A new class of glucosidase inhibitor: Analogues of the naturally occurring glucosidase inhibitor salacinol with different ring heteroatom substituents and acyclic chain extension

Article abstract of DOI:10.1021/jo052539r

Six chain-extended analogues of the naturally occurring glycosidase inhibitor salacinol, with ring-heteroatom variation, were synthesized for structure-activity studies with different glycosidase enzymes. The syntheses involved the reaction of PMB-protect

Full text of DOI:10.1021/jo052539r

A New Class of Glucosidase Inhibitor: Analogues of the Naturally
Occurring Glucosidase Inhibitor Salacinol with Different Ring
Heteroatom Substituents and Acyclic Chain Extension
Hui Liu,† Lyann Sim,‡ David R. Rose,‡ and B. Mario Pinto*,†
Department of Chemistry, Simon Fraser UniVersity, Burnaby, B.C., Canada V5A 1S6, and
Department of Medical Biophysics, UniVersity of Toronto and DiVision of Molecular and Structural
Biology, Ontario Cancer Institute, Toronto, ON, Canada M5G 2M9
bpinto@sfu.ca
ReceiVed December 11, 2005
Six chain-extended analogues of the naturally occurring glycosidase inhibitor salacinol, with ring-
heteroatom variation, were synthesized for structure-activity studies with different glycosidase enzymes.
The syntheses involved the reaction of PMB-protected D- and L- seleno-, thio-, and iminoarabinitol with
a benzylidene- and isopropylidene-protected 1,3-cyclic sulfate, derived from commercially available
D-sorbitol, in 1,1,1,3,3,3-hexafluoro-2-propanol containing potassium carbonate. Deprotection of the
products afforded the novel selenonium, sulfonium, and iminium analogues of salacinol containing
polyhydroxylated, monosulfated, extended acyclic chains of 6-carbons, differing in stereochemistry at
the stereogenic centers and ring-heteroatom constitution. Four of these compounds inhibit 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 micromolar range, thus providing lead
candidates for the treatment of Type 2 diabetes.
Introduction
charides to glucose. This enzyme inhibition delays glucose
absorption into the blood and results in a lowering or smoothing
of blood glucose levels.4
It is of interest that Nature seems to have selected non-
carbohydrate mimics as natural inhibitors of glycosidase en-
zymes, likely due to the intrinsic low affinities of carbohydrate-
protein interactions. Some naturally occurring compounds, such
as acarbose (1) and swainsonine (2), are potent glycosidase
The controlled inhibition of glycosidase enzymes plays
important roles in the biochemical processing of biopolymers
containing carbohydrates.1,2 For patients suffering from Type
2 diabetes, insulin secretion may be normal but the entry into
cells of glucose (normally mediated by insulin) is compromised.
Hence, the management of blood glucose levels for these
patients is crucial.3 One strategy to achieve this goal is to
administer drugs that can inhibit the activity of pancreatic
R-amylase and intestinal glucosidases that break down oligosac-
(2) For leading references: Essentials of Glycobiology; Varki, A.,
Cummings, R., Esko, J., Freeze, H., Hart, G., Marth, J., Eds.; Cold Spring
Harbor Laboratory Press: Cold Spring Harbor, New York, 1999. Elbein,
A. D.; Molyneux, R. J. In ComprehensiVe Natural Products Chemistry;
Pinto, B. M., Ed.; Barton, D. H. R., Nakanishi, K., Meth-Cohn, O., Ser.
Eds.; Elsevier: UK, 1999; Vol. 3, Chapter 7. Asano, N.; Nash, R. J.;
Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645-
1680. McCarter, J. D.; Withers, S. G. Curr. Opin. Struct. Biol. 1994, 4,
885-892. Ly, H. D.; Withers, S. G. Annu. ReV. Biochem. 1999, 68, 487-
522.
(3) Crivello, J. V. AdV. Polym. Sci. 1984, 62, 1-48. Sherwood, L.
Fundamentals of Physiology, 2nd ed.; West: New York, 1995; Chapter
17, p 517.
(4) Holman, R. R.; Cull, C. A.; Turner, R. C. Diabetes Care 1999, 22,
960-964. Jacob, G. S. Curr. Opin. Struct. Biol. 1995, 5, 605-611.
* To whom correspondence should be addressed. Tel: (604) 291-4152. Fax:
(604) 291-4860.
† Simon Fraser University.
‡ University of Toronto and Ontario Cancer Institute.
(1) For example: Garcia-Olmeda, F.; Salcedo, G.; Sanchez-Monge, R.;
Gomez, L.; Royo, L.; Carbonero, P. Oxford SurVeys of Plant Molecular
and Cell Biology; Clarendon Press: Oxford, 1987; Vol. 4, pp 275-334.
Bompard-Gilles, C.; Rousseau, P.; Rouge, P.; Payan, F. Structure 1996, 4,
1441-1452. Vallee, F.; Kadziola, A.; Bourne, Y.; Juy, M.; Rodenburg, K.
W.; Svensson, B.; Haser, R. Structure 1998, 6, 649-659. Strobl, S.; Maskos,
K.; Wiegand, G.; Huber, R.; GomisRuth, F.-X.; Glockshuber, R. Structure
1998, 6, 911-921.
10.1021/jo052539r CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/21/2006
J. Org. Chem. 2006, 71, 3007-3013
3007

Liu et al.
CHART 1
CHART 3
CHART 4
CHART 2
SCHEME 1
inhibitors (Chart 1).5 Acarbose is currently used for the oral
treatment of diabetes.4
Recently, a new class of glycosidase inhibitors, namely
salacinol (3) and kotalanol (4), with an intriguing inner-salt
sulfonium-sulfate structure was isolated from the roots and
stems of the plant Salacia reticulata (Chart 2).6-8 These
compounds have been found to be potent inhibitors of intestinal
glucosidase enzymes6-8 and thus should attenuate the undesir-
able spike in blood glucose that is experienced by diabetics after
consuming a meal rich in carbohydrates. The structural similari-
ties of 3 and 4 are obvious, with both possessing the same 1,4-
anhydrothio-D-arabinitol ring, the alditol chain of kotalanol 4
being extended by three carbons (Chart 2). It is believed that
the inhibition of glucosidases by salacinol and kotalanol is in
fact due to their ability to mimic both the shape and charge of
the oxacarbenium-ion-like transition state involved in the
enzymatic reactions.9-11
stronger inhibitory activities than salacinol, and in addition, we
found that analogues 5 and 6 and salacinol 3 showed discrimi-
nation on selectivity for certain glycosidase enzymes.14-17 These
studies have revealed interesting differences in the inhibitory
activities of these compounds for glycosidase enzymes of
different origin.
Interestingly, kotalanol 4 was claimed to have even greater
inhibitory power than salacinol for certain glycosidase enzymes.7
It was therefore of interest to examine homologues of salacinol
containing polyhydroxylated, sulfated chains. We have recently
reported the synthesis of such homologues containing five- and
six-carbon chains.18 We now report simpler synthetic routes to
six-carbon chain homologues, their selenium and nitrogen
congeners, and the corresponding diastereomers resulting from
changes in stereochemistry at the stereogenic centers in the
heterocyclic ring (7-12, Chart 4).
The syntheses of salacinol (1),10,11 its stereoisomers,12,13 the
selenium congener blintol (5),14,15 and the nitrogen congener
ghavamiol (6)16 have been reported (Chart 3). Blintol exhibited
(5) Bock, K.; Sigurskjold, B. Struct. Nat. Prod. Chem. 1990, 7, 29-86.
Stutz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond; Wiley-VCH: New York, 1999.
Results and Discussion
(6) Yoshikawa, M.; Murakami, T.; Shimada, H.; Matsuda, H.; Yamahara,
J.; Tanabe, G.; Muraoka, O. Tetrahedron Lett. 1997, 38, 8367-8370.
(7) Yoshikawa, M.; Murakami, T.; Yashiro, K.; Matsuda, H. Chem.
Pharm. Bull. 1998, 46, 1339-1340.
Retrosynthetic analysis indicated that the analogues 7-12
could be synthesized by alkylation of a protected anhydroalditol
at the ring heteroatom with a terminal 1,3-cyclic sulfate derived
from D-sorbitol (Scheme 1).
