Synthesis of sulfonium sulfate analogues of disaccharides and their conversion to chain-extended homologues of salacinol: New glycosidase inhibitors

Article abstract of DOI:10.1021/jo052252u

Four chain extended homologues of salacinol, a naturally occurring glycosidase inhibitor, were prepared for evaluation as inhibitors of glucosidase enzymes involved in the breakdown of carbohydrates. The syntheses involved the reactions of 1,4-anhydro-2,3

Full text of DOI:10.1021/jo052252u

Synthesis of Sulfonium Sulfate Analogues of Disaccharides and
Their Conversion to Chain-Extended Homologues of Salacinol:
New Glycosidase Inhibitors
Blair D. Johnston, Henrik H. Jensen, and B. Mario Pinto*
Department of Chemistry, Simon Fraser UniVersity, Burnaby, B.C., Canada V5A 1S6
bpinto@sfu.ca
ReceiVed October 28, 2005
Four chain extended homologues of salacinol, a naturally occurring glycosidase inhibitor, were prepared
for evaluation as inhibitors of glucosidase enzymes involved in the breakdown of carbohydrates. The
syntheses involved the reactions of 1,4-anhydro-2,3,5-tri-O-benzyl-4-thio-D-arabinitol with cyclic sulfate
derivatives of different monosaccharides. Debenzylation of the products afforded the novel sulfonium
sulfate derivatives of D-glucose, D-galactose, D-arabinose, and D-xylose that are of interest in their own
right as glycosidase inhibitors. Reduction to the corresponding alditols then afforded the homologues of
salacinol containing polyhydroxylated, acyclic chains of 5- and 6-carbons, differing in stereochemistry
at the stereogenic centers. Three of the chain-extended homologues inhibited recombinant human maltase
glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides
in the small intestine, with Ki values in the low micromolar range, of approximately the same magnitude
as salacinol, thus providing lead candidates for the treatment of Type 2 diabetes.
Introduction
site carboxylic acids and bind to enzymes as the ammonium
salts.4 We have proposed that sulfonium salts may mimic
ammonium salts and could thus act as glycosidase inhibitors.
Indeed, a sulfonium salt analogue 15 of the well-known bicyclic
azasugar castanospermine 2 was a weak (Ki, mM) inhibitor of
Sulfonium salts are known to exhibit enhanced stability in
comparison to their lighter congeners, the oxonium ions.
Nevertheless, these salts are reactive species and simple
sulfonium salts have found widespread use as photoinitiators
for cationic polymerizations1 or as precursors to the synthetically
important sulfur ylides.2 More highly functionalized sulfonium
salts are generally only encountered as proposed intermediates
in isomerization or rearrangement reactions.3
Sulfonium salts resemble tertiary amines yet bear permanent
positive charges. Amines are ubiquitous in physiologically active
compounds, and natural and synthetic sugar-mimetic amines are
well-known as inhibitors of glycosidase enzymes.4 It has often
been hypothesized that such inhibitors are protonated by active
glucoamylase G2 and bound to the enzyme in a high-energy
boat conformation, presumably resembling the oxacarbenium
ion transition state in the glycosidase-mediated hydrolysis
reaction.6 Other groups have also taken up this theme and the
synthesis of a sulfonium analogue of swainsonine7 and sulfo-
nium analogues of the 1-aza glycosidase inhibitor isofucofago-
* To whom correspondence should be addressed. Phone: (604) 291-4884.
Fax: (604) 291-5424.
(1) Crivello, J. V. AdV. Polym. Sci. 1984, 62, 1-48.
(2) Trost, B. M.; Melvin, L. S., Jr. Sulfur Ylides, Emerging Synthetic
Intermediates; Organic Chemistry, Vol. 31; Academic Press: New York,
1975.
(3) Fox, D. J.; House, D.; Warren, S. Angew. Chem., Int. Ed. 2002, 41,
2462-2482.
(4) Stutz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond; Wiley-VCH: New York, 1999.
(5) Svansson, L.; Johnston, B. D.; Gu, J.-H.; Patrick, B.; Pinto, B. M. J.
Am. Chem. Soc. 2000, 122, 10769-10775.
(6) Johnson, M. A.; Jensen, M. T.; Svensson, B.; Pinto, B. M. J. Am.
Chem. Soc. 2003, 125, 5663-5670.
(7) Izquierdo, I.; Plaza, M. T.; Aragon, F. Tetrahedron: Asymmetry 1996,
7, 2567-2575.
10.1021/jo052252u CCC: $33.50 © 2006 American Chemical Society
Published on Web 01/10/2006
J. Org. Chem. 2006, 71, 1111-1118
1111

Johnston et al.
mine have appeared.8 Most recently, Siriwardena et al.9 have
reported an inventive synthetic route for a sulfonium salt
analogue of the bicyclic glycosidase inhibitor swainsonine. This
compound was found to be a selective, potent inhibitor for
certain R-mannosidase enzymes.
A naturally occurring, stable sulfonium salt, salacinol 3,
having an internal sulfate counterion was isolated as one of the
physiologically active components of the medicinal plant Salacia
reticulata.10 This compound is the first of a new class of
naturally occurring glycosidase inhibitors, and is responsible,
at least in part, for the beneficial effects of the ingestion of
Salacia extracts as a traditional treatment for diabetes.11 It has
been found to be a potent inhibitor of intestinal glycosidase
enzymes,10,12-14 and should thus attenuate the undesirable spike
in blood glucose levels that is experienced by diabetics after
consuming a meal rich in carbohydrates.15 Another related
sulfonium sulfate, kotalanol 4,12 was subsequently isolated from
cinol,20 and six-membered-ring analogues of salacinol and its
heteroanalogues.21 Significantly, salacinol 3 and its selenium
analogue, blintol, have been shown to be very effective in
controlling blood glucose levels in rats after a carbohydrate meal,
thus providing lead candidates for the treatment of Type 2
diabetes.19c These agents act by inhibiting the membrane-bound
glucosidase enzymes in the small intestine that break down
oligosaccharides to glucose.19c The structure-activity studies
have revealed an interesting variation in the inhibitory power
of these compounds against glycosidase enzymes of different
origin. The molecular basis for this selectivity is being
investigated through structural studies of the enzyme-bound
inhibitors, using molecular modeling in conjunction with STD-
NMR techniques22 and X-ray crystallography.23
Initial findings with Golgi R-mannosidase II have indicated
that the alditol side chain extends out of the substrate binding
site,23 and thus the length of the chain may not be of particular
importance for binding specificity and inhibitor action with this
particular enzyme. However, the reported greater inhibitory
potency of kotalanol 4 than salacinol 3 with other glucosidase
enzymes12 suggests that this conclusion might not be general.
To test this hypothesis, and to provide new candidates for the
treatment of Type 2 diabetes, we now report the synthesis of
four salacinol analogues 5-8 having either a five- or six-carbon
alditol side chain.
the Salacia extracts and was shown to possess even greater
inhibitory power for certain glycosidase enzymes. A close
relationship to the prototypical salacinol structure is obvious,
with the alditol side chain being simply extended by three
carbons. Although the absolute configuration of the stereogenic
centers in the heptitol chain has not been reported, the 1,4-
thioanhydro pentitol portion of kotalanol 4 has the identical
D-arabinitol configuration as salacinol 3.
