Synthesis of analogues of salacinol containing a carboxylate inner salt and their inhibitory activities against human maltase glucoamylase

Article abstract of DOI:10.1016/j.carres.2007.06.003

The syntheses of analogues of the naturally occurring glycosidase inhibitor, salacinol, containing a carboxylate inner salt are described. Salacinol is a sulfonium ion with an internal sulfate counterion. The synthetic strategy relies on the nucleophilic

Full text of DOI:10.1016/j.carres.2007.06.003

Carbohydrate Research 342 (2007) 1661–1667
Synthesis of analogues of salacinol containing a carboxylate inner
salt and their inhibitory activities against human maltase
glucoamylase
Wang Chen,a Lyann Sim,b David R. Roseb,c and B. Mario Pintoa,*
aDepartment of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6
bDivision of Cancer Genomics and Proteomics, Ontario Cancer Institute, Toronto, Canada M5G 1L7
cDepartment of Medical Biophysics, University of Toronto, Toronto, Canada M5G 1L7
Received 2 May 2007; received in revised form 2 June 2007; accepted 2 June 2007
Available online 9 June 2007
Abstract—The syntheses of analogues of the naturally occurring glycosidase inhibitor, salacinol, containing a carboxylate inner salt
are described. Salacinol is a sulfonium ion with an internal sulfate counterion. The synthetic strategy relies on the nucleophilic attack
of 1,4-anhydro-2,3,5-tri-O-benzyl-4-thio-D- or L-arabinitol at the least hindered carbon of 4,5-anhydro-2,3-O-isopropylidene-D-
ribonic acid benzyl ester to yield coupled adducts. Deprotection of the coupled products gives the target compounds. The compound
derived from D-arabinitol inhibits recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the
breakdown of glucose oligosaccharides in the small intestine, with a Ki value of 10 1 lM.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Glycosidase inhibitors; Salacinol analogues; Carboxylate counterion; Thioarabinitol; Epoxide opening; Human maltase glucoamylase
1. Introduction
traditionally used in the Ayurvedic system of India
and Sri Lanka for the treatment of diabetes.6 The sulfo-
nium ion structure of these compounds has stimulated
different groups to carry out the synthesis of salacinol,7,8
and other carbohydrate-based cyclic sulfonium com-
pounds,9–15 such as 311 and 4 (Fig. 2),12 as a new class
of glycosidase inhibitors. Our group has reported hete-
roanalogues of salacinol having nitrogen16 or selenium17
instead of sulfur, namely ghavamiol 5 and blintol 6
(Fig. 2), respectively. We reasoned that the interaction
of a permanent positive charge with active site carboxyl-
ate residues would make a dominant contribution to the
interaction energy.
The structure of salacinol is unique in that the ring
sulfonium ion is stabilized by an internal sulfate coun-
terion.3a Structural modification of salacinol represents
a promising approach in the search for new glycosidase
inhibitors. The fact that salacinol has greater inhibitory
activity and specificity against a-glucosidases than the
methyl sulfonium ion (3) indicates that the hydroxyl
groups on the acyclic chain and/or the sulfate group
Glycosidases are fundamentally involved in the control
of several important biological phenomena such as the
breakdown of oligosaccharides, cell–cell adhesion, cell
growth, inflammatory processes, fertilization, and bac-
terial, viral and parasitic infections.1 Because glycoside
cleavage is a biologically widespread process, glycosi-
dase inhibitors have many potential applications. The
transition-state structure in the enzyme-mediated hydro-
lysis of glycosides is believed to be the oxacarbenium ion
with a distorted conformation. Thus, mimicking this dis-
torted, positively charged species is one factor that could
lead to a strong inhibitor of glycosidase enzymes.2
The a-glucosidase inhibitors salacinol 1 and kotalanol
2 (Fig. 1) have been isolated from Salacia reticulata
WIGHT,3,4 and Salacia oblonga and Salacia chinensis,5
*
Corresponding author. Tel.: +1 604 291 4152; fax: +1 604 291
4860; e-mail: bpinto@sfu.ca
0008-6215/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2007.06.003

1662
W. Chen et al. / Carbohydrate Research 342 (2007) 1661–1667
In addition, this compound was also active against D.
