Synthesis of D-lyxitol and D-ribitol analogues of the naturally occurring glycosidase inhibitor salacinol

Article abstract of DOI:10.1016/j.carres.2005.09.004

The synthesis of analogues of the naturally occurring glycosidase inhibitor, salacinol, in which the d-arabinitol ring has been replaced by d-lyxitol or d-ribitol, is described. Salacinol is one of the active principles in the aqueous extracts of Salacia reticulata, which are traditionally used in India and Sri Lanka for the treatment of Type II diabetes. The synthetic strategy relies on the nucleophilic attack of 1,4-anhydro-2,3,5-tri-O-p- methoxybenzyl-4-thio-d-lyxitol or 1,4-anhydro-2,3,5-tri-O-p-methoxybenzyl-4- thio-d-ribitol at the least hindered carbon of the benzylidene-protected l-cyclic sulfate derived from l-erythritol. Screening of these compounds against recombinant human maltase glucoamylase (MGA), a critical intestinal glucosidase involved in the processing of oligosaccharides of glucose into glucose itself, shows that they are not effective inhibitors of MGA and demonstrates the importance of the d-arabinitol configuration in the heterocyclic ring for effective inhibition.

Full text of DOI:10.1016/j.carres.2005.09.004

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 2612–2619
Synthesis of D-lyxitol and D-ribitol analogues of the
naturally occurring glycosidase inhibitor salacinol
Nag S. Kumar and B. Mario Pinto*
Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6
Received 2 August 2005; received in revised form 4 September 2005; accepted 5 September 2005
Available online 29 September 2005
Abstract—The synthesis of analogues of the naturally occurring glycosidase inhibitor, salacinol, in which the D-arabinitol ring has
been replaced by D-lyxitol or D-ribitol, is described. Salacinol is one of the active principles in the aqueous extracts of Salacia reti-
culata, which are traditionally used in India and Sri Lanka for the treatment of Type II diabetes. The synthetic strategy relies on the
nucleophilic attack of 1,4-anhydro-2,3,5-tri-O-p-methoxybenzyl-4-thio-D-lyxitol or 1,4-anhydro-2,3,5-tri-O-p-methoxybenzyl-4-
thio-D-ribitol at the least hindered carbon of the benzylidene-protected L-cyclic sulfate derived from L-erythritol. Screening of these
compounds against recombinant human maltase glucoamylase (MGA), a critical intestinal glucosidase involved in the processing of
oligosaccharides of glucose into glucose itself, shows that they are not effective inhibitors of MGA and demonstrates the importance
of the D-arabinitol configuration in the heterocyclic ring for effective inhibition.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Keywords: Glycosidase inhibitors, Salacinol analogues; Synthesis; Sulfonium salts
1. Introduction
with swainsonine (1) has led to a significant reduction
of tumor mass in human patients suffering from breast,
liver, lung cancer, and other malignancies.5,6 The bridge-
head nitrogen atom of swainsonine (1) is known to be
protonated at physiological pH and it is believed
that this provides stabilizing electrostatic interactions
between the inhibitor and a carboxylate residue in the
enzyme active site.7
Modification of cell surface oligosaccharides can lead to
disease states such as diabetes and cancer.1–3 This sug-
gests that the oligosaccharides play important roles in
multi-cellular systems and that inhibition of the glycosi-
dase enzymes involved in oligosaccharide processing on
glycoproteins might lead to therapeutic strategies. For
example, swainsonine (1), a plant derived alkaloid, is a
good inhibitor of Golgi a-mannosidase II.4 Treatment
Recently, Yoshikawa et al.8,9 described a new class of
a naturally occurring glycosidase inhibitor, salacinol (2),
OH
HO
HO
OH
H3C
HO
O
OH
OSO3
OH
O
HN
HO
OH
OH
S
HO
N
OH
O
O
HO
HO
OH
HO
O
HO
OH
HO
OH
HO
1
2
3
*
Corresponding author. Tel.: +1 604 291 4152; fax: +1 604 291 4860; e-mail: bpinto@sfu.ca
0008-6215/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2005.09.004

N. S. Kumar, B. M. Pinto / Carbohydrate Research 340 (2005) 2612–2619
2613
isolated from Salacia reticulata Wight (known as
kothalahimbutu in Singhalese), a plant used in Ayur-
vedic medicine for the treatment of Type II diabetes
mellitus. The structure of salacinol (2) possesses an
unusual zwitterion consisting of a sulfonium ion with
an internal sulfate counterion. The 1,4-anhydro-4-thio-
D-arabinitol moiety with the permanent positive charge
at the sulfur atom is postulated to bind to glycosidase
enzymes by mimicry of the shape and charge of the oxa-
carbenium-ion intermediate in the glycosidase-mediated
hydrolysis reaction. The inhibitory activities of salacinol
(2) against sucrase and maltase are nearly equivalent to
acarbose (3), which is clinically used for the treatment of
diabetes. However, the inhibitory activity of salacinol
(2) against isomaltase is greater than that of acarbose
(3).9 We10,11 and others12 have reported the synthesis
of salacinol (2), and we have also reported the synthesis
and glycosidase inhibitory properties of the heteroatom
congeners of salacinol (2) in which the ring sulfur atom
is replaced by nitrogen13 and selenium,14,15 and ana-
logues in which the stereochemistry of the heteroalditol
ring was changed from D-arabinitol to D-xylitol.16
We now report the total synthesis of the correspond-
ing analogues in which the heteroalditol ring is D-lyxitol
(4) and D-ribitol (5), and in which the stereochemistry at
C-3 and C-2, respectively, is inverted. These compounds
were required for the study of structure–activity rela-
tionships with glycosidase enzymes.