We16 and others17 have reported the synthesis of salacinol 3
and some of its enantio- and diastereoisomers. In addition, we
have undertaken a limited structure-activity study of related
compounds. Thus far, we have reported the synthesis and
glycosidase inhibitory activities of ammonium18 and sele-
nonium19 analogues of salacinol, other stereoisomers of sala-
(8) Ulgar, V.; Fernandez-Bolanos, J. G.; Bols, M. J. Chem. Soc., Perkin
Trans. 1 2002, 1242-1246.
(9) Siriwardena, A.; Strachan, H.; El-Dahar, S.; Way, G.; Winchester,
B.; Glushka, J.; Moremen, K.; Boons, G.-J. ChemBioChem 2005, 6, 845-
848.
(10) Yoshikawa, M.; Murakami, T.; Shimada, H.; Matsuda, H.; Yama-
hara, J.; Tanabe, G.; Muraoka, O. Tetrahedron Lett. 1997, 38, 8367-8370.
(11) Wolf, B. W.; Weisbrode, S. E. Food Chem. Toxicol. 2003, 41, 867-
874.
In the course of these studies we had occasion to prepare
and examine the stability of sulfonium-sulfate disaccharide
analogues. These compounds 9-12 are representatives of a new
class of carbohydrate derivatives since they are disaccharide
analogues in which a permanent positive charge resides on the
chain-linkage atom, which simultaneously acts as the ring
heteroatom for an anhydroalditol unit. This feature may ap-
proximate the partial positive charges that are generated on
analogous atoms in the transition states for enzyme-catalyzed
disaccharide hydrolysis reactions. Electrostatic and hydrogen-
bonding interactions of enzyme active-site functional groups
with the charged atom could enhance binding and lead to the
discovery of new glycosidase inhibitors.
(12) Yoshikawa, M.; Murakami, T.; Yashiro, K.; Matsuda, H. Chem.
Pharm. Bull. 1998, 46, 1339-1340.
(13) Yuasa, H.; Takada, J.; Hashimoto, H. Bioorg. Med. Chem. Lett.
2001, 11, 1137-1139.
(14) 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.
(15) Serasinghe, S.; Serasinghe, P.; Yamazaki, H.; Nishiguchi, K.;
Hombhanje, F.; Nakanishi, S.; Sawa, K.; Hattori, M.; Namba, T. Phytother.
Res. 1990, 4, 205-206.
(16) Ghavami, A.; Johnston, B. D.; Pinto, B. M. J. Org. Chem. 2001,
66, 2312-2317.
(17) Yuasa, H.; Takada, J.; Hashimoto, H. Tetrahedron Lett. 2000, 41,
6615-6618.
(20) 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.
(21) Szczepina, M. G.; Johnston, B. D.; Yuan, Y.; Svensson, B.; Pinto.
B. M. J. Am. Chem. Soc 2004, 126, 12458-12469.
(22) Wen, X.; Yuan Y.; Kuntz, D. A.; Rose, D. R.; Pinto B. M.
Biochemistry 2005, 44, 6729-6737.
(23) Kuntz, D.; Ghavami, A.; Johnston, B. D.; Pinto, B. M.; Rose D. R.
Tetrahedron: Asymmetry 2005, 16, 25-32.
(18) Ghavami, A.; Johnston, B. D.; Jensen, M. T.; Svensson, B.; Pinto,
B. M. J. Am. Chem. Soc. 2001, 123, 6268-6271.
(19) (a) Johnston, B. D.; Ghavami, A.; Jensen, M. T.; Svensson, B.; Pinto,
B. M. J. Am. Chem. Soc. 2002, 124, 8245-8250. (b) Liu, H.; Pinto, B. M.
J. Org. Chem. 2005, 70, 753-755. (c) Pinto, B. M.; Johnston, B. D.;
Ghavami, A.; Szczepina, M. G.; Liu, H.; Sadalapure, K. U.S. Patent, Filed
June 25, 2004.
1112 J. Org. Chem., Vol. 71, No. 3, 2006

Sulfonium Sulfate Analogues of Disaccharides
SCHEME 2
Results and Discussion
Our synthetic strategy was analogous to that used for the
synthesis of salacinol 3 and related structures in that it involved
the opening of a 1,3-cyclic sulfate ring by nucleophilic attack
of a thioether.16,17,20 A literature survey revealed the following
1,3-cyclic sulfates of carbohydrate derivatives as potential
acceptors: D-glucopyranoside-4,6-O-cyclic sulfates 1324 and
1425 as well as the D-xylose derivative 1526 and the D-galactose
derivative 16.27 These derivatives have been shown to react with
oxygen, nitrogen, or sulfur nucleophiles selectively at the
primary carbon. The methyl pyranosides 13 and 14 were rejected
due to the probable harsh conditions necessary for hydrolysis
of the glycoside bond during the deprotection of the proposed,
and possibly sensitive, sulfonium-ion intermediates. Compounds
15 and 16 were deemed to be more suitable and were prepared
The cyclic sulfate derivatives 15 and 16 were prepared
uneventfully. However, the trans fused [5.6] bicyclic systems
in compounds 21 and 22 impart considerably more ring strain
to these compounds than the cis fused [5.6] bicyclic compound
15 or the [6.6] cis or trans fused ring systems of compounds 16
or 18. This resulted in the formation of substantial amounts of
bridging sulfate dimers by intermolecular reactions during the
synthesis of 21 and 22. The careful control of reactant
concentration and temperature gave modest yields of monomeric
cyclic sulfates 21 and 22, which were isolated as pure crystalline
solids.
The required diol 20 was prepared by analogy to the methods
already reported for 19.30 Thus, benzyl D-arabinofuranoside 2431
was prepared by glycosylation of benzyl alcohol with the
glycosyl bromide 23,32 using the Helferich method. The benzoyl
protecting groups were removed to give 25 and the 3- and
5-positions were then blocked as the tetraisopropyldisiloxane
derivative 26. The 2-hydroxyl group was protected as the benzyl
ether 27 in a reaction that required careful monitoring to prevent
premature silyl group cleavage and subsequent benzylation of
the exposed hydroxyl groups. The silyl protecting group was
finally removed by treatment of 27 with fluoride to give the
diol 20 (Scheme 2).
by the literature methods. Three other cyclic sulfates were
prepared by new methods. Thus, benzyl D-glucopyranoside 4,6-
cyclic sulfate 18 was prepared by the Sharpless method28 from
the known benzyl D-glucopyranoside 17,29 and similar treatment
of the methyl or benzyl D-arabinofuranosides 1930 and 20 yielded
the cyclic sulfates 21 and 22 (Scheme 1).
SCHEME 1
(27) Dagron, F.; Lubineau, A. J. Carbohydr. Chem. 2000, 19, 311-
321.
(28) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538-
7539.
(29) Bazin, H. G.; Wolff, M. W.; Linhardt, R. J. J. Org. Chem. 1999,
64, 144-152.
(24) Bazin, H. G.; Linhardt, R. J. Synthesis 1999, 621-624.
(25) Calvo-Asin, J. A.; Calvo-Flores, F. G.; Exposito-Lopez, J. M.;
Hernandez-Mateo, F.; Garcia-Lopez, J. J.; Isac-Garcia, J.; Santoyo-Gonzalez,
F.; Vargas-Berenguel, A. J. Chem. Soc., Perkin Trans. 1 1997, 1079-1081.
