New synthetic routes to chain-extended selenium, sulfur, and nitrogen analogues of the naturally occurring glucosidase inhibitor salacinol and their inhibitory activities against recombinant human maltase glucoamylase

Article abstract of DOI:10.1021/jo071045m

(Chemical Equation Presented) Six heteroanalogues (X = S, Se, NH) of the naturally occurring glucosidase inhibitor salacinol, containing polyhydroxylated, acyclic chains of 6-carbons, were synthesized for structure-activity studies with different glycosid

Full text of DOI:10.1021/jo071045m

New Synthetic Routes to Chain-Extended Selenium, Sulfur, and
Nitrogen Analogues of the Naturally Occurring Glucosidase
Inhibitor Salacinol and their Inhibitory Activities against
Recombinant Human Maltase Glucoamylase
Hui Liu,† Ravindranath Nasi,† Kumarasamy Jayakanthan,† Lyann Sim,‡ Heather Heipel,‡
David R. Rose,‡ and B. Mario Pinto*,†
Department of Chemistry, Simon Fraser UniVersity, Burnaby, British Columbia, Canada V5A 1S6, and
Department of Medical Biophysics, UniVersity of Toronto and DiVision of Cancer Genomics and
Proteomics, Ontario Cancer Institute, Toronto, Canada M5G 1L7
bpinto@sfu.ca
ReceiVed May 17, 2007
Six heteroanalogues (X ) S, Se, NH) of the naturally occurring glucosidase inhibitor salacinol, containing
polyhydroxylated, acyclic chains of 6-carbons, were synthesized for structure-activity studies with different
glycosidase enzymes. The target zwitterionic compounds were synthesized by means of nucleophilic
attack of the PMB-protected 1,4-anhydro-4-seleno-, 1,4-anhydro-4-thio-, and 1,4-anhydro-4-imino-D-
arabinitols at the least hindered carbon atom of 1,3-cyclic sulfates. These 1,3-cyclic sulfates were derived
from D-glucose and D-galactose, and significantly, they utilized butane diacetal as the protecting groups
for the trans 2,3-diequatorial positions. Deprotection of the coupled products proceeded smoothly, unlike
in previous attempts with different protecting groups, and afforded the target selenonium, sulfonium,
and ammonium sulfates with different stereochemistry at the stereogenic centers. The four new
heterosubstituted compounds (X ) Se, NH) inhibited recombinant human maltase glucoamylase (MGA),
one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small
intestine. The two selenium derivatives each had Ki values of 0.10 µM, giving the most active compounds
to date in this general series of zwitterionic glycosidase inhibitors. The two nitrogen compounds also
inhibited MGA but were less active, with Ki values of 0.8 and 35 µM. The compounds in which X ) S
showed Ki values of 0.25 and 0.17 µM. Comparison of these data with those reported previously for
related compounds reinforces the requirements for an effective inhibitor of MGA. With respect to chain
extension, the configurations at C-2′ and C-4′ are critical for activity, the configuration at C-3′, bearing
the sulfate moiety, being unimportant. It would also appear that the configuration at C-5′ is important
but the relationship is dependent on the heteroatom.
Introduction
roots and stems of the plant Salacia reticulata. Salacinol has
been shown to be an inhibitor of intestinal glucosidase enzymes1-4
and, thus, capable of attenuating the spike in blood glucose
levels that is experienced by diabetics after consuming a meal
Recently, a new class of glycosidase inhibitor, namely
salacinol (1)1 and kotalanol (2)2 (Chart 1), with an intriguing
inner-salt sulfonium-sulfate structure, was isolated from the
(2) Yoshikawa, M.; Murakami, T.; Yashiro, K.; Matsuda, H. Chem.
Pharm. Bull. 1998, 46, 1339-1340.
* To whom correspondence should be addressed. Tel: (604) 291-4152. Fax:
(604) 291-4860.
† Simon Fraser University.
(3) Yuasa, H.; Takada, J.; Hashimoto, H. Bioorg. Med. Chem. Lett. 2001,
11, 1137-1139.
‡ University of Toronto and Ontario Cancer Institute.
(1) Yoshikawa, M.; Murakami, T.; Shimada, H.; Matsuda, H.; Yamahara,
J.; Tanabe, G.; Muraoka, O. Tetrahedron Lett. 1997, 38, 8367-8370.
(4) Yoshikawa, M.; Morikawa, T.; Matsuda, H.; Tanabe, G.; Muraoka,
O. Bioorg. Med. Chem. 2002, 10, 1547-1554.
10.1021/jo071045m CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/21/2007
6562
J. Org. Chem. 2007, 72, 6562-6572

Se, S, and N Analogues of Salacinol
CHART 1
rich in carbohydrates.5 It is noteworthy that a double blind study
of the effects of the extract from Salacia reticulata on human
patients with type II diabetes mellitus has shown that the extract
is an effective treatment of type 2 diabetes with side effects
comparable to the placebo control group.6 It is postulated that
the inhibition of glucosidases by salacinol and kotalanol is due
to their ability to mimic both the shape and charge of the oxa-
carbenium-ion-like transition state involved in the enzymatic
reactions.7 The structure of kotalanol is very similar to salacinol,
with the alditol side chain being extended by three carbons.
However, the absolute configuration of the stereogenic centers
in the heptitol chain has not been determined. The 1,4-
thioanhydropentitol portion of kotalanol has the identical
D-arabinitol configuration as salacinol.
CHART 2
through structural studies of the enzyme-bound inhibitors using
molecular modeling in conjunction with conformational analysis
by STD-NMR techniques18 and X-ray crystallography.19
Our previous studies had indicated that the stereochemistry
at the stereogenic center at the 2′ position of the side chain,
namely the S-configuration, might be critical for inhibitory
activity. Thus, the chain-extended sulfonium ions 6 and 9 with
the 2′-S-configuration were active against human maltase
glucoamylase with Ki values of similar magnitudes as those of
salacinol.15 However, the synthetic route that afforded com-
pounds 6 and 9 was not readily applicable to the syntheses of
the corresponding selenium analogues and did not afford these
compounds. Since the selenium congener of salacinol, blintol,
was shown to be a glucosidase inhibitor with a Ki value in the
same range as salacinol,9 the synthesis of chain-extended
selenium analogues of salacinol was of particular interest.
Accordingly, we have designed an alternative synthetic route
and report herein its application to the synthesis of the selenium,
sulfur, and nitrogen analogues 5-10 (Chart 2).
We and others have synthesized salacinol,7,8 as well as its
selenium (blintol, 3)9 and nitrogen (ghavamiol, 4)10 congeners
(Chart 1). Other stereoisomers of salacinol,11 analogues contain-
ing six-membered heterocyclic rings,12,13 and some chain-
extended analogues of salacinol have also been synthesized.14-16
The selenium analogue of salacinol, blintol, has been shown to
be very effective in controlling blood glucose levels in rats after
a carbohydrate meal, thus providing a lead candidate for the
treatment of type 2 diabetes.9 Structure-activity studies revealed
an interesting variation in the inhibitory power of these
compoundsagainstglycosidaseenzymesofdifferentorigin.9-12,14-17
The molecular basis for this selectivity is being investigated
(5) Serasinghe, S.; Serasinghe, P.; Yamazaki, H.; Nishiguchi, K.;
Hombhanje, F.; Nakanishi, S.; Sawa, K.; Hattori, M.; Namba, T. Phytother.
Res. 1990, 4, 205-206.
(6) Jayawardena, M. H. S.; de Alwis, N. M. W.; Hettigoda, V.; Fernando,
D. J. S. J. Ethnopharmacol. 2005, 97, 215-218.
(7) Ghavami, A.; Johnston, B. D.; Pinto, B. M. J. Org. Chem. 2001, 66,
2312-2317. Ghavami, A.; Sadalapure, K. S.; Johnston, B. D.; Lobera, M.;
Snider, B. B.; Pinto, B. M. Synlett 2003, 1259-1262.
Results and Discussion
(8) Yuasa, H.; Takada, J.; Hashimoto, H. Tetrahedron Lett. 2000, 41,
6615-6618.
Our synthetic strategy was analogous to that used for the
synthesis of the sulfonium analogues 6 and 915 in that it involved
the opening of a 1,3-cyclic sulfate ring by nucleophilic attack
of a protected heteroether (Scheme 1). However, in the previous
report of the synthesis of 6 and 9, benzyl groups were used to
protect both anhydroheteroalditols and cyclic sulfates, and
hydrogenolysis was used to remove the benzyl protecting
groups.15 The corresponding synthesis of the selenium analogues
using this strategy was unsuccessful owing to poisoning of the
catalyst. Our new strategy is reliant on the protection of the
trans-diequatorial 1,2-hydroxyl groups as a butane diacetal.
p-Methoxybenzyl (PMB) groups were used to protect the 2-,
3-, and 5-positions in the heteroanhydroalditols. However, for
the desired 1,3-cyclic sulfates derived from D-galactose and
D-glucose, PMB groups were deemed to be unsuitable since
they were susceptible to oxidation. Methods for selective
(9) Johnston, B. D.; Ghavami, A.; Jensen, M. T.; Svensson, B.; Pinto,
B. M. J. Am. Chem. Soc. 2002, 124, 8245-8250. Liu, H.; Pinto, B. M. J.
Org. Chem. 2005, 70, 753-755. Pinto, B. M.; Johnston, B. D.; Ghavami,
A.; Szczepina, M. G.; Liu, H.; Sadalapure, K. US Patent, Filed June 25,
2004.
(10) Ghavami, A.; Johnston, B. D.; Jensen, M. T.; Svensson, B.; Pinto,
B. M. J. Am. Chem. Soc. 2001, 123, 6268-6271. Muraoka, O.; Ying, S.;
Yoshikai, K.; Matsuura, Y.; Yamada, E.; Minematsu, T.; Tanabe, G.;
Matsuda, H.; Yoshikawa, M. Chem. Pharm. Bull. 2001, 49, 1503-1505.
(11) Ghavami, A.; Johnston, B. D.; Maddess, M. D.; Chinapoo, S. M.;
Jensen, M. T.; Svensson, B.; Pinto, B. M. Can. J. Chem. 2002, 80, 937-
942. Kumar, N. S.; Pinto, B. M. Carbohydr. Res. 2005, 340, 2612-2619.
(12) Szczepina, M. G.; Johnston, B. D.; Yuan, Y.; Svensson, B.; Pinto,
B. M. J. Am. Chem. Soc. 2004, 126, 12458-12469.
(13) Gallienne, E.; Benazza, M.; Demailly, G.; Bolte, J.; Lemaire, M.
Tetrahedron 2005, 61, 4557-4568.
(14) Liu, H.; Pinto, B. M. Can. J. Chem. 2006, 84, 497-505. Liu, H.;
Sim, L.; Rose, D. R.; Pinto, B. M. J. Org. Chem. 2005, 71, 3007-3013.
(15) Johnston, B. D.; Hensen, H. H.; Pinto, B. M. J. Org. Chem. 2006,
71, 1111-1118.
