Synthesis and conformational analysis of bicyclic sulfonium salts. Structures related to the glycosidase inhibitor australine

Article abstract of DOI:10.1021/jo051560p

The syntheses of eight sulfonium compounds with structures related to the naturally occurring pyrrolizidine alkaloid, australine, in which the bridgehead nitrogen atom is replaced by a sulfonium ion, are described. The synthetic strategy relies on the int

Full text of DOI:10.1021/jo051560p

VOLUME 71, NUMBER 8
APRIL 14, 2006
© Copyright 2006 by the American Chemical Society
Synthesis and Conformational Analysis of Bicyclic Sulfonium Salts.
Structures Related to the Glycosidase Inhibitor Australine
Nag S. Kumar and B. Mario Pinto*
Department of Chemistry, Simon Fraser UniVersity, Burnaby, British Columbia, Canada V5A 1S6
bpinto@sfu.ca
ReceiVed July 26, 2005
The syntheses of eight sulfonium compounds with structures related to the naturally occurring pyrrolizidine
alkaloid, australine, in which the bridgehead nitrogen atom is replaced by a sulfonium ion, are described.
The synthetic strategy relies on the intramolecular attack of a cyclic thioether across a terminal double
bond in the presence of a suitable electrophile. We postulate that these compounds, having a permanent
positive charge on the sulfur atom, will mimic the highly unstable oxacarbenium ion transition state in
a glycosidase-catalyzed hydrolysis reaction. The conformational preferences of these compounds, based
1
on analysis of H-1H vicinal coupling constants and 1D-NOESY data, are attributed to both steric and
electrostatic interactions. These compounds will be used in the study of structure-activity relationships
with glycosidase enzymes.
Introduction
activity relationships of the enzyme-catalyzed reaction and may
also provide chemotherapeutic agents for the treatment of viral
infections, cancer, and other metabolic disorders such as
diabetes.
The most important class of reversible glycosidase inhibitors
is composed of naturally occurring polyhydroxylated pyrrolidine,
piperidine, pyrrolizidine, and indolizidine alkaloids.8-14 These
are monocyclic and bicyclic amines such as (2R,5R,3R,4R)-
2,5-bis(hydroxymethyl)-3,4-dihydroxypyrrolidine (DMDP, 1),
deoxynojirimycin (2), alexine (3), australine (4), castanosper-
mine (5), and swainsonine (6). It is postulated that these
compounds mimic the shape and charge of the oxacarbenium-
like transition state for the enzyme-catalyzed hydrolysis reaction,
Cell surface carbohydrates play an essential role in biological
communication, including fertilization, infection, the inflam-
matory response, cell adhesion, and cancer metastasis.1-7 The
maturation of these oligosaccharides involves the trimming of
nascent glycoproteins by glucosidase and mannosidase enzymes
to provide the core structure that is required to build a more
complex glycoprotein by the action of glycosyltransferase
enzymes. Inhibiting these glucosidase enzymes by natural or
synthetic inhibitors provides a means of studying the structure-
* To whom correspondence should be addressed. Tel: (604) 291-4152. Fax:
(604) 291-4860.
(1) Holman, R. R.; Cull, C. A.; Turner, R. C. Diabetes Care 1999, 22,
960-964.
(8) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahe-
dron: Asymmetry 2000, 11, 1645-1680.
(2) Jacob, G. S. Curr. Opin. Struct. Biol. 1995, 5, 605-611.
(3) Dwek, R. A. Chem. ReV. 1996, 96, 683-720.
(4) 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.
(9) Watson, A. A.; Fleet, G. W. J.; Asano, N.; Molyneux, R. J.; Nash,
R. J. Phytochemistry 2001, 56, 265-295.
(10) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem. ReV.
2002, 102, 515-553.
(5) Asano, N. Glycobiology 2003, 13, 93-104.
(6) Vasella, A.; Davies, G. J.; Bohm, M. Curr. Opin. Chem. Biol. 2002,
6, 619-629.