OH
OH
OH
OH
OH
melanogaster Golgi mannosidase II (dGMII), with an
IC50 of 0.3 mM.22 We now report a synthetic route to
the corresponding sulfonium ion-inner carboxylates
8 and 9. These compounds also serve as the first repre-
sentatives of a new class of hitherto undescribed
molecules.
OH
OH
S
OSO3 OH
S
OSO3
HO
HO
HO
OH
HO
1
2
Figure 1. Structures of salacinol 1 and kotalanol 2.
2. Results and discussion
Retrosynthetic analysis indicated that the carboxylate
analogues A of salacinol could be obtained by alkylation
of thioarabinitols B at the sulfur atom (Scheme 1). The
alkylating agent could be epoxide C, whereby regioselec-
tive attack of the sulfur at the least hindered primary
center should afford the desired sulfonium ions.23 Epox-
ide C could be synthesized, in turn, from D-ribonolac-
tone D.
CF3SO3
OH
S
I
S
HO
OH
HO
OH
3
4
OH
OH
Thioarabinitol 12 was synthesized from D-xylose fol-
lowing the same strategy that was used by Satoh et al.
(Scheme 2).24 Thus, treatment of diol 10 with metha-
nesulfonyl chloride in pyridine afforded dimesylate 11
in 88% yield. Treatment of 11 with sodium sulfide in
DMF produced compound 12 in 95% yield. Starting
from L-xylose, enantiomer 1525 was synthesized in an
analogous fashion.
OH
OH
NH
OSO3
Se
OSO3
HO
HO
HO
OH
HO
OH
5
6
Figure 2. Structures of the cyclic sulfonium compounds 3 and 4,
ghavamiol 5, and blintol 6.
With 12 in hand, we turned our attention to the syn-
thesis of epoxide 19. D-Ribonolactone 16 was converted
to 2,3-O-isopropylidene-D-ribonolactone 1726 that was
then tosylated to give compound 18 in 88% yield
(Scheme 3). Treatment of 18 with sodium benzylate
afforded the desired epoxide 1927 in 86% yield.
are advantageous.18 Yuasa et al.19 reported that docking
of salacinol into the binding site of glucoamylase indi-
cated close contacts between the sulfate ion with
Arg305. Crystallographic analysis of the interactions
of Drosophila melanogaster Golgi a-mannosidase II with
salacinol and its analogues also shows that the sulfate
group does interact with residues in the enzyme active
site.20 However, a recent study reported that compounds
lacking the sulfate group are also active.21
An intriguing question is whether the corresponding
carboxylate analogues of salacinol will act as inhibitors
of glucosidases. We have recently described a novel class
of amino acids patterned after salacinol 1 that consist of
an iminoarabinitol alkylated with a polyhydroxylated
chain containing a carboxylate residue 7 (Fig. 3).22 This
compound was found to be an inhibitor of recombinant
human maltase glucoamylase, with a Ki value of 21 lM.
The coupling reaction was examined next. Regioselec-
tive ring opening of epoxide 19 by the nucleophilic at-
tack of the sulfur atom in thioether 12 occurred
rapidly in a mixture of CF3COOH and CH2Cl2 to give
20 in 58% yield. The unreacted starting materials were
recovered, and no other polar spot was observed on
TLC. Even after purification of compound 20 by flash
1
chromatography, the H and 13C NMR spectra showed
some extra peaks which could not be ascribed to the dia-
stereomer. We concluded that these peaks resulted either
from an inseparable impurity or by the presence of a
similar compound with another external negative coun-
terion. The compound was therefore processed as fol-
OH OH
OH OH
OH OH
O
O
CO2H
Cl
O
OH
O
OH
S
S
OH OH
NH
HO
HO
HO
HO
HO
OH
OH
HO
OH
7
8
9
Figure 3. Structures of compounds 7, 8, and 9.

W. Chen et al. / Carbohydrate Research 342 (2007) 1661–1667
1663
OH OH
CO2
BnO
OH
O
O
S
OH
O
S
O
HO
OBn
BnO
OBn
PGO
OPG
HO
HO
OH
OH
(A)
(B)
(D)
(C)
Scheme 1.