(16) Nasi. R.; Sim, L.; Rose, D. R.; Pinto, B. M. J. Org. Chem. 2007,
72, 180-186.
(17) Li, Y.; Scott, C. R.; Chamoles, N. A.; Chavami, A.; Pinto, B. M.;
Frantisek, T.; Gelb, M. H. Clin. Chem. 2004, 50, 1785-1790.
(18) Wen, X.; Yuan, Y.; Kuntz, D. A.; Rose, D. R.; Pinto, B. M.
Biochemistry 2005, 44, 6729-6738.
(19) Kuntz, D.; Ghavami, A.; Johnston, B. D.; Pinto, B. M.; Rose, D.
R. Tetrahedron: Asymmetry 2005, 16, 25-30.
J. Org. Chem, Vol. 72, No. 17, 2007 6563

Liu et al.
SCHEME 1
of additional ring strain in the opening of a cyclic sulfate was
beneficial.7,9-11 The BDA at the 2,3-positions of the cyclic
sulfates 14 and 15 would thus play a dual role as a protecting
group and a reaction facilitator for the coupling reactions with
the anhydro heteroalditols 11-13 (Chart 3). We reasoned that
after the coupling reactions the BDA and PMB groups could
be readily removed by treatment with trifluoroacetic acid.
The synthesis of the BDA-protected cyclic sulfate (14) started
from benzyl â-D-galactopyranoside (16)22 (Scheme 2). Follow-
ing the procedure described by Hense et al. for the preparation
of similar compounds,21 compound 16 was refluxed with 2,3-
butanedione, trimethyl orthoformate, and methanol, with CSA
as a catalyst, for 12 h. The resulting benzyl 2,3-O-[(2R,3R)-
2,3-dimethoxybutane-2,3-diyl]-â-D-galactopyranoside 17 was
then reacted with thionyl chloride to afford the corresponding
cyclic sulfites, which were subsequently oxidized with sodium
periodate and RuCl3 to afford the cyclic sulfate 14 in 60% yield
(Scheme 2).
CHART 3
The synthesis of the BDA-protected cyclic sulfate (15) started
from the benzyl â-D-glucopyranoside (18)23 (Scheme 3).
Compound 18 was refluxed with 2,3-butanedione, trimethyl
orthoformate, and methanol, with CSA as a catalyst, for 12 h
to give a mixture of the desired benzyl 2,3-O-[(2R,3R)-2,3-
dimethoxybutane-2,3-diyl]-â-D-glucopyranoside (19) and benzyl
3,4-O-[(2R,3R)-2,3-dimethoxybutane-2,3-diyl]-â-D-glucopyra-
noside (20). The ratio of products 19/20 was 1.8:1, which
suggested that the reaction had not proceeded with any
significant regioselectivity.21 Fortunately, compound 19 could
be readily separated from the reaction mixture by column
chromatography. The purified compound 19 was treated with
thionyl chloride to afford the cyclic sulfites, which were
protection of vicinal trans diequatorial diols are rare. In recent
years, Ley and co-workers20 have introduced dispiroketals as
protecting groups for trans diequatorial 1,2-diols, the high
selectivity in the protection of trans diequatorial 1,2-diols being
attributed to the combination of two factors: the formation of
the sterically less demanding trans ring junction and the control
of configuration at the two acetal centers by the operation of
anomeric effects.20 Recently, Hense et al.21 reported a convenient
method to utilize butane diacetal (BDA) protecting groups for
trans diequatorial 1,2-diols. We envisioned the use of butane
diacetal (BDA) protecting groups for the cyclic sulfates 14 and
15 (Chart 3). Our previous work also suggested that the release
SCHEME 2
SCHEME 3
6564 J. Org. Chem., Vol. 72, No. 17, 2007

Se, S, and N Analogues of Salacinol
SCHEME 4
SCHEME 5
SCHEME 6
subsequently oxidized by sodium periodate and RuCl3 to
afford the corresponding cyclic sulfate 15 in 67% yield
(Scheme 3).
The coupling reactions of the PMB-protected 1,4-anhydro-
4-seleno-D-arabinitol (11) and 1,4-anhydro-4-thio-D-arabinitol
(12) with the cyclic sulfate 14 were carried out in 1,1,1,3,3,3-
hexafluoroisopropyl alcohol (HFIP), which offers significant
advantage compared with other solvents.7,9,11,14 The cyclic
sulfate 14 reacted with the PMB-protected 1,4-anhydro-4-seleno-
D-arabinitol (11) and 1,4-anhydro-4-thio-D-arabinitol (12), to
give the corresponding protected selenonium and sulfonium
sulfates 21 and 22 in 72% and 75% yields, respectively (Scheme
4). Potassium carbonate was added to the reaction mixture to
neutralize any acid generated by the possible decomposition of
the cyclic sulfate 14 reacting with a trace amount of water.
However, the presence of K2CO3 also led to a significant amount
of byproduct from the reaction of the cyclic sulfate 14 with
HFIP anion. Based on this observation, the amount of K2CO3
added was greatly reduced in later trials, and no byproduct was
isolated. The presence of the cyclic sulfate 14 in slight excess
over the seleno- and thioalditols 11 and 12 also resulted in
improved yields. The coupling reactions of the PMB-protected
1,4-dideoxy-1,4-imino-D-arabinitol (13) with the cyclic sulfate
14 was carried out in dry acetone and proceeded smoothly to
give the corresponding protected ammonium sulfate 23 in 89%
yield (Scheme 5).
(20) Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.; Ince, S.
J.; Priepke, H. W. M.; Reynolds, D. J. Chem. ReV. 2001, 101, 53-80 and
the references within.
(21) Hense, A.; Ley, S. V.; Osborn, H. M. I.; Owen, D. R.; Poisson,
J.-F.; Warriner, S. L.; Wesson, K. E. J. Chem. Soc., Perkin Trans. 1997, 1,
2023-2031.
(22) Xia, J.; Alderfer, J. L.; Piskorz, C. F.; Matta, K. L. Chem. Eur. J.
2001, 7, 356-367.
(23) Smits, E.; Engberts, J. B. F. N.; Kellogg, R. M.; van Doren, H. A.
J. Chem. Soc., Perkin Trans. 1996, 1, 2873-2877.
J. Org. Chem, Vol. 72, No. 17, 2007 6565

Liu et al.
SCHEME 7
The coupling reactions of the cyclic sulfate 15 with the PMB-
protected 1,4-anhydro-4-seleno-D-arabinitol (11) and 1,4-anhy-
dro-4-thio-D-arabinitol (12) were carried out in HFIP to give
the corresponding protected selenonium and sulfonium sulfates
24 and 25 in 70% and 78% yields, respectively (Scheme 6).
The PMB-protected 1,4-dideoxy-1,4-imino-D-arabinitol (13) also
reacted with the cyclic sulfate 15 in dry acetone to afford the
ammonium sulfate 26 in 90% yield (Scheme 6).
due to the similarity in chromatographic mobilities, these minor
products could not be isolated free from the major isomers.
However, this type of minor product was not detected in the
reactions of the corresponding thioarabinitol 12.
Deprotection of the coupled products 21-26 was carried out
by a three-step procedure. Since PMB and BDA groups were
both sensitive to acidic conditions, they were readily cleaved
by treatment with TFA (Scheme 7). After rinsing away the
cleaved PMB and BDA groups, the residue was purified by
column chromatography to afford the corresponding compounds
27-32 as amorphous, hygroscopic solids. The benzyl protecting
groups at the anomeric positions in compounds 27-32 were
not cleaved after prolonged treatment with TFA at elevated
temperatures, only trace amounts of cleavage products being
observed.
The absolute stereochemistry at the heteroatom center of
compounds 27-32 was established by NOESY experiments.
For example, the NOESY spectrum of compound 27 (Figure
1) clearly exhibited the H-4 to H-1′b correlation, implying that
these two hydrogens are syn-facial. Therefore, C-1′ of the side
chain must be anti to C-5 of the sulfonium salt ring.
The reactivity of the PMB-protected 1,4-anhydroheteroalditols
11-13 with the cyclic sulfates 14 and 15 varied. The 1,4-
dideoxy-1,4-iminoarabinitol 13 was the most reactive of the
three and reacted with the cyclic sulfates 14 and 15 in good
yields. The PMB-protected 1,4-anhydro-4-seleno- and -thio-D-
arabinitols 11 and 12 were less reactive with the cyclic sulfates
14 and 15, and the reactions proceeded very slowly in acetone.
The polar solvent HFIP, which was believed to facilitate the
reactions by stabilizing the transition states, had to be used
instead. The PMB-protected 1,4-anhydro-4-seleno-D-arabinitol
11 was slightly more reactive than its sulfur counterpart 12, as
demonstrated by the different reaction temperatures required
in the coupling reactions. The coupling reaction of compound
11 with 14 and 15 proceeded smoothly at 60-65 °C to give
the desired products in moderate yields. However, attempts to
improve the yields further by raising the reaction temperatures
caused decomposition of the products. On the other hand,
reaction of the PMB-protected 1,4-anhydro-4-thio-D-arabinitol
12 with the cyclic sulfates 14 and 15 proceeded slowly at 65-
70 °C for 12 h, with about 30% of starting material 12 still
remaining. Raising the temperature to 75-80 °C resulted in
completion of the reactions in high yields.
Compounds 27-32 were subjected to hydrogenolysis in 90%
acetic acid using Pd(OH)2/C as the catalyst. After 24 h, the
anomeric benzyl groups of 27-32 were completely removed
to yield the corresponding hemiacetals. The crude hemiacetals
were subsequently reduced with NaBH4 in water to provide the
desired final products 5-10 (Scheme 8). The moderate yields
The selectivity for attack at the primary center of the cyclic
sulfates 14 and 15 over possible alternative attack of compounds
11-13 at the primary over the secondary cyclic sulfate center
was invariably excellent, and in no case were isolable quantities
of the regioisomers detected. In the case of the coupling reaction
of the selenoarabinitol 11 with the cyclic sulfates 14 and 15,
there was a detectable amount (5-10%) of the stereoisomers
that were diastereomeric at the selenonium center. However,
FIGURE 1. NOE correlations observed in the NOESY spectrum
of 27.