1,4-anhydro-2,3,5-tri-O-p-methoxybenzyl-4-thio-D-lyxi-
tol (6) and 1,4-anhydro-2,3,5-tri-O-p-methoxybenzyl-4-
thio-D-ribitol (7) with 2,4-O-benzylidene-L-erythritol-
1,3-cyclic sulfate (8), previously synthesized in our
laboratory,10,11 should afford compounds 4 and 5,
respectively.
The required compound 6 was prepared from com-
mercially available D-lyxose as shown in Scheme 2.
The starting material, 2,3,5-tri-O-benzyl-D-lyxofurano-
side (9), was prepared in three steps starting from D-lyx-
ose, as described by Postema et al.17 Reduction of 9 with
sodium borohydride afforded the diol 10 in 91% yield.
Selective protection of the primary hydroxyl group
using tert-butyldimethylsilylchloride gave 11 in 93%
yield. The D-lyxitol derivative 11 was converted to the
L-ribitol derivative 12 by a Mitsunobu reaction using
p-nitrobenzoic acid. Deprotection of the p-nitrobenzoyl
and tert-butyldimethylsilyl groups using sodium meth-
oxide and tetrabutylammonium fluoride, respectively,
gave the diol 13. Although the preparation of 13 from
L-ribose was reported by Elie et al.,18 the method was
not practical for large scale synthesis because L-ribose
is very expensive. Hence, we started with less expensive
D-lyxose to synthesize 13 by inverting the configuration
at C-4 using a Mitsunobu reaction. Compound 13 was
converted to the dimesylate using methanesulfonyl chlo-
ride in pyridine and the dimesylate was treated with
sodium sulfide to give 14 in 87% yield. To eliminate the
problematic hydrogenolysis step of removing the benzyl
ether groups after the coupling reaction between benzyl-
protected thio-D-lyxitol and 8, we decided to use p-meth-
oxybenzyl (PMB) protecting groups. The acid-sensitive
PMB group is a suitable choice because the benzylidene
group from the L-cyclic sulfate is also acid labile and
both could be cleaved in one pot by acid hydrolysis after
the coupling reaction between 8 and 6.11 Hence, the ben-
zyl protecting group was cleaved using Birch reduction
to give the triol 15 in 86% yield. Reprotection of triol
15 with PMB groups afforded the required compound
6 in 94% yield.
OH
OH
3'
4'
1' 2'
OH
OSO3
OH
OSO3
5
S
S
1
4
HO
HO
3
2
HO
OH
HO
OH
4
5
2. Results and discussion
The target compounds 4 and 5 could be synthesized by
alkylating the anhydro-alditol derivatives at the ring sul-
fur atom (Scheme 1). This route was chosen to provide
flexibility in synthesizing compounds having different
configurations of the sugar rings. The alkylation of
The required compound 7 was synthesized from com-
mercially available D-ribose (Scheme 3). Methyl 2,3,5-
tri-O-benzyl-D-ribofuranoside (16) was prepared in two
steps starting from D-ribose, as described by Barker and
Fletcher.19 With 16 in hand, 1,4-anhydro-4-thio-D-ribitol
OH
OH
O
S
S
S
OSO3
PO
O
+
O
HO
O
O
Ph
O
PO
OP
HO
OH
P = Protecting group
8
Scheme 1.

2614
N. S. Kumar, B. M. Pinto / Carbohydrate Research 340 (2005) 2612–2619
O
OH
3 steps
Ref. 13
NaBH4 / EtOH
OH
OBn
OH
OBn
BnO
BnO
D-Lyxose
BnO
BnO
10
9
TBDMSCl /
imidazole /
DMF
OBn
OH
p-NO2BzO
p-NO2BzOH / PPh3
DIAD / THF
OTBDMS
OBn
OTBDMS
OBn
BnO
BnO
BnO
11
12
1) NaOMe / MeOH
2) TBAF / THF
OBn
S
1) MsCl / pyr.
HO
OH
OBn
BnO
2) Na2S.9H2O / DMF
BnO
OBn
BnO
14
13
Li / NH3
-78 oC
S
S
NaH / DMF
PMBCl
PMBO
HO
PMBO
OPMB
HO
OH
6
15
Scheme 2.
O
S
S
2 steps
Ref. 19
OMe 9 steps
Ref. 20
OBn
NaH / DMF
PMBCl
BnO
HO
PMBO
PMBO
D-Ribose
BnO
HO
OH
OPMB
17
7
16
Scheme 3.
(17) was prepared in nine steps as described by Naka
et al.20 PMB protection of 17 afforded the desired com-
pound 7 in 91% yield. Although the synthesis of 7 was
reported earlier by Minakawa et al.,21 we employed an
alternative route (Scheme 3) similar to that described
above for the preparation of 6.
