Synthesis and conformational analysis of a sulfonium-ion analogue of the glycosidase inhibitor castanospermine

Article abstract of DOI:10.1021/ja002038h

The synthesis of a bridgehead sulfonium salt analogue (7) of the indolizidine alkaloid castanospermine has been achieved by a multistep procedure starting from 5-thio-D-glucopyranose pentaacetate. The compound was intended to test the theory that glycosid

Full text of DOI:10.1021/ja002038h

J. Am. Chem. Soc. 2000, 122, 10769-10775
10769
Synthesis and Conformational Analysis of a Sulfonium-Ion Analogue
of the Glycosidase Inhibitor Castanospermine
Lars Svansson,† Blair D. Johnston,† Jian-Hua Gu,† Brian Patrick,‡ and B. Mario Pinto*,†
Contribution from the Department of Chemistry, Simon Fraser UniVersity,
Burnaby, B.C., Canada V5A 1S6 and the Department of Chemistry,
UniVersity of British Columbia, VancouVer, B.C., Canada V6T 1Z1.
ReceiVed June 7, 2000
Abstract: The synthesis of a bridgehead sulfonium salt analogue (7) of the indolizidine alkaloid castanospermine
has been achieved by a multistep procedure starting from 5-thio-D-glucopyranose pentaacetate. The compound
was intended to test the theory that glycosidase inhibitory activity of the indolizidine alkaloids might be due
to electrostatic stabilization of a positively charged species in the enzyme active site and that a sulfonium salt
carrying a permanent positive charge might be advantageous. The structure of the bicylic sulfonium salt (7)
[3(R),4(S),5(R),6(S)-3,4,5-trihydroxy-cis-1-thioniabicyclo[4.3.0]nonane perchlorate] was confirmed by X-ray
crystallography. Analysis of the 1H NMR spectrum of compound 7 indicated that a similar conformation was
adopted in solution. This conformational preference, with hydroxyl groups in the more sterically hindered
axial orientations, has been attributed to the dominance of stabilizing electrostatic interactions between the
oxygen atoms and the sulfonium center.
Introduction
with the required charge-state would be to include in the
structure an atom that carries a permanent positive charge at a
suitable position. One obvious strategy would be to make this
atom a positively charged sulfur, because sulfonium salts are
known to be quite stable, as opposed to their highly unstable
oxonium ion counterparts. We, therefore, designed the castano-
spermine analogue 7 in which the bridgehead nitrogen atom is
replaced by a sulfonium ion. Our reasoning was further inspired
by the pioneering work of the late B. Belleau who synthesized
sulfonium-ion analogues of the morphinans, levorphanol and
isolevorphanol, and showed that they were agonists or antago-
nists of morphine for the opiate receptor.5a-d More recently,
the use of sulfonium salts as enzyme inhibitors has been
elegantly demonstrated in the field of sterol biosynthesis. The
cyclase enzyme that mediates the cyclization of the open-chain
oxidosqualene precursor to sterols is inhibited by sulfonium salt
Carbohydrates play critical roles in many biological proc-
esses.1 For example, the carbohydrate structures on glycoproteins
mediate a variety of host-microorganism interactions and are
also involved in host intercellular communication. The matura-
tion of glycoproteins involves the trimming of nascent glyco-
proteins by glucosidase and mannosidase enzymes to provide
the core structure that is necessary for the construction of more
complex glycoforms through the action of glycosyl transferase
enzymes.2 Inhibition of these enzymes by natural or synthetic
inhibitors provides a means of studying this important post-
translational modification of protein structure and function, and
can in some cases lead to therapeutic strategies. The best-known
inhibitors of glycosidase enzymes are analogues of carbohy-
drates in which one or more of the oxygen atoms have been
replaced by nitrogen.3 Monocyclic amines such as 1-deoxy-
nojirimycin (1) or bicyclic derivatives such as swainsonine (2)
or castanospermine (3) are postulated to bind to glycosidase
enzymes by mimicry of the shape and charge of the oxacar-
benium ion intermediate for the hydrolysis reaction.4 This
(1) For leading references: Dwek, R. A. Chem. ReV. 1996, 96, 683;
Varki, A.; Cummings, R.; Esko, J.; Freeze, H.; Hart, G.; Marth, J., Eds.
Essentials of Glycobiology; Cold Spring Harbor Laboratory Press: Cold
Spring Harbor, NY, 1999.
(2) For leading references: Herscovics, A. ComprehensiVe Natural
Products Chemistry; Pinto, B. M., Ed.; Barton, D. H. R., Nakanishi, K.,
Meth-Cohn, O., Ser. Eds.; Elsevier: U.K., 1999; Vol. 3; Ch. 2. Schachter,
H. ComprehensiVe Natural Products Chemistry; Pinto, B. M., Ed.; Barton,
D. H. R., Nakanishi, K., Meth-Cohn, O., Ser. Eds.; Elsevier: UK, 1999,
Vol. 3; Ch. 3; Brockhausen, I. ComprehensiVe Natural Products Chemistry,
Pinto, B. M., Ed.; Barton, D. H. R., Nakanishi, K., Meth-Cohn, O., Ser.
Eds.; Elsevier: UK, 1999; Vol. 3.
(3) Stutz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond: Weinheim: New York, Wiley-VCH; 1999.
(4) (a) McCarter, J. D.; Withers, S. G. Curr. Opin. Struct. Biol. 1994, 4,
855. Ly, H. D.; Withers, S. G. Annu. ReV. Biochem. 1999, 68, 487.
(5) (a) Belleau, B.; Gulini, U.; Gour-Salin, B. J.; Ahmed, F. R. Can. J.
Chem. 1985, 63, 1268. (b) Belleau, B.; Gulini, U.; Camicioli, R.; Gour-
Salin, B. J.; Sauve´, G. Can. J. Chem. 1986, 64, 110. (c) Lemaire, S.; Belleau,
B.; Jolicoeur, F. AdV. Biosci. 1989, 75, 105. (d) Jolicoeur, F. B.; Me´nard,
D.; Belleau, B.; Lemaire, S. Int. Narc. Res. Conf. 1990, 89, 49. (e)
Oehlschlager, A. C.; Singh, S. M.; Sharma, S. J. Org. Chem. 1991, 56,
3856. (f) Starch, D.; Zheng, Y. F.; Perez, A. L.; Oehlschlager, A. C.;
Prestwich, G. D.; Hartman, P. G. J. Med. Chem. 1997, 40, 201.
requires that the nitrogen atom be protonated in the enzyme
active site and that the interaction with the enzyme be dominated
by stabilizing electrostatic interactions with active site carbox-
ylate residues. An alternative means of providing an inhibitor
* To whom correspondence should be addressed. Tel: (604) 291-4327.
Fax: (604) 291-3765. E-mail: bpinto@sfu.ca.
† Simon Fraser University.
‡ University of British Columbia.
10.1021/ja002038h CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

10770 J. Am. Chem. Soc., Vol. 122, No. 44, 2000
SVansson et al.
mimics, either preformed or generated in situ, of the carbocation
intermediates.5e-f
Scheme 1
Recently, a new class of glycosidase inhibitor with an
intriguing inner-salt sulfonium-sulfate structure has been isolated
from the roots and stems of the plant Salacia reticulata. Extracts
of this plant have been traditionally used in the Ayurdevic
method of Indian medicine as a treatment for diabetes. The most
active ingredients of these extracts appear to be the sulfonium
salts salacinol6 (4) and kotalanol7 (5) both of which have an
anhydro alditol structure in common with well-known imino-
alditol inhibitors such as 1,4-dideoxy-1,4-imino-D-arabinitol (6).
that is present in castanospermine but should still serve as a
suitable model with which to test the theory. Related work has
been the subject of recent reports from other groups. Izquierdo
and co-workers10 have reported an intramolecular displacement
of the tosylate group by the sulfur atom of the thiolane derivative
8 to yield the swainsonine analogue 9. The five-membered ring
sulfonium salts 1011 and 1112 have also been prepared and tested
for their inhibition of glycosidase enzymes.