6566 J. Org. Chem., Vol. 72, No. 17, 2007

Se, S, and N Analogues of Salacinol
SCHEME 8
for the three-step deprotection sequence were due in part to the
difficulty in separation of the final products from contaminating
borate salts. Compounds 5-10 were obtained as hygroscopic
gums that were unsuitable for combustion analysis but were
characterized by spectroscopic methods. The 1H and 13C NMR
spectra of compounds 6 and 9 matched the data in our previous
publication.15 MALDI mass spectrometry for compounds 5-10
in the positive-ion mode typically showed base peaks for masses
attributable to sodium adduct ions (M + Na) and lower intensity
peaks corresponding to M + H and M + H - SO3 ions. The
compounds were also characterized by 1H and 13C NMR
spectroscopy and high-resolution mass spectrometry.
and 0.17 ( 0.02 µM, respectively. Thus, the configuration at
C-3′ does not appear to be critical for inhibitory activity since
all pairs, i.e., 5 and 8, 6 and 9, 7 and 10, show Ki values in the
same range as also recently deduced with other derivatives.16
It is of interest that the sulfonium ion 33 with the enantiomeric
configuration at C-5′ to 9 has a Ki value of 0.65 ( 0.10 µM.16
In contrast, the corresponding selenonium ion 34 with enan-
tiomeric configuration at C-5′ to 8 is just as active, with a Ki
CHART 4
Finally, we comment on the inhibitory activities of the
compounds synthesized in this and previous studies against
recombinant human maltase glucoamylase (MGA), a critical
intestinal glucosidase involved in the processing of oligosac-
charides of glucose into glucose itself. The selenium derivatives,
5 and 8, have Ki values of 0.10 ( 0.03 and 0.10 ( 0.01 µM,
respectively (Table 1). Both of the nitrogen analogues are less
active, 10 with a Ki value of 8 ( 1 µM and 7 with a Ki value
of 35 ( 2 µM. The sulfur analogues 6 and 9 were shown in a
previous study15 to be active, with Ki values of 0.25 ( 0.02
value of 0.14 ( 0.03 µM.16 The Ki values for the selenium
derivatives 5 and 8 are lower than for their lower homologue
blintol 3 (Ki ) 0.49 ( 0.05 µM),24 indicating the importance
of chain elongation relative to blintol 3. The sulfur derivatives
6 and 9 synthesized in this study are in the same range as those
for salacinol 1 (Ki ) 0.19 ( 0.02 µM) (Table 1). Further
rationalization of these data will have to await details of contacts
between the ligands and the active site of MGA from the X-ray
crystal structures of MGA complexes (Chart 4).
TABLE 1. Experimentally Determined Ki Valuesa
inhibitor
Ki (µM)
salacinol (1)
blintol (3)
ghavamiol (4)
0.19 ( 0.02c
0.49 ( 0.05c
NAb,d
Conclusions
5
6
7
8
0.10 ( 0.03
0.25 ( 0.02c
35 ( 2
Four hitherto elusive heteroanalogues (X ) Se, NH) of the
naturally occurring glucosidase inhibitor salacinol, containing
extended acyclic chains of six carbons, were synthesized. These
syntheses utilized the 1,3-cyclic sulfates derived from com-
mercially available D-glucose and D-galactose. The PMB and
butanediacetal protecting groups on the coupled products
0.10 ( 0.01
0.17 ( 0.02c
8 ( 1
9
10
33
34
0.65 ( 0.1e
0.14 ( 0.03e
a Analysis of MGA inhibition was performed using p-nitrophenyl R-D-
glucopyranoside as the substrate and measuring the release of glucose.
Absorbance measurements were averaged to give a final result. b NA: not
active. c Reference 24. d Reference 25. e Reference 16.
(24) Rossi, E. J; Sim, L.; Kuntz, D. A.; Hahn, D.; Johnston, B. D.;
Ghavami, A.; Szczepina, M. D.; Kumar, N. S.; Sterchi, E. E.; Nichols, B.
L.; Pinto, B. M.; Rose, D. R. FEBS J. 2006, 273, 2673-2683.
(25) Rose, D. R. Unpublished observations.
J. Org. Chem, Vol. 72, No. 17, 2007 6567

Liu et al.
column chromatography (hexane/EtOAc, 2:1) yielded compound
19 and 20 (19/20 ) 1.8:1) as colorless solids (11.4 g, 53% for 19,
6.3 g, 30% for 20, yields based on 18).
ensured facile deprotection with TFA. After hydrogenolysis to
cleave the anomeric benzyl groups and subsequent NaBH4
reduction of the resulting hemiacetals, the final compounds 5
to 10 were obtained. The four new target compounds inhibited
human maltase glucoamylase, with Ki values ranging from 0.10
to 35 µM. The selenium derivatives 5 and 8 represent the most
active compounds in this general series of compounds synthe-
sized to date. The two compounds in which X ) S previously
showed Ki values of 0.25 and 0.17 µM. These data, when
compared to those reported previously for related compounds,
reinforce the requirements for an effective inhibitor of MGA.
For compound 19: [R]22 -48.3 (c 1.0, CH2Cl2); 1H NMR
D
(CDCl3) δ 7.41-7.20 (m, 5H, Ar), 4.86 and 4.67 (2 d, 2H, JAB
)
12.3 Hz, CH2Ph), 4.62 (d, 1H, J1,2 ) 7.9 Hz, H-1), 3.84 (dd, 1H,
J5,6a ) 3.0, J6a,6b ) 12.0 Hz, H-6a), 3.79 (dd, 1H, J5,6b ) 4.4 Hz,
H-6b), 3.73 (t, 1H, J3,4 ) J4,5 ) 9.5 Hz, H-4), 3.67 (t, 1H, J2,3
)
J3,4 ) 9.5 Hz, H-3), 3.55 (dd, 1H, H-2), 3.34 (ddd, 1H, H-5), 3.26
and 3.25 (2 s, 6H, 2 × OCH3), 1.31 and 1.30 (2 s, 6H, 2 × CH3);
13C NMR (CDCl3) δ 137.8, 128.5, 127.9, 127.6 (CAr), 100.7 (C-
1), 99.8, 99.7 (2 × C(OMe)(OR)), 76.2 (C-5), 72.8 (C-3), 71.7
(CH2Ph), 69.5 (C-2), 68.2 (C-4), 62.6 (C-6), 48.2, 48.1 (2 × OCH3),
17.8 (2 × CH3). Anal. Calcd for C19H28O8: C, 59.36; H, 7.34.
Found: C, 59.18; H, 7.22.
Experimental Section
Enzyme Kinetics. Kinetic parameters of MGA with compounds
12 and 22 were determined using the pNP-glucose assay to follow
the production of p-nitrophenol upon addition of enzyme (500 nM).
The Ki obtained for salacinol 2 in this assay was identical to that
obtained using the glucose oxidase assay above. The assays were
carried out in 96-well microtiter plates containing 100 mM MES
buffer pH 6.5, inhibitor (at three different concentrations), and
p-nitrophenyl-D-glucopyranoside (pNP-glucose) as substrate (2.5,
3.5, 5, 7.5, 15, and 30 mM) with a final volume of 50 µL. Reactions
were incubated at 37 °C for 35 min and terminated by addition of
50 µL of 0.5 M sodium carbonate. The absorbance of the reaction
product was measured at 405 nm in a microtiter plate reader. All
reactions were performed in triplicate, and absorbance measure-
ments were averaged to give a final result. Reactions were linear
within this time frame. The program GraFit 4.0.14 was used to fit
the data to the Michaelis-Menten equation and estimate the kinetic
For compound 20: [R]22 +8.2 (c 1.0, CH2Cl2); 1H NMR
D
(CDCl3) δ 7.40-7.25 (m, 5H, Ar), 4.90 and 4.68 (2 d, 2H, JAB
)
11.7 Hz, CH2Ph), 4.47 (d, 1H, J1,2 ) 7.4 Hz, H-1), 3.88 (dd, 1H,
J5,6a ) 3.0, J6a,6b ) 12.0 Hz, H-6a), 3.75 (dd, 1H, J5,6b ) 4.8 Hz,
H-6b), 3.74-3.68 (m, 2H, H-3, H-4), 3.62 (dd, 1H, J2,3 ) 8.6 Hz,
H-2), 3.54 (ddd, 1H, H-5), 3.30 and 3.26 (2 s, 6H, 2 × OCH3),
1.34 and 1.30 (2 s, 6H, 2 × CH3); 13C NMR (CDCl3) δ 137.1,
128.8, 128.4, 128.3 (CAr), 102.9 (C-1), 99.9, 99.8 (2 × C(OMe)-
(OR)), 74.3 (C-5), 72.0 (CH2Ph), 71.9 (C-4), 71.5 (C-2), 66.0 (C-
3), 61.6 (C-6), 48.3, 48.2 (2 × OCH3), 17.9, 17.8 (2 × CH3). Anal.
Calcd for C19H28O8: C, 59.36; H, 7.34. Found: C, 59.08; H, 7.26.
Benzyl 2,3-O-[(2R,3R)-2,3-Dimethoxybutane-2,3-diyl]-â-D-ga-
lactopyranoside-4,6-cyclic Sulfate (14). To a solution of benzyl
2,3-O-[(2R,3R)-2,3-dimethoxybutane-2,3-diyl]-â-D-galactopyrano-
side (17) (10.0 g, 26.0 mmol) in CH2Cl2 (50 mL) and pyridine (50
mL) cooled at 0 °C was added thionyl chloride (4.7 mL, 64.4 mmol)
in CH2Cl2 (20 mL) dropwise. After the addition, the reaction
mixture was warmed to room temperature and stirred for 2 h. The
progress of the reaction was followed by TLC (hexane/EtOAc, 1:1).
When the starting material 22 had been essentially consumed, the
reaction mixture was poured into crushed ice (100 mL), extracted
with CH2Cl2 (2 × 100 mL), washed with brine (50 mL), and dried
over Na2SO4. After removal of the solvent and excess pyridine
under reduced pressure, the crude product was passed through a
short silica gel column. The cyclic sulfites were subsequently
dissolved in CH3CN-CCl4-H2O mixture (10:10:1, 84 mL), and
sodium periodiate (7.2 g, 33.8 mmol) was added. To this reaction
mixture was added RuCl3·3H2O (100 mg) as a catalyst. The reaction
mixture was stirred at room temperature for 3 h. The progress of
the reaction was followed by TLC (hexane/EtOAc, 2:1). When the
cyclic sulfites had been consumed, a single slightly less polar spot
was observed. The reaction mixture was filtered through a short
column of Celite, and the Celite was washed with CH2Cl2 (2 × 20
mL). The filtrate was combined, and the solvents were evaporated.
The residue was redissolved in CH2Cl2 (200 mL), washed with H2O
(2 × 20 mL) and brine (2 × 10 mL), and dried over Na2SO4.
Purification by column chromatography (hexane/EtOAc, 1:1) gave
compound 14 as a colorless solid (7.1 g, 60% for two steps): mp
123-125 °C dec; [R]22D -165.3 (c 1.0, CH2Cl2); 1H NMR (CDCl3)
δ 7.40-7.22 (m, 5H, Ar), 5.08 (d, 1H, J1,2 ) 3.0 Hz, H-1), 4.95
parameters, Km, Kmobs (Km in the presence of inhibitor), and Vmax
,
of the enzyme. Ki values for each inhibitor were determined by the
equation Ki ) [I]/((Kmobs/Km) ( 1). The Ki reported for each
inhibitor was determined by averaging the Ki values obtained from
three different inhibitor concentrations.
Benzyl 2,3-O-[(2R,3R)-2,3-Dimethoxybutane-2,3-diyl]-â-D-ga-
lactopyranoside (17). To a solution of benzyl â-D-galactopyrano-
side (16)21 (10.0 g, 37.0 mmol) in dry MeOH (200 mL) were added
2,3-butanedione (4.0 mL, 45.6 mmol), trimethyl orthoformate (25
mL, 0.23 mol). CSA (300 mg) was added as a catalyst at room
temperature, and the reaction mixture was then refluxed for 24 h.