(26) Bozo, E.; Boros, S.; Kuszmann, J.; Gacs-Baitz, E.; Parkanyi, L.
Carbohydr. Res. 1998, 308, 297-310.
(30) Yin, H.; D’Souza, F. W.; Lowary, T. L. J. Org. Chem. 2002, 67,
892-903.
(31) Hatanaka, K.; Kuzuhara, H. J. Carbohydr. Chem. 1985, 4, 333-
345.
(32) Ness, R. K.; Fletcher, H. G., Jr. J. Am. Chem. Soc. 1958, 80, 2007-
2010.
J. Org. Chem, Vol. 71, No. 3, 2006 1113

Johnston et al.
SCHEME 3
FIGURE 1. NOESY Correlations of Selected Protons in the Isomers
of 33.
part of the major R-isomer. The final yields of the coupled
products 29-33 in Scheme 3 refer to the pure R-isomers isolated
after one or two rounds of chromatography. The minor isomers
were produced in variable proportion (up to 20% in the case of
compound 31) but, due to the similarity in chromatographic
mobilities, they could not be obtained free of the major isomers
in most instances. However, in the case of the coupled product
33, almost pure fractions of the isomer 33â were obtained and
1
the product was characterized by NMR spectroscopy. The H
and 13C NMR spectra of 33â were very similar to those of the
major isomer 33R, but a NOESY spectrum showed clear H-5
to H-5′ and H-1b to H-5′ correlations, implying that these atoms
are syn-facial on the sulfonium salt ring. In contrast, the major
isomer 33R exhibited H-1a to H-5′ and H-4 to H-5′correlations,
as expected for the isomer of the opposite configuration at the
sulfonium center (Figure 1).
We initially approached the deprotection steps with some
apprehension of encountering problems in performing two or
three successive reactions in the presence of a reactive sulfonium
salt. This sense of unease was reinforced by our first attempts.
Treatment of the sulfonium salt 29, first with aqueous trifluo-
roacetic acid to remove the isopropylidene group, and then with
NaBH4 to reduce the hemiacetal led only to an intractable
mixture. Similarly, although hydrogenolysis of the benzyl groups
in compound 32 seemed to be successful, giving eventually a
single product according to TLC analysis of the reaction mixture,
removal of the catalyst by filtration and concentration led to
decomposition of this initial product to give extremely polar
material. We have been unable to develop an efficient depro-
tection protocol for compound 32.
In contrast, the corresponding benzyl glycoside 33 gave, upon
hydrogenolysis, a virtually quantitative yield of the hemiacetal
product 12 as a 1:1 R:â mixture. The crude product was stable
after removal of the solvent, and was even unchanged after
storage in aqueous solution for several days at ambient
temperature. Nevertheless, the crude product was generally
immediately reduced with NaBH4 to provide the desired alditol
sulfonium sulfate 8, in a yield of 66% for the two steps (Scheme
4). Analogous treatment of the protected compounds 30 and
31 gave the target compounds 6 and 7 via the intermediate
hemiacetal derivatives 10 and 11. The deprotection of compound
29 required a three-step procedure, which was eventually
implemented as either of two possible sequences to give 5
(Scheme 4). Removal of the benzyl groups first (Procedure A)
to yield the isopropylidene compound 34 was found to be
advantageous since the alternative method (Procedure B), to
give initially the 1,2-diol 35, was found to lead to partial
conversion to a methyl D-furanoside mixture 36 during the
subsequent hydrogenolysis reaction in MeOH solvent. The
methyl glycoside could be hydroyzed by re-treatment with
The thioether 28 was available from earlier work16 and could
be prepared more conveniently by a method analogous to that
developed for the corresponding selenium derivative.19 Com-
pound 28 was reacted with each of the cyclic sulfates 15, 16,
18, 21, and 22 to give the protected sulfonium sulfate com-
pounds 29-32 (Scheme 3). The solvent chosen for these
reactions was 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), which
we have found previously to offer significant advantages in
reactions that yield sulfonium salts from neutral precursors.33
Initial trials with the cyclic sulfate 15 showed that the addition
of K2CO3, which we had previously routinely included to ensure
that the reaction mixture did not become acidic through
hydrolysis of the cyclic sulfate by traces of water, was not
necessary. In the present case, the presence of base led to
decomposition of 15 and inferior yields of the desired coupled
product 29. All subsequent reactions were therefore performed
without base. In addition, use of the thioether 28 in slight excess
over the cyclic sulfate gave superior yields in certain cases.
The reactivity of the cyclic sulfates varied widely, with the
D-glucose derivative 18 being the least reactive and giving the
desired product 31 in a yield of just 31% after 42 h at 70 °C.
In contrast, the strained cyclic sulfate 22 was most reactive and
yielded the coupled product 33 in 85% yield after only 2.5 h at
40 °C. The selectivity for attack of the thioether 28 at the
primary over the secondary cyclic sulfate center was excellent,
and in no case were isolable quantities of the regioisomeric
products detected. There was evidence in the NMR spectra of
the crude reaction mixtures for minor amounts of stereoisomers
formed through electrophilic attack on the â-face of the thioether
28 to give products that were diastereomeric at the stereogenic
sulfur center. In all cases, the minor â-isomer was removed by
chromatography, albeit in most instances only by sacrificing
(33) Ghavami, A.; Sadalapure, K. S.; Johnston, B. D.; Lobera, M.; Snider,
B.; Pinto, B. M. Synlett 2003, 1259-1262.
1114 J. Org. Chem., Vol. 71, No. 3, 2006

Sulfonium Sulfate Analogues of Disaccharides
SCHEME 4a
a Reagents: (a) H2, Pd(C)/MeOH, (b) TFA/H2O, (c) NaBH4/H2O.
aqueous trifluoroacetic acid to give the intermediate hemiacetal
9 but this additional step resulted in a lower overall yield.
Reduction of the hemiacetal with NaBH4, as with the previous
compounds, gave compound 5. The sulfonium sulfates 5-12
were obtained as hygroscopic gums that were unsuitable for
combustion analysis. Despite intensive efforts they could not
be induced to crystallize. They were, however, extensively
characterized by spectroscopic methods. MALDI-TOF mass
spectrometry for compounds 5-8 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 - SO3H. The protected compounds 29-
33 fragmented to give M + H - SO3 base peaks and lower
intensity M + H and M + Na peaks. This behavior seems
general for this class of compound and is similar to that of
sulfated carbohydrates which show loss of sulfate ion in their
MALDI mass spectra.34 Both the protected and the deprotected
sulfonium compounds also exhibited variable intensity dimer
or trimer cluster-ion peaks at higher masses. The compounds
5-12 were also characterized by high-resolution mass spec-
trometry. The NMR spectra for compounds 9-12 showed two
sets of resonances corresponding to the mixture of R/â isomers
of the other resonances followed from analysis of the COSY
spectra. The NMR spectra for compounds 5-8 were also in
accord with the assigned structures, and were almost identical
with those of salacinol 3 for those portions of the sulfonium
salts having similar structure (see Tables 5 and 6). As was the
case with salacinol 3,16 the stereochemical integrity at the
stereogenic sulfur atom in each of 5-8 was maintained.