The inhibition of glycosidase enzymes by compounds 4 and 5
rivals, or in some cases exceeds, the most potent aminosugar
inhibitors, such as acarbose.8 It appears that the potential for
glycosidase inhibition by sulfonium salts has not been neglected
by nature, and thus, it is our contention that the synthesis of
sulfur analogues of the known nitrogen-based glycosidase
inhibitors may lead to glycosidase inhibitors with increased
potency and utility.
We have previously synthesized disaccharides in which the
ring oxygen atom of the nonreducing monosaccharide unit has
been replaced by sulfur and the interglycosidic atom is either
oxygen, sulfur, selenium, or nitrogen.9 These compounds are
weak-to-moderate inhibitors of glycosidase enzymes. They
appear to act as non-hydrolyzable substrate mimics that are
competitive inhibitors of the glycosidase enzymes. It is of
interest, therefore, to question whether the presence of a
sulfonium salt in 5-thioglucose derivatives would result in
increased inhibitory potencies. We report herein the synthesis
of the bicyclic compound 7 as a sulfonium-ion analogue of
castanospermine. Compound 7 lacks the hydroxyl group at C-7
Results and Discussion
The most direct method for the synthesis of a bicyclic
sulfonium salts such as A is the intramolecular displacement
of a suitable side-chain-leaving group by a cyclic thioether
(Scheme 1). This retrosynthetic analysis led to the extended-
chain, 1,5-anhydro-5-thio-D-glucitol derivative B as the key
intermediate.
Scheme 2 outlines the synthesis of the bromo derivative 32
corresponding to B. Two methods were developed. Initially,
5-thioglucose pentaacetate (12)13 was reacted with ethanethiol
and boron trifluoride etherate to give an R/â mixture of ethylthio
glycosides. Both isomers were obtained as pure crystalline
compounds after separation by chromatography. The pure
R-isomer, 13R was used for the following steps because the
â-isomer, 13â, or the mixture of 13R/13â proved to be less
suitable for some of the subsequent transformations. First, the
acetates were removed from 13R by methanolysis to give 14,
which was reacted with benzaldehyde dimethyl acetal to yield
the benzylidene derivative 15. Benzyl ether-protecting groups
were then introduced at the 2- and 3-positions to produce
compound 16. The benzylidene acetal was subjected to selective
reductive cleavage with Me3N:BH3 and AlCl314 to yield the 2,3,4
tri-O-benzyl derivative 17. Swern oxidation15 of the 6-OH group
then yielded the aldehyde 18. This sensitive intermediate was
(6) Yoshikawa, M.; Murakami, T.; Shimada, H.; Matsuda, H.; Yamahara,
J.; Tanabe. G.; Muraoka, O. Tetrahedron Lett. 1997, 38, 8367.
(7) Yoshikawa, M.; Murakami, T.; Yashiro, H.; Matsuda. H. Chem.
Pharm. Bull. 1998, 46, 1339.
(8) Schmidt, D. D.; Frommer, W.; Junge, B.; Mu¨ller, L.; Wingender,
W.; Truscheit, E.; Scha¨fer, D. Naturwissenschaften 1977, 64, 535.
(9) (a) Mehta, S.; Jordan, K. L.; Weimar, T.: Kreis, U. C.; Batchelor,
R. J.; Einstein, F. W. B.; Pinto, B. M. Tetrahedron: Asymmetry 1994, 5,
2367. (b) Andrews, J. S.; Pinto, B. M. Carbohydr. Res. 1995, 270, 51. (c)
Mehta, S.; Andrews, J. S.; Johnston, B. D.; Svensson, B.; Pinto, B. M. J.
Am. Chem. Soc. 1995, 117, 9783. (d) Andrews, J. S.; Weimar, T.; Frandsen,
T. P.; Svensson, B.; Pinto, B. M. J. Am. Chem. Soc. 1995, 117, 10799. (e)
Johnston, B. D.; Pinto, B. M. Carbohydr. Res. 1998, 310, 17. (f) Andrews,
J. S.; Johnston, B. D.; Pinto, B. M. Carbohydr. Res. 1998, 310, 27. (g)
Johnston, B. D.; Pinto, B. M. J. Org. Chem. 1998, 63, 5797.
(10) Izquierdo, I.; Plaza, M. T. Arago´n, F. Tetrahedron: Asymmetry 1996
7, 2567.
(11) Siriwardena, A. H.; Chiaroni, A.; Riche, C.; El-Daher, S.; Win-
chester, B.; Grierson, D. S. J. Chem. Soc., Chem. Commun. 1992, 1531.
(12) Yuasa, H.; Kajimoto, T.; Wong, C.-H. Tetrahedron Lett. 1994, 35,
8243.
(13) (a) Driguez, D.; Henrissat, B. Tetrahedron Lett. 1981, 22, 5061.
(b) Chiu, C.-W.; Whistler, R. L. J. Org. Chem., 1973, 38, 832.
(14) Ek, M.; Garegg, P. J.; Hultberg, H.; Oscarson, S. J. Carbohydr.
Chem. 1983, 2, 305.
(15) Tidwell, T. T. Org. React. 1990, 39, 297.

Sulfonium-Ion Analogue of Castanospermine
J. Am. Chem. Soc., Vol. 122, No. 44, 2000 10771
Scheme 2
Figure 1. Crystal and molecular structure of the sulfonium cation of
compound 7 (graphical output from NRCVAX Crystal Structure
System: Gabe, E. J.; LePage, Y.; Charland, J.-P.; Lee, F. L.; White, P.
S. J. Appl. Crystallogr. 1989, 22, 384).
sulfonium-ion stability in this case. Treatment of the bromide
32 with AgClO4 gave the sulfonium salt 34 as a stable
amorphous gum. No decomposition of compound 34 was noted
even after long-term storage at ambient temperature. The benzyl
groups were removed uneventfully by catalytic hydrogenolysis
of 34 using H2/Pd/C. The presence of the sulfur atom in 34 as
a sulfonium salt evidently prevented the poisoning of the
catalyst, which would be expected for a sulfide. The target
sulfonium salt 7 was isolated in a near quantitative yield as an
amorphous solid, and a crystalline sample was obtained by slow
evaporation of a MeOH/EtOAc solution.