However, the choice of protecting groups for the cyclic sulfate
merited careful consideration, especially in the case of the
selenonium analogues. Our previous studies14,15 had suggested
that the p-methoxybenzyl ether was the most appropriate
protecting group for the anhydroalditol moiety. Our previous
work also suggested that the release of ring strain in the opening
of a cyclic sulfate was beneficial. Accordingly, we envisioned
that the cyclic sulfate 13 (Chart 5), in which the 2,4-positions
were protected by a benzylidene acetal, would serve this
(8) Yoshikawa, M.; Murikawa, T.; Matsuda, H.; Tanabe, G.; Muraoka,
O. Bioorg. Med. Chem. 2002, 10, 1547-1550.
(9) Svansson, L.; Johnston, B. D.; Gu, J. H.; Patrick, B.; Pinto, B. M. J.
Am. Chem. Soc. 2000, 122, 10769-10775.
(10) Yuasa, H.; Takada, J.; Hashimoto, H. Tetrahedron Lett. 2000, 41,
6615.
(11) Ghavami, A. Johnston, B. D.; Pinto, B. M. J. Org. Chem. 2001,
66, 2312.
(12) Ghavami, A.; Sadalapure, K. S.; Johnston, B. D.; Lobera, M.; Snider,
B. B.; Pinto, B. M. Synlett 2003, 1259-1262.
(13) 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.
(14) Johnston, B. D.; Ghavami, A.; Jensen, M. T.; Svensson, B.; Pinto,
B. M. J. Am. Chem. Soc. 2002, 124, 8245-8250.
(15) 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.
(16) Ghavami, A.; Johnston, B. D.; Jensen, M. T.; Svensson, B.; Pinto,
B. M. J. Am. Chem. Soc. 2001, 123, 6268-6271.
(17) Li, Y.; Scott, C. R.; Chamoles, N. A.; Ghavami, A.; Pinto, B. M.;
Turecek, F.; Gelb, M. H. Clin. Chem. 2004, 50, 1785-1796.
(18) Johnston, B. D.; Hensen, H. J.; Pinto, B. M. J. Org. Chem. 2006,
ASAP.
3008 J. Org. Chem., Vol. 71, No. 8, 2006

A New Class of Glucosidase Inhibitor
CHART 5
SCHEME 4
SCHEME 5
SCHEME 2
SCHEME 3
L-selenoarabinitol 21 and L-thioarabinitol 22 in HFIP to give
the corresponding protected selenonium and sulfonium com-
pounds 23 and 24, respectively (Scheme 4).
function. The 5,6-positions could be protected with an isopro-
pylidene acetal. After the coupling reactions, the products could
then be readily deprotected by simple treatment with trifluoro-
acetic acid.
We turned next to the synthesis of the corresponding chain-
extended nitrogen analogues. The synthesis of the PMB
protected D- and L-iminoarabinitols 28 and 32 took advantage
of our established method for the synthesis of blintol (Scheme
5). Starting from L-xylose and D-xylose, respectively, the
corresponding dimesylates 26 and 3015 were prepared in overall
yields of 21% and 16%, respectively. The dimesylates 26 and
30 were subsequently treated with allylamine and heated to 90
°C in DMF for 12 h to yield the allylimino compounds 27 and
31, respectively. Compounds 27 and 31 were refluxed in 90%
aqueous acetonitrile with Wilkinson’s catalyst for 4 h to afford
the desired D-iminoarabinitol 28 and L-iminoarabinitol 32,
respectively.
The coupling reactions of 28 and 32 with the cyclic sulfate
13 were then carried out in acetone, as described previously
for the synthesis of ghavamiol 6.16 The reactions proceeded
smoothly at 55 °C to give the corresponding coupling products
33 and 35, respectively (Scheme 6).
The reactivities of the seleno-, thio-, and iminoarabinitols with
the cyclic sulfate 13 varied slightly. The iminoarabinitols were
the most reactive, while the thioarabinitols were the least reactive
of the three. Selectivity for attack of the seleno-, thio-, and
iminoarabinitol derivatives at the primary carbon of the cyclic
sulfate over possible alternative attack at the secondary carbon
was invariably excellent, and in no case were isolable quantities
of the regioisomers detected. Of note, in the case of the coupling
reactions of selenoarabinitols 17 and 21 with the cyclic sulfate
13, there was a small amount (less than 10%) of the stereo-
The synthesis of the cyclic sulfate 13, as depicted in Scheme
2, started from the commercially available D-sorbitol (14).
Following the reported method by Kuszmann et al.,19 D-sorbitol
was first treated with benzaldehyde in hydrochloric acid and
water to give 2,4-O-benzylidene-D-glucitol (15). Compound 15
was then reacted with 2,2-dimethoxypropane to afford the 2,4-
O-benzylidene-5,6-O-isopropylidene-D-glucitol (16).19 The glu-
citol derivative 16 was then converted to the cyclic sulfite by
treatment with thionyl chloride and pyridine, and the sulfite was
then oxidized with sodium periodate and ruthenium(III) chloride
as a catalyst to yield the desired cyclic sulfate 13, as a crystalline
solid in 75% yield.
The coupling reactions of the cyclic sulfate 13 with the
protected selenoarabinitols and thioarabinitols were investigated
first. The PMB-protected D-selenoarabinitol 17 and D-thio-
arabinitol 18 were prepared by methods described in our earlier
work.12,15 The cyclic sulfate 13 was reacted with D-seleno-
arabinitol 1715 and D-thioarabinitol 1812 to give the protected
selenonium and sulfonium compounds 19 and 20, respectively
(Scheme 3). The solvent 1,1,1,3,3,3-hexafluoro-2-propanol
(HFIP) offered significant advantage, as observed in our
previous work.12,14,15 For example, while the coupling reaction
of 17 with the cyclic sulfate 13 did not proceed in acetone at
100 °C, it proceeded in HFIP at 65 °C within 12 h to give 19
in 95% yield.
The PMB-protected L-selenoarabinitol 21 and L-thioarabinitol
22 were prepared as described for the corresponding D-isomers
17 and 18, respectively.15 The cyclic sulfate 13 was reacted with
(19) Kuszmann, J.; Medgyes, G.; Boros, S. Carbohydr. Res. 2004, 339,
2407-2414.
J. Org. Chem, Vol. 71, No. 8, 2006 3009

Liu et al.
SCHEME 6
FIGURE 1. NOE correlations observed in the NOESY spectrum of
8.
Conclusions
Three series of chain-extended analogues of the naturally
occurring glucosidase inhibitor salacinol were synthesized. The
analogues contained extended acyclic chains of six carbons, as
well as ring-heteroatom substitution (N, Se, S) and changes of
stereochemistry in the five-membered ring. These syntheses
utilized the 1,3-cyclic sulfate derived from commercially
available D-sorbitol in four steps. The PMB, isopropylidene
acetal, and benzylidene acetal protecting groups on the coupling
products ensured facile deprotection with TFA to yield the final
compounds 7 to 12. Compounds 7, 9, 11, and 12 show inhibition
of recombinant human maltase glucoamylase, a critical intestinal
glucosidase, in the micromolar range.
SCHEME 7
Experimental Section
Enzyme Activity Assay. Analysis of MGA inhibition was
performed using maltose as the substrate and measuring the release
of glucose. Reactions were carried out in 100 mM MES buffer pH
6.5 at 37 °C for 15 min. The reaction was stopped by boiling for
3 min. Twenty microliter aliquots were taken and added to 100 µL
of glucose oxidase assay reagent (Sigma) in a 96-well plate.
Reactions were developed for 1 h, and absorbance was measured
at 450 nm to determine the amount of glucose produced by MGA
activity in the reaction. One unit of activity is defined as the
hydrolysis of one mole of maltose per minute. All reactions were
performed in triplicate, and absorbance measurements were aver-
aged to give a final result.
