Synthesis of a novel class of sulfonium ions as potential inhibitors of UDP-galactopyranose mutase

Article abstract of DOI:10.1016/j.carres.2003.09.036

Two sulfonium salts of 1,4-anhydro-4-thio-D-galactitol, with structures related to the known sulfonium salt glycosidase inhibitor, salacinol, have been synthesized as potential inhibitors of UDP-galactopyranose mutase. The synthetic strategy relies on the alkylation reaction of 1,4-anhydro-2,3,5,6- tetra-O-benzyl-4-thio-D-galactitol at the sulfur atom with 2,4-O-benzylidene-D- or -L-erythritol-1,3-cyclic sulfate. In each case, the reaction proceeded stereoselectively to yield only one stereoisomer at the stereogenic sulfur atom. The effect of the polar solvent, 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), in promoting high-yielding reactions is highlighted. The target compounds are then obtained by hydrogenolysis.

Full text of DOI:10.1016/j.carres.2003.09.036

Carbohydrate
RESEARCH
Carbohydrate Research 339 (2004) 401–407
Synthesis of a novel class of sulfonium ions as potential inhibitors
of UDP-galactopyranose mutaseq
Ahmad Ghavami, Joan Jo-wen Chen and B. Mario Pinto*
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6
Received 28 August 2003; accepted 29 September 2003
Abstract—Two sulfonium salts of 1,4-anhydro-4-thio-
inhibitor, salacinol, have been synthesized as potential inhibitors of UDP-galactopyranose mutase. The synthetic strategy relies on
the alkylation reaction of 1,4-anhydro-2,3,5,6-tetra-O-benzyl-4-thio- -galactitol at the sulfur atom with 2,4-O-benzylidene- - or -L-
D-galactitol, with structures related to the known sulfonium salt glycosidase
D
D
erythritol-1,3-cyclic sulfate. In each case, the reaction proceeded stereoselectively to yield only one stereoisomer at the stereogenic
sulfur atom. The effect of the polar solvent, 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), in promoting high-yielding reactions is
highlighted. The target compounds are then obtained by hydrogenolysis.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Keywords: Galactofuranose; UDP-Galactopyranose mutase inhibitors; Salacinol analogues; Sulfonium salt
1. Introduction
mised individuals such as AIDS patients.13 The recog-
nition that -galactofuranose ( -Galf) residues play
D
D
Galactose is found to occur mostly in the pyranose form
in Nature; the rare furanose form only exists in micro-
organisms such as bacteria,1;2 protozoa,3 and fungi4 and
has never been found in mammalian cells.5 Thus, for
example, Galf is present in lipopolysaccharides (LPS) in
the outer membrane of Gram-negative bacteria, in var-
ious capsular or extracellular polysaccharides in both
Gram-negative and Gram-positive bacteria,5;6 and as
constituents of the oligosaccharide core of both the
glycoinositolphospholipid (GIPL) and lipopeptido-
phosphoglycan (LPPG) of Trypanosoma cruzi, and the
lipophosphoglycan (LPG) of Leishmania species.7–11
Galactofuranosyl residues also play important roles in
pathogenic mycobacteria such as Mycobacterium tuber-
culosis and M. leprae.12;13 In addition, Ôatypical myco-
bacteriaÕ, including the M. avium complex, cause
opportunistic infections in immunologically compro-
crucial roles in survival and infectivity of pathogens has
led to increased activity in developing therapeutic
strategies.
The sugar donor for galactofuranosyl residues is
UDP-Galf,14;15 which is produced in turn from UDP-
Galp. The interconversion of UDP-Galp and UDP-Galf
is catalyzed by the enzyme UDP-galactopyranose mu-
tase (Scheme 1).15–17 The reaction has been proposed to
proceed via a 1,4-anhydro-D-galactopyranose species
(Scheme 1), based on evidence that the anomeric C–O
bond is broken during the reaction.18;19 Evidence for the
active involvement of the coenzyme FAD in controlling
the catalytic efficiency of the enzyme has also been
provided,20;21 and a study of the inactivation of the en-
zyme with UDP-3-deoxy-3-fluoro-Galf has suggested
the possible involvement of a covalent intermediate.21
Recent evidence suggests that the ring contraction re-
action might be driven by attack of OH-4 at C-1 of a
glycosyl C-1 radical intermediate with concomitant
cleavage of the C-1–O-5 bond (Scheme 1).22 We note,
however, that the mechanisms proposed to date are
difficult to reconcile with the findings that UDP-4-de-
oxy-4-fluoro-Galp does not inhibit the reaction of
qSupplementary data associated with this article can be found at
doi:10.1016/j.carres.2003.09.036
* Corresponding author. Tel.: +1-604-291-4327; fax: +1-604-291-5424;
e-mail: bpinto@sfu.ca
0008-6215/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2003.09.036

402
A. Ghavami et al. / Carbohydrate Research 339 (2004) 401–407
Scheme 1.