We next turned our attention to the coupling reaction.
Thus, compound 18 was prepared by alkylation of
PMB-protected anhydro-4-thio-D-lyxitol 6 with the benz-
ylidene-protected L-cyclic sulfate 8 in 1,1,1,3,3,3-hexa-
fluoro-2-propanol (HFIP) containing K2CO3 at 70 ꢁC
in 90% yield (Scheme 4). The choice of HFIP as a sol-
vent was based on our previous work where the yield
of the coupling reaction was highest when HFIP was
used as a solvent.11 Potassium carbonate was used to
prevent the hydrolysis of the cyclic sulfate.10 The stereo-
chemistry at the sulfur center was assigned with the aid
of a NOESY experiment, which showed a correlation
between H-4 and H-10, suggesting that the L-erythritol
side chain and the C-4 substituent were trans to each
other. Deprotection of 18 proceeded smoothly in aque-
ous trifluoroacetic acid (TFA) to give the final com-
pound 4 in 78% yield.
Compound 5 was obtained in a similar manner by
coupling of 7 with the L-cyclic sulfate 8 to produce the
sulfonium salt 19 in 92% yield (Scheme 5). Deprotection
with aqueous TFA produced compound 5 in 81% yield.
Proof of stereochemistry at the stereogenic sulfur atom
was established as before with a NOESY experiment.
As a final point of interest, we comment on the screen-
ing of the compounds synthesized in this study against
recombinant human maltase glucoamylase (MGA), a

N. S. Kumar, B. M. Pinto / Carbohydrate Research 340 (2005) 2612–2619
2615
Ph
O
O
OH
OH
OSO3
S
OSO3
S
aq. TFA
HFIP
6
+
8
PMBO
PMBO
HO
K2CO3
OPMB
HO
OH
4
18
Scheme 4.
Ph
O
O
OH
OH
OSO3
S
OSO3
S
aq. TFA
HFIP
7
+
8
PMBO
PMBO
HO
K2CO3
OPMB
HO
OH
5
19
Scheme 5.
critical intestinal glucosidase involved in the processing
of oligosaccharides of glucose into glucose itself. Com-
pounds 4 and 5 were not effective inhibitors of MGA,
whereas salacinol 2 inhibited this enzyme with a Ki value
of 0.19 lM.22 Thus, it would appear that the D-arabini-
tol configuration in the heterocyclic ring displayed by
salacinol 2 is critical for activity, and the design of
new agents for the treatment of Type 2 diabetes should
incorporate this feature.
added sodium borohydride (0.215 g, 6.72 mmol) gradu-
ally. After stirring for 1.5 h at 0 ꢁC, the reaction was
quenched by the addition of AcOH and the reaction
mixture was concentrated. The residue was diluted with
EtOAc (200 mL) and washed with H2O (2 · 100 mL)
and brine (100 mL). The organic phase was dried over
anhydrous Na2SO4 and concentrated. The crude prod-
uct was purified by flash chromatography (hexanes/
EtOAc, 1:3–1:1) to give a colorless oil 10 (5.50 g,
1
97%); [a]D ꢀ20.5 (c 0.5, CHCl3); H NMR (CDCl3): d
7.38–7.25 (m, 15H, Ar), 4.74 and 4.54 (2H, 2d,
Ja,b = 11.5 Hz, CH2Ph), 4.63 (s, 2H, CH2Ph), 4.53 and
4.48 (2d, each 1H, Ja,b = 12.5 Hz, CH2Ph), 4.01 (1H,
ddd, J3,4 = 1.8 Hz, J4,5a = J4,5b = 6.1 Hz, H-4), 3.88
(1H, dd, J1a,1b = 11.7 Hz, J1a,2 = 4.1 Hz, H-1a), 3.81
(1H, dd, J2,3 = 5.9 Hz, H-3), 3.75 (1H, dd,
J1b,2 = 3.7 Hz, H-1b), 3.72 (1H, ddd, H-2), 3.55 (1H,
dd, J5a,5b = 9.9 Hz, H-5a), 3.47 (1H, dd, H-5b); 13C
NMR (CDCl3): d 137.84, 137.80, 137.75 (3Cipso),
128.52–127.79 (15C, Ar), 79.48 (C-2), 77.00 (C-3),
74.37, 73.44, 72.38 (3CH2Ph), 71.22 (C-5), 69.67 (C-4),
60.47 (C-1); MALDI-TOF MS: m/e 423.07 (M++H),
445.12 (M++Na), 4.61.11 (M++K). Anal. Calcd
for C26H30O5: C, 73.91; H, 7.16. Found: C, 74.05; H,
7.21.
3. Experimental
3.1. General
Optical rotations were measured at 23 ꢁC using a
Rudolph Research Autopol II polarimeter. H and 13C
1
NMR spectra were recorded on a Varian Inova spec-
trometer at frequencies of 500 and 125 MHz, respec-
tively. All assignments were confirmed with the aid of
two-dimensional 1H, 1H (gCOSY) or 1H, 13C (gHMQC)
experiments using standard Varian pulse programs.