When TLC analysis of aliquots (hexane/EtOAc, 1:1) showed total
consumption of the starting material, the reaction was stopped by
the addition of triethylamine (1 mL). Purification by column
chromatography (hexane/EtOAc, 2:1) yielded compound 17 as a
1
colorless solid (10.2 g, 72%): [R]22 -58.7 (c 1.0, CH2Cl2); H
D
NMR (CDCl3) δ 7.40-7.24 (m, 5H, Ar), 4.90 and 4.74 (2 d, 2H,
JAB ) 12.3 Hz, CH2Ph), 4.60 (d, 1H, J1,2 ) 8.0 Hz, H-1), 3.98 (dd,
1H, J2,3 ) 10.3 Hz, H-2), 3.95 (m, 1H, H-4), 3.94 (dd, 1H, J5,6a
)
6.7 Hz, H-6a), 3.81 (dd, 1H, J5,6b ) 4.6, J6a,6b ) 11.7 Hz, H-6b),
3.74 (dd, 1H, J3,4 ) 3.0 Hz, H-3), 3.57 (m, 1H, H-5), 3.28 and
3.25 (2 s, 6H, 2 × OCH3), 1.33 and 1.32 (2 s, 6H, 2 × CH3); 13C
NMR (CDCl3) δ 138.0, 128.4, 127.7, 127.6 (CAr), 100.9 (C-1),
100.5, 100.0 (2 × C(OMe)(OR)), 75.2 (C-5), 71.3 (CH2Ph), 70.4
(C-3), 68.4 (C-4), 67.1 (C-2), 62.7 (C-6), 48.3, 48.2 (2 × OCH3),
17.9, 17.8 (2 × CH3). Anal. Calcd for C19H28O8: C, 59.36; H, 7.34.
Found: C, 59.33; H, 7.30.
Benzyl 2,3-O-[(2R,3R)-2,3-Dimethoxybutane-2,3-diyl]-â-D-glu-
copyranoside (19) and Benzyl 3,4-O-[(2R,3R)-2,3-Dimethoxybu-
tane-2,3-diyl]-â-D-glucopyranoside (20). To a solution of benzyl
â-D-glucopyranoside (18)22 (15.0 g, 55.5 mmol) in dry MeOH (200
mL) were added 2,3-butanedione (6.0 mL, 68.4 mmol) and methyl
orthoformate (37.5 mL, 0.34 mol). CSA (300 mg) was added as a
catalyst at room temperature, and the reaction mixture was then
refluxed for 24 h. When TLC analysis of aliquots (hexane/EtOAc,
1:1) showed total consumption of the starting material and the
formation of two main products 19 and 20. The reaction was
stopped by the addition of triethylamine (1 mL). Purification by
and 4.70 (2 d, 2H, JAB ) 12.1 Hz, CH2Ph), 4.78 (dd, 1H, J5,6a
)
1.7, J6a,6b ) 12.3 Hz, H-6a), 4.68 (d, 1H, H-4), 4.63 (dd, 1H, J5,6b
) 0.9 Hz, H-6b), 4.00 (dd, 1H, J2,3 ) 10.4, J3,4 ) 7. Hz, H-3),
3.92 (dd, 1H, H-2), 3.66 (br s, 1H, H-5), 3.30 and 3.26 (2 s, 6H, 2
× OCH3), 1.34 and 1.31 (2 s, 6H, 2 × CH3); 13C NMR (CDCl3) δ
138.1, 128.6, 128.0, 127.6 (CAr), 100.9, 100.0 (2 × C(OMe)(OR)),
100.4 (C-4), 81.1 (C-1), 74.6 (C-6), 71.2 (CH2Ph), 67.6 (C-2), 66.1
(C-3), 64.8 (C-5), 48.5, 48.3 (2 × OCH3), 17.9, 17.6 (2 × CH3).
Anal. Calcd for C19H26O10S: C, 51.11; H, 5.87. Found: C, 51.30;
H, 5.79.
Benzyl 2,3-O-[(2R,3R)-2,3-Dimethoxybutane-2,3-diyl]-â-D-glu-
copyranoside-4,6-cyclic Sulfate (15). To a solution of benzyl 2,3-
O-[(2R,3R)-2,3-dimethoxybutane-2,3-diyl]-â-D-glucopyranoside (19)
(14.0 g, 36.4 mmol) in CH2Cl2 (50 mL) and pyridine (50 mL)
6568 J. Org. Chem., Vol. 72, No. 17, 2007

Se, S, and N Analogues of Salacinol
cooled to 0 °C was added thionyl chloride (6.6 mL, 90.4 mmol)
dissolved in CH2Cl2 (20 mL) dropwise. After the addition, the
reaction mixture was warmed to room temperature and stirred for
2 h. The progress of the reaction was followed by TLC (hexane/
EtOAc, 1:1). When the starting material 19 had been essentially
consumed, the reaction mixture was poured into crushed ice (100
mL), extracted with CH2Cl2 (2 × 100 mL), washed with brine (50
mL), and dried with Na2SO4. After removal of the solvent and
excess pyridine under reduced pressure, the crude product was
passed through a short silica gel column to give a mixture of cyclic
sulfites. The cyclic sulfites were subsequently dissolved in a CH3-
CN-CCl4-H2O mixture (10:10:1, 105 mL), and sodium periodiate
(9.3 g, 43.6 mmol) was added. To this reaction mixture was added
RuCl3·3H2O (100 mg) as a catalyst, and the reaction mixture was
stirred at room temperature for 3 h. The progress of the reaction
was followed by TLC (hexane/EtOAc, 2:1). When the cyclic sulfite
had been consumed, a single slightly less polar spot was observed.
The reaction mixture was filtered through a short column of Celite,
and the Celite was washed with CH2Cl2 (2 × 20 mL). The filtrates
were combined and the solvents evaporated. The residue was
dissolved in CH2Cl2 (200 mL), washed with H2O (2 × 50 mL)
and brine (2 × 50 mL), and dried over Na2SO4. Purification by
column chromatography (hexane/EtOAc, 1:1) gave compound 15
as a colorless solid (10.9 g, 67% for two steps): mp 132-135 °C;
[R]22D -169.0 (c 1.0, CH2Cl2); 1H NMR (CDCl3) δ 7.40-7.23 (m,
5H, Ar), 4.90 and 4.71 (2 d, 2H, JAB ) 12.1 Hz, CH2Ph), 4.74 (d,
1H, H-1), 4.70-4.68 (d, 1H, H-4), 4.67 (dd, 1H, J5,6a ) 10.4 Hz,
H-6a), 4.53 (dd, 1H, J5,6b ) 5.0, J6a,6b ) 10.6 Hz, H-6b), 4.02 (dd,
1H, J3,4 ) 9.9 Hz, H-3), 3.80 (ddd, 1H, J4,5 ) 10.3 Hz, H-5), 3.70
(dd, 1H, J2,3 ) 9.2, J1,2 ) 8.5 Hz, H-2), 3.28 and 3.26 (2 s, 6H, 2
× OCH3), 1.38 and 1.35 (2 s, 6H, 2 × CH3). 13C NMR (CDCl3) δ
138.3, 128.6, 128.2, 127.6 (CAr), 101.1 (C-1), 100.3, 100.2 (2 ×
C(OMe)(OR)), 80.7 (C-4), 72.0 (C-6), 71.8 (CH2Ph), 69.7 (C-2),
68.5 (C-3), 65.8 (C-5), 48.5, 48.3 (2 × OCH3), 17.7, 17.6 (2 ×
CH3). Anal. Calcd for C19H26O10S: C, 51.11; H, 5.87. Found: C,
51.15; H, 6.09.
3.20 (2 s, 6H, 2 × OCH3), 1.24 (s, 6H, 2 × CH3); 13C NMR ((CD3)2-
CO) δ 159.9, 159.8, 159.7, 138.6, 130.1, 130.0, 129.8, 129.7, 129.6,
129.5, 129.3, 128.4, 127.5, 127.0, 114.1, 114.0, and 113.9 (CAr),
101.3 (C-1′), 100.0, 99.4 (2 × C(OR)2(OMe)2), 83.8 (C-3), 82.9
(C-2), 74.4 (C-3′), 72.7, 71.6, 71.1, and 70.6 (4 × CH2Ph), 70.7
(C-5′), 68.5 (C-4′), 67.0 (C-5), 66.9 (C-2′), 64.1 (C-4), 54.9, 54.8,
and 54.7 (3 × OCH3), 47.9 (C-6′), 47.4, 47.2 (2 × OCH3), 44.7
(C-1), 17.45, 17.44 (2 × CH3); MALDI MS m/e 1027.22 (M+
+
Na), 1005.34 (M+ + H), 925.23 (M+ + H - SO3). Anal. Calcd
for C48H60O16SSe: C, 57.42; H, 6.02. Found: C, 57.11; H, 6.14.
Benzyl 2,3-O-[(2R,3R)-2,3-Dimethoxybutane-2,3-diyl]-4-O-sul-
foxy-6-deoxy-6-[1,4-dideoxy-2,3,5-tri-O-p-methoxybenzyl-1,4-
episulfoniumylidene-D-arabinitol]-â-D-galactopyranoside Inner
Salt (22). Reaction of 12 (800 mg, 1.57 mmol) with the cyclic
sulfate 14 (840 mg, 1.88 mmol) in HFIP (2.0 mL) for 12 h at 75-
80 °C gave compound 22 as a colorless, amorphous foam (1.12 g,
75% based on 12): [R]22 -47.2 (c 1.0, CH2Cl2); 1H NMR
D
((CD3)2O) δ 7.60-6.80 (m, 17H, Ar), 4.86 and 4.68 (2 d, 2H, JAB
) 13.0 Hz, CH2Ph), 4.67 and 4.59 (2 d, 2H, JAB ) 13.0 Hz, CH2-
Ph), 4.62 (m, 1H, H-2), 4.50 and 4.44 (2 d, 2H, JAB ) 11.4 Hz,
CH2Ph), 4.48-4.42 (m, 2H, ) H-1′, H-3), 4.41 (s, 2H, CH2Ph),
4.34 (ddd, 1H, H-5′), 4.29 (m, 1H, H-4′), 4.26 (dd, 1H, J5′,6′a
)
6.2, J6′a,6′b ) 13.1 Hz, H-6′a), 4.14 (dd, 1H, J5′,6′b ) 4.3 Hz, H-6′b),
4.10 (m, 1H, H-4), 4.09 (dd, 1H, J1a,1b ) 13.1 Hz, H-1a), 3.90 (dd,
1H, J4,5a ) 3.4 Hz, J5aa,5b ) 10.3 Hz, H-5a), 3.88 - 3.79 (m, 4H,
H-5b, H-1b, H-2′, H-3′), 3.78, 3.76 (2 s, 9H, 3 × OCH3), 3.26 and
3.19 (2 s, 6H, 2 × OCH3), 1.25 and 1.24 (2 s, 6H, 2 × CH3); 13C
NMR ((CD3)2CO) δ 159.9, 159.8, 159.7, 138.6, 138.5, 132.8, 130.4,
130.1, 130.0, 129.8, 129.7, 129.6, 128.4, 127.5, 127.1, 112.6, 112.6,
and 112.5 (CAr), 101.5 (C-1′), 100.0, 99.4 (2 × C(OR)2(OMe)2),
82.8 (C-3), 82.4 (C-2), 73.7, 72.9, 71.3, and 70.9 (4 × CH2Ph),
71.9 (C-4), 71.6 (C-5′), 68.5 (C-3′), 67.1 (C-5), 67.0 (C-2′), 65.2
(C-4′), 54.9, 54.8 (3 × OCH3), 49.0 (C-6′), 47.7, 47.4 (2 × OCH3),
47.2 (C-1), 17.5, 17.4 (2 × CH3); MALDI MS m/e 979.39 (M+
+
Na), 957.42 (M+ + H), 877.43 (M+ + H - SO3); HRMS calcd
for C48H60O16S2Na 979.3215, found 979.3217.