UDP-galactopyranose mutase in the direction pyranose
to furanose.23 UDP-Galf then serves as a donor in
glycosylation reactions catalyzed by UDP-Galf trans-
ferase (Scheme 2).24 Thus, one can envisage strategies to
block the incorporation of Galf into oligosaccharides
that comprise blocking the action of either UDP-
galactopyranose mutase or UDP-galactofuranosyl
transferase.
We propose that 4-thio Galf sulfonium salts 1 could
be potential inhibitors of UDP-galactopyranose mutase,
given that 1,4-dideoxy-1,4-imino-D
-galactitol (2)25 has
been shown to inhibit the enzyme.26 We argue that the
protonation of the nitrogen atom in the active site
provides electrostatic stabilization with carboxylate
residues, and that the permanent positive charge on the
sulfonium ion would serve to mimic this interaction.
There is precedent for such mimicry with glycosidase
enzymes, namely the glycosidase inhibitory activities of
salacinol (3)27–29 and the corresponding nitrogen ana-
logue, ghavamiol (4).30 We reasoned further that the
biologically important side chain of salacinol containing
an internal sulfate counterion would be advantageous in
Scheme 2.

A. Ghavami et al. / Carbohydrate Research 339 (2004) 401–407
403
stabilizing the compound, as is the case with salacinol
(3). We describe here the synthesis of 4-S-galactitol
sulfonium salt derivatives 1, based on the structure of
salacinol (3), as potential inhibitors of UDP-galacto-
pyranose mutase.
2. Results and discussion
Retrosynthetic analysis indicated that the target com-
pounds could be synthesized by alkylation on the ring
heteroatom of a 1,4-anhydro-4-thiogalactitol derivative
(Scheme 3). The compounds for alkylation could either
be the open-chain sulfate or the cyclic sulfate deriva-
tives.29;30 We proposed the use of cyclic sulfate deriva-
tives as alkylation reagents, specifically 2,4-O-
action of tetra-O-acetyl galactitol 7 with the cyclic sul-
fate 5 in acetone containing potassium carbonate at
55 ꢁC for 2 days led to no reaction. The reaction in DMF
instead of acetone also failed because of the opening of
the cyclic sulfate by acetate ion released from compound
7. The reaction of the deprotected galactitol compound
8 with the cyclic sulfate 5 in DMF at 70 ꢁC was also not
successful and produced several components. Therefore,
the coupling reaction was next attempted with tetra-O-
benzylidene-
sulfates.29;30
D
-
(5) and
L- (6) erythritol-1,3-cyclic
Methyl a-
1,2,3,5,6-penta-O-acetyl-4-thio-a-
D
-glucopyranoside was converted to
-galactofuranose, as
benzyl-D-galactitol 9.
D
described previously.31–33 The anhydrogalactitol deriva-
tive was then synthesized as follows. A deoxygenation
reaction was carried out by reductive deacetylation us-
ing trimethylsilyl (TMS) triflate and triethylsilane at
room temperature, as described for the synthesis of
anhydroalditols,34 to produce the 1,4-anhydro-4-thio-
galactitol compound 7, in 63% yield. The presence of the
adjacent acetate group at C-2 presumably facilitates the
deoxygenation process by stabilizing the thiacarbenium
ion intermediate.35
The reaction was first attempted in acetone at a
concentration of 100 mg/mL of compound 9. The reac-
tion proceeded, but the yield was not satisfactory.
