, 1H, J6a,6b 11.6, J6a,5 3.7, H-6a), 3.78
(dd, 1H, J6b,6a 11.6, J6b,5 1.9, H-6b), 3.66 (dd, 1H, J3,2
2.6, J3,4 9.5, H-3), 3.57 (ddd, 1H, J5,4 9.7, J5,6a 3.7, J5,6b
1.9, H-5), 2.83 (s, 3H, S(O)2CH3); 13C NMR (CDCl3): l
138.4, 138.2, 138.1, 137.9 (each s, ipso C), 128.4, 128.7,
128.6, 128.5, 128.4, 128.2, 128.2, 128.1, 127.9, 127.8,
127.8 (each d, aromatic C), 92.5 (d, C-1), 83.6, 81.2,
74.5, 74.1 (each d, C-2–5), 75.7, 85.6, 73.7, 73.0, 68.9
(each t, C6 and CH2Ph), 39.1 (q, SO2CH3); IR (KBr) w
3030, 2872, 1496, 1454, 1361 (SꢀO), 1316 (SꢀO), 1115,
963, 740 cm−1.
127.5 (each d, aromatic C), 99.5 (t, C-1), 81.5, 80.2,
74.1, 73.7 (each d, C3–6), 75.0, 73.4, 71.4, 69.4, 69.3
(each t, C-7 and CH2Ph); LRMS-ES: 559.2 [M+Na]+.
Acknowledgements
The authors thank the Health Research Board and
British Council for a travel grant for D.E.P. and
Dublin Corporation for funding for C.M.D.
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3.16. 2,6-Anhydro-3,4,6,7-tetra-O-benzyl-1-deoxy-D-
manno-hept-1-enitol, 9c
To a stirred solution of 15 (1 g, 1.66 mmol), KOH
supported on neutral alumina (2.0 g) and tert-butanol
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tions were washed with satd. brine (1×40 mL) and
water (1×40 mL) successively, dried (MgSO4), filtered
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4.95 (d, 1H, J 10.8, OCH2Ph), 4.91 (br s, 1H, H1a-),
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OCH2Ph), 4.39 (bs, 1H, H1b), 4.19 (t, 1H, J 9.0), 4.09
(d, 1H, J 3.2), 3.77–3.89 (m, 2H); 13C NMR (CDCl3): l
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8. (a) Griffin, F. K.; Paterson, D. E.; Murphy, P. V.;
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