Enzyme Kinetics. Kinetic parameters of recombinant MGA were
determined using the glucose oxidase assay to follow the production
of glucose upon addition of enzyme (15 nM) at increasing maltose
concentrations (from 1 mM to 3.5 mM) with a reaction time of 15
min. The program GraFit 4.0.14 was used to fit the data to the
Michaelis-Menten equation and estimate the kinetic parameters,
Km and Vmax, of the enzyme. Ki values for each inhibitor were
determined by measuring the rate of maltose hydrolysis by MGA
at varying inhibitor concentrations. Data were plotted in Lin-
eweaver-Burk plots (1/rate vs 1/[substrate]), and Ki values were
determined by the equation Ki ) Km[I]/(Vmax)m - Km, where m is
the slope of the line. The Ki reported for each inhibitor was
estimated by averaging the Ki values obtained from each of the
different inhibitor concentrations.
2,4-O-Benzylidene-5,6-O-isopropylidene-D-glucitol 1,3-Cyclic
Sulfate (13). The 2,4-O-benzylidene-5,6-O-isopropylidene-D-glu-
citol (16) was prepared by the literature method.17 To a solution of
16 (4.7 g, 15 mmol) in CH2Cl2 (80 mL)was added pyridine (10
mL) at room temperature. Thionyl chloride (1.65 mL, 22 mmol)
dissolved in CH2Cl2 (20 mL) was then added, and the mixture was
heated at 40-50 °C for 4 h. The progress of the reaction was
followed by TLC analysis of aliquots (developing solvent hexane/
EtOAc, 2:1). When starting material 16 had been essentially
consumed, the reaction mixture was cooled, poured into ice-water,
extracted with CH2Cl2 (100 mL), washed with brine (20 mL), and
dried over Na2SO4. After evaporation of the solvent, the crude sulfite
was passed through a short silica gel column. The resulting sulfite
isomers formed through electrophilic attack on the â-face of
the D-selenoarabinitol 17 and the R-face of the L-selenoarabinitol
21 to give products that were diastereomeric at the selenonium
center.
The deprotection of the coupled products 19, 20, 23, 24, 33,
and 34 was carried out by treatment with trifluoroacetic acid
(Scheme 7). The resulting residues were purified by flash
chromatography to yield compounds 7 to 12 as amorphous,
hygroscopic solids.
The absolute stereochemistry at the heteroatom center of
compounds 7-12 was established by NOESY NMR spectros-
copy (Figure 1). For example, in the NOESY spectrum of
compound 8, the H-4 to H-1′b correlation was clearly exhibited,
implying that they are syn-facial. Therefore, C-1′ of the side
chain must be anti to C-5 of the sulfonium salt ring (Figure 1).
However, the correlation of H-1′a or H-1′b with H-1a,1b could
not be clearly established owing to overlap of signals.
As a final point of interest, we comment on the inhibitory
activities of the compounds synthesized in this study against
recombinant human maltase glucoamylase (MGA), a critical
intestinal glucosidase involved in the processing of oligosac-
charides of glucose into glucose itself. Compounds 7 and 9,
with the D-arabinitol configuration in the heterocyclic ring
displayed by salacinol, have Ki values of 41 ( 7 and 26 ( 9
µM, respectively. In contrast, the sulfur analogue 8 is not active.
Of compounds 10-12, with the unnatural L-arabinitol config-
uration in the heterocyclic ring, the sulfur and nitrogen congeners
11 and 12 are active, with Ki values of 25 ( 5 and 5 ( 1 µM,
respectively.
3010 J. Org. Chem., Vol. 71, No. 8, 2006

A New Class of Glucosidase Inhibitor
was redissolved in a mixture of CH3CN, CCl4, and water (CH3-
CN/CCl4/H2O, 3:3:0.5, 65 mL). Ruthenium(III) chloride (50 mg)
was then added to the solution. At room temperature, NaIO4 (4.26
g, 20 mmol) was added to the mixture, and the mixture was stirred
for 2 h. When TLC analysis of aliquots (developing solvent hexane/
EtOAc, 1:1) showed total consumption of the starting material, the
reaction mixture was filtered through a short column of silica gel
and the silica gel was washed with CH2Cl2 (100 mL). The filtrate
was combined and evaporated to dryness. It was then redissolved
in EtOAc (100 mL), washed with water (50 mL), and dried over
Na2SO4. Purification by column chromatography (hexane/EtOAc,
1:1), followed by recrystallization with Hexane/EtOAc yielded 13
as a colorless, crystalline solid (3.9 g, 70%). Mp: 126-128 °C
(C-2), 73.0, 71.2 (2 CH2Ph), 70.8 (C-5), 68.6 (C-4), 58.4 (C-1′),
57.4 (C-1), 55.5 (CH2Ph), 55.4 (3 OCH3). Anal. Calcd for C32H39-
NO6: C, 72.02; H, 7.37; N, 2.62. Found: C, 71.89; H, 7.04; N,
2.63.
2,3,5-O-p-Methoxybenzyl-1,4-dideoxy-1,4-imino-D-arabini-
tol (28). To a solution of the N-allyl compound 27 (5.0 g, 9.3 mmol)
in 90% CH3CN (50 mL) was added Wilkinson’s catalyst (Rh-
(PPh)3Cl, 100 mg), and the reaction mixture was refluxed for 4 h.
The solvent was removed under reduced pressure, and the crude
product was purified by column chromatography (hexane/EtOAc,
1:1) to afford 28 as a colorless oil (3.5 g, 75%). [R]D: +0.8 (c 4.0,
CH2Cl2); 1H NMR (CDCl3) δ: 7.50-6.80 (m, 12H, Ar), 4.46 (m,
2H, CH2Ph), 4.47 and 4.43 (two d, 2H, JAB ) 10.9, CH2Ph), 4.49
and 4.41 (two d, 2H, JAB ) 11.4, CH2Ph), 3.97 (m, 1H, H-2), 3.82
(dd, 1H, J2,3 ) 4.3, J3,4 ) 3.0, H-3), 3.81, 3.80, 3.79 (three s, 3
OCH3), 3.58 (dd, 1H, J4,5b ) 5.0, J5a,5b ) 9.5, H-5b), 3.53 (dd, 1H,
J4,5a ) 3.6, H-5a), 3.25 (dd, 1H, H-4), 3.09 (d, 2H, H-1a, H-1b).
13C NMR (CD2Cl2) δ: 159.5, 159.4, 159.3, 133.2, 133.1, 133.0,
130.5, 130.4, 130.3, 130.2, 114.0, and 111.9 (12C, Ar), 85.3 (C-
3), 84.1 (C-2), 73.1, 71.8, 70.9 (3 CH2Ph), 70.1 (C-5), 64.2 (C-4),
55.5, 55.4, and 55.3 (3 OCH3), 51.1 (C-1). Anal. Calcd for C29H35-
NO6: C, 70.57; H, 7.15; N, 2.84. Found: C, 70.90; H, 7.21; N,
2.99.
1
dec. [R]D ) +12.3 (c 1.1, CH2Cl2). H NMR (CD2Cl2) δ: 7.50-
7.30 (m, 5H, Ar), 5.73 (s, 1H, CHPh), 5.07 (br t, 1H, J3,4 ) 1.4,
H-4), 4.98 (dd, 1H, J5,6b ) 1.8, J6a,6b ) 12.6, H-6b), 4.72 (dd, 1H,
J5,6a ) 1.3, H-6a), 4.36 (ddd, 1H, J1a,2 ) 3.6, J1b,2 ) 6.0, J2,3
)
8.9, H-2), 4.13 (dd, 1H, J1a,1b ) 9.0, H-1b), 4.09 (m, 1H, H-5),
4.08 (dd, 1H, H-1a), 3.94 (dd, 1H, H-3). 13C NMR (CD2Cl2) δ:
136.7, 129.8, 128.6, and 126.4 (4C, Ar), 110.2 ((CH3)2C), 101.0
(CHPh), 78.0 (C-3), 77.2 (C-4), 75.4 (C-6), 71.7 (C-2), 67.9 (C-
5), 66.7 (C-1), 27.1, and 24.8 (2 CH3). Anal. Calcd for C16H20O8S:
C, 51.60; H, 5.41. Found: C, 51.56; H, 5.41.