Therefore, the reaction was attempted again at a con-
centration of 200 mg compound 9 in 0.5 mL of acetone.
Under these reaction conditions, the reaction proceeded
reasonably well to give compound 10 in 60% yield, in-
dicating the need for extremely concentrated reaction
mixtures. The same reaction conditions were used for
the coupling reaction of compound 9 and 2,4-O-benzyl-
idene-L-erythritol-1,3-cyclic sulfate (6) to give the dia-
With the 1,4-anhydro-4-thio-galactitol compound 7 in
hand, the key coupling reaction was then attempted.
The effect of protecting groups, or the lack thereof, on
the anhydrogalactitol moiety was examined. The de-
protected galactitol 8 was obtained from 7 by methano-
lysis, and the benzylated galactitol 9 was synthesized
from compound 8, using NaH and benzyl bromide.
Compounds 7–9 were then investigated in reactions with
stereomeric compound 11 in 50% yield (Scheme 4). The
coupling reactions proceeded stereoselectively, and in
each case, only one isomer at the stereogenic sulfur atom
was isolated. We had previously shown that the polar
solvent, 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), had
a spectacular effect in promoting analogous reactions for
the synthesis of salacinol 336 and its selenium congener,
blintol 12.37 We reasoned that the higher yields were due
to better solvation by HFIP of the polar transition states
for the reactions and the adducts relative to the neutral
reactants. We therefore tested HFIP as a solvent for the
coupling reaction described here. The reaction of the
thioether 9 with the cyclic sulfate 5 in HFIP was much
faster and proceeded in excellent yield (88%) to stereo-
selectively give 13. Similarly, a dramatic increase in yield
was observed for the reaction of the thioether 9 with the
cyclic sulfate 6 in HFIP to give 14 (87%).
2,4-O-benzylidene-D-erythritol 1,3-cyclic sulfate 5. Re-
Compounds 10 and 11 were completely characterized
by 2D NMR techniques and microanalysis. Deprotec-
tion of 10 and 11 was accomplished with Pd(OH)2/C/H2
in aqueous 80% acetic acid to effect the hydrogenolytic
cleavage of the benzyl and benzylidene groups, and gave
13 and 14 in yields of 84% and 96%, respectively
(Scheme 4). Compounds 13 and 14 were also completely
characterized by 2D NMR techniques (see figures,
Scheme 3.

404
A. Ghavami et al. / Carbohydrate Research 339 (2004) 401–407
Scheme 4.
1
Supplementary Data section). The stereochemistry at
the stereogenic sulfur atom in 13 and 14 was confirmed
by NOESY correlations. Thus, a correlation between
H-10 and H-4 for each isomer confirmed the trans rela-
tionship between the erythritol side chain and the C-4
substituent on the anhydrogalactitol moiety. The barrier
to inversion at the sulfonium center must be substantial
since no epimerization was observed in these or related
compounds.29;38 The target compounds 13 and 14 will be
tested for inhibition of UDP-galactopyranose mutase.
1H (NOESYTP), and H (MLEVTP) experiments using
standard Bruker pulse programs. Processing of the
spectra was performed with standard UXNMR (Bruker)
and WINNMR software. Zero filling of the acquired
data (512 t1 values and 2K data points in t2) led to a final
data matrix of 1K · 1K ðF1 ꢀ F2Þ data points. MALDI-
TOF mass spectra were obtained for samples in a 2,5-
dihydroxybenzoic acid matrix using a PerSeptive Bio-
systems Voyager-DE instrument. High-resolution mass
spectra were LSIMS (Fab), and were run on a Kratos
Concept H double-focusing mass spectrometer at 10,000
RP. Analytical thin-layer chromatography (TLC) was
performed on aluminum plates precoated with E. Merck
Silica Gel 60F-254 as the adsorbent. The developed
plates were air-dried, exposed to UV light and/or
sprayed with a solution containing 1% Ce(SO4)2 and
1.5% molybdic acid in 10% aq H2SO4, and heated.
Compounds were purified by flash column chromato-
graphy on E. Merck Kieselgel 60 (230–400 mesh). Sol-
vents were distilled before use and were dried, as
necessary, by literature procedures. Solvents were
evaporated under reduced pressure and below 50 ꢁC.