General Procedure for the Preparation of Selenonium,
Sulfonium, and Ammonium Sulfates 21-26. A mixture of the
1,4-anhydro-2,3,5-O-p-methoxybenzyl-4-seleno-D-arabinitol 11 or
1,4-anhydro-2,3,5-O-p-methoxybenzyl-4-thio-D-arabinitol 12 and
the cyclic sulfate 14 or 15 in HFIP was placed in a sealed tube,
and K2CO3 (10 mg) was added. In the case of the reaction of 1,4-
dideoxy-1,4-imino-2,3,5-tri-O-p-methoxybenzyl-D-arabinitol 13 with
the cyclic sulfates 14 and 15, dry acetone was used instead of HFIP.
The stirred reaction mixture was heated at the indicated temperature
for the indicated time, as given below. The progress of the reaction
was followed by TLC (EtOAc/MeOH, 10:1). When the limiting
reagent had been essentially consumed, the mixture was cooled to
room temperature, diluted with CH2Cl2, and then evaporated to give
a syrupy residue. Purification by column chromatography (EtOAc
to EtOAc/MeOH, 10:1) gave the purified selenonium, sulfonium,
and ammonium salts 21-26.
Benzyl 2,3-O-[(2R,3R)-2,3-Dimethoxybutane-2,3-diyl]-4-O-sul-
foxy-6-deoxy-6-[1,4-dideoxy-2,3,5-tri-O-p-methoxybenzyl-1,4-
iminonium-D-arabinitol]-â-D-galactopyranoside Inner Salt (23).
Reaction of 13 (1.0 g, 2.02 mmol) with the cyclic sulfate 14 (1.09
g, 2.43 mmol) in dry acetone (3.0 mL) for 12 h at 55-60 °C gave
compound 23 as a colorless, amorphous foam (1.69 g, 89% based
on 13): [R]22D -38.5 (c 1.0, CH2Cl2); 1H NMR (CD2Cl2; pH ) 8)
δ 7.55-6.78 (m, 17H, Ar), 4.85 and 4.58 (2 d, 2H, JAB ) 12.4 Hz,
CH2Ph), 4.73 (m, 1H, H-4′), 4.52 and 4.35 (2 d, 2H, JAB ) 11.7
Hz, CH2Ph), 4.45 (m, 1H, H-1′), 4.62 (m, 1H, H-2), 4.50 and 4.44
(2 d, 2H, JAB ) 11.4 Hz, CH2Ph), 4.48-4.42 (m, 2H, ) H-3),
4.41 and 4.34 (2 d, 2H, JAB ) 11.8 Hz, CH2Ph), 4.31 and 4.27
(2d, 2H, JAB ) 11.5 Hz, CH2Ph), 3.88 - 3.70 (m, 5H, H-2, H-3,
H-2′, H-3′, H-5′), 3.76, 3.75, and 3.73 (3s, 9H, 3 × OCH3), 3.56
(dd, 1H, J4,5a ) 5.1, J5a,5b ) 9.9 Hz, H-5a), 3.44 (dd, 1H, J4,5b
)
3.8 Hz, H-5b), 3.34-3.20 (m, 2H, H-6′b, H-1′b), 3.27 and 3.24 (2
s, 6H, 2 × OCH3), 3.00-2.62 (m, 3H, H-6′a, H-1a, H-4), 1.32 and
1.23 (2 s, 6H, 2 × CH3); 13C NMR (CD2Cl2) δ 159.5, 159.4, 159.3,
137.8, 130.4, 130.1, 129.9, 129.8, 129.4, 128.4, 127.8, 127.7, 127.6,
113.9, 113.8, 113.7 (CAr), 112.0 (C-1′), 100.5, 100.0 (2 × C(OR)2-
(OMe)2), 84.2 (C-2), 81.1 (C-5′), 75.8 (C-4′), 74.7 (C-3), 72.7, 71.1,
71.0, and 70.6 (4 × CH2Ph), 70.4 (C-4), 69.3 (C-3′), 68.6 (C-5),
67.5 (C-2′), 58.4 (C-1), 55.4, 55.3, and 55.2 (3 × OCH3), 55.0
(C-6′), 48.5, 48.2 (2 × OCH3), 17.6, 17.5 (2 × CH3); MALDI MS
m/e 962.66 (M+ + Na), 939.63 (M+ + H), 860.78 (M+ + H -
SO3); HRMS calcd for C48H60NO16S 938.3640, found 938.3638.
Benzyl 2,3-O-[(2R,3R)-2,3-Dimethoxybutane-2,3-diyl]-4-O-sul-
foxy-6-deoxy-6-[1,4-dideoxy-2,3,5-tri-O-p-methoxybenzyl-1,4-
episelenoniumylidene-D-arabinitol]-â-D-glucopyranoside Inner
Salt (24). Reaction of 11 (800 mg, 1.43 mmol) with the cyclic
sulfate 15 (770 mg, 1.72 mmol) in HFIP (2.0 mL) for 12 h at 65-
70 °C gave compound 24 as a colorless, amorphous foam (1.01 g,
Benzyl 2,3-O-[(2R,3R)-2,3-dimethoxybutane-2,3-diyl]-4-O-sul-
foxy-6-deoxy-6-[1,4-dideoxy-2,3,5-tri-O-p-methoxybenzyl-1,4-
episelenoniumylidene-D-arabinitol]-â-D-galactopyranoside Inner
Salt (21). Reaction of 11 (800 mg, 1.43 mmol) with the cyclic
sulfate 14 (770 mg, 1.72 mmol) in HFIP (2.0 mL) for 12 h at 65-
70 °C gave compound 21 as a colorless, amorphous foam (1.04 g,
72% based on 11): [R]22 -48.4 (c 1.0, CH2Cl2); 1H NMR
D
((CD3)2O) δ 7.45-6.85 (m, 17H, Ar), 4.95 and 4.68 (2 d, 2H, JAB
) 12.7 Hz, CH2Ph), 4.76 (m, 1H, H-3′), 4.72 (ddd, 1H, H-2), 4.68
(d, 1H, J1′,2′ ) 7.4 Hz, H-1′), 4.64 and 4.60 (2 d, 2H, JAB ) 11.7
Hz, CH2Ph), 4.58 (m, 1H, H-3), 4.50 and 4.42 (2d, 2H, JAB ) 11.5
Hz, CH2Ph), 4.42 (m, 1H, H-5′), 4.32 and 4.28 (2 d, 2H, JAB
)
11.7 Hz, CH2Ph), 4.20 (dd, 1H, J5′,6′a ) 6.2 Hz, H-6′a), 4.18 (m,
1H, H-4), 4.14 (dd, 1H, J5′,6′b ) 2.1, J6′a,6′b ) 12.0 Hz, H-6′b),
3.96 (dd, 1H, J1a,1b ) 12.4, J1a,2 ) 1.3 Hz, H-1a), 3.90-3.87 (m,
2H, H-2′, H-4′), 3.79, 3.78, 3.75 (3 s, 9H, 3 × OCH3), 3.81-3.77
(m, 2H, H-5a, H-5b), 3.63 (dd, 1H, J1b,2 ) 3.2 Hz, H-1b), 3.23 and
70% based on 11): [R]22 -47.5 (c 1.0, CH2Cl2); 1H NMR
D
J. Org. Chem, Vol. 72, No. 17, 2007 6569

Liu et al.
((CD3)2O) δ 7.45-6.83 (m, 17H, Ar), 4.90 and 4.72 (2 d, 2H, JAB
) 12.4 Hz, CH2Ph), 4.84 (m, 1H, H-2), 4.73 (d, 1H, J1′,2′ ) 8.3
Hz, H-1′), 4.65 and 4.53 (2 d, 2H, JAB ) 11.3 Hz, CH2Ph), 4.66-
4.62 (m, 2H, CH2Ph), 4.59 (m, 1H, H-3), 4.46 and 4.42 (2 d, 2H,
JAB ) 11.9 Hz, CH2Ph), 4.36 (dd, 1H, J5′,6′a ) 3.1, J6′a,6′b ) 12.1
Hz, H-6′a), 4.33 (m, 1H, H-4), 4.30 (t, 1H, J3′,4′ ) J4′,5′ ) 9.5 Hz,
SO3). Anal. Calcd for C48H60KNO16S: C, 58.94; H, 6.18; N, 1.43.
Found: C, 58.65; H, 6.03; N, 1.45.
General Procedure for the Preparation of the Sulfate Salts
27-32. The protected coupled products 21-26 were dissolved in
CH2Cl2 (2 mL), TFA (10 mL) was then added, and the mixture
was stirred for 2 h at rt. The progress of the reaction was followed
by TLC analysis of aliquots (EtOAc/MeOH/H2O, 7:3:1). When the
starting material had been consumed, TFA and CH2Cl2 were
removed under reduced pressure. The residue was rinsed with CH2-
Cl2 (4 × 2 mL), and the CH2Cl2 was decanted to remove the cleaved
protecting groups. The remaining gum was dissolved in methanol
and purified by column chromatography (EtOAc and EtOAc/
MeOH, 2:1) to give the purified compounds 27-32 as colorless,
amorphous, and hygroscopic solids.