(7) Heightman, T. D.; Vasella, A. Angew. Chem., Int. Ed. 1999, 38, 750-
770.
(11) Elbein, A. D. Annu. ReV. Biochem. 1987, 56, 497-534.
(12) Elbein, A. D. FASEB J. 1991, 5, 3055-3063.
(13) Winchester, B.; Fleet, G. W. J. Glycobiology 1992, 2, 199-210.
(14) Stu¨tz, A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin
and Beyond; Weinheim; New York: Wiley-VCH: 1999.
10.1021/jo051560p CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/12/2005
J. Org. Chem. 2006, 71, 2935-2943
2935

Kumar and Pinto
thus making them good glycosidase inhibitors.15,16 The bridge-
head nitrogen atoms in these compounds are protonated at
physiological pH, and it is believed that this provides the
stabilizing electrostatic interactions between the inhibitor and
the carboxylate residues in the enzyme active site.
intriguing innersalt sulfonium sulfate structures has led to
significant synthetic efforts to derive sulfonium salts with
potential glycosidase inhibitory activity.26-34
We report herein the synthesis of the sulfonium ions 7-14,
together with their conformational analysis, as inferred from
1H-1H vicinal coupling constants (3JH,H) of the ring protons
and one-dimensional nuclear Overhauser enhancement spec-
troscopy (1D-NOESY) experiments. The effects of both elec-
trostatic and steric interactions on the conformations of these
compounds are described.
Preparation of structurally modified analogues of these
naturally occurring compounds has generated much interest since
the biological activity of these molecules varies substantially
with the number, position, and the stereochemistry of the centers
bearing hydroxyl groups, as well as the ring size.17-22 We,
therefore, designed the analogues (7-14) in which the bridge-
head nitrogen atom is replaced by a sulfonium ion as candidate
glycosidase inhibitors. We reasoned that the permanent positive
charge on the sulfur atom would mimic the highly unstable
oxacarbenium ion transition state and enhance the electrostatic
interactions between the inhibitor and the enzyme. These
compounds (7-14) can be considered to be either sulfonium
analogues of alexine (3) and australine (4) or the ring-contracted
analogues of swainsonine (6).
The synthesis of bicyclic sulfonium salts to serve as glycosi-
dase inhibitors has precedent in the work of Siriwardena and
co-workers.23-25 Most recently, they have reported the synthesis
of compound 15 and shown that it not only is a potent inhibitor
of several mannosidases but also exhibits more selectivity than
swainsonine.25 In addition, the discovery of a new class of
glycosidase inhibitor, salacinol (16) and kotalanol (17), with
Results and Discussion
Synthesis. Retrosynthetic analysis of compounds 7-14
(15) McCarter, J. D.; Withers, S. G. Curr. Opin. Struct. Biol. 1994, 4,
885-892.
revealed that they could be synthesized from a common
(16) Ly, H. D.; Withers, S. G. Annu. ReV. Biochem. 1999, 68, 487-
522.
(26) Yoshikawa, M.; Murakami, T.; Shimada, H.; Matsuda, H.; Yama-
hara, J.; Tanabe, G.; Muraoka, O. Tetrahedron Lett. 1997, 38, 8367-8370.
(27) Yoshikawa, M.; Murakami, T.; Yashiro, K.; Matsuda, H. Chem.
Pharm. Bull. 1998, 46, 1339-13340.
(17) Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61, 5546-
5556.
(18) Bell, A. A.; Pickering, L.; Watson, A. A.; Nash, R. J.; Pan, Y. T.;
Elbein, A. D.; Fleet, G. W. J. Tetrahedron Lett. 1997, 38, 5869-5872.
(19) White, J. D.; Hrnciar, P.; Yokochi, A. F. T. J. Am. Chem. Soc. 1998,
120, 7359-7360.