3. Experimental section
3.1. General
Melting points were determined on a Fisher–Johns
melting point apparatus and are uncorrected. Optical
rotations were measured with a Rudolph Research
1
Autopol II automatic polarimeter. H NMR and 13C
NMR spectra were recorded on a Bruker AMX-400
NMR spectrometer at 400.13 and 100.6 MHz, for pro-
ton and carbon, respectively. Chemical shifts are given
in ppm downfield from TMS for those spectra measured
in CDCl3 or CD3OD and from 2,2-dimethyl-2-silapen-
tane-5-sulfonate (DSS) for those spectra measured in
D2O. Chemical shifts and coupling constants were ob-
tained from a first-order analysis of the spectra. All
assignments were confirmed with the aid of two-
3.2. 1,4-Anhydro-2,3,5,6-tetra-O-acetyl-4-thio-
D
-galactitol 7
1,2,3,5,6-Penta-O-acetyl-4-thio-a-
D
-galactofuranose
(4.72 g, 12.0 mmol) was dissolved in CH3CN (70 mL).
TMSOTf (4.4 mL, 24.3 mmol) was added to the reaction
mixture, followed by the addition of freshly distilled
1
1
dimensional H/1H (COSYDFPT), H/13C (INVBTP),

A. Ghavami et al. / Carbohydrate Research 339 (2004) 401–407
405
Et3SiH (5.7 mL, 35.7 mmol). The reaction mixture was
kept at room temperature under nitrogen for 24 h. The
reaction mixture was then diluted with CH2Cl2 (50 mL)
and washed with water (3 · 50 mL) and satd aq
NaHCO3 (3 · 50 mL), then dried over MgSO4. The sol-
vent was removed, and the product was purified by
column chromatography (8:3 toluene–hexanes) as a
mixture was diluted with EtOAc (30 mL) and washed
with water (3 · 30 mL), dried over MgSO4, and then
concentrated. The crude material was purified by col-
umn chromatography (9:1 hexanes–EtOAc) to obtain
the title compound 9 as a syrup (1.91 g, 74%). ½aꢁ )34ꢁ
D
(c 1.1, CH2Cl2); 1H NMR (CDCl3): d 7.38–7.21 (20H, m,
Ar), 4.69 and 4.55 (2H, 2d, JA;B 11.6 Hz, CH2Ph), 4.65
and 4.41 (2H, 2d, JA;B 11.6 Hz, CH2Ph), 4.60 and 4.54
(2H, 2d, JA;B 11.9 Hz, CH2Ph), 4.18 (1H, ddd, J1b;2 7.0,
colorless syrup (2.63 g, 63%). ½aꢁ )5ꢁ (c 1.0, CHCl3); 1H
D
NMR (CDCl3): d 5.34–5.30 (2H, m, H-2, H-3), 5.28
(1H, ddd, J4;5 7.6, J5;6b 6.3, J5;6a 3.7 Hz, H-5), 4.43 (1H,
dd, J6a;6b 12.0, J5;6a 3.7 Hz, H-6a), 4.08 (1H, dd, J6a;6b
12.0, J5;6b 6.3 Hz, H-6b), 3.53 (1H, dd, J3;4 4.3, J4;5
7.6 Hz, H-4), 3.22 (1H, dd, J1a;1b 11.8, J1a;2 4.9 Hz, H-1a),
2.91 (1H, dd, J1a;1b 11.8, J1b;2 5.2 Hz, H-1b), 2.11, 2.10,
2.07, 2.05 (12H, 4s, COOCH3); 13C NMR (CDCl3): d
170.49, 170.03, 169.94, 169.59 (4COOCH3), 77.80, 77.62
(C-2, C-3), 70.80 (C-5), 63.78 (C-6), 50.23 (C-4), 32.63
(C-1), 20.86, 20.81, 20.67 (4COOCH3); MALDI-TOF
MS: m=e 371.295 (M+Na). Anal. calcd for C14H20O8S:
C, 48.27; H, 5.79. Found: C, 48.41; H, 5.79.