OH
OMs
S
OH
OMs
BnO
BnO
BnO
BnO
BnO
BnO
4 steps
MsCl
Na2S
DMF
D-xylose
L-xylose
Pyridine
BnO
BnO
BnO
BnO
OBn
OBn
BnO
OBn
10
11
12
OH
OMs
S
OH
OMs
4 steps
MsCl
Na2S
DMF
Pyridine
OBn
OBn
BnO
OBn
13
14
15
Scheme 2.
OH
OTs
OH
O
O
O
O
O
O
O
O
NaOBn
OBn
Actone
TsCl
Et3N/CH2Cl2
DMF
Conc.H2SO4
O
O
O
O
O
HO
O
OH
16
17
18
19
Scheme 3.
lows for the purpose of characterization. Counterion ex-
change and deprotection of the hydroxyl groups on the
side chain were achieved in a mixture of concentrated
hydrochloric acid and methanol, the resulting com-
pound 21 being purified by flash chromatography.
Hydrogenolysis of the coupled compound 21 over Pd–
C catalyst did not go as planned to give compound 8
(Scheme 4) because of poisoning of the catalyst. Debenz-
ylation of the protected compound 21 was therefore
accomplished by treatment with boron trichloride14 in
CH2Cl2, affording 8 in 50% yield. No other product
was obtained. The stereochemistry at the sulfur atom
was determined by means of a 1D-NOE experiment.
Compound 9, the diastereomer of 8, was similarly
obtained by reaction of thioether 15 with epoxide 19
to produce the protected compound 22 in 66% yield
(Scheme 5). Unreacted starting materials were recov-
ered, and no other polar spot was observed on TLC.
mined by means of a 1D-NOE experiment. Treatment of
23 with boron trichloride in CH2Cl2 afforded 9 in 52%
yield. No other product was obtained.
OH
O
O
OBn
O
R
S
S
O
O
OBn
CF3CO2H/CH2Cl2
BnO
BnO
+
O
O
BnO
BnO
OBn
OBn
20
12
19
Conc.HCl/MeOH
OH OH
OH OH
O
OBn
Cl
H2, Pd/C
O
O
OH
OH
S
S
1
As with compound 20, the H and 13C NMR spectra
HO
BnO
BCl3/CH2Cl2
showed that no diastereomer had been formed. Coun-
terion exchange and deprotection of the hydroxyl
groups on the side chain gave compound 23 in 75%
yield. The stereochemistry at the sulfur atom was deter-
HO
BnO
OH
OBn
21
8
Scheme 4.

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W. Chen et al. / Carbohydrate Research 342 (2007) 1661–1667
cessing of the spectra was performed with standard
OH
O
UXNMR and WINNMR software (Bruker) or MESTREC
software (Varian). MALDI mass spectra were obtained
on a PerSeptive Biosystems, Voyager DE time-of-flight
spectrometer for samples dispersed in a 2,5-dihydroxy-
benzoic acid matrix. High resolution mass spectra
were obtained by the electrospray ionization (ESI)
technique, using a TOF mass spectrometer at 10,000
RP.
O
OBn
O
R
S
S
O
O
OBn
BnO
BnO
+
CF3CO2H/CH2Cl2
O
O
BnO
BnO
OBn
OBn
22
15
19
Conc.HCl/MeOH
OH OH
OH OH
3.2. Enzyme activity assay
O
OBn
Cl
H2, Pd/C
O
O
OH
OH
S
S
Analysis of MGA inhibition was performed using malt-
ose as the substrate, and measuring the release of glu-
cose. Reactions were carried out in 100 mM MES
buffer, pH 6.5, at 37 °C for 15 min. The reaction was
stopped by boiling for 3 min. Aliquots (20 lL) were
taken and added to 100 lL of glucose oxidase assay
reagent (Sigma) in a 96-well plate. Reactions were
developed for 1 h and absorbance was measured at
450 nm to determine the amount of glucose produced
by MGA activity in the reaction. One unit of activity
is defined as the hydrolysis of 1 mol of maltose per min-
ute. All reactions were performed in triplicate and
absorbance measurements were averaged to give a final
result.