As a final point of interest, we comment on the glycosidase
inhibitory properties of 5-12 against recombinant human
maltase glucoamylase (MGA), a critical intestinal glucosidase
involved in the processing of oligosaccharides of D-glucose into
D-glucose itself, and of relevance to the control of Type 2
diabetes. Significantly, although compound 5 did not inhibit the
activity of MGA, compounds 6-8 showed Ki values of 0.25,
0.26, and 0.17 µM, respectively.35 For purposes of comparison,
salacinol inhibits MGA with a Ki value of 0.19 µM.35 It is clear
that the stereochemistry of the C-4′ stereogenic center is critical
for activity. The disaccharide analogues 9-12 were not active
against MGA. Compounds 6-8, together with others synthe-
sized previously in our program, will serve as useful probes to
map the enzyme-active sites of MGA and other related enzymes.
Experimental Section
1
at the hemiacetal center. In the H NMR spectra, coupling
constants between H-1 and H-2 allowed the assignment of these
resonances to either the R- or the â-isomer and the assignment
Benzyl 2,3-Di-O-benzyl-â-D-glucopyranoside-4,6-cyclic Sulfate
(18). Benzyl 2,3-di-O-benzyl-â-D-glucopyranoside29 (1.63 g, 3.62
(35) Rossi, E. J.; Kuntz, D. A.; Sim, L.; Hahn, D.; Johnston, B. D.;
Ghavami, A.; Szczepina, M. G.; Kumar, N. S.; Sterchi, E. E.; Nichols, B.
L.; Pinto, B. M.; Rose, D. R. J. Med. Chem. Submitted for publication.
(34) Fukuyama, Y.; Ciancia, M.; Nonami, H.; Cerezo, A. S.; Erra-
Balsells, R.; Matulewicz, M. C. Carbohydr. Res. 2002, 337, 1553-1562.
J. Org. Chem, Vol. 71, No. 3, 2006 1115

Johnston et al.
mmol) and triethylamine (2.5 mL) were dissolved in CH2Cl2 (60
mL) and the mixture was stirred at room temperature. Thionyl
chloride (0.60 mL, 8.2 mmol) was added dropwise and allowed to
react for 20 min. The mixture was diluted with CH2Cl2 and washed
with cold water (2 × 50 mL). The organic phase was dried over
MgSO4 and concentrated to a dark orange-brown syrup that was
filtered through a short column of silica gel with hexanes:EtOAc,
3:1, and again concentrated to give a pale orange syrup (1.57 g).
Analysis by TLC (hexanes:EtOAc, 3:1) showed that two products
of approximately equal proportion had been formed. The mixture
of cyclic sulfites was dissolved in CCl4:CH3CN (1:1, 60 mL) and
the solution was stirred at room temperature. Sodium periodate (3.2
g, 15 mmol), RuCl3:H2O (56 mg, 0.25 mmol), and water (30 mL)
were added sequentially. The dark-colored mixture was stirred for
15 min at room temperature and transferred to a separatory funnel
with the aid of additional CH2Cl2 (50 mL). Without shaking, the
organic phase was separated and the aqueous phase was extracted
with CH2Cl2 (50 mL). The combined organic phase was treated
with ethylene glycol (0.2 mL) and concentrated to a black syrup.
This was dissolved in EtOAc (150 mL) and filtered through Celite
to remove black RuO2. The filtrate was washed with saturated
aqueous NaHCO3 (50 mL), dried over MgSO4, and concentrated
to give a yellow syrup. Purification by column chromatography on
silica gel (hexanes:EtOAc,1:1) yielded the cylic sulfate 18 as a
colorless syrup (1.48 g, 80%), which crystallized on standing, and
was recrystallized from Et2O/hexanes: mp 73-81°C, [R]D -28 (c
1.4, CHCl3); 1H NMR (CDCl3) δ 7.4-7.2 (15H, m, Ar), 4.89, 4.64
(2H, 2d, JA,B ) 11.7 Hz, CH2Ph), 4.85, 4.71 (2H, 2d, JA,B ) 10.8
Hz, CH2Ph), 4.79, 4.73 (2H, 2d, JA,B ) 11.1 Hz,CH2Ph), 4.66 (1H,
11.0 Hz, J5a,5b ) 9.8 Hz, H-5a), 4.66 (1H, dd, J4,5b ) 4.9 Hz, H-5b),
4.65 and 4.57 (2H, 2d, JA,B ) 11.7 Hz, CH2Ph), 4.26 (1H, ddd,
H-4), 4.18 (1H, dd, H-2), 3.39 (3H, s, OCH3); 13C NMR (CDCl3)
δ 136.5 (Cipso, Ar), 128.6 (2C), 128.3, and 128.0 (2C) (5CAr), 109.6
(C-1), 86.7 (C-3), 83.7 (C-2), 73.7 (C-5), 72.9 (CH2Ph), 67.9 (C-
4), 56.3 (OCH3); MALDI MS m/e 355.08 (M+ + K), 339.08 (M+
+ Na). Anal. Calcd for C13H16O7S: C, 49.36; H, 5.10. Found: C,
49.56; H, 5.12.
Benzyl 2-O-Benzyl-r-D-arabinofuranoside-3,5-cyclic Sulfate
(22). The diol 20 (1.37 g, 4.15 mmol) was converted to the cyclic
sulfate 22 in two steps (via the intermediate cyclic sulfite), using
the same procedure detailed above for the preparation of the cyclic
sulfate 21 from diol 19. The syrupy product (1.23 g) after column
chromatography was found to contain approximately 15% of a
1
sulfate-dimer impurity by H NMR analysis. Crystallization from
EtOAc:hexanes gave pure 22 (838 mg, 48%) as small colorless
needles: mp 84-86°C, [R]D +84 (c 1.2, CHCl3); 1H NMR (CDCl3)
δ 7.40-7.27 (10H, m, Ar), 5.18 (1H, d, J1,2 ) 2.8 Hz, H-1), 4.80
(1H, dd, J2,3 ) 7.6 Hz, J3,4 ) 10.2 Hz, H-3), 4.76 and 4.50 (2H,
2d, JA,B ) 11.7 Hz, CH2Ph), 4.74 (1H, dd, J4,5a ) 11.0 Hz, J5a,5b
)
9.8 Hz, H-5a), 4.67 (1H, dd, J4,5b ) 4.9 Hz, H-5b), 4.62 and 4.53
(2H, 2d, JA,B ) 11.7 Hz, CH2Ph), 4.33 (1H, ddd, H-4), 4.28 (1H,
dd, H-2); 13C NMR (CDCl3) δ 136.5 (2C, 2 × Cipso, Ar), 128.6-
127.9 (10 × CAr), 107.5 (C-1), 86.7 (C-3), 83.7 (C-2), 73.7 (C-5),
72.8 and 70.7 (2 × CH2Ph), 68.1 (C-4); MALDI MS m/e 415.00
(M+ + Na). Anal. Calcd for C19H120O7S: C, 58.15; H, 5.14.
Found: C, 58.06; H, 5.17.