J1a;2 5.6, J2;3 5.8 Hz, H-2), 4.08 (1H, dd, J2;3
J3;4 ¼ 5.8 Hz, H-3), 3.81 (1H, q, J4;5 ¼ J5;6a ¼ J5;6b
¼
¼
5.4 Hz, H-5), 3.59 (1H, dd, J6a;6b 10.2, J5;6a 5.4 Hz, H-6a),
3.56 (1H, dd, J6a;6b 10.2, J5;6b 5.4 Hz, H-6b), 3.53 (1H,
dd, J3;4 5.8, J4;5 5.4 Hz, H-4), 2.99 (1H, dd, J1a;1b 10.8,
J1a;2 5.6 Hz, H-1a), 2.86 (1H, dd, J1a;1b 10.8, J1b;2 7.0 Hz,
H-1b); 13C NMR (CDCl3): d 138.40, 138.28, 138.07,
138.02 (4Cipso), 128.43–127.62 (20CAr), 85.30 (C-2),
84.36 (C-3), 78.23 (C-5), 73.40, 72.99, 72.17, 71.84
(4CH2Ph), 71.65 (C-6), 50.66 (C-4), 31.45 (C-1). Anal.
calcd for C34H36O4S: C, 75.52; H, 6.71. Found: C, 75.62;
H, 6.65.
3.3. 1,4-Anhydro-4-thio-
D
-galactitol 8
3.5. 1,4-Anhydro-2,3,5,6-tetra-O-benzyl-4-[(R)-[(2R,3R)-
2,4-benzylidenedioxy-3-(sulfooxy)butyl]sulfoniumyl-
idene]-D-galactitol inner salt 10
Compound 7 (2.58 g, 7.41 mmol) was dissolved in
MeOH (30 mL), and 1 M NaOMe (2 mL) was added.
The reaction mixture was kept at room temperature
under nitrogen overnight. Then, Rexyn-101 (Hþ) ion-
exchange resin was added to the reaction mixture until
the pH was ꢂ5. The resin was removed by filtration, and
the filtrate was dried over MgSO4, and concentrated.
Column chromatography (16:2:1 EtOAc–MeOH–H2O)
afforded pure syrupy compound, which crystallized later
3.5.1. Reaction in acetone. Compound
1.78 mmol) was dissolved in acetone (2 mL), and 2,4-O-
benzylidene-
-erythritol-1,3-cyclic sulfate 517 (580 mg,
9 (0.96 g,
D
2.13 mmol), and K2CO3 (50 mg) were added. The reac-
tion mixture was stirred at 70 ꢁC under nitrogen over-
night. The reaction mixture was then filtered and
concentrated. The crude product was purified by column
chromatography first with CH2Cl2 to elute the nonpolar
starting materials, then (19:1 CH2Cl2–MeOH) to obtain
the title compound 10 (0.86 g, 60%). The syrupy product
was crystallized and recrystallized from CH2Cl2/hex-
anes.
on storage (1.27 g, 95%), mp 71–72 ꢁC. ½aꢁ )75ꢁ (c 0.3,
D
1
H2O); H NMR (D2O): d 4.14 (1H, ddd, J1b;2 8.4, J1a;2
7.5, J2;3 6.4 Hz, H-2), 3.94–3.88 (2H, m, H-3, H-5), 3.56
(1H, dd, J6a;6b 11.8, J6a;5 4.7 Hz, H-6a), 3.50 (1H, dd,
J6a;6b 11.8, J6b;5 7.0 Hz, H-6b), 3.25 (1H, m, H-4), 2.95
(1H, dd, J1a;1b 10.8, J1a;2 7.5 Hz, H-1a), 2.68 (1H, dd,
J1a;1b 10.8, J1b;2 8.4 Hz, H-1b); 13C NMR (D2O): d 80.55
(C-3), 79.08 (C-2), 73.44 (C-5), 66.79 (C-6), 52.73 (C-4),
33.56 (C-1); MALDI-TOF MS: m=e 202.804 (M+Na).
Anal. calcd for C6H12O4S: C, 39.99; H, 6.71. Found: C,
39.95; H, 6.78.
3.5.2. Reaction in HFIP. Compound
0.37 mmol) was dissolved in HFIP (0.5 mL), and 2,4-O-
benzylidene- -erythritol 1,3-cyclic sulfate 5 (130 mg,
9 (200 mg,
D
1.2 equiv), and K2CO3 (10 mg) were added. The reaction
mixture was stirred at 70 ꢁC under nitrogen overnight.