(20) Denmark, S. E.; Martinborough, E. A. J. Am. Chem. Soc. 1999,
121, 3046-3056.
(21) Denmark, S. E.; Hurd, A. R. J. Org. Chem. 2000, 65, 2875-2886.
(22) Denmark, S. E.; Herbert, B. J. Org. Chem. 2000, 65, 2887-2896.
(23) Siriwardena, A. H.; Chiaroni, A.; Riche, C.; El-Daher, S.; Win-
chester, B.; Greirson, D. S. J. Chem. Soc., Chem. Commun. 1992, 1531-
1533.
(24) Gonzalez-Outeirino, J.; Glushka, J.; Siriwardena, A.; Woods, R. J.
J. Am. Chem. Soc. 2004, 126, 6866-6867.
(25) Siriwardena, A.; Strachan H.; El-Daher, S.; Way, G.; Winchester,
B.; Glushka, J.; Moremen, K.; Boons, G.-J. ChemBioChem 2005, 6, 845-
848.
(28) Matsuda, H.; Murakami, T.; Yashiro, K.; Yamahara, J.; Yoshikawa,
M. Chem. Pharm. Bull. 1999, 47, 1725-1729.
(29) Yuasa, H.; Takada, J.; Hashimoto, H. Tetrahedron Lett. 2000, 41,
6615-6618.
(30) Ghavami, A.; Johnston, B. D.; Pinto, B. M. J. Org. Chem. 2001,
66, 2312-2317.
(31) Yoshikawa, M.; Morikawa, T.; Matsuda, H.; Tanabe, G.; Muraoka,
O. Bioorg. Med. Chem. 2002, 10, 1547-1554.
(32) 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.
(33) Ghavami, A.; Sadalapure, K. S.; Johnston, B. D.; Lobera, M.; Snider
B. B.; Pinto, B. M. Synlett 2003, 9, 1259-1262.
(34) Szczepina M. G.; Johnston, B. D.; Yuan Y.; Svensson B.; Pinto, B.
M. J. Am. Chem. Soc. 2004, 126, 12458-12469.
2936 J. Org. Chem., Vol. 71, No. 8, 2006

Synthesis and Conformational Analysis of Bicyclic Sulfonium Salts
SCHEME 1
methanolysis to give 21. The second sequence was higher
yielding and shorter than the first.
To synthesize compounds 7-9, the primary hydroxyl group
in 21 was converted to a tosylate that was treated, in turn, with
allylmagnesium bromide to give compound 22 (Scheme 3).
After tosylation, there was always a small amount of a more
polar compound present, as indicated by TLC. We reasoned
that this polar compound might be the bicyclic sulfonium salt
formed from the thioether displacement of the tosylate. The polar
compound was in equilibrium with the less polar tosylated
compound and could not be isolated by column chromatography.
This type of sulfur participation was reported earlier by Hughes
et al.,36,37 who applied the ring contraction of a 5-thiopyranoside
to make a 4-thiofuranoside. We employed the same strategy to
add an allyl group at C-5. Usually, the formation of a C-C
bond by displacement of a tosylate group with a Grignard
reagent is low yielding or is transition metal-catalyzed,38-41 but
in this case the reaction proceeded smoothly at ambient
temperature. We believe that allylmagnesium bromide reacts
with the intermediate strained bicyclic sulfonium salt to give
compound 22.
SCHEME 2
Compound 22 was treated with triflic acid at -5 °C to give
spontaneously an inseparable 1:1 mixture of 23 and 24 (Scheme
4). At lower temperatures, the reaction was inconveniently slow
and at higher temperatures, only decomposition of the starting
material was observed. The ring junction of these bicyclic
compounds (23, 24) is cis as expected since the trans isomer
would be strained and of higher energy, in agreement with the
work of Cere and co-workers.42,43 The stereochemistry at C-7
was assigned with the aid of a 1D-NOESY experiment which
showed a correlation between H-1a and H-8 for compound 23
and a correlation between H-1a and H-7 for compound 24.