N-Allyl-2,3,5-O-p-methoxybenzyl-1,4-dideoxy-1,4 -imino-D-
arabinitol (27). The dimesylate (26) was prepared by a literature
method.15 To a solution of the dimesylate 26 (8.0 g, 12.0 mmol) in
DMF (30 mL) was added allylamine (10 mL, 0.13 mol), and the
reaction mixture was heated at 90 °C for 12 h. The reaction mixture
was poured into water (100 mL), extracted with Et2O (4 × 50 mL),
washed with water (10 × 20 mL), and dried over Na2SO4. After
evaporation of the solvent, the crude product was purified by
column chromatography (hexane/EtOAc, 1:1) to give 27 as a
2,3,5-O-p-Methoxybenzyl-1,4-dideoxy-1,4-imino-L-arabini-
tol (32). To a solution of the N-allyl compound 31 (3.0 g, 5.6 mmol)
in 90% CH3CN (50 mL) was added Wilkinson’s catalyst (Rh-
(PPh)3Cl, 100 mg), and the reaction mixture was refluxed for 4 h.
The solvent was removed under reduced pressure, and the crude
product was purified by column chromatography (hexane/EtOAc,
1:1) to give 32 as a colorless oil (1.9 g, 70%). [R]D: -0.34 (c 0.6,
CH2Cl2). 1H NMR (CDCl3) δ: 7.24-6.84 (m, 12H, Ar), 4.46 (m,
2H, CH2Ph), 4.48 and 4.45 (two d, 2H, JAB ) 11.5, CH2Ph), 4.44
and 4.40 (two d, 2H, JAB ) 11.5, CH2Ph), 3.98 (m, 1H, H-2), 3.84
(dd, 1H, J2,3 ) 4.6, J3,4 ) 1.6, H-3), 3.82, 3.81, 3.80 (three s, 3
OCH3), 3.58 (dd, 1H, J4,5b ) 5.1, J5a,5b ) 10.2, H-5b), 3.52 (dd,
1
colorless oil (5.4 g, 85%). [R]D: -8.6 (c 2.2, CH2Cl2). H NMR
(CDCl3) δ: 7.20-6.70 (m, 12H, Ar), 5.85 (dddd, 1H, J1a′,2′ ) 7.4,
J1b′,2′ ) 5.8, J2′,3a′ ) 9.9, J2′,3b′ ) 17.1, H-2′), 5.10 (d, 1H, H-3b′),
5.02 (d, 1H, H-3a′), 4.34 (s, 2H, CH2Ph), 4.38 and 4.28 (two d,
2H, JAB ) 12.0, CH2Ph), 3.82 (m, 2H, CH2Ph), 3.80 (dd, 1H, J2,3
) 4.0, J1a,2 ) 4.8, H-2), 3.76 (dd, 1H, J3,4 ) 5.1, H-3), 3.72, 3.71,
1H, J4,5a ) 5.7, H-5a), 3.20 (ddd, 1H, H-4), 3.06 (dd, 1H, J1b,2
)
4.6, J1a,1b ) 12.3, H-1b), 3.05 (dd, 1H, J1a,2 ) 3.0, H-1a). 13C NMR
(CD2Cl2) δ: 159.5, 159.4, 159.3, 130.6, 130.5, 130.4, 129.6, 129.5,
129.4, 114.1, 114.0, and 113.9 (12C, Ar), 85.5 (C-3), 84.4 (C-2),
73.1, 71.7, 70.9 (3 CH2Ph), 70.2 (C-5), 64.3 (C-4), 55.5, 55.4, and
55.3 (3 OCH3), 51.2 (C-1). Anal. Calcd for C29H35NO6: C, 70.57;
H, 7.15; N, 2.84. Found: C, 70.70; H, 6.95; N, 3.02.
and 3.70 (three s, 9H, 3 OCH3), 3.48 (dd, 1H, J4,5b ) 5.2, J5a,5b
)
9.8, H-5b), 3.44 (dd, 1H, H-1b′), 3.40 (dd, 1H, J4,5a ) 6.6, H-5a),
3.05 (d, 1H, J1a,1b ) 10.4, H-1b), 2.92 (dd, 1H, J1a′2′ ) 7.4, J1a′,1b′
) 12.8, H-1a′), 2.64 (m, 1H, H-4), 2.50 (dd, 1H, H-1a). 13C NMR
(CD2Cl2) δ: 159.4, 159.3, 159.2, 133.2, 133.1, 132.9, 130.8, 130.7,
130.6, 128.3, 112.0, and 111.9 (12 C, Ar), 135.9 (C-2′), 114.0 (C-
3′), 85.5 (C-3), 81.2 (C-2), 73.0, 71.2 (2 CH2Ph), 70.8 (C-5), 68.6
(C-4), 58.3 (C-1′), 57.3 (C-1), 56.5 (CH2Ph), 55.5 (3 OCH3). Anal.
Calcd for C32H39NO6: C, 72.02; H, 7.37; N, 2.62. Found: C, 71.74;
H, 7.16; N, 2.84.
General Procedure for the Preparation of Selenium and
Sulfonium Sulfates 19, 23, 20, and 24. A mixture of the
selenoarabinitol 17 or 21 or the thioarabinitol 18 or 22 and the
cyclic sulfate 13 in HFIP (1,1,1,3,3,3-hexafluoro-2-propanol) was
placed in a reaction vessel, and K2CO3 (20 mg) was added. The
stirred reaction mixture was heated in a sealed tube at the indicated
temperature for the indicated time, as given below. The progress
of the reaction was followed by TLC analysis of aliquots (develop-
ing solvent EtOAc/MeOH, 10:1). When the limiting reagent had
been essentially consumed, the mixture was cooled, diluted with
CH2Cl2, and evaporated to give a syrupy residue. Purification by
column chromatography (EtOAc to EtOAc/MeOH, 10:1) gave the
purified selenonium salts 19, 23 and sulfonium salts 20, 24.
2,3,5-Tri-O-p-methoxybenzyl-1,4-dideoxy-1,4-[[(2R,3S,4R,5R)-
2,4-benzylidenedioxy-5,6-isopropylidenedioxy-3-(sulfooxy)hexyl]-
episelenoniumylidene]-D-arabinitol Inner Salt (19). Reaction of
the selenoarabinitol 17 (500 mg, 0.89 mmol) with the cyclic sulfate
13 (430 mg, 1.1 mmol) in HFIP (2 mL) for 12 h at 65 °C gave
compound 19 as a colorless, amorphous solid (790 mg, 95% based
N-Allyl-2,3,5-O-p-methoxybenzyl-1,4-dideoxy-1,4-imino-L-
arabinitol (31). The dimesylate (30) was prepared by a literature
method.15 To a solution of the dimesylate 30 (3.6 g, 5.4 mmol) in
DMF (30 mL) was added allylamine (10 mL, 0.13 mol), and the
reaction mixture was heated at 90 °C for 12 h. The reaction mixture
was poured into water (100 mL), extracted with Et2O (4 × 50 mL),
washed with water (10 × 20 mL), and dried over Na2SO4. After
evaporation of the solvent, the crude product was purified by
column chromatography (hexane/EtOAc, 1:1) to give 31 as a
colorless oil (2.5 g, 85%). [R]D: +15.7 (c 3.0, CH2Cl2). 1H NMR
(CDCl3) δ: 7.30-6.80 (m, 12H, Ar), 5.93 (dddd, 1H, J1a′,2′ ) 7.3,
J1b′,2′ ) 5.6, J2′,3a′ ) 9.9, J2′,3b′ ) 17.1, H-2′), 5.18 (d, 1H, H-3b′),
5.10 (d, 1H, H-3a′), 4.46 and 4.43 (two d, 2H, JAB ) 12.1, CH2-
Ph), 4.41 (s, 2H, CH2Ph), 4.41 and 4.36 (two d, 2H, JAB ) 11.9,
CH2Ph), 3.85 (m, 1H, H-2), 3.83 (m, 1H, H-3), 3.80, 3.79, and
3.78 (three s, 9H, 3 OCH3), 3.56 (dd, 1H, J4,5b ) 5.5, J5a,5b ) 10.9,
H-5b), 3.52 (m, 1H, H-1b′), 3.48 (dd, 1H, J4,5a ) 6.3, H-5a), 3.12
(d, 1H, H-1b), 3.00 (dd, 1H, J1a′,1b′ ) 12.9, H-1a′), 2.72 (m, 1H,
H-4), 2.56 (dd, 1H, J1a,2 ) 4.8, H-1a). 13C NMR (CD2Cl2) δ: 159.4,
159.3, 159.2, 130.9, 130.8, 130.7, 130.6, 130.5, 129.6, 129.5, 112.0,
and 111.9 (12C, Ar), 135.9 (C-2′), 114.0 (C-3′), 85.5 (C-3), 81.2
1
on 17). [R]D: -39 (c 1.0, CH2Cl2). H NMR (CD2Cl2) δ: 7.50-
6.80 (m, 17H, Ar), 5.70 (s, 1H, CHPh), 4.60 (m, 1H, H-4′), 4.55-
(dd, 1H, J2′,3′ ) 8.2, H-2′), 4.53-4.48 (m, 5H, H-3′, 2CH2Ph), 4.44
(m, 1H, H-2), 4.43 and 4.38 (two d, 2H, JAB ) 11.4, CH2Ph), 4.28
(m, 2H, H-3, H-6′a), 4.25 (dd, 1H, J1′a,1′b ) 11.8, J1′b,2′ ) 1.9, H-1′b),
4.23-4.17 (m, 3H, H-5′, H-4, H-6′b), 4.00 (dd, 1H, J4,5a ) 5.9,
J5a,5b ) 9.8, H-5a), 3.92 (dd, 1H, J1′a,2′ ) 5.9, J1′a,1′b ) 11.8, H-1′a),
3.80 (m, 1H, H-5b), 3.81, 3.80, and 3.79 (three s, 9H, 3 OCH3),
J. Org. Chem, Vol. 71, No. 8, 2006 3011

Liu et al.