HO
BnO
BCl3/CH2Cl2
HO
BnO
23
OH
OBn
9
Scheme 5.
Finally, we comment on the inhibitory activities of the
compounds synthesized in this study against recombi-
nant human maltase glucoamylase (MGA), a critical
intestinal glucosidase involved in the processing of
oligosaccharides of glucose into glucose itself. Only
compound 9, with the D-arabinitol configuration in the
heterocyclic ring displayed by salacinol, was active, with
a Ki value of 10 1 lM. Salacinol itself has a Ki value of
0.19 0.02 lM.28
3.3. Enzyme kinetics
Kinetic parameters of recombinant MGA were deter-
mined using the glucose oxidase assay to follow the pro-
duction of glucose upon addition of enzyme (15 nM) at
increasing maltose concentrations (1–3.5 mM) with a
reaction time of 15 min. The program GRAFIT 4.0.14
was used to fit the data to the Michaelis–Menten equa-
3. Experimental
3.1. General
Optical rotations were measured at 23 °C on an Auto-
pol II automatic polarimeter. Analytical thin-layer
chromatography (TLC) was performed on aluminum
plates precoated with Merck Silica Gel 60F-254 as
the adsorbent. The developed plates were air-dried, ex-
posed to UV light, and/or sprayed with a solution con-
taining 1% Ce(SO4)2 and 1.5% molybdic acid in 10%
aq H2SO4, and heated. Compounds were purified by
flash chromatography on Kieselgel 60 (230–400 mesh).
1H and 13C NMR spectra were recorded on the follow-
ing: Bruker AMX-400 NMR spectrometer at
400.13 MHz, Bruker AMX-600 NMR spectrometer at
600.13 MHz, and Varian INOVA 500 NMR spectro-
meter at 499.97 MHz. Chemical shifts are given in ppm
downfield from TMS for those spectra measured in
CDCl3 and 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.
Assignments were fully supported by two-dimensional
1H,1H (COSY), and 1H,13C (HMQC) experiments
using standard Bruker or Varian pulse programs. Pro-
tion and estimate the kinetic parameters, Km and Vmax
,
of the enzyme. Ki values for each inhibitor were deter-
mined by measuring the rate of maltose hydrolysis by
MGA at varying inhibitor concentrations. Data were
plotted in Lineweaver–Burk plots (1/rate vs 1/[sub-
strate]), and Ki values were determined by the equation
Ki = Km[I]/(Vmax)m ꢀ Km, where ‘m’ is the slope of the
line. The Ki reported was estimated by averaging the
Ki values obtained from each of the different inhibitor
concentrations.
3.4. 2,3-O-Isopropylidene-D-ribonolactone (17)26
To a suspension of D-ribonolactone 16 (10 g, 68 mmol)
in acetone (200 mL) was added concentrated sulfuric
acid (4 mL) dropwise while the solution was cooled in
an ice bath. The starting material dissolved in 5 min.
The mixture was stirred for 12 h at room temperature.
Ammonia gas was passed through the ice-cooled
solution. The resulting white solid was filtered and the

W. Chen et al. / Carbohydrate Research 342 (2007) 1661–1667
1665
filtrate was concentrated under reduced pressure. The
crude product was purified by column chromatography
(1:3 hexanes–EtOAc) to afford 17 as a white solid
(10.6 g, 80%): mp 134–137 °C; lit.26 mp 135–138 °C.