not isolated but was immediately reacted in situ with carbo-
ethoxymethylene triphenylphosphorane to give the gluco-
octenouronate derivative 19 by Wittig chain extension.16
The R,â-unsaturated ester was reduced in two steps: first,
I
Analysis of compounds 34 and 7 by H and 13C NMR
spectroscopy initially provided some doubt as to the true identity
of these compounds. Both bicyclic derivatives were initially
17
5
with NaBH4/CoCl2 to give the saturated ester 20 and then,
expected to favor the C2 conformation for the six-membered
with LiAlH4 to give the primary alcohol 21. At this stage, the
thioglycoside was removed by radical reduction using n-Bu3SnH/
AIBN18 to yield the 1-deoxy derivative 22. Alternatively, the
same series of reactions was applied to the known tetraacetate
2318 of 1,5-anhydro-5-thio-D-glucitol to yield compound 22 in
seven steps (23f24f25f26f27f28f29f30f22), with
similar overall yield. The second route avoided the separation
of R- and â-isomers of 13 and was judged to be more convenient
for the large-scale synthesis. The alcohol 22 was mesylated to
give the sulfonate ester 31, which was displaced by a bromide
ion to yield the key intermediate 32. Compound 32 (or for that
matter, compound 31) might be expected to undergo spontane-
ous cyclization to yield the desired bicyclic sulfonium salt, but
both compounds were unexpectedly stable under ambient
conditions. Nevertheless, after storage as a neat amorphous solid
for several months at room temperature, the bromide 32 yielded
a small amount of a more polar compound, as indicated by TLC
analysis. This product was isolated by column chromatography
and was shown to be the bicyclic sulfonium salt 33, but this
compound quickly equilibrated in CDCl3 solution over 1 day
to give a mixture of 33 and the open-chain sulfide 32 (ratio
32:33 > 10:1 by NMR). Evidently, the bromide counterion in
the sulfonium salt 33 opens the five-membered ring by
nucleophilic attack at C-9 to regenerate 32. A nonnucleophilic
counterion was, therefore, proposed as a prerequisite for
ring, thus placing all three of the oxygen substituents, as well
as C-7 (heterocyclic numbering), of the fused five-membered
ring in the less sterically hindered, equatorial positions. How-
1
ever, the vicinal H NMR coupling constants for compounds
34 and 7 could not be reconciled with this assumption. Both of
the compounds showed J3,4, J4,5, and J5,6 values of 3-4 Hz,
which are much smaller than the 8-10 Hz that one would
predict for the axial-axial, vicinal coupling constants in 1,5-
anhydro-D-glucitol derivatives. In addition, although formation
of the sulfonium salt 34 had resulted in the expected downfield
shifts in the 13C spectrum for the carbons R to the sufonium
center19 (i.e., C-2 and C-6 in 34), the remaining six-membered-
ring carbon resonances were observed to shift upfield by
approximately 10 ppm. These trends were maintained after
deprotection to yield 7, thus indicating that the anomalous shifts
for 34 could not be attributed to the shielding effects of the
bulky benzyl-protecting groups. The 10-ppm upfield shifts in
the resonances for the carbons that are â and γ to the sulfur
atom in 34 and 7 as compared to the corresponding resonances
for 32 are much larger than would be expected19 for conversion
of a sulfide to a sulfonium salt.
1
Furthermore, the observed H and 13C NMR chemical shift
differences between the sulfonium salt 7 and the sulfide 32 were
quite different from the literature values10 for the related
sulfonium salt 9 and its sulfide precursor 8. Proof of the structure
of compound 7 was, therefore, obtained by X-ray crystal-
lography. This structure (Figure 1) indicated that compound 7
was, indeed, the desired sulfonium salt derivative but that the
(16) Zhdanov, Y. A.; Alexeev, Y. E.; Alexeeva, V. G. AdV. Carbohydr.
Chem. Biochem. 1972, 27, 237.
(17) Chung, S.-K. J.Org. Chem. 1979, 44, 1014.
(18) Korth, H.-G.; Sustmann, R.; Gro¨ninger, K. S.; Leisung, M.; Giese,
B. J. Org. Chem. 1988, 53, 4364.
(19) Willer, R. L.; Eliel, E. L. Org. Magn. Reson. 1977, 9, 285.

10772 J. Am. Chem. Soc., Vol. 122, No. 44, 2000
SVansson et al.
2
six-membered ring adopted a C5 conformation, with all three
conformation. The driving force that favors conformation C
must, therefore, be substantial. We attribute the stabilization of
compounds 34 and 7 in conformations with the polar substituents
in axial positions to the stabilizing electrostatic interactions of
the oxygen atoms with the positive sulfonium ion center. In
the C-type conformations for compounds 34 and 7, the axial
substituents at the 3- and 6-positions provide two gauche
electrostatic interactions of the polar groups with the sulfonium
center. The axial oxygen substituent at C-4 can also provide
stabilizing electrostatic interactions. In the alternative D-type
conformation, the electrostatic attraction would be much less
important because the polar groups would then be anti to the
sulfonium center. For the C-type conformation, the stabilizing
gauche electrostatic interactions must be of sufficient magnitude
to offset the nonbonded interactions. This explanation could
account for the observed diaxial conformations in the solid state
of S-methyl thianium ions 3821 and 3922 with polar acetoxy
substituents at the 3- or 4-position, respectively. It is noteworthy
hydroxyl groups and the C-7 substituent in axial orientations.
If this conformation is also present in solution, then the
unexpectedly small 1H NMR coupling constants in compounds
34 and 7 are but typical values for coupling between equatorial-
equatorial vicinal protons. Accordingly, the upfield 13C NMR
chemical shifts for C-3, C-4, and C-5 in compounds 34 and 7
must be due to the effects of steric compression on carbons
bearing 1,3 diaxial substituents. The unexpected conformations
for 34 and 7, thus, explained the NMR data, and the X-ray
structure ensured that no configurational ambiguity remained.
We were, therefore, forced to conclude that the NMR data
presented by Izquierdo et al.10 for compound 9 are in error and
that the data reported may actually be those of the tosylate
precursor, sulfide 8. The equilibration of sulfonium salts with
their sulfide precursors, as we have observed for compound 33,
may have caused the confusion in this case.
The conformational preference of the sulfonium salt 7 is of
some interest because the question of why such a seemingly
high-energy conformation would predominate both in solution
and in the solid state is less clear. A literature report20 concerning
the conformational preferences of the parent bicyclo [4.3.0]
sulfonium salt 35 and some of its methyl-substituted derivatives,
36 and 37, provides results that are pertinent to the present case.
The unsubstituted sulfonium salt 35 was found to be exclusively
cis-fused, with a preferred conformation in which the six-
membered ring is in a normal chair conformation and C-7 of
the five-membered ring occupies the axial position with respect
to the six-membered ring. This conformation matches the
that Eliel and co-workers23 have found that, although the ∆G°
value for the equilibrium of 3-methylthiotetrahydropyran (40)
is -1.21 kcal mol-1 in CH2Cl2 (in favor of the equatorial
isomer), the corresponding ∆G° value for the methylated
analogue (41) is +0.55 kcal mol-1. The stabilizing gauche
O-C-C-S+ interaction in 41 can be estimated by evaluating
the nonbonded interactions in the axial conformer. The latter
can be estimated, in turn, from the A value of Me2S+ (-1.09
preferred conformations determined for compounds 34 and 7
in the present work. The reasons advanced by Cere` et al.20 for
the overwhelming preference for conformation C, with an axial
C-7, over the alternative conformation D, with an equatorial
C-7, are speculative. In fact, conformation D does not seem to
display any steric interactions that are significantly different from
those in conformation C. Indeed, it was found that placing one
or more methyl groups at the C-2 or C-4 positions cis to the
fused five-membered ring resulted in a change in the preferred
conformation of 36 or 37 from a C-type to a D-type. In the
D-type conformations, both the C-7 and the methyl group at
either C-2 or C-4 assume positions that are equatorial relative
to the six-membered ring.
kcal mol-1 23
)
and the ratio of the conformational free energies
for the axial-equatorial equilibria in 3-Me-tetrahydropyran (1.43
kcal mol-1 24 and methylcyclohexane (1.80 kcal mol-1).25 This
)
procedure yields a value for the O-C-C-S+ interaction in 41
of 1.42 kcal mol-1. We conclude, therefore, that conformation
C of 7 or 34 is favored by O3-C-C-S+ and O5-C-C-S+
stabilizing interactions, worth ≈2.84 kcal mol-1, with an
additional contribution from the O4-C-C-C-S+ electrostatic
interaction.