3.52 (dd, 1H, J1b,2 ) 1.1, J1a,1b ) 12.3, H-1b), 3.30 (dd, J1a,2
)
) 5.7, J1′a,1′b ) 12.5, H-1′a), 3.96 and 3.83 (two d, 2H, JAB
)
11.3, CH2Ph), 3.74 (dd, 1H, J3,4 ) 7.9, H-4), 3.72, 3.70, 3.68 (three
s, 9H, three OCH3), 3.49 (dd, 1H, J1a,1b ) 13.1, J1a,2 ) 3.2, H-1a),
3.3, 1H, H-1a), 1.36 and 1.38 (two s, 6H, 2 CH3). 13C NMR (CD2-
Cl2) δ: 160.0, 159.9, 159.7, 137.4, 130.2, 129.8, 129.7, 129.6,
129.5, 128.6, 128.5, 128.3, 114.3, 114.2, 114.1, 114.0 (16C, Ar),
108.3 ((CH3)2C), 101.0 (CHPh), 84.5 (C-2), 82.2 (C-3′), 79.3 (C-
5′), 75.8 (CH2Ph), 74.0 (C-2′), 73.3 and 71.8 (2 CH2Ph), 71.6 (C-
3), 70.8 (C-4′), 67.0 (C-5), 65.0 (C-6′), 64.2 (C-4), 55.5, 55.4, and
55.3 (3 OCH3), 48.6 (C-1′), 47.4 (C-1), 26.4, 25.5 (2 CH3).
HRMS: calcd for C45H55O14SSe 931.2477. found 931.2471.
2,3,5-Tri-O-p-methoxybenzyl-1,4-dideoxy-1,4-[[(2R,3S,4R,5R)-
2,4-benzylidenedioxy-5,6-isopropylidenedioxy-3-(sulfooxy)hexyl]-
episelenoniumylidene]-L-arabinitol Inner Salt (23). Reaction of
the selenoarabinitol 21 (400 mg, 0.72 mmol) with the cyclic sulfate
13 (350 mg, 0.93 mmol) in HFIP (2 mL) for 12 h at 65 °C gave
compound 23 as a colorless, amorphous solid (630 mg, 95% based
3.40 (dd, 1H, J4, 5b ) 9.4, H-5b), 3.20 (dd, 1H, J4,5a ) 6.7, J5a,5b
)
9.5, H-5a), 1.27 and 1.29 (two s, 6H, two CH3). 13C NMR (CD2-
Cl2) δ: 160.1, 160.0, 159.7, 137.5, 130.2, 129.8, 129.7, 129.6,
129.5, 128.6, 128.5, 128.2, 126.5, 114.2, 114.1, and 113.9 (16C,
Ar), 108.3 (CHPh), 101.1 ((CH3)2C), 82.5 (C-2), 82.1 (C-3′), 79.2
(C-3), 75.9 (C-5′), 73.8 (C-2′), 72.9, 72.0, 71.6 (3 CH2Ph), 70.6
(C-4′), 66.6 (C-5), 66.4 (C-4), 64.9 (C-6′), 55.5, 55.4, and 55.3 (3
OCH3), 49.7 (C-1′), 48.2 (C-1), 26.4 and 25.6 (2 CH3). Anal. Calcd
for C45H54O14S2: C, 61.21; H, 6.16. Found: C, 61.25; H, 6.13.
2,3,5-Tri-O-p-methoxybenzyl-1,4-dideoxy-1,4-[[(2R,3S,4R,5R)-
2,4-benzylidenedioxy-5,6-isopropylidenedioxy-3-(sulfooxy)hexyl]-
iminoniumlidene]-D-arabinitol Inner Salt (33). A mixture of the
iminoarabinitol 28 (450 mg, 0.9 mmol) and the cyclic sulfate 13
(470 mg, 1.2 mmol) in acetone (2 mL) containing K2CO3 (20 mg)
was warmed at 55 °C in a sealed reaction vessel with stirring for
12 h. The progress of the reaction was followed by TLC analysis
of the aliquots (developing solvent EtOAc/MeOH, 10:1). When the
iminoarabinitol 28 had been completely consumed, the mixture was
cooled, diluted with CH2Cl2, and evaporated to give a syrupy
residue. Purification by column chromatography (EtOAc to EtOAc/
MeOH, 10:1) gave the iminium salt 33 as an amorphous solid (600
mg, 77% based on 28). [R]D: +10 (c 0.5, CH2Cl2). 1H NMR (CD2-
Cl2) δ: 7.50-6.73 (m, 17H, Ar), 5.54 (s, 1H, CHPh), 4.56-4.53
(m, 2H, H-3′, H-5′), 4.52 and 4.38 (two d, 2H, JAB ) 12.4, CH2-
Ph), 4.46 and 4.36 (two d, 2H, JAB ) 12.0, CH2Ph), 4.20 and 4.14
(two d, 2H, JAB ) 11.5, CH2Ph), 4.15 (m, 1H, H-2′), 4.11 (dd, 1H,
J5′,6′b ) 4.2, J6′a,6′b ) 8.6, H-6′b), 4.09 (dd, 1H, J5′,6′a ) 6.1, H-6′a),
3.89 (br d, 1H, J3′,4′ ) 6.7, H-4′), 3.74 (m, 1H, H-3), 3.77, 3.75,
3.73 (three s, 9H, 3 OCH3), 3.65 (d, 1H, J1b,2 ) 3.5, H-2), 3.58
(dd, 1H, J4,5b ) 4.1, J5a,5b ) 10.0, H-5b), 3.43 (dd, 1H, J4,5a <1,
H-5a), 3.30 (m, 2H, H-1′b, H-1b), 3.14 (dd, 1H, J1′a,1′b ) 12.1,
J1′a,2′ ) 6.1, H-1′a), 2.96 (dd, 1H, J1a,2 <1, J1a,1b ) 10.1, H-1a),
2.80 (m, 1H, H-4), 1.18 and 1.21 (two s, 6H, 2 CH3). 13C NMR
(CD2Cl2) δ: 159.6, 159.5, 159.4, 138.1, 130.3, 130.2, 130.1, 129.9,
129.8, 129.4, 128.9, 128.3, 126.3, 113.9, 113.8, 113.7 (16C, Ar),
109.2 (CHPh), 100.8 ((CH3)2C), 79.8 (C-2), 79.7 (C-3), 77.1 (C-
4′), 74.6 (C-3′), 73.0 (C-2′), 71.6, 71.1, 71.0 (3 CH2Ph, C-5′), 68.4
(C-4), 65.6 (C-5), 59.2 (C-6′), 56.4 (C-1), 55.4, 55.3, 55.2 (3 OCH3),
55.2 (C-1′), 27.0 and 25.6 (2 CH3). Anal. Calcd for C45H54-
KNO14S: C, 59.78; H, 6.02; N, 1.55. Found: C, 60.01; H, 6.07;
N, 1.55.