TOF MS: m/z 699.42 (Mz). Without further purification,
compound 20 (190 mg, 0.27 mmol) was dissolved in a
mixture of concentrated HCl (1 mL) and methanol
(40 mL). The mixture was stirred at room temperature
for 6 h. The solvent was removed under reduced pres-
sure and column chromatography (8:1 CH2Cl2–MeOH)
of the crude product gave 21 as a colorless oil (128 mg,
3.5. 2,3-O-Isopropylidene-5-O-p-toluenesulfonyl-D-ribono-
lactone (18)27
1
71%). [a]D +20 (c 1.0, CH2Cl2). H NMR (CD2Cl2): d
7.43–7.35 (20H, m, Ar), 5.07 (2H, 2d, JA,B = 11.1 Hz,
CO2CH2Ph), 4.51–4.31 (6H, m, 3OCH2Ph), 4.49 (1H,
m, H-20), 4.45 (1H, m, H-2), 4.42 (1H, m, H-4), 4.21
(1H, m, H-30), 4.18 (1H, m, H-40), 4.13 (1H, m, H-
10b), 4.07 (1H, m, H-3), 4.06 (1H, m, H-1b), 3.96 (1H,
m, H-10a), 3.32 (1H, br, H-1a), 3.28 (1H, m, H-50b),
3.23 (1H, m, H-50a); 13C NMR (CD2Cl2): d 173.54 (C-
5), 139.13, 138.39, 138.35, 137.84 (4Cipso), 130.57–
129.52 (20CAr), 84.88 (C-30), 84.82 (C-20), 77.12 (C-3),
75.34, 74.11, 73.87 (3OCH2Ph), 75.06 (C-4), 69.06 (C-
50), 68.89 (C-2), 68.58 (CO2CH2Ph), 67.04 (C-40), 53.74
(C-1), 49.57 (C-10). MALDI-TOF MS: m/z 659.20
(M+). Anal. Calcd for C38H43ClO8S: C, 65.65; H, 6.23.
Found: C, 65.62; H, 6.40.
To a solution of compound 17 (1.0 g, 5.3 mmol) in
CH2Cl2 (25 mL) was added Et3N (0.59 g, 1.1 equiv).
After 5 min, tosyl chloride (1.2 g, 1.2 equiv) was added
in portions at 0 °C and the resulting mixture was stirred
at room temperature for 16 h. The reaction mixture was
poured into water (40 mL) and CH2Cl2 (30 mL). The or-
ganic phase was dried (Na2SO4) and concentrated on a
rotary evaporator. The product was purified by flash
chromatography (3:1 hexanes–EtOAc) to afford 18 as
1
a white solid (1.6 g, 88%). H NMR (CDCl3): d 7.77–
7.37 (4 H, 2d, JA,B = 8.2 Hz, Ar), 4.77 (1H, d,
J2,3 = 5.6 Hz, H-2), 4.75 (1H, d, H-3), 4.68 (1H, dd,
H-4), 4.34 (1H, dd, J4,5b = 1.9 Hz, J5a,5b = 11.2 Hz, H-
5b), 4.18 (1H, dd, J4,5a = 2.5 Hz, H-5a), 2.47 (3H, s,
CH3Ph), 1.46 and 1.39 (6H, 2s, C(CH3)2).
3.8. 5-(1,4-Dideoxy-1,4-episulfoniumylidene-L-arabini-
tol)-5-deoxy-D-ribonate inner salt (8)
3.6. 4,5-Anhydro-2,3-O-isopropylidene-D-ribonic acid
benzyl ester (19)27
Compound 21 (100 mg, 0.14 mmol) was dissolved in
CH2Cl2 (5 mL). BCl3 was passed through the solution
for 2 min at ꢀ78 °C. The solution was stirred at
ꢀ78 °C for 1 h. Air was passed through the reaction
flask until no white gas formed. H2O was added slowly
to quench the reaction. The resulting mixture was con-
centrated under reduced pressure. Column chromato-
graphy (7:3:1 EtOAc–MeOH–H2O and then pure
H2O) of the crude product gave 8 as a colorless oil
A solution of sodium benzylate prepared from benzyl
alcohol (0.71 g, 6.57 mmol) and NaH (60 mg, 1.5 mmol)
in DMF (7.1 mL) was added to compound 18 (0.5 g,
1.46 mmol) in DMF (1.1 mL) at 0 °C. The reaction mix-
ture was stirred for 1 h and the solvent was removed
under high vacuum. The white solid was filtered and
the filtrate was concentrated. The crude product was
purified by column chromatography (5:1 hexanes–
EtOAc) to afford 19 as a colorless oil (350 mg, 86%).