H-4′), 4.16 (dd, 1H, J5′,6′b ) 3.3 Hz, H-6′b), 4.08 (dd, 1H, J1a,1b
)
12.4 Hz, H-1a), 4.08-4.02 (m, 1H, H-5′), 3.86-3.76 (m, 3H, H-3′,
H-5a, H-5b), 3.80, 3.79, 3.77 (3 s, 9H, 3 × OCH3), 3.75 (dd, 1H,
J1b,2 ) 3.2, H-1b), 3.62 (dd, 1H, J2′,3′ ) 9.7, H-2′), 3.24 and 3.21
(2 s, 6H, 2 × OCH3), 1.26 and 1.25 (2 s, 6H, 2 × CH3); 13C NMR
((CD3)2O) δ 164.5, 164.4, 164.3, 143.0, 134.7, 134.4, 134.3, 134.2,
134.0, 133.9, 133.0, 132.2, 132.0, 118.6, 118.5, and 118.4(CAr),
105.1 (C-1′), 104.1, 104.0 (2 × C(OR)2(OMe)2), 88.8 (C-3), 87.7
(C-2), 77.9 (C-4′), 77.2 (C-5′), 77.2, 76.3, 75.9, and 75.3 (4 × CH2-
Ph), 74.6 (C-2′), 74.5 (C-3′), 71.4 (C-5), 70.0 (C-4), 59.5, 59.4 (3
× OCH3), 52.5 (C-6′), 51.8, 51.7 (2 × OCH3), 50.0 (C-1), 21.9,
21.7 (2 × CH3); MALDI MS m/e 1027.19 (M+ + Na), 1005.13
(M+ + H), 925.24 (M+ + H - SO3). Anal. Calcd for C48H60O16-
SSe: C, 57.42; H, 6.02. Found: C, 57.12; H, 6.09.
Benzyl 4-O-Sulfoxy-6-deoxy-6-[1,4-dideoxy-1,4-episelenoni-
umylidene-D-arabinitol]-â-D-galactopyranoside Inner Salt (27).
To a solution of 21 (900 mg, 0.90 mmol) in CH2Cl2 (2 mL) was
added TFA (10 mL) to yield compound 27 as a colorless,
amorphous, and hygroscopic solid (427 mg, 90%): [R]22 +11.6
D
1
(c 1.0, H2O); H NMR (CD3OD) δ 7.46-7.24 (m, 5H, Ar), 4.92
Benzyl 2,3-O-[(2R,3R)-2,3-Dimethoxybutane-2,3-diyl]-4-O-sul-
foxy-6-deoxy-6-[1,4-dideoxy-2,3,5-tri-O-p-methoxybenzyl-1,4-
episulfoniumylidene-D-arabinitol]-â-D-glucopyranoside Inner
Salt (25). Reaction of 12 (800 mg, 1.57 mmol) with the cyclic
sulfate 15 (840 mg, 1.88 mmol) in HFIP (2.0 mL) for 12 h at 75-
80 °C gave compound 25 as a colorless, amorphous foam (1.17 g,
78% based on 12): [R]22D -48.0 (c 1.0, CH2Cl2); 1H NMR ((CD3)2-
and 4.70 (2 d, 2H, JAB ) 11.9 Hz, CH2Ph), 4.73-4.70 (m, 1H,
H-2), 4.67-4.65 (m, 1H, H-4′), 4.49-4.44 (m, 2H, H-1′, H-3),
4.24-4.20 (m, 1H, H-5′), 4.15-4.10 (m, 1H, H-4), 3.99 (dd, 1H,
J4,5a ) 5.7, J5a,5b ) 11.7 Hz, H-5a), 3.94 (dd, 1H, J5′,6′a ) 5.3,
J6′a,6′b ) 11.5 Hz, H-6′a), 3.92 (dd, 1H, H-6′b), 3.91 (dd, 1H, J4,5b
) 2.4 Hz, H-5b), 3.73 (dd, 1H, J1a,2 ) 2.0, J1a,1b ) 11.9 Hz, H-1a),
3.70 (dd, 1H, J1b,2 ) 3.1 Hz, H-1b), 3.64 (dd, 1H, J3′,4′ ) 3.1, J2′,3′
) 9.8 Hz, H-3′), 3.58 (dd, 1H, J1′,2′ ) 7.7 Hz, H-2′); 13C NMR
(CD3OD) δ 137.9, 128.2, 128.0, 127.6 (CAr), 103.2 (C-1′), 79.3
(C-3), 78.7 (C-2), 77.2 (C-4′), 72.4 (C-4), 72.3 (C-3′), 71.5 (CH2-
Ph), 71.2 (C-2′), 69.6 (C-5′), 59.8 (C-6′), 47.3 (C-1), 44.5 (C-5);
MALDI MS m/e 553.22 (M+ + Na), 531.23 (M+ + H), 451.33
(M+ + H - SO3); HRMS calcd for C18H26O11SSeNa 553.0253,
found 553.0252.
CO) δ 7.45-6.85 (m, 17H, Ar), 4.89 and 4.70 (2 d, 2H, JAB
)
12.5 Hz, CH2Ph), 4.75 (m, 1H, H-2), 4.67 and 4.53 (2 d, 2H, JAB
) 11.2 Hz, CH2Ph), 4.66-4.60 (m, 3H, H-1′, CH2Ph), 4.54 (m,
1H, H-3), 4.48 (m, 2H, CH2Ph), 4.38 (dd, 1H, J1a,2 ) 3.4, J1b,2
)
3.1 Hz, H-1b), 4.10 (m, 2H, H-5′, H-6′a), 3.94-3.83 (m, 3H, H-5a,
H-5b, H-6′b), 3.82-3.79 (m, 1H, H-3′), 3.80, 3.79 and 3.78 (3 s,
9H, 3 × OCH3), 3.62 (dd, 1H, J1′,2′ ) 8.1, J2′,3′ ) 9.8 Hz, H-2′),
3.25 and 3.22 (2 s, 6H, 2 × OCH3), 1.25 and 1.24 (2 s, 6H, 2 ×
CH3); 13C NMR ((CD3)2CO) δ 164.6, 164.5, 142.9, 134.8, 134.7,
134.5, 134.3, 133.0, 132.2, 131.9, 118.7, 118.6, 118.5 (CAr), 105.3
(C-1′), 104.0 (2 × C(OR)2(OMe)2), 88.1 (C-3), 87.0 (C-2), 77.4,
76.3, 76.1, and 75.5 (4 × CH2Ph), 76.9 (C-4′), 76.8 (C-5′), 74.5
(C-3′), 74.4 (C-2′), 71.3 (C-5), 70.2 (C-4), 59.5, 59.4 (3 × OCH3),
53.6 (C-1), 52.0 (C-6′), 51.9, 51.7 (2 × OCH3), 21.9, 21.8 (2 ×
CH3); MALDI MS m/e 979.47 (M+ + Na), 957.46 (M+ + H),
877.50 (M+ + H - SO3); HRMS calcd for C48H60O16S2Na
979.3215, found 979.3215.
Benzyl 4-O-Sulfoxy-6-deoxy-6-[1,4-dideoxy-1,4-episulfoniu-
mylidene-D-arabinitol]-â-D-galactopyranoside Inner Salt (28).
To a solution of 22 (900 mg, 0.94 mmol) in CH2Cl2 (2 mL) was
added TFA (10 mL) to yield compound 28 as a colorless,
amorphous, and hygroscopic solid (395 mg, 87%): [R]22 +21.3
D
1
(c 1.0, H2O); H NMR (CD3OD) δ 7.46-7.26 (m, 5H, Ar), 4.92
and 4.72 (2 d, 2H, JAB ) 12.0 Hz, CH2Ph), 4.73 (m, 1H, H-4′),
4.63 (m, 1H, H-2), 4.50 (d, 1H, J1′,2′ ) 7.8 Hz, H-1′), 4.39 (m, 1H,
H-3), 4.24 (m, 1H, H-5′), 4.14-4.06 (m, 2H, H-4, H-5a), 3.96 (dd,
1H, J5′,6′a ) 9.6, J6′a,6′b ) 13.3 Hz, H-6′a), 3.91 (dd, 1H, J4,5b
)
9.2, J5a,5b ) 10.1 Hz, H-5b), 3.84 (dd, 1H, J5′,6′b ) 2.7 Hz, H-6′b),
3.80-3.73 (m, 2H, H-1a, H-1b), 3.73 (dd, 1H, J3′,4′ ) 3.0 Hz, H-3′),
3.59 (dd, 1H, J2′,3′ ) 9.7 Hz, H-2′); 13C NMR (CD3OD) δ 137.9,
128.2, 127.9, 127.7 (CAr), 103.3 (C-1′), 78.4 (C-3), 78.0 (C-2), 76.6
(C-4′), 72.2 (C-3′), 72.1 (C-4), 71.6 (CH2Ph), 71.1 (C-2′), 69.6 (C-
5′), 59.6 (C-5), 49.7 (C-1), 47.3 (C-6′); MALDI MS m/e 505.19
(M+ + Na), 483.16 (M+ + H), 403.28 (M+ + H - SO3); HRMS
calcd for C18H26O11S2Na 505.0809, found 505.0807.
Benzyl 2,3-O-[(2R,3R)-2,3-dimethoxybutane-2,3-diyl]-4-O-sul-
foxy-6-deoxy-6-[1,4-dideoxy-2,3,5-tri-O-p-methoxybenzyl-1,4-
iminonium-D-arabinitol]-â-D-glucopyranoside Inner Salt (26).