1
on 21). [R]D: -14 (c 2.8, CH2Cl2). H NMR (CD2Cl2) δ: 7.50-
6.80 (m, 17H, Ar), 5.73 (s, 1H, CHPh), 4.69 (br s, 1H, H-4′), 4.64
(dd, 1H, J1′a, 2′ ) 6.9, J1′b,2′ ) 5.5, H-2′), 4.54 (ddd, 1H, J5′,6′a
)
9.9, J5′,6b′ ) 3.5, J4′,5′ ) 6.5, H-5′), 4.48 (d, 2H, CH2Ph), 4.44 (m,
1H, H-2), 4.37 (m, 1H, H-3), 4.32-4.24 (m, 3H, H-3′, H-6′a,
H-6′b), 4.32 and 4.25 (two d, 2H, JAB ) 11.5, CH2Ph), 4.16 (br d,
1H, J1′a,1′b ) 11.9, H-1′b), 4.03 (dd, 1H, J1′a,2′ ) 6.9, H-1′a), 4.00
(m, 1H, H-1b), 4.10 and 3.95 (two d, 2H, JAB ) 11.6, CH2Ph),
3.88 (m, 1H, H-4), 3.81, 3.80, and 3.79 (three s, 9H, 3 OCH3),
3.56 (dd, 1H, J1a,2 ) 2.7, J1a,1b ) 12.2, H-1a), 3.44 (dd, 1H, J4,5b
)
9.6, J5a,5b ) 9.7, H-5b), 3.24 (dd, 1H, J4,5a ) 6.7, H-5a), 1.38 and
1.42 (two s, 6H, 2 CH3). 13C NMR (CD2Cl2) δ: 160.0, 159.9, 159.7,
137.6, 130.1, 130.0, 129.8, 129.7, 129.6, 129.5, 128.8, 128.7, 128.5,
114.2, 114.1, 113.9 (16C, Ar), 108.5 ((CH3)2C), 101.2 (CHPh), 83.1
(C-3′), 82.9 (C-2), 79.1 (C-5′), 75.8 (C-2′), 73.9 72.8, and 71.9 (3
CH2Ph), 71.4 (C-3), 71.3 (C-4′), 66.7 (C-5), 65.3 (C-4), 65.0 (C-
6′), 55.5, 55.4, and 55.3 (3 OCH3), 47.4 (C-1′), 45.2 (C-1), 26.5,
25.6 (2 CH3). HRMS: calcd for C45H55O14SSe 931.2477, found
931.2479.
2,3,5-Tri-O-p-methoxybenzyl-1,4-dideoxy-1,4-[[(2R,3S,4R,5R)-
2,4-benzylidenedioxy-5,6-isopropylidenedioxy-3-(sulfooxy)hexyl]-
episulfoniumylidene]-D-arabinitol Inner Salt (20). Reaction of
the thioarabinitol 18 (500 mg, 0.98 mmol) with the cyclic sulfate
13 (470 mg, 1.27 mmol) in HFIP (1.5 mL) for 12 h at 75 °C gave
compound 20 as a colorless, amorphous solid (731 mg, 85% based
1
on 18). [R]D: -26 (c 1.0, CH2Cl2). H NMR (CD2Cl2) δ: 7.50-
6.82 (m, 17H, Ar), 5.56 (s, 1H, CHPh), 4.53-4.50 (m, 2H, H-4′,
H-5′), 4.49 and 4.41 (two d, 2H, JAB ) 11.7, CH2Ph), 4.42 (m,
1H, H-2′), 4.42 and 4.32 (two d, 2H, JAB ) 11.2, CH2Ph), 4.36
and 4.32 (two d, 2H, JAB ) 11.5, CH2Ph), 4.34-4.28 (m, 2H, H-2,
H-3), 4.26 (dd, 1H, J5′,6′b ) 6.4, J6′a,6′b ) 8.6, H-6′b), 4.20 (dd, 1H,
J5′,6′a ) 6.6, H-6′a), 4.09 (dd, 1H, J1′b,2′ ) 7.1, J1′a,1′b ) 13.3, H-1′b),
4.08-4.04 (m, 2H, H-3′, H-4), 4.04 (dd, 1H, J1′a,2′ ) 4.0, H-1′a),
3.86-3.81 (m, 2H, H-1b, H-5b), 3.81, 3.80, 3.79 (3s, 9H, 3 OCH3),
2,3,5-Tri-O-p-methoxybenzyl-1,4-dideoxy-1,4-[[(2R,3S,4R,5R)-
2,4-benzylidenedioxy-5,6-isopropylidenedioxy-3-(sulfooxy)hexyl]-
iminoniumlidene]-L-arabinitol Inner Salt (34). A mixture of the
iminoarabinitol 32 (450 mg, 0.9 mmol) and the cyclic sulfate 13
(470 mg, 1.2 mmol) in acetone (2 mL) containing K2CO3 (20 mg)
was warmed at 55 °C in a sealed reaction vessel with stirring for
12 h. The progress of the reaction was followed by TLC analysis
of the aliquots (developing solvent EtOAc/MeOH, 10:1). When the
iminoarabinitol 32 had been completely consumed, the mixture was
cooled, diluted with CH2Cl2, and evaporated to give a syrupy
residue. Purification by column chromatography (EtOAc to EtOAc/
MeOH, 10:1) gave the iminium salt 34 as an amorphous solid (620
mg, 81% based on 32). [R]D: +15 (c 1.0, CH2Cl2); 1H NMR (CD2-
Cl2) δ: 7.38-6.68 (m, 17H, Ar), 5.57 (s, 1H, CHPh), 4.51-4.47
(m, 2H, H-3′, H-5′), 4.36 and 4.31 (two d, 2H, JAB ) 11.8, CH2-
Ph), 4.54 and 4.17 (two d, 2H, JAB ) 11.8, CH2Ph), 4.15 and 4.06
(two d, 2H, JAB ) 11.6, CH2Ph), 4.04-4.01 (m, 3H, H-6′a, H-6′b,
H-2′), 3.86 (dd, 1H, J3′,4′ ) 6.3, H-4′), 3.69 (m, 2H, H-2, H-3),
3.76 (dd, 1H, J5a,5b ) 9.4, J4,5a ) 8.8, H-5a), 3.58(dd, 1H, J1a,2
)
3.5, J1a,1b ) 13.2, H-1a), 1.37 (s, 6H, two CH3). 13C NMR (CD2-
Cl2) δ: 160.1, 160.0, 159.8, 137.5, 133.4, 133.2, 133.1, 130.2,
129.9, 129.8, 129.5, 128.5, 126.3, 114.3, 114.2, and 114.1 (16C,
Ar), 108.3 (CHPh), 101.3 ((CH3)2C), 82.7 (C-2), 82.1 (C-3), 79.3
(C-3′), 75.9 (C-5′), 74.6 (C-2′), 73.5, 72.0, 71.8 (3 CH2Ph), 69.5
(C-4′), 67.0 (C-5), 66.0 (C-4), 64.8 (C-6′), 55.4, 55.3, and 55.2 (3
OCH3), 49.2 (C-1′), 48.9 (C-1), 26.4, and 25.6 (2 CH3). HRMS:
calcd for C45H55O14S2 883.3033, found 883.3031.