1H NMR (CD2Cl2): d 7.42–7.37 (5H, m, Ar), 5.22 and
5.17 (2H, 2d, JA,B = 12.1 Hz, CH2Ph), 4.80 (1H, d,
J2,3 = 6.9Hz, H-2), 4.11 (1H, dd, H-3), 2.93 (1H, ddd,
J3,4 = 6.19 Hz, J4,5a = 3.9 Hz, J4,5b = 2.6 Hz, H-4),
2.64 (1H, dd, J5a,5b = 5.2 Hz, H-5b), 2.61 (1H, dd, H-
5a), 1.58 and 1.39 (6H, 2s, C(CH3)2).
1
(21 mg, 50%). [a]D +29 (c 0.2, H2O). H NMR (D2O):
d 4.68 (1H, dt, J1 ;2 ¼ 3:7 Hz, H-20), 4.40 (1H, t,
0
0
J2 ;3 ¼ J3 ;4 ¼ 3:3 Hz, H-30), 4.22 (1H, b, H-2), 4.14
0
0
0
0
(1H, d, J3,4 = 2.7 Hz, H-4), 4.08 (1H, ddd, H-40), 4.03
(1H, dd, J4 ;5 b ¼ 5:2 Hz, J5 a;5 b ¼ 12:3 Hz, H-50b), 3.95
0
0
0
0
(1H, b, H-3), 3.91 (1H, dd, J4 ;5 a ¼ 8:1 Hz, H-50a),
3.82 (2H, m, H-1), 3.78 (2H, d, H-10); 13C NMR
(D2O): d 179.81 (C-5), 79.87 (C-30), 79.01 (C-20), 76.89
(C-3), 75.55 (C-4), 71.99 (C-40), 69.55 (C-2), 61.38
(C-50), 51.80 (C-1), 49.17 (C-10). MALDI-TOF MS: m/z
321.35 (M++Na), 299.48 (M++H). HRMS: (M+H)
calcd for C10H19O8S, 299.0801; found, 299.0801.
0
0
3.7. Benzyl-5-(2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-epi-
sulfoniumylidene-L-arabinitol)-5-deoxy-D-ribonate
chloride (21)
A mixture of compound 19 (130 mg, 0.47 mmol) and
compound 12 (196 mg, 1.0 equiv) was dissolved in dry
CH2Cl2 (2 mL) and CF3CO2H (53 mg, 1.0 equiv) was
added. The mixture was stirred at room temperature
for 3 h. The solvent was removed under reduced pres-
sure, and column chromatography (EtOAc–MeOH–
H2O, 40:1:1) of the crude product gave 20 as a colorless
oil that was reacted as follows (190 mg, 58%). MALDI-
3.9. Benzyl-5-(2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-epi-
sulfoniumylidene-D-arabinitol)-5-deoxy-D-ribonate
triflate (23)
A mixture of compound 19 (277 mg, 1 mmol) and com-
pound 15 (417 mg, 1.0 equiv) was dissolved in dry
CH2Cl2 (2 mL) and CF3CO2H (113 mg, 1.0 equiv) was

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W. Chen et al. / Carbohydrate Research 342 (2007) 1661–1667
added. The mixture was stirred at room temperature for
3 h and the solvent was removed under reduced pres-
sure. Column chromatography (EtOAc–MeOH–H2O
40:1:1) of the crude product gave 22 as a colorless oil
(460 mg, 66%; MALDI-TOF MS: m/z 699.46 M+) that
was reacted as follows. Without further purification,
compound 22 (200 mg, 0.23 mmol) was dissolved in a
mixture of concentrated HCl (1 mL) and methanol
(40 mL). The mixture was stirred at rt for 6 h. The sol-
vent was removed under reduced pressure. The resulting
chloride salt was stirred with silver triflate (117 mg, 2.0
equiv) in CH2Cl2 (2 mL) for 1 h. The mixture was con-
centrated and column chromatography (8:1 CH2Cl2–
MeOH) of the crude product gave 23 as a colorless oil
(142 mg, 75%). [a]D +15 (c 0.9, CH2Cl2). 1H NMR
(CD3OD): d 7.40–7.20 (20H, m, Ar), 5.17 (2H, s,
CO2CH2Ph), 4.67–4.44 (6H, m, 3OCH2Ph), 4.63 (1H,
d, H-20), 4.43 (1H, s, H-30), 4.35 (1H, d, J3,4 = 3.5 Hz,
51.50 (C-1), 49.66 (C-10). HRMS: (M+H) calcd for
C10H19O8S, 299.0801; found, 299.0795.