Benzyl 2,3,5-Tri-O-benzoyl-r-D-arabinofuranoside (24).31 To
a stirred mixture of mercuric cyanide (5.20 g, 20.6 mmol) in CH3-
CN (50 mL) was added benzyl alcohol (2.0 mL, 19 mmol) and the
glycosyl bromide 2332 (5.25 g, 10.0 mmol). The mixture was stirred
for 0.5 h at room temperature and then concentrated by rotary
evaporation to remove most of the solvent. The residue was
partitioned between Et2O (150 mL) and water (50 mL). The organic
phase was washed with saturated NaHCO3 (30 mL), water (30 mL),
and brine (30 mL) and dried over MgSO4. Solvent removal gave
the crude product contaminated with mercury salts and excess
benzyl alcohol. Purification by colmn chromatography on silica gel
(hexanes:EtOAc, 3:1) yielded the benzyl glycoside 24 as a colorless
syrup, which crystallized on standing. Recrystallization from EtOH
gave the pure compound 24 (4.73 g, 86%): mp 92-93°C (lit.31
mp 89-90°C); [R]D +9.3 (c 1.1, CHCl3)(lit.31 [R]D +10.1 (c 1.04,
ddd, J4,5 ) 10.4 Hz, H-4), 4.65 (1H, dd, J5,6a ) 10.5 Hz, J6a,6b
10.7 Hz, H-6a), 4.63 (1H, d, J1,2 ) 7.7 Hz, H-1), 4.56 (1H, dd,
)
J5a,6b ) 5.2 Hz, H-6b), 3.75 (1H, ddd, H-5), 3.73 (1H, dd, J2,3
)
8.7 Hz, J3,4 ) 9.2 Hz, H-3), 3.52 (1H, dd, H-2); 13C NMR (CDCl3)
δ 137.7, 137.4 and 136.4 (3 × CdO, OBz), 128.6-127.9 (18CAr),
103.1 (C-1), 84.2 (C-4), 81.4 (C-2), 79.4 (C-3), 75.5, 75.4 and 71.9
(3 × CH2Ph), 71.8 (C-6), 64.4 (C-5); MALDI MS m/e 551.13 (M+
+ K), 535.12 (M+ + Na). Anal. Calcd for C27H28O8S: C, 63.27;
H, 5.51. Found: C, 63.58; H, 5.47.
Methyl 2-O-Benzyl-r-D-arabinofuranoside-3,5-cyclic Sulfate
(21). Methyl 2-O-benzyl-R-D-arabinofurananoside 1930 (1.47 g, 5.78
mmol) and triethylamine (3.0 mL) were dissolved in CH2Cl2 (75
mL) and the mixture was stirred at room temperature. A solution
of thionyl chloride (0.70 mL, 9.6 mmol) in CH2Cl2 (20 mL) was
added dropwise over 15 min and allowed to react for 30 min. The
mixture was diluted with CH2Cl2 (100 mL) and washed with ice-
water (50 mL), cold saturated NaHCO3 solution (50 mL), and cold
water (20 mL). The organic phase was dried over MgSO4 and
concentrated to a dark orange-brown syrup that was filtered through
a short column of silica gel with hexanes:EtOAc (1:2), and again
concentrated to give a clear red oil (1.59 g). Analysis by TLC
(hexanes:EtOAc, 3:1) showed that two products of approximately
equal proportion had been formed. The mixture of cyclic sulfites
was dissolved in CCl4:CH3CN (1:1, 40 mL), water (30 mL) was
added, and the two-phase mixture was stirred rapidly at room
temperature. RuCl3:H2O (18 mg, 0.08 mmol) was added followed
by small portions of NaIO4 (1.59 g, 7.43 mmol in total) added over
45 min, while monitoring the progress of the reaction by TLC. A
slightly more-polar, major product was formed along with more
polar byproducts. The dark-colored mixture was stirred for an
additional 15 min at room temperature and then processed to give
crude 21 by the same procedure described above for the preparation
of compound 18. Purification by column chromatography on silica
gel (hexanes:EtOAc, 3:1 to 1:1) yielded the cyclic sulfate 21 as a
colorless crystalline solid (1.01 g, 55%). Also isolated was a sample
of the major byproduct as a colorless solid (216 mg). A sample of
compound 21 was recrystallized from EtOAc/hexanes to give large
leaflets: mp 97-98°C, [R]D +12 (c 1.1, CHCl3); 1H NMR (CDCl3)
δ 7.40-7.30 (5H, m, Ar), 4.97 (1H, d, J1,2 ) 2.8 Hz, H-1), 4.79
1
CHCl3)); H NMR data were identical with the literature data;31
13C NMR (CDCl3) δ 166.2, 165.8 and 165.3 (3 × CdO, 3 × OBz),
137.4-126.9 (24 × CAr), 105.1 (C-1), 82.0 (C-2), 81.4 (C-4), 77.9
(C-3), 68.9 (CH2Ph), 63.9 (C-5).
Benzyl 3,5-O-(1,1,3,3-Tetraisopropyldisiloxane-1,3-diyl)-r-D-
arabinofuranoside (26). The tribenzoate 24 (4.48 g, 8.11 mmol)
was added to MeOH (150 mL) and the heterogeneous mixture was
placed under a nitrogen atmosphere. A solution of NaOMe in
MeOH (1.0 M, 4.0 mL) was added and the mixture was stirred at
room temperature for 3 h. The starting material slowly dissolved
during the first hour. Upon completion of the reaction, as judged
by TLC analysis, the NaOMe was neutralized by addition of excess
Rexyn 101 H+ ion-exchange resin, the resin was removed by
filtration, and the solution was concentrated. The syrupy residue
was shaken with hexanes (3 × 50 mL) to dissolve methyl benzoate,
and the hexane extracts were decanted from the insoluble, crude,
triol product 25 (2.02 g, after 3 h under high vacuum). The triol
was dissolved in pyridine (30 mL) and a solution of 1,3-dichloro-
1,1,3,3-tetraisopropyldisiloxane (4.0 mL, 12 mmol) in CH2Cl2 (30
mL) was added dropwise at room temperature. The mixture was
stirred for 2 h, diluted with CH2Cl2 (100 mL), and washed with
saturated NaHCO3 (50 mL). The aqueous phase was extracted with
CH2Cl2 (50 mL) and the combined extracts were dried over MgSO4
and concentrated by rotary evaporation, first at water aspirator
pressure and then under high vacuum to remove pyridine. Purifica-
tion by column chromatography on silica gel (hexanes:EtOAc, 5:1)
yielded compound 26 as a colorless syrup (3.58 g, 91% for 2 steps):
(1H, dd, J2,3 ) 7.6 Hz, J3,4 ) 10.2 Hz, H-3), 4.72 (1H, dd, J4,5a
)
1116 J. Org. Chem., Vol. 71, No. 3, 2006

Sulfonium Sulfate Analogues of Disaccharides
[R]D +47 (c 1.0, CHCl3); 1H NMR (CDCl3) δ 7.44-7.25 (5H, m,
mixture was cooled, then diluted with CH2Cl2 and evaporated to
give a syrupy residue. Purification by column chromatography
(CHCl3 to CHCl3:MeOH, 10:1) gave the purified sulfonium salts
29-33.