It is also of relevance that S-adenosyl methionine (SAM) 42
has been found to prefer overwhelmingly a conformation in
which the sulfonium center is gauche to the ring oxygen of the
ribofuranose moiety.26 This is not the case for the related neutral
species, S-adenosyl homocysteine 43 (SAH). The authors of
this study have speculated that this preferred conformation for
SAM places the S-methyl group in an exposed position that
may have some significance in enzyme-catalyzed methyl-
(21) Jensen, B. Acta Chem. Scand. B 1981, 35, 607.
(22) Jensen, B. Acta Chem. Scand. B 1979, 33, 359.
(23) Ruano, J. L. G.; Rodr´ıguez, J.; Alcudia, F.; Llera, J. M.; Olefirowicz,
E. M.; Eliel, E. L. J. Org. Chem. 1987, 52, 4099.
(24) Eliel, E. L.; Hargrave, K. D.; Pietrusiewicz, K. M.; Manoharan, M.
J. Am. Chem. Soc. 1982, 104, 3635.
(25) Wiberg, K. B.; Hammer, J. D.; Castejon, H.; Bailey, W. F.; DeLeon,
E. L.; Jarret, R. M. J. Org. Chem. 1999, 64, 2085.
(26) Stolowitz, M. L.; Minch, M. J. J. Am. Chem. Soc. 1981, 103, 6015.
The C-type conformation of compound 7 exhibits an unfavor-
able 1,3 diaxial OH-OH interaction and a 1,3 diaxial CH2-
OH interaction that would be relieved by assuming a D-type
(20) Cere`, V.; Paolucci, C.; Pollicino, S.; Sandri, E.; Fava, A. J. Org.
Chem. 1982, 47, 2861.

Sulfonium-Ion Analogue of Castanospermine
J. Am. Chem. Soc., Vol. 122, No. 44, 2000 10773
and all hydroxyl hydrogens were refined isotropically. All other
hydrogens were included in calculated positions. The absolute config-
uration was assigned on the basis of the lowest residuals from a parallel
refinement of both enantiomers. All calculations were performed using
the teXsan29 crystallographic software package of Molecular Structure
Corp.
Ethyl 2,3,4,6-Tetra-O-acetyl-1,5-dithio-r- and â-D-glucopyrano-
side (13r and 13â). Boron trifluoride diethyl etherate (28 mL, 0.10
mol) was added dropwise to a stirred solution of 1,2,3,4,6-penta-O-
acetyl-5-thio-R-D-glucopyranoside13 (11.46 g, 28.20 mmol) and ethane-
thiol (6.0 mL, 81 mmol) in CH2Cl2 (70 mL) under N2 at 0 °C. The
cooling bath was removed and the reaction mixture was stirred at room
temperature for 6 h. The reaction was quenched by slowly pouring the
mixture into an excess of saturated aqueous NaHCO3. The phases were
separated and the aqueous layer was extracted using CH2Cl2 (2 × 150
mL). The combined extracts were dried, filtered, and concentrated. The
mixture was separated by column chromatography (hexanes:EtOAc,
2:1); each isomer was crystallized from Et2O:hexanes to yield 13R (5.15
g, 45%) and 13â (3.25 g, 28%). 13R: mp 116 °C; [R]19 +275 (c
D
1
1.05, CHCl3); Rf 0.36 (hexanes:EtOAc, 2:1); H NMR (400.13 MHz,
CDCl3) δ 5.37 (dd, 1H, J2,3 ) 10.0, J3,4 ) 9.5 Hz, H-3), 5.25 (dd, 1H,
J4,5 ) 10.5 Hz, H-4), 5.23 (dd, 1H, J1,2 ) 4.5 Hz, H-2), 4.50 (d, 1H,
H-1), 4.41 (dd, 1H, J6a,6b ) 12.0, J5,6a ) 5.0 Hz, H-6a), 4.07 (dd, 1H,
J5,6b ) 3.5 Hz, H-6b), 3.69 (ddd, 1H, H-5), 2.72-2.59 (m, 2H, SCH2-
CH3), 2.08, 2.07, 2.02, 2.00 (4s, each 3H, 4 × COCH3), 1.24 (t, 3H, J
) 7.5 Hz, SCH2CH3); 13C NMR (100.6 MHz, CDCl3) δ 170.49, 169.87,
169.51(2C) (4 × COCH3), 74.69 (C-2), 72.40 (C-4), 71.37 (C-3), 61.25
(C-6), 49.13 (C-1), 39.46 (C-5), 25.81 (SCH2CH3), 20.73, 20.59, 20.51
(2C) (4 × COCH3), 14.02 (SCH2CH3). Anal. Calcd for C16H24O8S2:
transfer reactions involving SAM. We would add that this
conformation is likely to be preferred because of electrostatic
attraction between the sulfonium salt and the ring oxygen. Such
interactions may have more biological importance than has
previously been recognized.
Conclusions
C, 47.04; H, 5.92. Found: C, 47.20; H, 5.96. 13â: mp 102 °C; [R]19
D
The preparation of compound 7, a bicyclic sulfonium
analogue of the glycosidase inhibitor castanospermine, has been
achieved. The ring opening reaction of the sulfonium salt 33
described above raises the possibility that compound 7 might
function as an irreversible inhibitor by covalent modification
of active-site nucleophilic residues. The conformation of
compound 7, both in the solid state and in solution, reflects the
dominance of electrostatic effects over steric effects. The activity
of this compound as a glycosidase inhibitor will be the subject
of future investigations. The relevance of the preferred confor-
mation of compound 7 to both the conformations and the
mechanism-of-action of related amino-sugar glucosidase inhibi-
tors such as castanospermine is also of interest and will be the
subject of further investigations in this laboratory.
-2.0 (c 1.02, CHCl3); Rf 0.29 (hexanes:EtOAc, 2:1); 1H NMR (400.13
MHz, CDCl3) δ 5.25 (dd, 1H, J4,5 ) 10.5, J3,4 ) 9.5 Hz, H-4), 5.16
(dd, 1H, J1,2 ) 10.5, J2,3 ) 9.5 Hz, H-2), 5.03 (dd, 1H, H-3), 4.23 (dd,
1H, J6a,6b ) 12.0, J5,6a ) 6.0 Hz, H-6a), 4.10 (dd, 1H, J5,6b ) 3.5 Hz,
H-6b), 3.81 (d, 1H, H-1), 3.26 (ddd, 1H, H-5), 2.78-2.62 (m, 2H, SCH2-
CH3), 2.06, 2.05, 2.00, 1.98 (4s, each 3H, 4 × COCH3), 1.24 (t, 3H, J
) 7.5 Hz, SCH2CH3); 13C NMR (100.6 MHz, CDCl3) δ 170.45, 169.66,
169.36, 169.31 (4 × COCH3), 74.62 (C-3), 73.22 (C-2), 71.99 (C-4),
61.37 (C-6), 47.82 (C-1), 44.50 (C-5), 24.93 (SCH2CH3), 20.58, 20.52
(2C), 20.47 (4 × COCH3), 14.52 (SCH2CH3). Anal. Calcd for
C16H24O8S2: C, 47.04; H, 5.92. Found: C, 47.33; H, 5.83.