Acknowledgments
We are grateful to Blair D. Johnston for helpful discus-
sions and to the Canadian Institutes of Health Research
for financial support.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.carres.
2007.06.003.
References
0
0
0
0
H-4), 4.30 (1H, dd, J4 ;5 b ¼ 6:7 Hz, J4 ;5 a ¼ 9:6 Hz,
H-40), 4.24 (1H, ddd, J1a,2 = 7.2 Hz, J1b,2 = 3.4 Hz,
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H-2), 4.02 (1H, d, J1 a;1 b ¼ 13:1 Hz, H-10b), 3.96 (1H,
dd, J2,3 = 6.3 Hz, H-3), 3.84 (1H, dd, J1a,1b = 13.0 Hz,
H-1b), 3.80 (1H, dd, H-50b), 3.79 (1H, dd,
0
0
J1 a;2 ¼ 3:1 Hz, H-10a), 3.73 (1H, dd, H-1a), 3.70 (1H,
0
0
dd, J5 a;5 b ¼ 10:0 Hz, H-50a); 13C NMR (CD3OD): d
173.40 (C-5), 138.56–138.02 (4Cipso), 129.98–129.19
(20CAr), 84.45 (C-20), 84.11 (C-30), 76.30 (C-3), 74.46
(C-4), 73.68, 73.31, 73.15 (3OCH2Ph), 68.55 (C-2),
68.02 (C-50), 67.88 (CO2CH2Ph), 67.66 (C-40), 51.84
(C-1), 49.81 (C-10). MALDI-TOF MS: m/z 659.25
(M+). Anal. Calcd for C39H43F3O11S2: C, 57.91; H,
5.36. Found: C, 57.55; H, 5.49.
0
0
3.10. 5-(1,4-Dideoxy-1,4-episulfoniumylidene-D-arabini-
tol)-5-deoxy-D-ribonate inner salt (9)
Compound 23 (150 mg, 0.21 mmol) was dissolved in
CH2Cl2 (10 mL). BCl3 was passed through the solution
for 2 min at ꢀ78 °C. The solution was stirred at
ꢀ78 °C for 1 h. Air was passed through the reaction
flask until no white gas formed. H2O was added slowly
to quench the reaction. The resulting mixture was con-
centrated under reduced pressure. Column chromato-
graphy (7:3:1 EtOAc–MeOH–H2O and then pure
H2O) of the crude product gave 9 as a colorless oil
1
(33 mg, 52%). [a]D ꢀ12 (c 0.6, H2O). H NMR (D2O):
d 4.57 (1H, dt, J1 ;2 ¼ 3:8 Hz, H-20), 4.26 (1H, dd,
0
0
J2 ;3 ¼ 3:5 Hz, H-30), 4.09 (1H, ddd, J1a,2 = 8.8 Hz,
0
0
J1b,2 = 3.1 Hz, J2,3 = 5.5 Hz, H-2), 4.01 (1H, d,
0
0
J3,4 = 3.7 Hz, H-4), 3.96 (1H, dd, J4 ;5 b ¼ 4:7 Hz,
J5 a;5 b ¼ 12:1 Hz, H-50b), 3.89 (1H, ddd, J3 ;4 ¼ 3:2 Hz,
0
0
0
0
J4 ;5 a ¼ 8:1 Hz, H-40), 3.86 (1H, dd, H-3), 3.77 (1H, m,
H-50a), 3.75 (1H, dd, J1a,1b = 13.4 Hz, H-1b), 3.72
(2H, d, H-10), 3.64 (1H, dd, H-1a); 13C NMR (D2O): d
179.47 (C-5), 79.35 (C-30), 78.65 (C-20), 76.56 (C-3),
75.14 (C-4), 71.50 (C-40), 69.14 (C-2), 61.02 (C-50),
0
0

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