Ar), 4.97 (1H, d, J1,2 ) 2.7 Hz, H-1), 4.78, 4.49 (2H, 2d, JA,B
)
11.8 Hz, CH2Ph), 4.25 (1H, dd, J2,3 ) 6.1 Hz, H-2), 4.19-4.15
(1H, 2nd order m, H-3), 4.02-3.91 (3H, m, H-4, H-5a, H-5b),
1.12-0.98 (24H, m, 4 × CH(CH3)2; 13C NMR (CDCl3) δ 137.8,
(Cipso, Ar), 128.4 (2C), 127.9 (2C) and 127.7 (5 × CAr), 106.3 (C-
1), 82.9 (C-2), 81.1 (C-4), 77.6 (C-3), 69.6 (CH2Ph), 61.8 (C-5),
17.5, 17.3 (3C), 17.2, 17.1, 17.05, 17.00, 13.5, 13.2, 12.9 and 12.6
(12C, 4 × CH(CH3)2); MALDI MS m/e 505.19 (M+ + Na). Anal.
Calcd for C24H42O6Si2: C, 59.71; H, 8.77. Found: C, 59.37; H,
8.99.
5-Deoxy-5-[2,3,5-tri-O-benzyl-1,4-dideoxy-1,4-episufonium-
ylidene-D-arabinitol]-1,2-O-isopropylidene-3-O-sulfoxy-r-D-
xylofuranose Inner Salt (29). Reaction of the thioether 28 (833
mg, 2.03 mmol) with the cyclic sulfate 15 (649 mg, 2.57 mmol) in
HFIP (2.5 mL) for 44 h at 70 °C gave compound 29 as a colorless
crystalline solid (1.16 g, 85%). A sample was recrystallized from
MeOH: mp 149-151°C; [R]D -10 (c 1.0, CHCl3). See Tables 1
and 2 for NMR data. MALDI MS m/e 695.18 (M+ + Na),
673.13 (M+ + H), 593.20 (M+ + H - SO3). Anal. Calcd for
C34H40O10S2: C, 60.70; H, 5.99. Found: C, 60.81; H, 5.86.
Benzyl 2,3-Di-O-benzyl-6-deoxy-6-[2,3,5-tri-O-benzyl-1,4-
dideoxy-1,4-episufoniumylidene-D-arabinitol]-4-O-sulfoxy-â-D-
galactopyranose Inner Salt (30). Reaction of the thioether 28 (431
mg, 1.02 mmol) with the cyclic sulfate 16 (588 mg, 1.15 mmol) in
HFIP (3.0 mL) for 42 h at 70 °C gave compound 30 as a colorless
gummy solid (571 mg, 60%). [R]D -7.6 (c 1.1, CHCl3). See Tables
1 and 2 for NMR data. MALDI MS m/e 955.39 (M+ + Na), 853.42
(M+ + H - SO3). Anal. Calcd for C53H56O11S2: C, 68.22; H, 6.05.
Found: C, 68.48; H, 6.09.
Benzyl 2,3-Di-O-benzyl-6-deoxy-6-[2,3,5-tri-O-benzyl-1,4-
dideoxy-1,4-episufoniumylidene-D-arabinitol]-4-O-sulfoxy-â-D-
glucopyranose Inner Salt (31). Reaction of the thioether 28 (937
mg, 2.22 mmol) with the cyclic sulfate 18 (1.12 g, 2.17 mmol) in
HFIP (4.0 mL) for 42 h at 70 °C gave, after chromatography,
partially purified compound 31 as a colorless gummy solid (1.02
g, 50%), containing a minor amount of a more-polar isomer.
Analysis of this material by 1H NMR showed it to be ∼80% pure
and that the minor isomer could be tentatively identified as the
diastereomer at the sulfonium center. Repurification by chroma-
tography (CHCl3:MeOH, 20:1) keeping only those fractions which
were pure by TLC yielded compound 31 (639 mg, 31%) as a gum:
[R]D -8.7 (c 1.2, CHCl3). See Tables 1 and 2 for NMR data.
MALDI MS m/e 955.53 (M+ + Na), 933.60 (M+ + H), 853.54
(M+ + H - SO3). Anal. Calcd for C53H56O11S2: C, 68.22; H, 6.05.
Found: C, 68.34; H, 6.02.
Methyl 2-O-Benzyl-5-deoxy-5-[2,3,5-tri-O-benzyl-1,4-dideoxy-
1,4-episufoniumylidene-D-arabinitol]-3-O-sulfoxy-r-D-arabino-
furanose Inner Salt (32). Reaction of the thioether 28 (487 mg,
1.16 mmol) with the cyclic sulfate 21 (322 mg, 1.02 mmol) in HFIP
(2.5 mL) for 3 h at 40 °C gave compound 32 as a colorless gummy
solid (756 mg, quantitative). Analysis by NMR showed the presence
of an 8:1 ratio of isomers at the sulfonium center. See Tables 1
and 2 for NMR data of the major isomer 32. MALDI MS m/e
759.13 (M+ + Na), 737.18 (M+ + H), 657.16 (M+ + H - SO3).
Anal. Calcd for C39H44O10S2: C, 63.57; H, 6.02. Found: C, 63.36;
H, 6.01.
Benzyl 2-O-Benzyl-5-deoxy-5-[2,3,5-tri-O-benzyl-1,4-dideoxy-
1,4-episufoniumylidene-D-arabinitol]-3-O-sulfoxy-r-D-arabino-
furanose Inner Salt (33). Reaction of the thioether 28 (514 mg,
1.22 mmol) with the cyclic sulfate 22 (448 mg, 1.06 mmol) in HFIP
(3.0 mL) for 2.5 h at 40 °C gave the major isomer 33r as a pale-
yellow amorphous, hard foam (763 mg, 85%). A sample of the
minor isomer 33â suitable for NMR analysis (see Tables 1 and 2)
was obtained with a purity of >80% from the early chromatographic
fractions. For the major isomer 33r: [R]D +40 (c 1.6, CHCl3).
See Tables 1 and 2 for NMR data. MALDI MS m/e 813.25 (M+ +
H), 733.24 (M+ + H - SO3). Anal. Calcd for C45H48O10S2: 66.48;
H, 5.95. Found: C, 66.64; H, 5.88.
Benzyl 2-O-Benzyl-r-D-arabinofuranoside (20). The silyl
protected compound 26 (3.50 g, 7.26 mmol) was dissolved in DMF
(20 mL) and cooled by stirring in an ice bath under N2. Benzyl
bromide (2.0 mL, 17 mmol) was added in a single portion followed
by 60% NaH/oil (0.37 g, 9.2 mmol), added carefully in small
portions over 10 min. The reaction mixture was stirred at 0 °C for
1.5 h. Cold Et2O (150 mL) and ice-water (50 mL) were added
and the organic phase was separated. The aqueous phase was
extracted with more Et2O (100 mL) and the combined extracts were
washed with water (2 × 50 mL), then brine (30 mL), and dried
over MgSO4. The solvents were evaporated and the residue was
warmed under high vacuum to remove the excess benzyl bromide
by distillation. The crude benzylated product 27 (4.12 g) was found
to be approximately 90% pure as judged by analysis of the 1H NMR
spectrum, and was used directly in the following procedure.