Debenzylation of compounds 23 and 24 gave the desired
products 7 and 8, respectively.
Compound 9 was also synthesized starting from the common
intermediate 22. Treatment of compound 22 with bromine at 0
°C afforded the bicyclic sulfonium salt as a 4:1 diastereomeric
mixture, with a bromide counterion. The counterion was
immediately exchanged to triflate, using silver triflate, to give
compound 25 (Scheme 4), since our previous work had shown
precursor C (Scheme 1). Compounds A and B could be
synthesized by intramolecular addition of the cyclic thioether
across the double bond in the presence of a suitable electrophile.
Compound C could, in turn, be synthesized from D.
Scheme 2 outlines two methods for the synthesis of 21,
corresponding to D. Compound 18 was synthesized from
commercially available L-xylose in six steps using the procedure
of Satoh et al.35 Compound 18 was initially debenzylated using
standard Birch reduction to give compound 19.33 The primary
hydroxyl group was then selectively protected using a trityl
group to give 20. The two secondary hydroxyl groups were
protected as their benzyl ethers, and the trityl group was removed
to give the desired precursor 21. Alternatively, compound 21
was synthesized directly from 18 by selective removal of the
primary benzyl ether using 1.5% H2SO4/Ac2O to give the
corresponding acetate, which was subsequently removed by
SCHEME 3
SCHEME 4
J. Org. Chem, Vol. 71, No. 8, 2006 2937

Kumar and Pinto
SCHEME 5
that the bromide counterion resulted in reversible ring opening
in a related bicyclic sulfonium salt.44 The diastereomeric mixture
25 was treated with silver oxide in aqueous THF under mild
conditions to give the alkene 26, the sulfonium center making
the elimination reaction more facile because of the acidity of
H-7. Even storing compound 25 for several months at room
temperature, resulted in spontaneous elimination to give com-
pound 26. Finally, the benzyl groups were removed to give the
desired product 9.
Compounds 10-14 were synthesized from 21 as shown in
Scheme 5. Swern oxidation of compound 21 using TFAA45
afforded compound 27 which subsequently was treated with
allylmagnesium bromide to give a 1:2 mixture of diastereomers
29 and 28.
Compounds 11 and 14 were synthesized from compound 29
(Scheme 5). Treatment of compound 29 with bromine gave the
bicyclic sulfonium salt whose bromide counterion was ex-
changed with triflate using silver triflate. The corresponding
salt, when subjected to treatment with aqueous silver oxide,
underwent elimination to give compound 31. The stereochem-
istry at C-5 of compound 31 was suggested by the absence of
a H3/H5 correlation in the 1D-NOESY spectrum; the stereo-
chemistry of compound 29 was thus assigned by inference.
Deprotection of the benzyl groups gave the target compound
11. Reduction of the double bond using Pd/C gave a 4:1
diastereomeric mixture of which compound 14 was the major
product. The stereochemistry at C-7 was assigned by means of
a 1D-NOESY experiment which showed a correlation between
H-1a and H-8. The diastereoselectivity can be explained by the
fact that compound 11 has a concave structure and the addition
of hydrogen takes place from the least hindered, convex face.
The same series of reactions was applied to compound 28 to
synthesize compound 10. Reduction of the double bond using
Pd/C gave a 3:2 diastereomeric mixture of 12 and 13. With the
aid of 1D-NOESY experiments, the stereochemistry at C-7 was
assigned such that the structure 13 was attributed to the isomer
which showed a strong correlation between H-1a and H-7
whereas structure 12 was assigned to the isomer which showed
no correlation between H-1a and H-7, but a correlation between
H-1a and H-8. The reduction of the double bond in compound
10 was less diastereoselective, presumably because the hydroxyl
group at C-5 blocks the convex face of compound 10.