Ethyl 1,5-dithio-r-D-glucopyranoside (14). Compound 13R (4.75
g, 11.6 mmol) was dissolved in a NaOMe/MeOH solution (0.05 M, 50
mL). The mixture was stirred for 0.5 h at room temperature and then
neutralized by stirring with Rexyn 101 H+ ion-exchange resin. The
resin was removed by filtration, and the filtrate was evaporated to
dryness. The crude product was obtained in quantitative yield and was
used directly in the next step. An analytically pure sample was obtained
by crystallization from EtOH:Et2O to yield compound 14 as a colorless
Experimental Section
Chromatographic and spectroscopic techniques have been described
previously.9 Optical rotations were measured at the specified temper-
crystalline solid: mp 131-132 °C; [R]19 +398 (c 0.85, EtOH); Rf
1
ature using a Rudolph Research Autopol II polarimeter. H and 13C
D
0.68 (EtOAc:MeOH:H2O, 7:2:1); 1H NMR (400.13 MHz, D2O) δ 4.26
(d, 1H, J1,2 ) 4.5 Hz, H-1), 3.99 (dd, 1H, J2,3 ) 9.5 Hz, H-2), 3.89
(dd, 1H, J6a,6b ) 12.0, J5,6a ) 5.0 Hz, H-6a), 3.85 (dd, 1H, J5,6b ) 4.0
Hz, H-6b), 3.54 (dd, 1H, J4,5 ) 10.0, J3,4 ) 9.5 Hz, H-4), 3.45 (dd,
1H, H-3), 3.23 (ddd, 1H, H-5), 2.78-2.62 (m, 2H, SCH2CH3), 1.22 (t,
3H, J ) 7.5 Hz, SCH2CH3); 13C NMR (100.6 MHz, D2O) δ 77.54
(C-3), 77.37 (C-2), 76.39 (C-4), 62.74 (C-6), 54.67 (C-1), 46.91 (C-
5), 28.59 (SCH2CH3), 16.26 (SCH2CH3). Anal. Calcd for C8H16O4S2:
C, 39.98; H, 6.71. Found: C, 40.13; H, 6.86.
NMR spectra were recorded at 400.13 and 100.6 MHz, respectively.
All assignments were confirmed with the aid of two-dimensional 1H,1H
(COSYDFTP) or 1H,13C (INVBTP) experiments using standard Bruker
pulse programs. Crystallographic data for compound 7 C8H15O7SCl:
Colorless plates, fw ) 290.72, monoclinic, P21, Z ) 6, a ) 11.7546(6),
b ) 8.5384(5), c ) 17.847(1) Å, â ) 105.94(1)°, T ) -100 °C, R )
0.038 (calculated on F, I > 3.00σ(I)), GOF ) 1.28. The data were
collected on a Rigaku/ADSC CCD area detector in two sets of scans
(æ ) 0.0-190.0°, ø ) -90°; and ω ) -18.0-23.0, ø ) -90°), using
0.50° oscillations with 58.0-s exposures. The crystal-to-detector distance
was 40.51 mm with a detector swing angle of -5.54°. The structure
was solved by direct methods27 and expanded using Fourier tech-
niques.28 The structure was found to contain three salt moieties in the
asymmetric unit. All non-hydrogen atoms were refined anisotropically,
Ethyl 4,6-O-Benzylidene-1,5-dithio-r-D-glucopyranoside (15). To
a solution of compound 14 (2.79 g, 11.61 mmol) and p-toluenesulfonic
acid (300 mg, 1.58 mmol) in acetonitrile (50 mL) was added
benzaldehyde dimethyl acetal (5.3 mL, 35.3 mmol) and the resulting
mixture was stirred for 20 h at room temperature. Saturated aqueous
NaHCO3 (50 mL) was added, and the mixture was concentrated to a
small volume. The aqueous residue was partitioned between water (50
mL) and CH2Cl2 (250 mL). The aqueous phase was further extracted
using CH2Cl2 (50 mL) and the combined extracts were dried, filtered,
(27) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna,
R. J. Appl. Crystallogr. 1999, 32, 115.
(28) Beurskens, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W. P.; de
Gelder, R.; Israel, R.; Smits, J. M. M. The DIRDIF-94 Program System,
Technical Report of the Crystallography Laboratory, University of Nijmegen,
The Netherlands, 1994.
(29) Crystal Structure Analysis Package, Molecular Structure Corporation,
1985 and 1992.

10774 J. Am. Chem. Soc., Vol. 122, No. 44, 2000
SVansson et al.
and concentrated. The residue was purified by column chromatography
(hexanes:EtOAc, 1:1), followed by crystallization from EtOAc:hexanes
was added dropwise over 2 min. The mixture was stirred for 15 min at
-78 °C, then Et3N (6 mL, 43 mmol) was added in one portion, and
the mixture was warmed to room temperature. The crude solution of
the aldehyde 18 was treated with (carboethoxymethylene)-triphenyl-
phosphorane (3.60 g, 10.3 mmol) and the resulting mixture was stirred
for 1 h at room temperature. The solvent was removed by rotary
evaporation, and the residue was dissolved in Et2O (75 mL). Insoluble
material was removed by filtration and washed with Et2O (50 mL).
The combined washings and filtrate were concentrated, and the residue
was purified by column chromatography (hexanes:EtOAc, 6:1), fol-
lowed by crystallization from Et2O:hexanes to give 19 (3.68 g, 73%):
mp. 83-85 °C; [R]19D +149 (c 1.05, CHCl3); Rf 0.32 (hexanes:EtOAc,
6:1); 1H NMR (400.13 MHz, CDCl3) δ 7.42-7.22 (m, 15H, Ph), 6.90
(dd, 1H, J6,7 ) 16.0, J5,6 ) 9.0 Hz, H-6), 6.08 (dd, 1H, J5,7 ) 1.0 Hz,
H-7), 4.91 and 4.75 (2d, each 1H, Ja,b ) 10.5 Hz, CH2Ph), 4.80 and
4.58 (2d, each 1H, Ja,b ) 10.5 Hz, CH2Ph), 4.75 and 4.68 (2d, each
1H, Ja,b ) 11.5 Hz, CH2Ph), 4.23-4.17 (m, 2H, OCH2CH3), 4.19 (d,
1H, J1,2 ) 4.5 Hz, H-1), 4.06 (ddd, 1H, J4,5 ) 10.0, J5,6 ) 9.0 Hz,
H-5), 4.04 (dd, 1H, J2,3 ) 9.0 Hz, H-2), 3.81 (dd, 1H, J3,4 ) 9.0 Hz,
H-3), 3.58 (dd, 1H, H-4), 2.76-2.62 (m, 2H, SCH2CH3), 1.29 (t, 3H,
J 7.0 Hz, OCH2CH3), 1.27 (t, 3H, J ) 7.5 Hz, SCH2CH3); 13C NMR
(100.6 MHz, CDCl3) δ 165.61 (CdO), 142.93 (C-6), 138.64-127.53
(18C, Ph), 125.22 (C-7), 85.08 (C-4), 83.69 (C-2), 83.03 (C-3), 76.32
(CH2Ph), 75.63 (CH2Ph), 72.24 (CH2Ph), 60.48 (OCH2CH3), 50.61 (C-
1), 42.75 (C-5), 25.51 (SCH2CH3), 14.20 and 14.12 (OCH2CH3 and
SCH2CH3). Anal. Calcd for C33H38O5S2: C, 68.48; H, 6.62. Found:
C, 68.70; H, 6.77.
to give 15 (3.26 g, 86%): mp 172-173 °C; [R]19 +357 (c 1.01,
D
CHCl3); Rf 0.33 (hexanes:EtOAc, 1:1); 1H NMR (400.13 MHz, CDCl3)
δ 7.53-7.37 (m, 5H, Ph), 5.60 (s, 1H, PhCH), 4.25 (dd, 1H, J6a,6b
)
11.0, J5,6a ) 5.0 Hz, H-6a), 4.19 (d, 1H, J1,2 ) 4.5 Hz, H-1), 4.08 (dd,
1H, J2,3 ) 9.0 Hz, H-2), 3.79 (dd, 1H, J5,6b ) 11.0 Hz, H-6b), 3.77
(dd, 1H, J3,4 ) 9.0 Hz, H-3), 3.73 (dd, 1H, H-3), 3.57 (ddd, 1H, J4,5
)
9.0 Hz, H-5), 3.05 and 2.98 (2 brs, each 1H, OH-2 and OH-3), 2.74
(q, 2H, J ) 7.5 Hz, SCH2CH3), 1.31 (t, 3H, SCH2CH3); 13C NMR
(100.6 MHz, CDCl3) δ 137.37, 129.32, 128.37, 126.33 (Ph), 102.05
(PhCH), 83.94 (C-4), 75.17 (C-2), 73.14 (C-3), 68.12 (C-6), 53.41 (C-
1), 36.34 (C-5), 26.81 (SCH2CH3), 14.20 (SCH2CH3). Anal. Calcd for
C15H20O4S2: C, 54.85; H, 6.14. Found: C, 54.87; H, 6.14.