The syrupy compound 27 was dissolved in dry THF (70 mL)
and stirred while a 1.0 M solution of n-Bu4NF in THF (16 mL, 16
mmol) was added. The reaction mixture was kept for 0.5 h at room
temperature and concentrated to a brown residue. Nonpolar material
was removed by shaking with hexanes (3 × 50 mL) and decanting
the hexanes solution from the crude, insoluble diol product. The
crude product was dissolved in EtOAc (150 mL), washed with brine
(20 mL), dried over MgSO4, and concentrated. The residue was
purified by flash chromatography (hexanes:EtOAc, 1:3) to give diol
20 (1.50 g, 66%) as a colorless syrup, which crystallized on
standing: mp 73-74 °C; [R]D +99 (c 1.1, CHCl3); MALDI MS
m/e 353.02 (M+ + Na). Anal. Calcd for C19H22O5: C, 69.07; H,
6.71. Found: C, 68.90; H, 6.79.
1
NMR data for compound 20: H NMR (CDCl3) δ 7.4-7.2
(10H, m, Ar), 5.16 (1H, s, J1,2 ≈ 0 Hz, H-1), 4.77 and 4.51 (2H,
2d, JA,B ) 11.7 Hz, CH2Ph), 4.61 and 4.54 (2H, 2d, JA,B ) 11.7
Hz, CH2Ph), 4.17 (1H, ddd, J3,4 ) 3.1 Hz, J4,5a ) 3.1 Hz, J4,5b
)
4.2 Hz, H-4), 4.15 (1H, ddd, J3,OH ) 9.8 Hz, J2,3 ) 1.1 Hz, H-3),
3.96 (1H, d, H-2), 3.83 (1H, ddd, J5a,5b ) 11.7 Hz, J5a,OH ) 4.5
Hz, H-5a), 3.77 (1H,ddd, J5b,OH ) 7.0 Hz, H-5b), 2.51 (1H, d, OH-
3), 2.14 (1H, dd, OH-5); 13C NMR (CDCl3) δ 137.1 (2C, 2 × Cipso
,
Ar), 128.6 (4C), 128.1 (3C) 128.0, and 127.9 (2C) (10 × CAr),
104.9 (C-1), 87.6 (C-2), 86.4 (C-4), 75.6 (C-3), 71.9 and 69.1 (2
× CH2Ph), 62.6 (C-5).
NMR data for intermediate compound 27: 1H NMR (CDCl3)
δ 7.4-7.2 (10H, m, Ar), 5.02 (1H, d, J1,2 ) 2.4 Hz, H-1), 4.76 and
4.49 (2H, 2d, JA,B ) 11.9 Hz, CH2Ph), 4.59 and 4.55 (2H, 2d, JA,B
) 11.9 Hz, CH2Ph), 4.30-4.27 (1H, 2nd order m, H-3), 4.04 (1H,
dd, J2,3 ) 5.9 Hz, H-2), 4.02-3.91 (3H, m, H-4, H-5a, H-5b), 1.12-
0.90 (24H, m, 4 × CH(CH3)2); 13C NMR (CDCl3) δ 137.9 and
137.9, (2 × Cipso, Ar), 128.4 (2C), 128.3 (2C), 127.9 (2C), 127.6
(2C), 127.6 and 127.6 (10 × CAr), 104.8 (C-1), 89.8 (C-2), 80.8
(C-4), 76.6 (C-3), 72.5 and 69.3 (2 × CH2Ph), 61.8 (C-5), 17.5,
17.4 (3C), 17.1 (3C), 17.0, 13.5, 13.2, 12.9 and 12.6 (12C, 4 ×
CH(CH3)2).
General Procedure for the Preparation of Sulfonium Sulfates
29-33. A mixture of the thioether 28 (1.00-1.15 equiv) and the
cyclic sulate 15, 16, 17, 18, or 19 (0.79-1.00 equiv) in HFIP (1.0-
3.0 mL/mmol of 28) was placed in a sealed reaction vessel and
warmed with stirring for the indicated time at the temperatures given
below. The progress of the reaction was followed by TLC analysis
of aliquots (developing solvent CHCl3:MeOH, 10:1). When the
limiting starting compound had been essentially consumed, the
1,4-Dideoxy-1,4-[[2S,3R,4S-2,4,5-trihydroxy-3-(sulfooxy)pen-
tyl]episufoniumylidene]-D-arabinitol (5). Procedure A: The
protected sulfonium salt 29 (252 mg, 0.375 mmol) was dissolved
in MeOH (20 mL) and stirred at room temperature with 10% Pd/C
catalyst (227 mg) under 1 atm of H2 for 17 h. Analysis by TLC
(CHCl3:MeOH, 7:3) showed the formation of a single product (Rf
0.3). The catalyst was removed by filtration through Celite with
J. Org. Chem, Vol. 71, No. 3, 2006 1117

Johnston et al.
additional MeOH and the filtrate was evaporated to give the crude
isopropylidene compound 34 as a gummy residue (137 mg). The
residue was dissolved in 50% aq trifluoroacetic acid (3.0 mL) and
kept at room temperature for 4 h. Evaporation of the solvent gave
the crude hemiacetal, 3-O-sulfoxy-5-deoxy-5-[1,4-dideoxy-1,4-
episufoniumylidene-D-arabinitol]-R/â-D-xylofuranose inner salt (9,
R:â ) 5:4) as a pale-yellow glass (121 mg, 89%). See Tables 3
and 4 for NMR data of 9. MALDI MS m/e 385.02 (M+ + Na),
363.04 (M+ + H), 283.08 (M+ + H - SO3).
Reduction of the hemiacetal 10 (430 mg, 1.10 mmol) with
NaBH4, as described above for compound 9, gave the sulfonium
sulfate 6 (232 mg, 54%) as a colorless glass. [R]D +18 (c 0.72,
MeOH). See Tables 5 and 6 for NMR data of 6. MALDI MS m/e
416.94 (M+ + Na), 315.03 (M+ + H - SO3); HRMS. Calcd for
C11H22O11S2Na (M + Na): 417.0501. Found: 417.0498.
1,4-Dideoxy-1,4-[[2S,3S,4R,5S-2,4,5,6-tetrahydroxy-3-(sulfooxy)-
hexyl]episufoniumylidene]-D-arabinitol (7). The protected sulfo-
nium salt 31 (602 mg, 0.645 mmol) was dissolved in HOAc (22
mL). Water (2.2 mL) was added and the mixture was stirred at
room temperature with 10% Pd/C catalyst (520 mg) under 1 atm
of H2 for 22 h. Analysis by TLC (EtOAc:MeOH:H2O, 6:3:1)
showed the formation of a single product (Rf 0.15). The catalyst
was removed by filtration through Celite with additional water and
the filtrate was evaporated to a syrup. Water (3 × 30 mL) was
added and evaporated to remove residual HOAc. The crude
hemiacetal, 4-O-sulfoxy-6-deoxy-6-[1,4-dideoxy-1,4-episufonium-
ylidene-D-arabinitol]-R/â-D-glucopyranose inner salt (11, R:â )
1:1), was obtained as a colorless foam (263 mg, quantitative). See
Tables 3 and 4 for NMR data of 11. MALDI MS m/e 414.99 (M+
+ Na), 313.05 (M+ + H - SO3).