Processing of the spectra was performed with MesRec
software. Matrix-assisted laser desorption ionization
time-of-flight (MALDI-TOF) mass spectra were ob-
tained using 2,5-dihydroxybenzoic acid as a matrix on
a PerSeptive Biosystems Voyager-DE spectrometer.
Column chromatography was performed with Merck
Silica gel 60 (230–400 mesh).
3.3. 2,3,5-Tri-O-benzyl-1-O-tert-butyldimethylsilyl-D-
lyxitol (11)
A mixture of 10 (5.24 g, 12.4 mmol), imidazole (3.72 g,
54.6 mmol), and TBDMSCl (2.07 g, 13.6 mmol) in dry
DMF (50 mL) was stirred at 0 ꢁC under N2 for
30 min. The reaction was quenched by the addition of
ice (20 mL), and the reaction mixture was partitioned
3.2. 2,3,5-Tri-O-benzyl-D-lyxitol (10)
To a stirred solution of 2,3,5-tri-O-benzyl-D-lyxofurano-
side 9 (5.64 g, 13.4 mmol) in EtOH (150 mL) at 0 ꢁC was

2616
N. S. Kumar, B. M. Pinto / Carbohydrate Research 340 (2005) 2612–2619
between Et2O (200 mL) and H2O (100 mL). The sepa-
rated organic phase was washed with H2O (100 mL)
and brine (100 mL). The organic layer was dried over
anhydrous Na2SO4 and concentrated. The residue was
purified by flash chromatography (hexanes/EtOAc,
3:1) to give a colorless oil 11 (6.164 g, 93%); [a]D
3.5. 1,4-Anhydro-2,3,5-tri-O-benzyl-4-thio-D-lyxitol (14)
To a stirred solution of 13 (6.01 g, 14.2 mmol) in pyri-
dine (60 mL) at 0 ꢁC under N2 was added methanesulfo-
nyl chloride (2.70 mL, 2.5 equiv) dropwise. The mixture
was stirred at 0 ꢁC for 2 h and concentrated under high
vacuum. The residue was diluted with EtOAc (200 mL)
and the organic phase was washed with H2O (100 mL),
1 M HCl (100 mL), saturated aqueous NaHCO3
(2 · 100 mL), and brine (100 mL). The organic layer
was dried over anhydrous Na2SO4 and concentrated.
The residue was dissolved in dry DMF (60 mL) together
with Na2SÆ9H2O (4.61 g, 1.3 equiv). The mixture was
stirred at 105 ꢁC for 2 h. After cooling to room temper-
ature, the mixture was diluted with Et2O (200 mL) and
washed with H2O (3 · 100 mL), followed by brine
(100 mL). The organic layer was dried over anhydrous
Na2SO4 and concentrated. The crude product was puri-
fied by a flash chromatography (hexanes/EtOAc, 5:1) to
give a colorless oil 14 (5.20 g, 87%); [a]D +94.0 (c 0.93,
1
ꢀ14.4 (c 0.9, CHCl3); H NMR (CDCl3): d 7.35–7.25
(15H, m, Ar), 4.74 and 4.60 (2H, 2d, Ja,b = 11.7 Hz,
CH2Ph), 4.69 and 4.51 (2H, 2d, Ja,b = 11.9 Hz, CH2Ph),
4.51 and 4.45 (2H, 2d, Ja,b = 11.6 Hz, CH2Ph), 4.05 (1H,
dddd, J3,4 = 2.3 Hz, J4,5a = J4,5b = 5.9 Hz, J4,OH
5.9 Hz, H-4), 3.88 (1H, dd, J1a,1b = 11.0 Hz, J1a,2
=
=
4.2 Hz, H-1a), 3.78 (1H, dd, J1b,2 = 4.9 Hz, H-1b),
3.77 (1H, dd, J2,3 = 4.1 Hz, H-3), 3.73 (1H, ddd, H-2),
3.54 (1H, dd, H-5a), 3.49 (1H, dd, H-5b), 3.02 (1H, d,
OH), 0.89 (9H, s, (CH3)3CSi), 0.05 (6H, s, (CH3)2Si);
13C NMR (CDCl3): d 149.11, 145.62, 140.95 (3Cipso),
128.35–127.60 (15C, Ar), 80.25 (C-2), 77.25 (C-3),
73.65, 73.26, 72.84 (3CH2Ph), 71.16 (C-5), 69.75 (C-4),
62.04 (C-1), 25.88 (3C, (CH3)3CSi) 18.23 (1C, CSi),
ꢀ5.40, ꢀ5.44 (2C, (CH3)2Si); MALDI-TOF MS: m/e
537.89 (M++H), 559.33 (M++Na). Anal. Calcd
for C32H44O5Si: C, 71.60; H, 8.26. Found: C, 71.44;
H, 8.34.