The reaction mixture was then filtered and concentrated.
The crude product was purified by column chromato-
graphy, first with CH2Cl2 to elute the nonpolar starting
materials, then with (19:1 CH2Cl2–MeOH) to obtain the
title compound 10 (260 mg, 87%) as a white foam, mp
3.4. 1,4-Anhydro-2,3,5,6-tetra-O-benzyl-4-thio-
D
-galactitol 9
Compound 8 (0.86 g, 4.77 mmol) was dissolved in dried,
freshly distilled DMF (25 mL), the reaction flask was
cooled with an ice bath, then NaH (60% in mineral oil,
0.86 g, 21.5 mmol) was added slowly into the solution.
Benzyl bromide (2.7 mL, 22.7 mmol) was added drop-
wise into the reaction mixture. The ice bath was then
removed, and the reaction mixture was stirred at room
temperature overnight under nitrogen. The reaction
65–66 ꢁC. ½aꢁ )8ꢁ (c 1.0, CH2Cl2); 1H NMR (CDCl3): d
D
7.46–7.09 (25H, m, Ar), 5.37 (1H, s, CHPh), 4.65 (1H,
ddd, J2 ;3 ¼ J3 ;4 ax ¼ 9.7, J3 ;4 eq 5.4 Hz, H-30), 4.56–4.50
(1H, m, H-2), 4.53–4.47 (1H, m, H-40eq), 4.47–4.24 (8H,
m, CH2Ph), 4.31–4.29 (1H, m, H-3), 4.30–4.24 (1H, m,
H-10a), 4.17–4.10 (2H, m, H-20, H-4), 4.06 (1H, dd,
0
0
0
0
0
0
J1 b;1 a 13.5, J1 a;2 2.2 Hz, H-10b), 3.93 (1H, dd, J1a;1b 13.5,
0
0
0
0

406
A. Ghavami et al. / Carbohydrate Research 339 (2004) 401–407
J1b;2 1.6 Hz, H-1a), 3.75 (1H, dd, J1a;1b 13.5, J1b;2 3.8 Hz,
H-1b), 3.71–3.68 (2H, m, H-40ax, H-5), 3.37 (1H, dd,
J6a;6b 10.8, J6a;5 3.8 Hz, H-6a), 3.32 (1H, dd, J6a;6b 10.8,
J6b;5 4.3 Hz, H-6b); 13C NMR (CDCl3): d 137.06–136.02
(5Cipso), 129.17–126.56 (25CAr), 101.71 (CHPh), 83.23
(C-3), 82.59 (C-2), 76.45 (C-20), 74.47 (C-5), 73.53, 73.03,
72.23, 72.20 (4CH2Ph), 69.69 (C-4), 69.42 (C-6), 69.27
(C-40), 66.46 (C-30), 49.11 (C-10), 47.10 (C-1); MALDI-
TOF MS: m=e 813.117 (M). Anal. calcd for
C45H48O10S2: C, 66.48; H, 5.95. Found: C, 66.47; H,
5.91.
room temperature in a stainless steel pressure bomb
under 120 psi hydrogen for 3 days. The reaction mixture
was filtered through Celite, and then MeOH was used to
wash the Celite. (Caution! Extreme fire hazard.) The
solvent was evaporated and coevaporated with toluene.