NMR data for the intermediate compound 34: 1H NMR (D2O)
δ 6.17 (1H, d, J1,2 ) 3.7 Hz, H-1′), 5.05 (1H, d, J2′,3 ∼ 0 Hz, H-2′),
4.95 (1H, d, J3′,4′ ) 2.9 Hz, H-3′), 4.87 (1H, ddd, J4′,5′a ) 3.3 Hz,
J4′,5′b ) 7.8 Hz, H-4′), 4.79 (1H, ddd, H-2), 447 (1H, dd, J2,3 ) 3.3
Hz, J3,4 ) 2.9 Hz, H-3), 4.17 (1H, ddd, H-4), 4.16 (1H, dd, J4,5a
4.7 Hz, J5a,5b ) 14.0 Hz, H-5a), 4.05 (1H, dd, J5′a,5′b ) 13.8 Hz,
H-5′a), 3.98 (1H, dd, J1a,1b ) 12.7 Hz, H-1a), 3.97 (1H, dd, J4,5b
)
)
11.0 Hz, H-5b), 3.95 (1H, dd, J1b,2 ) 3.1 Hz, H-1b), 3.94 (1H, dd,
J4′,5′b ) 7.8 Hz, H-5′b), 1.57 and 1.40 (6H, 2 × s, each 3H,
C(CH3)2); 13C NMR (D2O) δ 114.2 (C(CH3)2), 105.4 (C-1′), 83.6
(C-2′), 81.3 (C-3′), 78.2 (C-3), 77.4 (C-2), 75.6 (C-4′), 71.3 (C-4),
59.8 (C-5), 48.3 (C-1), 44.8 (C-5′), 26.2 and 25.8 (C(CH3)2).
Procedure B: The protected sulfonium salt 29 (254 mg, 0.378
mmol) was dissolved in TFA (3.0 mL) and the mixture was stirred
at room temperature until the solid dissolved. Water (3.0 mL) was
added and the mixture was placed in a 45 °C bath for 2 h. Analysis
by TLC (CHCl3:MeOH, 7:3) showed formation of a single product
(Rf 0.8). The solvents were evaporated to give the crude hemiacetal
35 as an anomeric mixture (R:â ) 5:4) The mixture was dissolved
in MeOH (20 mL) and hydrogenolyzed over 10% Pd/C catalyst
(200 mg) at room temperature for 18 h. Filtration through Celite
with additional MeOH and evaporation of the solvent gave a
colorless foam that was shown by NMR analysis to consist of four
compounds which were tentatively identified to be an anomeric
mixture of the hemiacetal 9 together with an anomeric mixture of
the corresponding methyl glycoside 35. Re-treatment of the mixture
with 50% aq TFA (6.0 mL, rt, 4 h) resulted in hydrolysis of most
of the methyl glycoside. Filtration through silica gel (EtOAc:MeOH:
H2O) to remove polar impurities, followed by solvent removal gave
the crude compound 9 (101 mg, 74% ) that was identical by NMR
with that obtained above by procedure A.
Reduction of the hemiacetal 11 (255 mg, 0.650 mmol) with
NaBH4, as described above for compound 9, gave the sulfonium
sulfate 7 (165 mg, 64%) as a colorless glass. [R]D +13 (c 0.92,
MeOH). See Tables 5 and 6 for NMR data of 7. MALDI MS m/e
416.94 (M+ + Na), 315.00 (M+ + H - SO3); HRMS. Calcd for
C11H22O11S2Na (M + Na): 417.0501. Found: 417.0499.
1,4-Dideoxy-1,4-[[2S,3S,4R-2,4,5-trihydroxy-3-(sulfooxy)pen-
tyl]episufoniumylidene]-D-arabinitol (8). The protected sulfonium
salt 33 (677 mg, 0.789 mmol) was dissolved in HOAc (20 mL).
Water (2.0 mL) was added and the mixture was stirred at room
temperature with 10% Pd/C catalyst (510 mg) under 1 atm of H2
for 6 h. Analysis by TLC (EtOAc:MeOH:H2O, 6:3:1) showed
formation of a single product (Rf 0.25). The catalyst was removed
by filtration through Celite with additional water and the filtrate
was evaporated to a syrup. Water (3 × 20 mL) was added and
evaporated to remove residual HOAc. The crude hemiacetal, 3-O-
sulfoxy-5-deoxy-5-[1,4-dideoxy-1,4-episufoniumylidene-D-arabini-
tol]-R/â-D-arabinose inner salt (12, R:â ) 1:1), was obtained as a
colorless foam (294 mg, quantitative). See Tables 3 and 4 for NMR
The hemiacetal 9 (101 mg, 0.279 mmol) was dissolved in water
(8.0 mL). The solution was stirred at room temperature while
NaBH4 (44 mg, 1.2 mmol) was added in small portions over 30
min. Stirring was continued for another 20 min and the mixture
was acidified to pH e4 by dropwise addition of 2 M HCl. The
solution was evaporated to dryness and then coevaporated with
anhydrous MeOH (3 × 30 mL). The semisolid residue was purified
by column chromatograhy on silica gel (EtOAc:MeOH:H2O, 6:3:
1) to give the product 5 as a colorless gum (86 mg, 85%). [R]D
+19 (c 0.32, MeOH). See Tables 5 and 6 for NMR data of 5.
MALDI MS m/e 386.89 (M+ + Na), 285.01 (M+ + H - SO3);
HRMS. Calcd for C10H20O10S2Na (M + Na): 387.0396. Found:
387.0382.
1,4-Dideoxy-1,4-[[2S,3R,4R,5S-2,4,5,6-tetrahydroxy-3-(sulfooxy)-
hexyl]episufoniumylidene]-D-arabinitol (6). The protected sul-
fonium salt 30 (460 mg, 0.493 mmol) was dissolved in MeOH (50
mL) and the mixture was stirred at room temperature with 10%
Pd/C catalyst (580 mg) under 1 atm of H2 for 24 h. Analysis by
TLC (EtOAc:MeOH:H2O, 6:3:1) showed the formation of a single
product (Rf 0.10). The catalyst was removed by filtration through
Celite, using additional MeOH, and the filtrate was evaporated to
give the crude hemiacetal, 4-O-sulfoxy-6-deoxy-6-[1,4-dideoxy-
1,4-episufoniumylidene-D-arabinitol]-R/â-D-galactopyranose inner
salt (10, R:â ) 1:1) as a colorless foam (184 mg, 95%). See Tables
3 and 4 for NMR data of 10. MALDI MS m/e 414.89 (M+ + Na),
392.93 (M+ + H), 312.93 (M+ + H - SO3).
data of 12. MALDI MS m/e 384.97 (M+ + Na), 363.02 (M+
+
H), 283.07 (M+ + H - SO3).
Reduction of the hemiacetal 12 (283 mg, 0.781 mmol) with
NaBH4, as described above for compound 9, gave the sulfonium
sulfate 8 (194 mg, 66%) as a colorless glass. [R]D -4.7 (c 1.0,
MeOH). See Tables 5 and 6 for NMR data of 8. MALDI MS m/e
386.95 (M+ + Na), 364.97 (M+ + H), 285.05 (M+ + H - SO3);
HRMS. Calcd for C10H20O10S2Na (M + Na): 387.0396. Found:
387.0386.
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada and University Medi-
cal Discoveries, Inc. for financial support.
Note Added after ASAP Publication. There was an error
in structure 4 in the version published ASAP January 10, 2006;
the corrected version was published ASAP January 11, 2006.
Supporting Information Available: Tables of 1H and 13C NMR
data for the compounds synthesized in this study and copies of 1H
and 13C NMR spectra for compounds 5, 6, 7, and 8. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO052252U
1118 J. Org. Chem., Vol. 71, No. 3, 2006