Ethyl 2,3-Di-O-benzyl-4,6-O-benzylidene-1,5-dithio-r-D-gluco-
pyranoside (16). To an ice-cold suspension of sodium hydride (1.9 g,
47.5 mmol) in DMF (70 mL) was added dropwise a solution of
compound 15 (3.6 g, 11.0 mmol) in DMF (20 mL). The mixture was
stirred for 10 min, after which benzyl bromide (5.5 mL, 46.2 mmol)
was added. The resulting mixture was stirred for an additional 2 h and
then quenched with methanol (10 mL), followed by water (10 mL).
The mixture was concentrated, and the residue was partitioned between
water (100 mL) and Et2O (300 mL). The aqueous phase was extracted
using additional Et2O (50 mL) and the combined organic layers were
dried, filtered, and concentrated. The residue was purified by column
chromatography (toluene:EtOAc, 15:1), followed by crystallization from
EtOAc:hexanes to give 16 (5.14 g, 92%): mp 108-109 °C; [R]19
D
+137 (c 1.03, CHCl3); Rf 0.55 (hexanes:EtOAc, 4:1); 1H NMR (400.13
MHz, CDCl3) δ 7.56-7.23 (m, 15H, Ph), 5.67 (s, 1H, PhCH), 4.84
and 4.81 (2d, each 1H, Ja,b ) 12.0 Hz, CH2Ph) 4.78 and 4.73 (2d, each
1H, Ja,b ) 11.5 Hz, CH2Ph), 4.28 (dd, 1H, J6a,6b ) 11.0, J5,6a ) 4.5 Hz,
H-6a), 4.26 (d, 1H, J1,2 ) 4.5 Hz, H-1), 4.04 (dd, 1H, J2,3 ) 9.5 Hz,
H-2), 3.93 (dd, 1H, J4,5 ) J3,4 ) 9.5 Hz, H-4), 3.87 (dd, 1H, H-3),
3.81 (dd, 1H, J5,6b ) 11.0 Hz, H-6b), 3.66 (ddd, 1H, H-5), 2.78-2.65
(m, 2H, SCH2CH3), 1.30 (t, 3H, J ) 7.5 Hz, SCH2CH3); 13C NMR
(100.6 MHz, CDCl3) δ 138.8-126.05 (18C, Ph), 101.45 (PhCH), 84.99
(C-4), 82.98 (C-2), 80.55 (C-3), 76.40 (CH2Ph), 72.51 (CH2Ph), 68.27
(C-6), 51.05 (C-1), 36.47 (C-5), 25.70 (SCH2CH3), 14.14 (SCH2CH3).
Anal. Calcd for C29H32O4S2: C, 68.47; H, 6.34. Found: C, 68.65; H,
6.53.
Ethyl 2,3,4-Tri-O-benzyl-6,7-dideoxy-1,5-dithio-r-D-gluco-octo-
pyranoside (21). To a solution of compound 19 (3.68 g, 6.36 mmol)
and CoCl2:(H2O)6 (1.80 g, 7.57 mmol) in a mixture of EtOH (90 mL)
and THF (30 mL) at 0 °C was added NaBH4 (0.580 g, 15.3 mmol) in
portions. The mixture was stirred at room temperature for 3 h and then
poured into water (100 mL). The mixture was concentrated to a small
volume and extracted with Et2O (2 × 150 mL). The combined organic
layers were dried, filtered, and concentrated to give the saturated ester
derivative 20. Compound 20 was dissolved in Et2O (20 mL), and the
solution was added dropwise to a mixture of LiAlH4 (0.400 g, 10.5
mmol) in Et2O (200 mL) at 0 °C. The mixture was stirred for 30 min
and then quenched by dropwise addition of MeOH (3 mL), followed
by water (5 mL). The mixture was washed with aqueous 1 M HCl (50
mL) and saturated aqueous NaHCO3 (50 mL), was dried, filtered, and
concentrated. The residue was purified by column chromatography
(hexanes:EtOAc, 3:1), followed by crystallization from Et2O:hexanes
to give 21 (2.61 g, 76%): mp 88-90 °C; [R]19D +166 (c 1.05, CHCl3);
Rf 0.39 (hexanes:EtOAc, 2:1); 1H NMR (400.13 MHz, CDCl3) δ 7.42-
7.24 (m, 15H, Ph), 4.94 and 4.62 (2d, each 1H, Ja,b ) 10.5 Hz, CH2Ph),
4.92 and 4.66 (2d, each 1H, Ja,b ) 10.5 Hz, CH2Ph), 4.75 and 4.66
(2d, each 1H, Ja,b ) 11.5 Hz, CH2Ph), 4.18 (d, 1H, J1,2 ) 4.5 Hz, H-1),
4.03 (dd, 1H, J2,3 ) 9.0 Hz, H-2), 3.79 (dd, 1H, J3,4 ) 9.0 Hz, H-3),
3.65-3.54 (m, 2H, H-8a, H8b), 3.44 (dd, 1H, J4,5 ) 10.0 Hz, H-4),
3.26 (ddd, 1H, J5,6a ) 10.0, J5,6b ) 3.5 Hz, H-5), 2.75-2.60 (m, 2H,
SCH2CH3), 2.09 (m, 1H, H-6a), 1.77-1.67 (m, 1H, H-7a), 1.63-1.53
(m, 1H, H-7b), 1.48-1.39 (m, 1H, H-6b), 1.26 (t, 3H, J ) 7.5 Hz,
SCH2CH3), 1.21 (t, 1H, J8,OH ) 5.5 Hz, OH); 13C NMR (100.6 MHz,
CDCl3) δ 138.85-127.49 (18C, Ph), 85.71 (C-4), 84.15 (C-2), 83.83
(C-3), 76.23 (CH2Ph), 75.77 (CH2Ph), 72.10 (CH2Ph), 62.55 (C-8),
49.79 (C-1), 41.36 (C-5), 30.04 (C-7), 25.64 (C-6), 25.41 (SCH2CH3),
14.25 (SCH2CH3). Anal. Calcd for C31H3804S2: C, 69.11; H, 7.11.
Found: C, 68.91; H, 7.13.