1
CHCl3); H NMR (CDCl3): d 7.38–7.22 (15H, m, Ar),
4.88 and 4.78 (2H, 2d, Ja,b = 11.6 Hz, CH2Ph), 4.68
(2H, s, CH2Ph) 4.49 (2H, s, CH2Ph), 4.20 (1H, dd,
J2,3 = 3.1 Hz, J3,4 = 3.8 Hz, H-3), 4.04 (1H, ddd,
J1a,2 = 9.2 Hz, J1b,2 = 6.3 Hz, H-2), 3.89 (1H, dd,
J4,5a = 7.3 Hz, J5a,5b = 8.7 Hz, H-5a), 3.58 (1H, m, H-
4), 3.54 (1H, dd, J4,5b = 6.6 Hz, H-5b), 3.07 (1H, dd,
J1a,1b = 9.2 Hz, H-1a), 2.92 (1H, dd, H-1b); 13C NMR
(CDCl3): d 138.85, 138.33, 138.27 (3Cipso), 128.68–
127.64 (15C, Ar), 83.71 (C-2), 78.99 (C-3), 73.81,
73.56, 72.37 (3CH2Ph), 70.42 (C-5), 40.92 (C-4), 30.56
(C-1); MALDI-TOF MS: m/e 421.29 (M++H), 443.29
(M++Na), 459.29 (M++K), 511.32 (M++Bn), 313.28
(M+ꢀOBn). Anal. Calcd for C26H28O3S: C, 74.25; H,
6.71. Found: C, 74.02; H, 6.73.
3.4. 2,3,5-Tri-O-benzyl-D-ribitol (13)
A solution of 11 (6.50 g, 12.1 mmol) in THF (60 mL)
containing p-nitrobenzoic acid (4.06 g, 24.2 mmol)
and triphenylphosphine (6.36 g, 24.2 mmol) was cooled
to 0 ꢁC. A solution of diisopropylazodicarboxylate
(4.8 mL, 24.2 mmol) in THF (30 mL) was added to
the mixture over 2 h. After stirring for 20 h at ambient
temperature, the reaction mixture was concentrated
and then partitioned between Et2O (200 mL) and
H2O (100 mL). The organic phase was washed with
saturated aqueous NaHCO3 (3 · 50 mL), followed by
brine (50 mL). The organic layer was dried over anhy-
drous Na2SO4 and concentrated under vacuum. The
residue was dissolved in MeOH (50 mL) and 1 N
NaOMe/MeOH (1.0 mL) was added. The mixture
was stirred at room temperature for 1 h and concen-
trated. The residue was partitioned between Et2O
(150 mL) and H2O (100 mL). The organic layer was
washed with brine (50 mL), dried over anhydrous
Na2SO4, and concentrated. The residue was re-dis-
solved in THF (50 mL) and a solution of tetrabutylam-
monium fluoride (1 M in THF, 13.0 mL, 13.0 mmol)
was added. The mixture was stirred at room tempera-
ture for 1.5 h and partitioned between Et2O (150 mL)
and H2O (50 mL). The organic layer was washed with
brine (50 mL), dried over anhydrous Na2SO4, and con-
centrated. The crude product was purified by flash
chromatography (hexanes/EtOAc, 4:1–1:1) to give a
colorless oil 13 (2.80 g, 57%). See Ref. 18 for experi-
mental data.
3.6. 1,4-Anhydro-4-thio-D-lyxitol (15)
To condensed NH3 (ꢁ30 mL) at ꢀ78 ꢁC was added lith-
ium metal (four small pieces) gradually. A solution of 14
(0.70 g, 1.7 mmol) in Et2O (5 mL) was then added to the
mixture dropwise. The mixture was stirred at ꢀ78 ꢁC to
ambient temperature for 5 h. The reaction was quenched
by the addition of MeOH (5 mL) and concentrated. The
crude product was purified by flash chromatography
(CH2Cl2/MeOH, 1:10–1:8) to give a colorless oil 15
(0.215 g, 86%); [a]D +4.0 (c 0.2, CHCl3); 1H NMR
(CDCl3): d 4.38 (1H, dd, J2,3 = 4.3 Hz, J3,4 = 6.7 Hz,
H-3), 4.26 (1H, ddd, J1a,2 = 5.9 Hz, J1b,2 = 5.2 Hz, H-
2), 4.01 (1H, dd, J4,5a = 2.6 Hz, J5a,5b = 11.9 Hz, H-
5a), 3.69 (1H, dd, J4,5b = 5.0 Hz, H-5b), 3.56 (1H,
ddd, H-4), 3.04 (1H, dd, J1a,1b = 11.5 Hz, H-1a), 2.89
(1H, dd, H-1b); 13C NMR (CDCl3): d 76.62 (C-2),
74.23 (C-3), 60.16 (C-5), 55.70 (C-4), 37.43 (C-1). Anal.
Calcd for C5H10O3S: C, 39.98; H, 6.71. Found: C, 39.62;
H, 6.65.

N. S. Kumar, B. M. Pinto / Carbohydrate Research 340 (2005) 2612–2619
2617
3.7. 1,4-Anhydro-2,3,5-tri-O-p-methoxybenzyl-4-thio-D-
lyxitol (6)
K2CO3 (5 mg). The mixture was stirred in a sealed tube
at 70 ꢁC for 16 h. The reaction mixture was concentrated
and the crude product was purified by flash chromato-
graphy (CH2Cl2/MeOH, 1:0–15:1) to give an amorphous
A solution of 15 (0.201 g, 1.33 mmol) in DMF (20 mL)
was added to a suspension of NaH (60% in oil,
175 mg, 3.3 equiv) in DMF (30 mL) at 0 ꢁC under N2.