The crude product was purified by column chromato-
graphy (7:3:1 EtOAc–MeOH–H2O) to give the title
compound 13 as a white foam (75 mg, 84%). ½aꢁ )19ꢁ (c
D
1
0.1, MeOH); H NMR (CD3OD): d 4.58 (1H, ddd, J1a;2
3.7, J2;3 3.2 Hz, H-2), 4.38 (1H, dd, J2;3 ¼ J3;4 ¼ 3.2 Hz,
H-3), 4.31 (1H, ddd, J2 ;3 7.6, J1 a;2 2.9 Hz, H-20), 4.27
0
0
0
0
(1H, ddd, J2 ;3 7.6, J3 ;4 a 3.4, J3 ;4 b 3.2 Hz, H-30), 4.05
0
0
0
0
0
0
3.6. 1,4-Anhydro-2,3,5,6-tetra-O-benzyl-4-[(R)-[(2S,3S)-
2,4-benzylidenedioxy-3-(sulfooxy)butyl]sulfoniumyl-
(1H, ddd, H-5), 4.02 (1H, dd, J4;5 6.9, J3;4 2.7 Hz, H-4),
3.97 (1H, dd, J1 a;1 b 13.4, J1 a;2 2.9 Hz, H-10a), 3.93 (1H,
0
0
0
0
dd, J4 a;4 b 12.2, J3 ;4 a 3.4 Hz, H-40a), 3.82 (1H, dd, J4 a;4 b
0
0
0
0
0
0
idene]-
D
-galactitol inner salt 11
12.2, J3 ;4 b 3.2 Hz, H-40b), 3.82–3.75 (2H, m, H-1a, H-
10b), 3.74 (1H, dd, J6a;6b 11.4, J5;6a 3.4 Hz, H-6a), 3.70
(1H, dd, J6a;6b 11.4, J5;6b 3.7 Hz, H-6b), 3.67 (1H, dd,
J1a;1b 13.1, J1a;2 3.7 Hz, H-1b); 13C NMR (CD3OD): d
81.10 (C-30), 79.96 (C-3), 78.47 (C-2), 73.01 (C-4), 70.66
(C-5), 68.05 (C-20), 65.45 (C-6), 61.65 (C-40), 51.75 (C-
10), 49.79 (C-1); HRMS calcd for C10H20O10S2 (M+H):
365.0576. Found: 365.0570.
0
0
3.6.1. Reaction in acetone. Compound 9 (0.496 g,
0.92 mmol) was dissolved in acetone (1 mL) and 2,4-O-
benzylidene-L
-erythritol 1,3-cyclic sulfate 617 (0.31 g,
1.13 mmol), and K2CO3 (25 mg) were added. The reac-
tion was carried out as described for the case of 10. The
title compound 11 (0.38 g, 51%) was obtained as a white
foam.
3.6.2. Reaction in HFIP. Compound
0.18 mmol) was dissolved in HFIP (1 mL), and 2,4-O-
benzylidene- -erythritol-1,3-cyclic sulfate (70 mg,
9 (100 mg,
3.8. 1,4-Anhydro-4-[(R)-[(2S,3S)-2,4-dihydroxy-3-(sulfo-
oxy)butyl]sulfoniumylidene]-D-galactitol inner salt 14
L
6
1.2 equiv), and K2CO3 (10 mg) were added. The reaction
was carried out as described for the case of 10. The title
compound 11 (132 mg, 88%) was obtained as a white
Compound 11 (130 mg, 0.16 mmol) in 80% AcOH
(5 mL) containing Pd(OH)2/C (80 mg) was treated as
described for the case of 10. The title compound 14 was
1
foam. ½aꢁ +10ꢁ (c 1.1, CH2Cl2); H NMR (CDCl3): d
D
7.36–7.05 (25H, m, Ar), 5.10 (1H, s, CHPh), 4.61 (1H,
obtained as a white foam (56 mg, 96%). ½aꢁ +48ꢁ (c 0.7,
D
dd, J4 eq;4 ax 11.0, J3 ;4 eq 5.5 Hz, H-40eq), 4.48 and 4.37
(2H, 2d, JA;B 11.8 Hz, CH2Ph), 4.45 and 4.35 (2H, 2d,
JA;B 10.7 Hz, CH2Ph), 4.45–4.34 (6H, m, CH2Ph, H-30,
H-10a, H-2, H-4), 4.28 and 4.21 (2H, 2d, JA;B 12.0 Hz,
CH2Ph), 4.23 (1H, m, H-3), 4.15 (1H, ddd,
0
0
0
0
1
MeOH); H NMR (D2O): d 4.68 (1H, ddd, J1b;2 5.0, J2;3
4.4 Hz, H-2), 4.43 (1H, dd, J2;3 ¼ J3;4 ¼ 4.4 Hz, H-3), 4.36