2,3,5-Tri-O-p-methoxybenzyl-1,4-dideoxy-1,4-[[(2R,3S,4R,5R)-
2,4-benzylidenedioxy-5,6-isopropylidenedioxy-3-(sulfooxy)hexyl]-
episulfoniumylidene]-L-arabinitol Inner Salt (24). Reaction of
the thioarabinitol 22 (400 mg, 0.78 mmol) with the cyclic sulfate
13 (372 mg, 1.0 mmol) in HFIP (1.5 mL) for 12 h at 75 °C gave
compound 24 as a colorless, amorphous solid (570 mg, 83% based
3.68, 3.66, and 3.65 (three s, 9H, 3 OCH3), 3.57 (dd, 1H, J4,5b
)
3.3, J5a,5b ) 10.0, H-5b), 3.38 (dd, 1H, J1′a,1′b ) 13.3, J1′b,2′ ) 5.6,
H-1′b), 3.28 (dd, 1H, J4,5a ) 2.9, H-5a), 3.16 (dd, 1H, J1a,1b ) 10.3,
H-1b), 2.58 (m, 2H, H-4, H-1′a), 2.53 (dd, 1H, J1a,2 ) 3.9, H-1a),
1.27 and 1.34 (two s, 6H, 2 CH3). 13C NMR (CD2Cl2) δ: 159.7,
159.5, 159.4, 138.1, 130.2, 130.1, 130.0, 129.9, 129.7, 129.4, 128.9,
128.3, 126.2, 114.0, 113.9, and 113.8 (16C, Ar), 109.3 (CHPh),
1
on 22). [R]D: +21 (c 4.4, CH2Cl2). H NMR (CD2Cl2) δ: 7.50-
6.70 (m, 17H, Ar), 5.58 (s, 1H, CHPh), 4.50-4.46 (m, 2H, H-4′,
H-5′), 4.42 (ddd, 1H, J1′a,2′ ) 5.7, J1′b,2′ ) 3.2, J2′,3′ ) 9.8, H-2′),
4.37 (s, 2H, CH2Ph), 4.22-4.10 (m, 8H, H-6′b, H-1′b, H-2, H-3,
H-3′, CH2Ph), 3.87 (dd, 1H, J1b,2 ) 1, H-1b), 3.85 (dd, 1H, J1′a,2′
3012 J. Org. Chem., Vol. 71, No. 8, 2006

A New Class of Glucosidase Inhibitor
100.9 ((CH3)2C), 83.5 (C-2), 80.4 (C-3), 79.6 (C-4′), 77.6 (C-2′),
74.7 (C-3′), 72.7 (CH2Ph), 71.2 (two CH2Ph, C-5′, C-4), 66.9 (C-
5), 65.6 (C-6′), 58.1 (C-1), 55.4 (3 OCH3, C-1′), 26.9, and 25.7
(two CH3). Anal. Calcd for C45H54KNO14S: C, 59.78; H, 6.02; N,
1.55. Found: C, 60.12; H, 6.17; N, 1.60.
2.6, J6′a,6′b ) 11.6, H-6′b), 3.68 (ddd, 1H, J5′,6′a ) 5.7, H-5′), 3.54
(dd, 1H, H-6′a). 13C NMR (D2O) δ: 78.0 (C-3), 77.6 (C-3′), 76.9
(C-2), 70.4 (C-5′), 69.9 (C-4), 68.9 (C-4′), 67.6 (C-2′), 62.7 (C-
6′), 59.3 (C-5), 48.6 (C-1′), 46.9 (C-1). HRMS: calcd for
C11H22O11S2Na (M + Na) 417.0501, found 417.0500.
General Procedure for the Deprotection of the Coupling
Products To Yield the Final Compounds 7-12. The protected
coupling products 19, 20, 23, 24, 33, or 34 were dissolved in CH2-
Cl2 (2 mL), TFA (10 mL) was then added, and the mixture was
stirred for 6-8 h at room temperature. The progress of the reaction
was followed by TLC analysis of aliquots (developing solvent
EtOAc/MeOH/H2O, 7:3:1). When the starting material had been
consumed, the TFA and CH2Cl2 were removed under reduced
pressure. The residue was rinsed with CH2Cl2 (4 × 2 mL), and the
CH2Cl2 was decanted to remove the cleaved protecting groups. The
remaining gum was dissolved in MeOH and purified by column
chromatography (EtOAc and EtOAc/MeOH, 2:1) to give the
purified compounds 7-12 as colorless, amorphous, and hygroscopic
solids.
1,4-Dideoxy-1,4-[[(2R,3S,4R,5R)-2,4,5,6-tetrahydroxy-3-(sul-
fooxy)hexyl]episulfoniumylidene]-L-arabinitol Inner Salt (11).
To a solution of 24 (400 mg) in CH2Cl2 (2 mL) was added TFA
(10 mL) to yield the compound 11 as a colorless, amorphous, and
1
hygroscopic solid (165 mg, 75%). [R]D: -9.6 (c 0.5, MeOH). H
NMR (D2O) δ: 4.63 (ddd, 1H, J1a,2 ) 4.0, J1b,2 ) 4.0, J2,3 ) 3.3,
H-2), 4.57 (dd, 1H, J2′,3′ ) 5.0, J3′,4′ ) 1.2, H-3′), 4.50 (ddd, J2′,3′
) 5.0, H-2′), 4.35 (br t, 1H, J2,3 ) 3.3, H-3), 4.07 (ddd, 1H, J3,4
)
2.7, J4,5a ) 1.9, J4,5b ) 5.1, H-4), 3.99 (dd, 1H, J5a,5b ) 12.4, H-5b),
3.87 (dd, 1H, H-5a), 3.85 (dd, 1H, J1′b,2′ ) 4.0, J1′a,1′b ) 9.6, H-1′b),
3.83 (dd, 1H, J1′a,2′ ) 3.9, H-1′a), 3.80 (dd, 1H, J4′,5′ ) 8.8, H-4′),
3.75 (m, 2H, H-1a, H-1b), 3.71 (dd, 1H, J5′,6′b ) 2.7, J6′a,6′b ) 11.6,
H-6′b), 3.68 (ddd, 1H, J5′,6′a ) 5.6, H-5′), 3.54 (1H, dd, H-6′a).
13C NMR (D2O) δ: 77.9 (C-3), 77.6 (C-3′), 76.9 (C-2), 70.4 (C-
5′), 69.9 (C-4), 68.9 (C-4′), 67.5 (C-2′), 62.7 (C-6′), 59.3 (C-5),
48.6 (C-1′), 46.9 (C-1). HRMS: calcd for C11H22O11S2Na (M +
Na) 417.0501, found 417.0501.
1,4-Dideoxy-1,4-[[(2R,3S,4R,5R)-2,4,5,6-tetrahydroxy-3-(sul-
fooxy)hexyl]episelenoniumylidene]-D-arabinitol Inner Salt (7).
To a solution of 19 (500 mg) in CH2Cl2 (2 mL) was added TFA
(10 mL) to yield the compound 7 as a colorless, amorphous, and
hygroscopic solid (160 mg, 67%). [R]D: -21 (c 0.1, H2O). 1H NMR
(D2O) δ: 4.70 (m, 1H, H-2), 4.55 (dd, 1H, J2′,3′ ) 4.9, J3′,4′ ) 1.3,
H-3′), 4.49 (ddd, 1H, J1′b,2′ ) 9.7, J1′a,2′ ) 3.9, H-2′), 4.39 (dd, 1H,
J3,4 ) 3.1, J2,3 ) 3.7, H-3), 4.14 (ddd, 1H, J4,5a ) 8.3, J4,5b ) 5.2,
J3,4 ) 3.1, H-4), 3.96 (dd, 1H, J5a,5b ) 12.6, H-5b), 3.91 (dd, 1H,
J1′a,1′b ) 12.1, H-1′b), 3.87 (dd, 1H, H-5a), 3.81 (dd, 1H, H-1′a),
1,4-Dideoxy-1,4-[[(2R,3S,4R,5R)-2,4,5,6-tetrahydroxy-3-(sul-
fooxy)hexyl]iminoniumylidene]-D-arabinitol Inner Salt (9). To
a solution of 33 (800 mg) in CH2Cl2 (2 mL) was added TFA (10
mL) to yield the compound 9 as a colorless, amorphous, and
1
hygroscopic solid (236 mg, 68%). [R]D: -11 (c 0.5, MeOH). H
NMR (D2O) δ: 4.56 (dd, 1H, J2′,3′ ) 5.3, J3′,4′ ) 1.2, H-3′), 4.40
(ddd, 1H, J1′a,2′, ) 7.0, J1′b,2′ ) 1.8, J2′,3′ ) 5.3, H-2′), 4.27 (ddd,
3.78 (dd, 1H, J4′,5′ ) 9.2, H-4′), 3.71 (dd, 1H, J5′,6′b ) 2.8, J6′a,6′b
)
1H, J1a,2 ) 5.1, J1b,2 ) 2.5, J2,3 ) 2.9, H-2), 4.01 (dd, 1H, J3,4 )
11.6, H-6′b), 3.69 (m, 1H, H-5′), 3.67 (br d, 2H, H-1a, H-1b), 3.54
(dd, 1H, J5′,6′a ) 5.6, H-6′a). 13C NMR (D2O) δ: 78.6 (C-3), 78.2
(C-3′), 77.8 (C-2), 70.5 (C-5′), 70.1 (C-4), 69.2 (C-4′), 67.7 (C-
2′), 62.7 (C-6′), 59.4 (C-5), 46.5 (C-1′), 44.4 (C-1). HRMS: calcd
for C11H22O11SSeNa (M + Na) 464.9946, found 464.9945.