Ethyl 2,3,4-Tri-O-benzyl-1,5-dithio-r-D-glucopyranoside (17). A
solution of AlCl3 (3.90 g, 29.2 mmol) in Et2O (20 mL) was added
dropwise to a stirred mixture of compound 16 (5.00 g, 9.83 mmol),
Me3N:BH3 (1.4 g, 19.2 mmol), and molecular sieves (2 g) in CH2Cl2
(60 mL) and Et2O (20 mL) at 0 °C. After 30 min at 0 °C, the mixture
was filtered through a pad of Celite, the solids were washed with
CH2Cl2, and the combined filtrate and washings were stirred with 1 M
aqueous H2SO4 (20 mL) for 30 min. The organic layer was separated,
washed with aqueous NaHCO3 solution, dried, filtered, and concen-
trated. The residue was purified by column chromatography (hexanes:
EtOAc, 4:1), followed by crystallization from Et2O:hexanes to give 17
(4.3 g, 86%): mp 70-71 °C; [R]19 +186 (c 1.03, CHCl3); Rf 0.24
D
1
(hexanes:EtOAc, 4:1); H NMR (400.13 MHz, CDCl3) δ 7.43-7.25
(m, 15H, Ph), 4.95 and 4.77 (2d, each 1H, Ja,b ) 10.5 Hz, CH2Ph),
4.95 and 4.71 (2d, each 1H, Ja,b ) 11.0 Hz, CH2Ph), 4.76 and 4.67
(2d, each 1H, Ja,b ) 11.5 Hz, CH2Ph), 4.22 (d, 1H, J1,2 ) 4.5 Hz, H-1),
4.02 (dd, 1H, J2,3 ) 9.0 Hz, H-2), 3.92 (dd, 1H, J6a,6b ) 11.5, J5,6a
4.0 Hz, H-6a), 3.83 (dd, 1H, J3,4 ) 9.0 Hz, H-3), 3.77 (dd, 1H, J5,6a
)
)
4.0 Hz, H-6a), 3.73 (dd, 1H, J4,5 ) 10.0 Hz, H-4), 3.41 (ddd, 1H, H-5),
2.75-2.62 (m, 2H, SCH2CH3), 1.67 (bs, 1H, 6-OH), 1.27 (t, 3H, J )
7.5 Hz, SCH2CH3); 13C NMR (100.6 MHz, CDCl3) δ 138.77-127.53
(18C Ph), 83.92 (C-2), 83.80 (C-3), 82.60 (C-4), 76.18 (CH2Ph), 75.57
(CH2Ph), 72.24 (CH2Ph), 62.03 (C-6), 50.11 (C-1), 43.73 (C-5), 25.52
(SCH2CH3), 14.16 (SCH2CH3). Anal. Calcd for C29H34O4S2: C, 68.20;
H, 6.71. Found: C, 67.84; H, 6.62.
(E)-Ethyl (Ethyl 2,3,4-Tri-O-benzyl-6,7-dideoxy-1,5-dithio-r-D-
gluco-oct-6-enopyranosid)-uronate (19). A solution of DMSO (1.36
mL, 19.2 mmol) in CH2Cl2 (10 mL) was added dropwise over 2 min
to a solution of oxalyl chloride (1.10 mL, 12.6 mmol) in CH2Cl2 (40
mL) at -78 °C. The resulting mixture was stirred for 5 min and then
a solution of compound 17 (4.45 g, 8.71 mmol) in CH2Cl2 (20 mL)
1,5-Anhydro-6,7-dideoxy-2,3,4-tri-O-benzyl-5-thio-D-gluco-octi-
tol (22). (a) From compound 21: A solution of (n-Bu)3SnH (0.43 mL,
1.6 mmol) and AIBN (8.0 mg, 0.15 mmol) in toluene (2 mL) was added
over 6 h to a refluxing solution of compound 21 (427 mg, 0.792 mmol)
in toluene (10 mL). After the addition was complete, the mixture was
refluxed for an additional 15 min and then concentrated to a small
volume and purified by column chromatography (tolueneftoluene:
EtOAc, 1:1). Crystallization from Et2O:hexanes yielded 22 (337 mg,
89%): mp 95-97 °C; [R]19D +2.8 (c 1.06, CHCl3); Rf 0.28 (hexanes:
1
EtOAc, 2:1); H NMR (400.13 MHz, CDCl3) δ 7.36-7.24 (m, 15H,
Ph), 4.95 and 4.81 (2d, each 1H, Ja,b ) 10.5 Hz, CH2Ph), 4.95 and
4.63 (2d, each 1H, Ja,b ) 10.5 Hz, CH2Ph), 4.71 (s, 2H, CH2Ph), 3.77-

Sulfonium-Ion Analogue of Castanospermine
J. Am. Chem. Soc., Vol. 122, No. 44, 2000 10775
3.67 (m, 1H, H-2), 3.65-3.55 (m, 2H, H-8a, H-8b), 3.46-3.47 (m,
2H, H-3, H-4), 2.78 (dd, 1H, J1eq,1ax 13.5, J1eq,2 ) 4.5 Hz, H-1eq), 2.73
(ddd, 1H, J4,5 ) 9.5, J5,6a ) 3.0, J5,6b ) 9.5 Hz, H-5), 2.52 (dd, 1H,
J1ax,2 ) 11.0 Hz, H-1ax), 2.17-2.08 (m, 1H, H-6a), 1.78-1.67 (m,
1H, H-7a), 1.64-1.53 (m, 1H, H-7b), 1.44-1.34 (m, 1H, H-6b), 1.22
(bs 1H, 8-OH); 13C NMR (100.6 MHz, CDCl3) δ 138.86-127.51 (18C,
Ph), 85.65 and 87.81 (C-3 and C-4), 82.74 (C-2), 76.19 (CH2Ph), 75.97
(CH2Ph), 72.82 (CH2Ph), 62.67 (C-8), 46.78 (C-5), 30.71 (C-1), 30.05
(C-7), 26.80 (C-6). Anal. Calcd for C29H34O4S: C, 72.77; H, 7.16.
Found: C, 72.92; H, 7.27. (b) From compound 23: application of the
sequence. (i) Methanolysis of acetates to give 24, (ii) 4,6-O-benzylidene
formation to give 25, (iii) benzylation to give 26, (iv) regioselective
benzylidene reductive cleavage to give 27, (v) oxidation of the 6-OH
to an aldehyde 28 and then Wittig chain extension to give 29, (vi)
NaBH4/CoCl2 reduction of the double bond to give 30, and (vii)
reduction of the ester with LiALH4 to give 22 was carried out exactly
as described for the thioglycoside series (13Rf14f15f16f17f
18f19f20f21). The modified sequence proceeded uneventfully to
give compound 22 in an overall yield of 26%. Compound 22 prepared
by this route was identical in all respects to that obtained above.
1,5-Anhydro-2,3,4,6-tetra-O-acetyl-5-thio-D-glucitol (23). A solu-
tion of 1,2,3,4,6-penta-O-acetyl-5-thio-R-D-glucopyranoside13 (3.90 g,
9.60 mmoL) in CH2Cl2 (40 mL) was cooled with stirring in an ice-
bath while 35 wt % HBr/HOAc solution (7.0 mL, 40 mmol) was added
dropwise. The cooling bath was removed and the mixture was stirred
at room temperature for 4h. After dilution with CH2Cl2 (100 mL), the
solution was washed with ice/water (2 × 30 mL), cold saturated aqueous
NaHCO3 (2 × 50 mL), and aqueous NaCl (50 mL). The CH2Cl2 solution
was dried over MgSO4 and concentrated give an R/â mixture of glycosyl
bromides as a syrup. This was dissolved in toluene (120 mL) and a
portion of the toluene (≈20 mL) was removed by distillation to ensure
dryness. A solution of (n-Bu)3SnH (4.3 g, 15 mmoL) and AIBN (0.51
g, 3.1 mmoL) in toluene (100 mL) was added dropwise over 4 h to the
refluxing mixture through the condensor. Reflux was continued for a
further 16 h. The mixture was cooled and concentrated to a syrup.
Purification by column chromatography (hexanes:EtOAc, 3:2) yielded
23 as a crystalline solid (3.39 g, 97%): mp 103-105 °C, lit.18 mp
100-102 °C.
CDCl3) δ 138.77-127.49 (18C, Ph), 87.68 and 85.40 (C-3 and C-4),
82.58 (C-2), 76.15 (CH2Ph), 75.98 (CH2Ph), 72.76 (CH2Ph), 46.26 (C-
5), 33.38 (C-8), 30.65 (C-1), 30.06 (C-7), 29.14 (C-6). Anal. Calcd for
C29H33O3SBr: C, 64.32; H, 6.14. Found: C, 64.16; H, 6.20.