Reaction of 13 (1.0 g, 2.02 mmol) with the cyclic sulfate 15 (1.09
g, 2.43 mmol) in dry acetone (3.0 mL) for 12 h at 55-60 °C gave
compound 26 as a colorless, amorphous foam (1.71 g, 90% based
on 13): [R]22D -39.1 (c 1.0, CH2Cl2); 1H NMR (CD2Cl2; pH ) 8)
δ 7.42-6.60 (m, 17H, Ar), 4.72 and 4.47 (2 d, 2H, JAB ) 12.2 Hz,
CH2Ph), 4.55-4.49 (m, 1H, H-1′), 4.49 and 4.24 (2 d, 2H, JAB
)
Benzyl 4-O-Sulfoxy-6-deoxy-6-[1,4-dideoxy-1,4-iminonium-D-
arabinitol]-â-D-galactopyranoside Inner Salt (29). To a solution
of 23 (1.2 g, 1.28 mmol) in CH2Cl2 (2 mL) was added TFA (10
11.9 Hz, CH2Ph), 4.36 and 4.34 (2 d, 2H, JAB ) 12.0 Hz, CH2Ph),
4.18-4.14 (m, 1H, H-4′), 4.14 and 4.08 (2 d, 2H, JAB ) 11.3 Hz,
CH2Ph), 3.87 (t, 1H, J2′,3′ ) J3′,4′ ) 9.8 Hz, H-3′), 3.80-3.60 (m,
3H, H-2, H-3, H-5′), 3.68, 3.67, and 3.66 (3 s, 9H, 3 × OCH3),
3.53 (m, 1H, H-5a), 3.50 (dd, 1H, H-2′), 3.40-3.25 (m, 2H, H-6′a,
H-5b), 3.23 (dd, 1H, H-1a), 3.16 and 3.13 (2 s, 6H, 2 × OCH3),
2.72-2.55 (m, 3H, H-1b, H-4, H-6′b), 1.19 and 1.18 (2 s, 6H, 2 ×
CH3); 13C NMR (CD2Cl2) δ 159.5, 159.4, 159.3, 137.9, 137.8,
130.2, 130.1, 130.0, 129.8, 129.4, 128.2, 127.7, 127.5, 127.4, 114.0,
113.9, and 112.1 (CAr), 100.0 (C-1′), 99.8, 99.7 (2 2 × C(OR)2-
(OMe)2), 84.7 (C-2), 79.9 (C-5′), 75.5 (C-4′), 74.8 (C-3), 72.8, 71.2,
70.9, and 70.8 (4 × CH2Ph), 70.8 (C-3′), 70.0 (C-4), 69.9 (C-2′),
67.6 (C-5), 58.4 (C-1), 55.4, 55.3, and 55.2 (3 × OCH3), 52.1 (C-
6′), 48.4, 48.0 (2 × OCH3), 17.7, 17.6 (2 × CH3); MALDI MS
m/e 962.97 (M+ + Na), 940.00 (M+ + H), 860.13 (M+ + H -
mL) to yield compound 29 as a colorless, amorphous, and
1
hygroscopic solid (505 mg, 85%): [R]22 -1.3 (c 1.0, H2O); H
D
NMR (D2O; pH ) 8) δ 7.34-7.22 (m, 5H, Ar), 4.76 and 4.60 (2
d, 2H, JAB ) 11.7 Hz, CH2Ph), 4.50 (m, 1H, H-4′), 4.37 (d, 1H,
J1′,2′ ) 7.9 Hz, H-1′), 3.95 (ddd, 1H, H-2), 3.79-3.72 (m, 2H, H-3,
H-5′), 3.58 (dd, 1H, J3′,4′ ) 3.2 Hz, H-3′), 3.58-3.55 (m, 2H, H-5a,
H-5b), 3.40 (dd, 1H, J2′,3′ ) 10.0 Hz, H-2′), 3.04 (dd, 1H, J5′,6′a
2.2, J6′a,6′b ) 14.1 Hz, H-6′a), 2.91 (dd, 1H, J1a,2 ) 1.2, J1a,1b
)
)
11.1 Hz, H-1a), 2.68 (dd, 1H, J1b,2 ) 5.8 Hz, H-1b), 2.59 (dd, 1H,
J5′,6′b ) 8.4 Hz, H-6′b), 2.45 (ddd, 1H, H-4); 13C NMR (D2O) δ
136.7, 128.8, 128.7, 128.6 (CAr), 101.8 (C-1′), 78.8 (C-4′), 78.7
(C-3), 75.7 (C-2), 73.5 (C-5′), 72.0 (C-4), 71.9 (C-3′), 71.8 (CH2-
Ph), 70.9 (C-2′), 60.6 (C-5), 59.9 (C-1), 55.3 (C-6′); MALDI MS
6570 J. Org. Chem., Vol. 72, No. 17, 2007

Se, S, and N Analogues of Salacinol
m/e 488.04 (M+ + Na), 466.11 (M+ + H), 386.19 (M+ + H -
SO3); HRMS calcd for C18H26NO11S 464.1221, found 464.1224.
Benzyl 4-O-Sulfoxy-6-deoxy-6-[1,4-dideoxy-1,4-episelenoni-
umylidene-D-arabinitol]-â-D-glucopyranoside Inner Salt (30). To
a solution of 24 (900 mg, 0.90 mmol) in CH2Cl2 (2 mL) was added
TFA (10 mL) to yield compound 30 as a colorless, amorphous,
When the starting material had been essentially consumed, the pH
of the reaction mixture was carefully adjusted to 4 by the addition
of a 2 M HCl solution. After removal of the solvents under reduced
pressure, the residue was purified by column chromatography
(EtOAc and EtOAc/MeOH/H2O, 3:2:1) to give the purified
compounds 5-10 as colorless, amorphous, hygroscopic solids.
1,4-Dideoxy-1,4-[[(2S,3R,4R,5S)-2,4,5,6-tetrahydroxy-3-(sul-
foxy)hexyl]episelenoniumylidene]-D-arabinitol (5). Compound 27
(400 mg, 0.76 mmol) was dissolved in 90% AcOH (10 mL), Pd-
(OH)2/C (20%, 400 mg) was added, and the reaction mixture was
subjected to hydrogenolysis for 24 h at room temperature. The
resulting hemiacetals were reduced with NaBH4 (35 mg, 0.92 mmol)
and hygroscopic solid (389 mg, 82%): [R]22 -7.2 (c 1.0, H2O);
D
1H NMR (CD3OD) δ 7.46-7.24 (m, 5H, Ar), 4.90 and 4.72 (2 d,
2H, JAB ) 12.1 Hz, CH2Ph), 4.70-4.68 (m, 1H, H-2), 4.54 (d,
1H, J1′,2′ ) 7.9 Hz, H-1′), 4.45 (m, 1H, H-3), 4.14 (t, 1H, J3′,4′
)
J4′,5′ ) 8.9 Hz, H-4′), 4.14-4.10 (m, 1H, H-4), 4.08 (dd, 1H, J4,5a
) 2.8 Hz, H-5a), 3.98 (dd, 1H, J5′,6′a ) 5.7, J6′a,6′b ) 12.0 Hz, H-6′a),
3.97-3.92 (m, 1H, H-5′, H-6′b), 3.90 (dd, 1H, J5a,5b ) 12.3 Hz,
H-5b), 3.75-3.71 (m, 2H, H-1a, H-1b), 3.64 (dd, 1H, J3′,4′ ) 8.9
Hz, H-3′), 3.40 (dd, 1H, J1′,2′ ) 8.4 Hz, H-2′); 13C NMR (CD3OD)
δ 137.8, 128.3, 128.0, 127.7 (CAr), 102.7 (C-1′), 79.3 (C-3), 78.7
(C-2), 78.5 (C-4′), 74.4 (C-3′), 73.6 (C-2′), 73.0 (C-4), 71.7 (CH2-
Ph), 70.4 (C-5′), 59.7 (C-6′), 47.5 (C-1), 45.3 (C-5); MALDI MS
m/e 553.25 (M+ + Na), 531.28 (M+ + H), 451.31 (M+ + H -
SO3); HRMS calcd for C18H26O11SSeNa 553.0253, found 553.0251.
Benzyl 4-O-Sulfoxy-6-deoxy-6-[1,4-dideoxy-1,4-episulfoniumy-
lidene-D-arabinitol]-â-D-glucopyranoside Inner Salt (31). To a
solution of 25 (900 mg, 0.94 mmol) in CH2Cl2 (2 mL) was added
TFA (10 mL) to yield compound 31 as a colorless, amorphous,
to give compound 5 (123 mg, 50%) as a colorless, amorphous,
1
hygroscopic solid: [R]22 +43.3 (c 1.0, H2O); H NMR (D2O) δ
D
4.68 (dt, 1H, H-2), 4.51 (ddd, 1H, H-2′), 4.38 (dd, 1H, J2,3 ) 3.6,
H-3), 4.30 (dd, 1H, J2′,3′ ) 1.3, J3′,4′ ) 9.1 Hz, H-3′), 4.05 (ddd,
1H, J3,4 ) 3.1, H-4), 3.97 (dd, 1H, J4,5a ) 5.1, J5a,5b ) 12.5 Hz,
H-5a), 3.89 (dt, 1H, J5′,6′a ) J5′,6′b ) 6.3 Hz, H-5′), 3.87-3.84 (m,
2H, H-1′a, H-1′b), 3.83 (dd, 1H, J4,5b ) 3.8 Hz, H-5b), 3.72 (dd,
1H, J4′,5′ ) 0.9 Hz, H-4′), 3.69-3.64 (2d, 2H, H-1a, H-1b), 3.54
(d, 2H, H-6′a, H-6′a); 13C NMR (D2O) δ 78.8 (C-3′), 78.5 (C-3),
77.7 (C-2), 69.6 (C-4), 69.5 (C-5′), 68.7 (C-4′), 65.6 (C-2′), 62.8
(C-6′), 59.4 (C-5), 48.6 (C-1′), 44.8 (C-1); MALDI MS m/e 465.27
(M+ + Na), 363.36 (M+ + H - SO3); HRMS calcd for C11H22O11-
SSeNa 464.9940, found 464.9943.
and hygroscopic solid (408 mg, 90%): [R]22 -8.2 (c 1.0, H2O);
D
1H NMR (D2O) δ 7.36-7.26 (m, 5H, Ar), 4.72 (s, 2H, CH2Ph),
4.55 (ddd, 1H, H-2), 4.52 (d, 1H, J1′,2′ ) 8.1 Hz, H-1′), 4.28 (m,
1H, H-3), 4.07 (dd, 1H, J4′,5′ ) 9.2 Hz, H-4′), 3.96-3.90 (m, 2H,
H-5′, H-6′a), 3.86 (dd, 1H, J4,5a ) 8.3, J5a,5b ) 15.4 Hz, H-5a),
3.80-3.71 (m, 3H, H-4, H-5b, H-6′b), 3.62 (dd, 1H, J1a,2 ) 4.1,
J1a,1b ) 13.2 Hz, H-1a), 3.56 (t, 1H, J2′,3′ ) J3′,4′ ) 9.4 Hz, H-3′),
3.53 (dd, 1H, J1b,2 ) 5.1 Hz, H-1b), 3.29 (dd, 1H, J2′,3′ ) 9.4 Hz,
H-2′); 13C NMR (D2O) δ 136.9, 129.0, 128.8, 128.7 (CAr), 102.4
(C-1′), 77.8 (C-3), 77.5 (C-4′), 76.8 (C-2), 73.5 (C-3′), 73.0 (CH2-
Ph), 72.7 (C-2′), 70.2 (C-5′), 70.1 (C-4), 58.7 (C-5), 47.6 (C-6′),
1,4-Dideoxy-1,4-[[(2S,3R,4R,5S)-2,4,5,6-tetrahydroxy-3-(sul-
foxy)hexyl]episulfoniumy lidene]-D-arabinitol (6). Compound 28
(300 mg, 0.62 mmol) was dissolved in 90% AcOH (10 mL), Pd-
(OH)2/C (20%, 300 mg) was added, and the reaction mixture was
subjected to hydrogenolysis for 24 h at room temperature. The
resulting hemiacetals were reduced with NaBH4 (29 mg, 0.77 mmol)
to give compound 6 (127 mg, 52%) as a colorless, amorphous,
hygroscopic solid. The 1H NMR and 13C NMR data matched those
reported in our previous publication.14
1,4-Dideoxy-1,4-[[(2S,3R,4R,5S)-2,4,5,6-tetrahydroxy-3-(sul-
foxy)hexyl]iminonium]-D-arabinitol (7). Compound 29 (500 mg,
1.07 mmol) was dissolved in 90% AcOH (10 mL), Pd(OH)2/C
(20%, 500 mg) was added, and the reaction mixture was subjected
to hydrogenolysis for 24 h at room temperature. The resulting
hemiacetals were reduced with NaBH4 (50 mg, 1.32 mmol) to give
compound 7 (250 mg, 62%) as a colorless, amorphous, hygroscopic
solid: [R]22D +44.5 (c 1.0, H2O); 1H NMR (D2O + K2CO3) δ 4.27
47.4 (C-1); MALDI MS m/e 505.41 (M+ + Na), 483.36 (M+
+
H), 403.44 (M+ + H - SO3); HRMS calcd for C18H26O11S2Na
505.0809, found 505.0809.