1,4-Dideoxy-1,4-[[(2R,3S,4R,5R)-2,4,5,6-tetrahydroxy-3-(sul-
fooxy)hexyl]episelenoniumylidene]-L-arabinitol Inner Salt (10).
To a solution of 23 (500 mg) in CH2Cl2 (2 mL) was added TFA
(10 mL) to yield the compound 10 as a colorless, amorphous, and
hygroscopic solid (210 mg, 71%). [R]D: -45 (c 0.1, H2O). 1H NMR
(D2O) δ: 4.69 (m, 1H, H-2), 4.57 (dd, J3′,4′ ) 1.3, J2′,3′ ) 4.9, 1H,
H-3′), 4.48 (ddd, 1H, J1′a,2′ ) 9.2, J1′b,2′ ) 4.6, H-2′), 4.37 (t, J2,3
) J3,4 ) 3.2, 1H, H-3), 4.05 (ddd, 1H, J4,5a ) 8.6, J3,4 ) 3.2, J4,5b
) 5.1, H-4), 3.98 (dd, 1H, J5a,5b ) 12.5, J4,5b ) 5.1, H-5b), 3.86
(dd, 1H, H-5a), 3.85 (dd, 1H, H-1′b), 3.82 (dd, 1H, J1′a,1′b ) 12.3,
H-1′a), 3.77 (dd, 1H, J4′,5′ ) 4.9, H-4′), 3.72 (dd, 1H, J5′,6′a ) 5.3,
J5′,6′b ) 1.8, H-5′), 3.68 (br d, 2H, H-1a, H-1b), 3.67 (dd, 1H, J6′a,6′b
) 11.2, H-6′b), 3.53 (dd, 1H, H-6′a). 13C NMR (D2O) δ: 78.4
(C-3), 78.1 (C-3′), 77.8 (C-2), 70.5 (C-5′), 69.7 (C-4), 69.2 (C-4′),
67.2 (C-2′), 62.7 (C-6′), 59.4 (C-5), 46.4 (C-1′), 44.9 (C-1).
HRMS: calcd for C11H22O11SSeNa (M + Na) 464.9946, found
464.9944.
3.6, H-3), 3.90 (dd, 1H, J5a,5b ) 12.7, J4,5b ) 4.6, H-5b), 3.87 (dd,
1H, J4,5a ) 6.7, H-5a), 3.77 (dd, 1H, J4′,5′ )9.1, J3′,4′ ) 1.2, H-4′),
3.71 (dd, 1H, J1′a,1′b ) 11.8, H-1′b), 3.68 (dd, 1H, J1a,1b ) 12.8,
H-1b), 3.67 (m, 1H, H-5′), 3.64 (d, J6′a,6′b ) 13.2, H-6′b), 3.53 (dd,
1H, H-1′a), 3.52 (m, 2H, H-1a, H-4), 3.45 (d, 1H, H-6′a). 13C NMR
(D2O) δ: 77.1 (C-3′), 75.8 (C-3), 75.1 (C-4), 73.6 (C-2), 70.4 (C-
5′), 68.5 (C-4′), 66.2 (C-2′), 62.7(C-1), 58.6 (C-1′), 58.1 (C-6′),
57.9 (C-5). HRMS: calcd for C11H23NO11SNa (M + Na) 400.0889,
found 400.0887.
1,4-Dideoxy-1,4-[[(2R,3S,4R,5R)-2,4,5,6-tetrahydroxy-3-(sul-
fooxy)hexyl]iminoniumylidene]-L-arabinitol Inner Salt (12). To
a solution of 34 (600 mg) in CH2Cl2 (2 mL) was added TFA (10
mL) to yield the compound 12 as a colorless, amorphous, and
1
hygroscopic solid (265 mg, 80%). [R]D: -35 (c 0.1, MeOH). H
NMR (D2O) δ: 4.53 (dd, J3′,4′ ) 1.2, J2′,3′ ) 5.2, 1H, H-3′), 4.49
(m, 1H, H-2′), 4.24 (m, 1H, H-2), 4.00 (m, 1H, H-3), 3.88 (dd,
1H, J5a,5b ) 12.5, J4,5b ) 4.9, H-5b), 3.85 (dd, 1H, J4,5a ) 7.3,
H-5a), 3.77 (dd, 1H, J4′,5′ ) 9.0, J3′,4′ ) 1.2, H-4′), 3.73 (dd, 1H,
J1′a,1′b ) 11.8, H-1′b), 3.71 (dd, 1H, H-1′a), 3.66 (dd, 1H, J1a,1b
)
12.8, H-1b), 3.65 (m, 1H, H-5′), 3.54-3.49 (m, 4H, H-1a, H-4,
H-6′a, H-6′b). 13C NMR (D2O) δ: 77.2 (C-3′), 75.9 (C-3), 75.8
(C-4), 74.1 (C-2), 70.4 (C-5′), 68.5 (C-4′), 66.9 (C-2′), 62.8(C-1),
60.9 (C-1′), 58.8 (C-6′), 58.6 (C-5). HRMS: calcd for C11H23NO11-
SNa (M + Na) 400.0889, found 400.0887.
1,4-Dideoxy-1,4-[[(2R,3S,4R,5R)-2,4,5,6-tetrahydroxy-3-(sul-
fooxy)hexyl]episulfoniumylidene]-D-arabinitol Inner Salt (8). To
a solution of 20 (500 mg) in CH2Cl2 (2 mL) was added TFA (10
mL) to yield the compound 8 as a colorless, amorphous, and
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada for financial
support and to B. D. Johnston for helpful discussions.
1
hygroscopic solid (136 mg, 61%). [R]D: -19 (c 0.2, MeOH). H
NMR (D2O) δ: 4.62 (ddd, 1H, J2,3 ) 3.4, J1a,2 ) 3.4, J1b,2 ) 6.7,
H-2), 4.57 (dd, 1H, J3′,4′ ) 1.4, J2′,3′ ) 5.0, H-3′), 4.49 (ddd, 1H,
Supporting Information Available: General experimental
procedures and copies of 1H and 13C NMR spectra for compounds
19, 23, 20, and 7-12. This material is available free of charge via
the Internet at http://pubs.acs.org.
J1′a,2′ ) 3.9, J1′b,2′ ) 8.9, J2′,3′ ) 5.0, H-2′), 4.35 (dd, 1H, J3,4
)
2.7, H-3), 4.06 (ddd, 1H, J4,5a ) 8.4, J4,5b ) 4.8, H-4), 3.99 (dd,
1H, J5a,5b ) 12.4, H-5b), 3.87 (dd, 1H, H-5a), 3.85 (dd, 1H, J1′b,2′
) 8.9, J1′a,1′b ) 13.5, H-1′b), 3.83 (dd, 1H, H-1′a), 3.80 (dd, 1H,
J4′,5′ ) 8.8, H-4′), 3.75 (m, 2H, H-1a, H-1b), 3.71 (dd, 1H, J5′,6′b
)
JO052539R
J. Org. Chem, Vol. 71, No. 8, 2006 3013