(1H, ddd, J1 b;2 8.8, J2 ;3 7.2, J1 a;2 3.3 Hz, H-20), 4.33
0
0
0
0
0
0
(1H, ddd, J2 ;3 7.2, J3 ;4 a 3.3 Hz, H-30), 4.17 (1H, m, H-
0
0
0
0
0
0
5), 4.10 (1H, dd, J4;5 6.6 Hz, H-4), 3.95 (1H, dd, J4 a;4 b
J1 ;2 ¼ J2 ;3 ¼ 7:9, J1 ;2 2.5 Hz, H-20), 4.11 (1H, dd, J1a;1b
0
0
0
0
0
0
12.7, J3 ;4 a 3.3 Hz, H-40a), 3.93 (1H, dd, J1 a;1 b 13.7, J1 a;2
0
0
0
0
0
0
13.4, J1a;2 2.1 Hz, H-1a), 3.73–3.64 (3H, m, H-10b, H-1b,
3.3 Hz, H-10a), 3.84 (1H, dd, J4 a;4 b 12.7 Hz, H-40b), 3.83
0
0
H-5), 3.61 (1H, dd, J4 eq;4 ax ¼ J3 ;4 ax ¼ 11.0 Hz, H-40ax),
3.31 (1H, dd, J6a;6b 10.7, J5;6a 3.8 Hz, H-6a), 3.28 (1H, dd,
J6a;6b 10.7, J5;6b 4.7 Hz, H-6b); 13C NMR (CDCl3): d
136.94, 136.46, 136.06, 135.99 (5Cipso), 129.22–126.47
(25CAr), 101.27 (CHPh), 82.57 (C-2), 82.38 (C-3), 76.75
(C-20), 74.91 (C-5), 73.41, 73.06, 72.03, 71.83 (4CH2Ph),
69.54 (C-40), 68.99 (C-6), 68.86 (C-4), 67.88 (C-30), 46.93
(C-10), 46.79 (C-1); MALDI-TOF MS: m=e 813.34 (M).
Anal. calcd for C45H48O10S2: C, 66.48; H, 5.95. Found:
C, 66.39; H, 5.87.
0
0
0
0
(1H, dd, J6a;6b 12.7 Hz, H-6a), 3.81 (1H, dd, J1a;1b
13.2 Hz, H-1a), 3.78 (1H, dd, J1 b;2 8.8 Hz, H-10b), 3.71
(1H, dd, J6a;6b 12.7 Hz, H-6b), 3.68 (1H, dd, J1a;1b
13.2 Hz, H-1b); 13C NMR (D2O): d 83.08 (C-30), 80.57
(C-3), 78.53 (C-2), 71.55 (C-4), 71.39 (C-5), 68.26 (C-20),
66.29 (C-6), 62.05 (C-40), 51.24 (C-10), 47.23 (C-1);
MALDI-TOF MS: m=e 365.02 (M+H); HRMS
calcd for C10H20O10S2 (M+H): 365.0576. Found:
365.0569.
0
0
3.7. 1,4-Anhydro-4-[(R)-[(2R,3R)-2,4-dihydroxy-3-(sulfo-
oxy)butyl]sulfoniumylidene]-
D
-galactitol inner salt 13
Supplementary Data
Compound 10 (200 mg, 0.25 mmol) was dissolved in
80% AcOH (6 mL), then Pd(OH)2/C (120 mg) was added
to the solution. The reaction mixture was stirred at
This paper contains nine pages of Supplementary
Data that can be accessed via the web version of this
paper.

A. Ghavami et al. / Carbohydrate Research 339 (2004) 401–407
407
16. Koplin, R.; Brisson, J. R.; Whitfield, C. J. Biol. Chem.
1997, 272, 4121–4128.
Acknowledgements
17. Weston, A.; Stern, R. J.; Lee, R. E.; Nassau, P. M.;
Monsey, D.; Martin, S. L.; Sherman, M. S.; Besra, G. S.;
Duncan, K.; McNeil, M. R. Tuber. Lung Dis. 1997, 78,
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18. Barlow, J. N.; Grivin, M. E.; Blanchard, J. S. J. Am.
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We are grateful to the Natural Sciences and Engineering
Research Council of Canada for financial support and
the Michael Smith Foundation for Health Research for
a trainee fellowship (to A.G.).
19. Barlow, J. N.; Blanchard, J. S. Carbohydr. Res. 2000, 328,
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