Benzyl 4-O-Sulfoxy-6-deoxy-6-[1,4-dideoxy-1,4-iminonium-D-
arabinitol]-â-D-glucopyranoside Inner Salt (32). To a solution
of 26 (1.2 mg, 1.28 mmol) in CH2Cl2 (2 mL) was added TFA (10
mL) to yield compound 32 as a colorless, amorphous, and
1
hygroscopic solid (517 mg, 87%): [R]22 -2.5 (c 1.0, H2O); H
(dd, 1H, J3′,4′ ) 8.6, J3′,2′ ) 1.3 Hz, H-3′), 4.06 (ddd, 1H, J2′,1a′ )
D
NMR (D2O; pH ) 8) δ 7.34-7.23 (m, 5H, Ar), 4.74 and 4.62 (2
d, 2H, JAB ) 11.7 Hz, CH2Ph), 4.44 (d, 1H, J1′,2′ ) 8.0 Hz, H-1′),
3.95 (ddd, 1H, H-2), 3.85 (dd, 1H, J4′,5′ ) 9.5 Hz, H-4′), 3.77 (dd,
1H, J2,3 ) 2.9, J3,4 ) 5.2 Hz, H-3), 3.57 (d, 2H, H-5a, H-5b), 3.54
(m, 1H, H-5′), 3.53 (dd, 1H, J3′,4′ ) 9.3 Hz, H-3′), 3.34 (dd, 1H,
4.8, J2′,1b′ ) 8.0 Hz, H-2′), 3.95 (ddd, 1H, J2,1a) 2.1, J2,1b ) 5.8
Hz, H-2), 3.84 (dt, 1H, J5′,4′ ) 1.5, J5′,6 ) 5.5 Hz, H-5′), 3.78 (dd,
1H, J3,2 ) 2.8, J3,4 ) 5.2 Hz, H-3), 3.72 (dd, 1H, H-4′), 3.57 (dd,
1H, J5a,5b ) 12.0, J5a,4 ) 5.2 Hz, H-5a), 3.56 (dd, 1H, J5b,4 ) 4.3
Hz, H-5b), 3.53 (d, 2H, H2-6), 2.97 (dd, 1H, J1a′,1b′ ) 13.2 Hz,
H-1a′), 3.94 (dd, 1H, J1a,1b ) 11.3, H-1a), 2.70 (dd, 1H, H-1b′),
2.50 (dd, 1H, H-1b′), 2.42 (ddd, 1H, H-4); 13C NMR (D2O) δ 78.9
(C-3′), 78.8 (C-3), 75.8 (C-2), 72.4 (C-4), 70.0 (C-5′), 69.1 (C-4′),
68.6 (C-2′), 62.9 (C-6′), 60.6 (C-5), 59.8 (C-1), 58.0 (C-1′); MALDI
MS m/e 400.09 (M+ + Na), 298.35 (M+ + H - SO3); HRMS
calcd for C11H22NO11S 376.0908, found 376.0912.
1,4-Dideoxy-1,4-[[(2S,3S,4R,5S)-2,4,5,6-tetrahydroxy-3-(sul-
foxy)hexyl]episelenonium ylidene]-D-arabinitol (8). Compound
30 (400 mg, 0.76 mmol) was dissolved in 90% AcOH (10 mL),
Pd(OH)2/C (20%, 400 mg) was added, and the reaction mixture
was subjected to hydrogenolysis for 24 h at room temperature. The
resulting hemiacetals were reduced with NaBH4 (35 mg, 0.92 mmol)
H-6′a), 3.24 (dd, 1H, J2′,3′ ) 9.4 Hz, H-2′), 2.94 (dd, 1H, J1a,2
1.2 Hz, H-1a), 2.68 (dd, 1H, J1b,2 ) 5.8, J1a,1b ) 11.3 Hz, H-1b),
)
2.46 (ddd, 1H, J4,5a ) J4,5b ) 10.1 Hz, H-4), 2.38 (dd, 1H, J5′,6′b
)
8.7, J6′a,6′b ) 14.2 Hz, H-6′b); 13C NMR (D2O) δ 136.7, 128.9,
128.6, 128.5 (CAr), 101.2 (C-1′), 78.8 (C-4′), 78.7 (C-3), 75.8 (C-
2), 74.3 (C-3′), 74.2 (C-5′), 73.1 (C-2′), 72.1 (C-4), 72.0 (CH2Ph),
60.5 (C-5), 60.2 (C-1), 54.8 (C-6′); MALDI MS m/e 488.05 (M+
+ Na), 466.12 (M+ + H), 386.23 (M+ + H - SO3); HRMS calcd
for C18H26NO11S 464.1221, found 464.1220.
General Procedure for the Preparation of the Final Com-
pounds 5-10. The partially deprotected compounds 27-32 were
dissolved in 90% AcOH (10 mL), Pd(OH)2/C (20%, 300-500 mg,
depending on the amount of starting material) was added, and the
reaction mixture was subjected to hydrogenolysis for 24 h at rt.
After the Pd(OH)2/C was filtered, water (100 mL) was used to wash
it repeatedly. The combined filtrate was then evaporated under
reduced pressure. The remaining gum was dissolved in water (20
mL), and the pH of the solution was carefully adjusted to 8 by
addition of 2 M NaOH solution. NaBH4 (1.2 equiv of starting
material) was slowly added to the reaction mixture. The progress
of the reaction was followed by TLC (EtOAc/MeOH/H2O, 7:3:1).
to give compound 8 (108 mg, 43%) as a colorless, amorphous,
1
hygroscopic solid: [R]22 +22.3 (c 1.0, H2O); H NMR (D2O) δ
D
4.66 (m, 1H, J1a,2 ) J1b,2 ) 7.8 Hz, H-2), 4.36 (dd, 1H, J2,3 ) 3.5,
J3,4 ) 3.0 Hz, H-3), 4.32 (ddd, 1H, H-2′), 4.26 (dd, 1H, J2′,3′
)
1.5, J3′,4′ ) 7.3 Hz, H-3′), 4.04 (ddd, 1H, J4,5a ) 5.1, J4,5b ) 9.1
Hz, H-4), 3.94 (dd, 1H, J5a,5b ) 12.5 Hz, H-5a), 3.94 (dd, 1H, J1′a,2′
) 3.8, J1′a,1′b ) 12.3 Hz, H-1′a), 3.82 (dd, 1H, J1′b,2′ ) 5.9 Hz,
H-1′b), 3.78 (m, 3H, H-5b, H-4′, H-5′)), 3.67 (d, 2H, H-1a, H-1b),
3.62 (dd, 1H, J5′,6′a ) 3.4, J6′a,6′b ) 8.5 Hz, H-6′a), 3.51 (dd, 1H,
J. Org. Chem, Vol. 72, No. 17, 2007 6571

Liu et al.
J5′,6′b ) 5.8 Hz, H-6′b); 13C NMR (D2O) δ 80.0 (C-3′), 78.5 (C-3),
77.6 (C-2), 71.6 (C-5′), 70.0 (C-4), 69.0 (C-4′), 66.5 (C-2′), 62.3
(C-6′), 59.4 (C-5), 48.5 (C-1′), 45.0 (C-1); MALDI MS m/e 465.13
(M+ + Na), 363.23 (M+ + H - SO3); HRMS calcd for C11H22O11-
SSeNa 464.9940, found 464.9939.
1,4-Dideoxy-1,4-[[(2S,3S,4R,5S)-2,4,5,6-tetrahydroxy-3-(sul-
foxy)hexyl]episulfoniumylidene]-D-arabinitol (9). Compound 31
(300 mg, 0.62 mmol) was dissolved in 90% AcOH (10 mL), Pd-
(OH)2/C (20%, 300 mg) was added, and the reaction mixture was
subjected to hydrogenolysis for 24 h at room temperature. The
resulting hemiacetals were reduced with NaBH4 (29 mg, 0.77 mmol)
to give compound 9 (95 mg, 39%) as a colorless, amorphous,
hygroscopic solid. The 1H NMR and 13C NMR data matched those
reported in our previous publication.14
1,4-Dideoxy-1,4-[[(2S,3S,4R,5S)-2,4,5,6-tetrahydroxy-3-(sul-
foxy)hexyl]iminonium]-D-arabinitol (10). Compound 32 (500 mg,
1.07 mmol) was dissolved in 90% AcOH (10 mL), Pd(OH)2/C
(20%, 500 mg) was added, and the reaction mixture was subjected
to hydrogenolysis for 24 h at room temperature. The resulting
hemiacetals were reduced with NaBH4 (50 mg, 1.32 mmol) to give
compound 10 (218 mg, 54%) as a colorless, amorphous, hygro-
scopic solid: [R]22D -2.7 (c 1.0, H2O); 1H NMR (D2O + K2CO3)
δ 4.26 (dd, 1H, J2′,3′ ) 5.0, J3′,4')′ ) 2.1 Hz, H-3′), 3.97 (m, 2H,
H-2, H-2′), 3.80 (dd, 1H, J4′,5′ ) 6.4 Hz, H-4′), 3.77 (dd, 1H, J3,4
) 4.9, J3,2 ) 2.8 Hz, H-3), 3.73 (ddd, 1H, J5′,6a′ )3.6, J5′,6b′ ) 6.3
Hz, H-5′), 3.61 (dd, 1H, J6a′,6b′ ) 12.0 Hz, H-6a′), 3.57 (dd, 1H,
J5a,5b ) 9.8, J5a,4 ) 5.6 Hz, H-5a), 3.55 (dd, 1H, J5b,4 ) 5.3 Hz,
H-5b), 3.50 (dd, 1H, H-6b′), 3.09 (dd, 1H, J1a,2 ) 5.1, J1a,1b ) 13.3
Hz, H-1a), 2.98 (dd, 1H, J1a′,1b′ ) 11.3, J1a′,2′ ) 1.8 Hz, H-1a′),
2.71 (dd, 1H, J1b′,2′ ) 5.7 Hz, H-1b′), 2.44 (ddd, 1H, H-4), 2.39
(dd, 1H, J1a,2 ) 7.6 Hz, H-1b); 13C NMR (D2O) δ 80.4 (C-3′),
78.7 (C-3), 75.8 (C-2), 72.3 (C-4), 71.9 (C-5′), 70.6 (C-4′), 69.6
(C-2′), 62.4 (C-6′), 60.9 (C-1), 59.7 (C-5), 56.9 (C-1′); MALDI
MS m/e 400.03 (M+ + Na), 298.22 (M+ + H - SO3); HRMS
calcd for C11H22NO11S 376.0908, found 376.0908.
Acknowledgment. We are grateful to the Canadian Institutes
of Health Research for financial support and to B. D. Johnston
for helpful discussions.
Supporting Information Available: General experimental
1
procedures and copies of H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO071045M
6572 J. Org. Chem., Vol. 72, No. 17, 2007