After stirring at 0 ꢁC for 45 min, p-methoxybenzyl chlo-
ride (0.687 g, 3.3 equiv) was added dropwise. The reac-
tion mixture was stirred at room temperature for 2 h
and then quenched by the addition of ice (20 mL). The
mixture was diluted with H2O (50 mL) and extracted
with Et2O (3 · 100 mL). The organic phase was dried
over anhydrous Na2SO4 and concentrated. The crude
product was purified by flash chromatography (hex-
anes/EtOAc, 8:1–5:1) to give a colorless oil 6 (0.640 g,
1
solid 18 (124 mg, 90%): [a]D ꢀ11.6 (c 0.5, CHCl3); H
NMR (CDCl3): d 7.46–6.84 (17H, m, Ar), 5.36 (1H, s,
CH2Ph), 4.85 (1H, ddd, J1a,2 = 6.1 Hz, J1b,2 = 8.6 Hz,
J2,3 = 2.5 Hz, H-2), 4.70 and 4.45 (2H, 2d, Ja,b
=
11.0 Hz, CH2Ar), 4.60 (2H, s, CH2Ar), 4.57 (1H, dd,
J3 ,4a = 5.5 Hz, J4a 4b = 11.0 Hz, H-4a0), 4.53 (1H, dd,
J3,4 = 3.9 Hz, H-3), 4.44 (1H, m, H-30), 4.33 (1H, m,
H-4), 4.30 and 4.26 (2H, 2d, Ja,b = 11.7 Hz, CH2Ar),
4.26–4.21 (2H, m, H-20, H-1a0), 4.19 (1H, dd,
0
0
0
0
J1a 1b = 13.6 Hz, H-1b0), 3.91 (1H, dd, J1a,1b = 12.9 Hz,
H-1a), 3.81 (1H, dd, J4,5a = 4.6 Hz, J5a,5b = 9.8 Hz, H-
5a), 3.80 (3H, s, CH3OAr), 3.79 (3H, s, CH3OAr),
0
0
1
94%): [a]D ꢀ2.08 (c 0.3, CHCl3); H NMR (CDCl3): d
0
0
7.28–7.19 (6H, m, Ar), 6.90–6.79 (6H, m, Ar), 4.76
and 4.59 (2H, 2d, Ja,b = 11.4 Hz, CH2Ar), 4.48 (2H, s,
CH2Ar), 4.43 and 4.42 (2H, 2d, Ja,b = 11.4 Hz CH2Ar),
4.14 (1H, dd, J2,3 = 3.1 Hz, J3,4 = 4.0, H-3), 3.98 (1H,
ddd, J1a,2 = 9.2 Hz, J1b,2 = 6.1 Hz, H-2), 3.82 (1H, dd,
J4,5a = 7.2 Hz, J5a,5b = 8.7 Hz, H-5a), 3.81 (3H, s,
CH3OAr), 3.80 (3H, s, CH3OAr), 3.79 (3H, s, CH3OAr),
3.53 (1H, ddd, J4,5b = 6.6 Hz H-4), 3.47 (1H, dd, H-5b),
3.01 (1H, dd, J1a,1b = 9.3 Hz, H-1a), 2.86 (1H, dd, H-
1b); 13C NMR (CDCl3): d 159.45, 159.42, 159.32
(3Cipso), 131.01–113.84 (15C, Ar), 83.41 (C-2), 78.38
(C-3), 73.34, 73.20, 72.03 (3CH2Ar), 70.08 (C-5),
55.52, 55.49, 55.47 (3CH3OAr), 45.98 (C-4), 30.59
(C-1); MALDI-TOF MS: m/e 511.28 (M++H), 533.26
(M++Na), 549.21 (M++K). Anal. Calcd for C29H34-
O6S: C, 68.21; H, 6.71. Found: C, 67.90; H, 7.09.
3.76 (3H, s, CH3OAr), 3.74 (1H, dd, J3 4b = 3.9 Hz,
H-4b0), 3.71 (1H, dd, J4,5b = 4.6 Hz, H-5b), 3.54 (1H,
dd, H-1b); 13C NMR (CDCl3): d 159.86, 159.81,
159.77 (3Cipso, PMB), 137.04 (1Cipso, Ph), 130.32–
113.98 (20C, Ar), 101.50 (1C, CH2Ph), 81.51 (C-2),
78.33 (C-3), 76.01 (C-20), 74.24, 73.38, and 73.29
(3CH2Ar), 69.54 (C-40), 67.72 (C-30), 65.41 (C-5),
62.55 (C-4), 54.15–53.29 (3C, CH3OAr), 47.63 (C-10),
41.40 (C-1); MALDI-TOF MS: m/e 783.45 (M++H),
805.21 (M++Na), 821.84 (M++K). Anal. Calcd for
C40H46O12S2: C, 61.36; H, 5.92. Found: C, 61.61; H,
6.04.