3(R),4(S),5(R),6(S)-3,4,5-Tribenzyloxy-cis-1-thioniabicyclo[4.3.0]-
nonane Perchlorate (34). A solution of compound 32 (546 mg, 1.01
mmol) in acetonitrile (5 mL) was treated with AgClO4 (420 mg, 2.03
mmol) for 24 h at room temperature. The solvent was removed, and
the residue was partitioned between CH2Cl2 (200 mL) and water (50
mL). The organic phase was dried, filtered, concentrated, and purified
by column chromatography (CH2Cl2:MeOH 35:1) to yield compound
34 as a colorless foam (434 mg, 77%): [R]24 +3.3 (c 1.20, CHCl3);
D
Rf 0.6 (EtOAc:MeOH:H2O, 10:2:1); 1H NMR (400.13 MHz, CDCl3) δ
7.38-7.17 (m, 15H, Ph), 4.68 and 4.56 (2d, each 1H, Ja,b ) 11.5 Hz,
CH2Ph), 4.60 and 4.54 (2d, each 1H, Ja,b ) 11.7 Hz, CH2Ph), 4.49 and
4.44 (2d, each 1H, CH2Ph), 4.21-4.17 (m, 1H, H-6), 4.13-3.99 (m,
1H, H-3), 3.98 (dd, 1H, J4,5 ) J5,6 ) 3.2 Hz, H-5), 3.87 (ddd, J9a9b
)
12.0, J8b,9a ) 8.0, J8a,9a ) 3.5 Hz, H-9a), 3.79 (dd, 1H, J3,4 ) 3.9 Hz,
H-4), 3.78 (dd, 1H, J2a,2b ) 13.0, J2a,3 ) 6.5 Hz, H-2a), 3.49-3.39 (m,
1H, H-9b), 3.34 (dd, 1H, J2b,3 ) 2.0 Hz, H-2b), 2.53-2.31 (m, 3H,
H-7a, H-7b, H-8a), 2.22-2.09 (m, 1H, H-8b); 13C NMR (100.6 MHz,
CDCl3) δ 136.74-128.10 (18C, Ph), 74.38 (C-4), 73.14 (C-5), 73.00
(CH2Ph), 72.44 (CH2Ph), 71.62 (CH2Ph), 71.36 (C-3), 56.83 (C-6),
43.26 (C-9), 34.17 (C-2), 31.02(C-7), 27.28 (C-8). Anal. Calcd for
C29H33ClO7S: C, 62.08; H, 5.93. Found: C, 61.92; H, 6.00.
3(R),4(S),5(R),6(S)-3,4,5-Trihydroxy-cis-1-thioniabicyclo[4.3.0]-
nonane Perchlorate (7). To a solution of compound 34 in glacial acetic
acid (15 mL) was added palladium hydroxide catalyst (20% Pd/C,
Degussa type E101NE/W, 188 mg), and the mixture was stirred at room
temperature in a bomb that was pressurized with H2 to 52 psi. After
21 h, the catalyst was removed by filtration through Celite with the
aid of EtOH (80 mL). The filtrate was concentrated on a rotary
evaporator and then evaporated again with water (20 mL) to remove
the remaining acetic acid. This yielded compound 7 as a pale-yellow
syrup (132 mg, 94%), which was essentially pure by 1H NMR analysis.
An analytically pure sample was obtained by crystallization from
MeOH:EtOAc as colorless leaflets: mp 79-80 °C; [R]24D +35 (c 0.56,
1
MeOH); H NMR (400.13 MHz, CD3OD) δ 4.21 (ddd, 1H, J2a,3
)
1,5-Anhydro-8-bromo-6,7,8-trideoxy-2,3,4-tri-O-benzyl-5-thio-D-
gluco-octitol (32). To an ice-cold solution of compound 22 (500 mg,
1.04 mmol) in pyridine (10 mL) was added methanesulfonyl chloride
(0.12 mL, 1.6 mmol) in one portion. The mixture was stirred for 30
min at room temperature, after which small portions of ice were added
and the resulting mixture was stirred for an additional 10 min. The
solvent was evaporated, and the aqueous residue was partitioned
between CH2Cl2 (200 mL) and aqueous 1 M HCl (50 mL). The organic
phase was washed with saturated aqueous NaHCO3 (50 mL), dried,
filtered, and concentrated to dryness to give the crude mesylate
derivative 31. This was dissolved in THF (15 mL) and reacted with
LiBr (360 mg, 4.15 mmol) at reflux for 1 h. The solvent was evaporated,
and the residue was partitioned between CH2Cl2 (200 mL) and water
(50 mL). The organic phase was dried, filtered, and concentrated. The
residue was purified by column chromatography (hexanes:EtOAc, 12:
J2b,3 ) J3,4 ) 3.7 Hz, H-3), 4.17 (dd, 1H, J4,5 ) J5,6 ) 4.1 Hz, H-5),
3.95 (ddd, 1H, J6,7a ) 10.4, J6,7b ) 5.9 Hz, H-6), 3.86 (dd, 1H, H-4),
3.73 (ddd, J9a,9b ) 12.7, J8a,9a ) 8.5, J8b,9a ) 3.6 Hz, H-9a), 3.54 (d,
2H, H-2a, H-2b), 3.51-3.43 (m, 1H, H-9b), 2.80-2.68 (m, 1H, H-7a),
2.53-2.41 (m, 2H, H-7b, H-8a), 2.18-2.05 (m, 1H, H-8b); 13C NMR
(100.6 MHz, CD3OD) δ 70.75 (C-4), 69.96 (C-5), 68.73 (C-3), 61.17
(C-6), 44.13 (C-9), 38.63 (C-2), 32.309 (C-7), 27.99 (C-8). Anal. Calcd
for C8H15ClO7S: C, 33.05; H, 5.20. Found: C, 33.25; H, 5.12.
Acknowledgment. This work is dedicated, with respect, to
the memory of B. Belleau. We are grateful to the Natural
Sciences and Engineering Research Council of Canada for
financial support.
1) to give 32 as a white solid (546 mg, 97%): mp 63-65 °C; [R]24
Supporting Information Available: Views of the three
cations in the asymmetric unit, text and tables giving additional
crystallographic details and tables listing atomic coordinates,
anisotropic displacement parameters, distances, angles, possible
hydrogen bonds, nonbonded contacts, and structure factors. This
material is available free of charge via the Internet at
http://pubs.acs.org.
D
+4.1 (c 1.22, CHCl3); Rf 0.32 (hexanes:EtOAc, 15:1); 1H NMR (400.13
MHz, CDCl3) δ 7.39-7.22 (m, 15H, Ph), 4.95 and 4.79 (2d, each 1H,
Ja,b ) 10.5 Hz, CH2Ph), 4.93 and 4.63 (2d, each 1H, Ja,b ) 10.5 Hz,
CH2Ph), 4.69 (s, 2H, CH2Ph), 3.74-3.67 (m, 1H, H-2), 3.43-3.32 (m,
4H, H-3, H-4, H-8a, H-8b), 2.76 (dd, 1H, J1eq,1ax ) 13.4, J1eq,2 ) 4.3
Hz, H-1eq), 2.73-2.66 (m, 1H H-5), 2.51 (dd, 1H, J1ax,2 ) 11.0 Hz,
H-1ax), 2.29-2.19 (m, 1H, H-6a), 2.08-1.97 (m, 1H, H-7a), 1.94-
1.83 (m, 1H, H-6b), 1.47-1.37 (m, 1H, H-7b); 13C NMR (100.6 MHz,
JA002038H