3.10. 2,3,5-Tri-O-p-methoxybenzyl-1,4-dideoxy-1,4-
[[(2S,3S)-2,4-O-benzylidene-3-(sulfooxy)butyl]-(R)-epi-
sulfoniumylidene]-D-ribitol inner salt (19)
3.8. 1,4-Anhydro-2,3,5-tri-O-p-methoxybenzyl-4-thio-D-
ribitol (7)
To a solution of 1,4-anhydro-2,3,5-tri-O-p-methoxybenz-
yl-4-thio-D-ribitol (7) (300 mg, 588 mmol) and the L-
cyclic sulfate 8 (192 mg, 1.2 equiv) in HFIP (1.5 mL)
was added K2CO3 (20 mg). The mixture was stirred in
a sealed tube at 70 ꢁC for 16 h. The reaction mixture
was concentrated and the crude product was purified
by flash chromatography (CH2Cl2/MeOH, 1:0–20:1) to
give a white foam 19 (425 mg, 92%): [a]D +64.2 (c 0.3,
A solution of 17 (0.510 g, 3.4 mmol) in DMF (30 mL)
was added to a suspension of NaH (60% in oil,
0.449 g, 3.3 equiv) in DMF (50 mL) at 0 ꢁC under N2.
After stirring at 0 ꢁC for 45 min, p-methoxybenzyl
bromide (1.74 g, 3.3 equiv) was added dropwise. The
reaction mixture was stirred at room temperature for
2 h and then quenched by the addition of ice (20 mL).
The mixture was diluted with H2O (100 mL) and
extracted with Et2O (3 · 100 mL). The organic phase
was dried over anhydrous Na2SO4 and concentrated.
The crude product was purified by flash chromatogra-
phy (hexanes/EtOAc, 8:1–5:1) to give a white solid 7
(1.58 g, 91%). See Ref. 21 for experimental data.
1
CHCl3); H NMR (CDCl3): d 7.42–6.84 (17H, m, Ar),
5.53 (1H, s, CH2Ph), 4.66 and 4.54 (2H, 2d, Ja,b
=
0
0
0
0
11.3 Hz, CH2Ar), 4.53 (1H, ddd, J2 3 = J3 ,4a = 9.8 Hz,
J3 ,4b = 5.3 Hz, H-30), 4.48 (1H, dd, J4a 4b = 10.8 Hz,
0
0
0
0
H-4a0), 4.45 (1H, d, J1a ,1b = 13.9 Hz, H-1a0), 4.85
(1H, dd, J1a,2 = J2,3 = 2.6 Hz, H-2), 4.44 and 4.27 (2H,
2d, Ja,b = 11.2 Hz, CH2Ar), 4.34 and 4.19 (2H, 2d,
0
0
0
0
Ja,b = 11.9 Hz, CH2Ar), 4.23 (1H, dd, J1b ,2b = 2.9 Hz,
H-20), 4.15 (1H, dd, J3,4 = 9.5 Hz, H-3), 4.01 (1H, dd,
H-1b0), 3.82 (3H, s, CH3OAr), 3.81 (3H, s, CH3OAr),
3.80 (3H, s, CH3OAr), 3.76 (1H, dd, H-4b0), 3.68
(1H, ddd, J4,5a = J4,5b = 2.0 Hz, H-4), 3.58 (2H, br s,
H-1a, H-1b), 3.34 (1H, dd, J5a,5b = 10.9 Hz, H-5a),
3.29 (1H, dd, H-5b); 13C NMR (CDCl3): d 160.08,
160.05, 159.95 (3Cipso, PMB), 136.82 (1Cipso, Ph),
3.9. 2,3,5-Tri-O-p-methoxybenzyl-1,4-dideoxy-1,4-
[[(2S,3S)-2,4-O-benzylidene-3-(sulfooxy)butyl]-(S)-epi-
sulfoniumylidene]-D-lyxitol inner salt (18)
To a mixture of 6 (90 mg, 0.176 mmol) and the L-cyclic
sulfate 8 (57 mg, 1.2 equiv) in HFIP (0.5 mL) was added

2618
N. S. Kumar, B. M. Pinto / Carbohydrate Research 340 (2005) 2612–2619
0
0
136.82–114.09 (20C, Ar), 101.44 (1C, CH2Ph), 81.66
(C-3), 76.64 (C-20), 76.34 (C-2), 73.64, 73.10, 72.51
(3CH2Ar), 69.16 (C-40), 65.68 (C-30), 64.09 (C-4),
62.17 (C-5), 55.50–55.46 (3CH3OAr), 51.34 (C-10),
43.68 (C-1); MALDI-TOF MS: m/e 783.31 (M++H),
805.34 (M++Na), 821.87 (M++K). Anal. Calcd for
C40H46O12S2: C, 61.36; H, 5.92. Found: C, 61.19; H,
5.98.
3.84 (1H, dd, H-5b), 3.83 (1H, dd, J4a 4b = 12.9 Hz,
H-4a0), 3.80 (1H, dd, H-1b), 3.72 (1H, dd, H-4b0), 3.65
(1H, dd, J1a,1b = 14.5 Hz, H-1a), 3.40 (1H, dd, H-1b);
13C NMR (D2O): d 79.80 (C-30), 75.19 (C-3), 73.33
(C-2), 65.41 (C-20), 65.13 (C-4), 59.74 (C-40), 57.35
(C-5), 51.06 (C-10), 44.3 (C-1); MALDI-TOF MS:
m/e 335.07 (M++H), 357.01 (M++Na). Anal. Calcd
for C9H18O9S2: C, 32.33; H, 5.43. Found: C, 32.12; H,
5.67.
3.11. 1,4-Dideoxy-1,4-[[(2S,3S)-2,4-dihydroxy-3-
(sulfooxy)butyl]-(S)-episulfoniumylidene]-D-lyxitol
inner salt (4)
Acknowledgments
We thank K. S. Sadalapure for his initial work on the
ribitol analogue (5) of salacinol and B. D. Johnston
for helpful discussion. We also thank the Natural Sci-
ences and Engineering Research Council of Canada
for financial support and the Michael Smith Foundation
for Health Research for a trainee fellowship (to N.S.K.).
To a stirred solution of 18 (120 mg, 0.153 mmol) in TFA
(10 mL) was added H2O (1 mL) and the reaction mix-
ture was stirred at ambient temperature for 2 h. The
reaction mixture was concentrated and the crude prod-
uct was purified by flash chromatography (CH2Cl2/
MeOH, 3:1 to EtOAc/MeOH/H2O, 6:3:1) to give an
amorphous solid 4 (30 mg, 78%); [a]D +8.2 (c 0.2,
H2O); 1H NMR (H2O): d 4.85 (1H, ddd, J1a,2
6.8 Hz, J1b,2 = 9.6 Hz, J2,3 = 3.0 Hz, H-2), 4.61 (1H,
=
References
0
0
dd, J3,4 = 3.2 Hz, H-3), 4.38 (1H, ddd, J2 3 = 7.4 Hz,
J3 4a = 2.9 Hz, J3 4b = 9.6 Hz, H-30), 4.34–4.26 (2H,
m, H-20, H-4), 4.18 (1H, dd, J4,5a = 5.1 Hz,
J5a,5b = 12.3 Hz, H-5a), 4.02 (1H, dd, J4,5b = 9.4 Hz,
0
0
0
0
1. Holman, R. R.; Cull, C. A.; Turner, R. C. Diabetes Care
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0
0
0
0
H-5b), 3.94 (1H, dd, J1a ,1b = 12.6 Hz, J1a ,2 = 3.3 Hz,
H-1a0), 3.84 (1H, dd, J1b ,2 = 3.5 Hz, H-1b0), 3.83 (1H,
0
0
dd, J4a 4b = 13.6 Hz, H-4a0), 3.73 (1H, dd, J1a,1b
=
0
0
13.3 Hz, H-1a), 3.72 (1H, dd, H-4b0), 3.62 (1H, dd, H-
13
1b); C NMR (D2O): d 82.91 (C-30), 76.08 (C-2),
75.34 (C-3), 68.79 (C-4), 68.01 (C-20), 62.06 (C-10),
60.32 (C-5), 50.91 (C-40), 43.84 (C-1); MALDI-TOF
MS: m/e 335.04 (M++H), 357.11 (M++Na). Anal.
Calcd for C9H18O9S2: C, 32.33; H, 5.43. Found: C,
32.02; H, 5.45.
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H.; Yamahara, J.; Tanabe, G.; Muraoka, O. Tetrahedron
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3.12. 1,4-Dideoxy-1,4-[[(2S,3S)-2,4-dihydroxy-3-
(sulfooxy)butyl]-(R)-episulfoniumylidene]-D-ribitol
inner salt (5)
11. Ghavami, A.; Sadalapure, K. S.; Johnston, B. D.; Lobera,
M.; Snider, B. B.; Pinto, B. M. Synlett 2003, 9, 1259–
1262.
12. Yuasa, H.; Takada, J.; Hashimoto, H. Tetrahedron Lett.
2000, 41, 6615–6618.
13. Ghavami, A.; Johnston, B. D.; Jensen, M. T.; Svensson,
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To a stirred solution of 19 (202 mg, 0.258 mmol) in TFA
(20 mL) was added H2O (2 mL) and the reaction mix-
ture was stirred at ambient temperature for 2 h. The
reaction mixture was concentrated and the crude prod-
uct was purified by flash chromatography (CH2Cl2/
MeOH, 3:1 to EtOAc/MeOH/H2O, 6:3:1) to give an
amorphous solid 5 (69 mg, 81%); [a]D +40.9 (c 0.3,
1
H2O); H NMR (H2O): d 4.57 (1H, ddd, J1a,2 = J2,3
=
=
0
0
3.3 Hz, J1b,2 = 2.0 Hz, H-2), 4.28 (1H, ddd, J1a ,2
J2 ,3 = 3.6 Hz, J1b ,2 = 7.1 Hz, H-20), 4.26 (1H, dd,
0
0
0
0
0
0
0
0
J3,4 = 8.4 Hz, H-3), 4.22 (1H, ddd, J2 3 = J3 ,4b
=
=
=
3.3 Hz, J3 4a = 7.5 Hz, H-30), 4.06 (1H, dd, J4,5a
3.2 Hz, J5a,5b = 12.4 Hz, H-5a), 4.03 (1H, dd, J1a ,1b
13.2 Hz, H-1a0), 3.93 (1H, ddd, J4,5b = 5.4 Hz, H-4),
0
0
0
0
17. Postema, M. H. D.; Calimente, D.; Liu, L.; Behrmann, T. L.
J. Org. Chem. 2000, 65, 6061–6068.

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2619
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