Conformational Analysis. Application of the Karplus rela-
1
tionship46 to the observed vicinal H-1H coupling constants
led to the proposed conformations of compounds 7-14 (Table
1). These conformations were further confirmed with the aid
of one-dimensional nuclear Overhauser enhancement spectros-
copy (1D-NOESY) experiments (Figure 1). We suggest that ring
2
A of compounds 8-14 exists in a E conformation since the
vicinal coupling constant between H(1a)-H(2), H(2)-H(3), and
H(3)-H(4) is small (0.0-2.4 Hz), whereas the coupling constant
between H(1b)-H(2) is ∼4.0-4.8 Hz (Figure 2). This is in
agreement with the 1D-NOESY experiments where compounds
8-14 do not show any H(1a)/H(3) NOE correlation since they
(35) Satoh, H.; Yoshimura, Y.; Sakata, S.; Miura, S.; Machida, H. Bioorg.
Med. Chem. Lett. 1998, 8, 989-992.
(36) Clegg, W.; Hughes, N. A.; Wood, C. J. J. Chem. Soc., Chem.
Commun. 1975, 300.
2
adopt a E conformation in which both H(1a) and H(3) are in
(37) Hughes, N. A.; Wood, C. J. J. Chem. Soc., Perkin Trans. 1 1986,
695-700.
pseudoequatorial orientations. This conformation would place
the hydroxyl groups at C-2 and C-3 in pseudoaxial positions, a
higher energy conformation than the E2 conformation in which
the hydroxyl groups occupy pseudoequatorial positions. Similar
results were noted in our previous work in which the preferred
conformation of the bicyclic sulfonium ion positioned the
hydroxyl groups in axial orientations. The conformational
preference was attributed to favorable electrostatic attraction
between the hydroxyl groups with the sulfonium center which
outweighed the steric effects.34,44 On the other hand, ring A of
compound 7 adopts an E2 conformation since it exhibits an
(38) Dias, L. C.; Oliveira, L. G.; Sousa, M. A.; Ellensohn, R. M.
ARKIVOC 2005, 6, 62-87.
(39) Terao, J.; Todo, H.; Watanabe, H.; Ikumi, A.; Kambe, N. Angew.
Chem., Int. Ed. 2004, 43, 6180-6182.
(40) Terao J.; Naitoh, Y.; Kuniyasu, H.; Kambe, N. Chem. Lett. 2003,
32, 890-891.
(41) Hanessian, S.; Thavonekham, B.; DeHoff, B. J. Org. Chem. 1989,
54, 5831-5833.
(42) Cere, V.; Paolucci, C.; Pollicino, S.; Sandri, E.; Fava, A. J. Org.
Chem. 1981, 47, 2861.
(43) Calderoni, C.; Cere, V.; Pollicino, S.; Sandri, E.; Fava, A.; Guerra,
M. J. Org. Chem. 1980, 45, 2641-2649.
(44) Svansson, L.; Johnston, B. D.; Gu, J.-H.; Patrick, B.; Pinto, B. M.
J. Am. Chem. Soc. 2000, 122, 10769-10775.
(45) Omura, K.; Sharma, A. K.; Swern, D. J. Org. Chem. 1976, 41, 957-
962.
(46) Karplus, M. J. Am. Chem. Soc. 1963, 85, 2870-2871.
2938 J. Org. Chem., Vol. 71, No. 8, 2006

Synthesis and Conformational Analysis of Bicyclic Sulfonium Salts
FIGURE 1. Observed NOE correlations for compounds 7-14.
compounds 7 and 12; hence, they are present in a 6E conforma-
tion. Based on analysis of vicinal coupling constants, we also
propose that ring B of compounds 8 and 13 has an E6
conformation, as corroborated by 1D-NOESY experiments
which showed a NOE correlation between H(5b)/H(7) and H(4)/
H(6b) for compound 13. Both compounds 8 and 13 showed a
NOE correlation between H(8)/H(6a) and also between H(8)/
H(6b), which implies that the methyl group is in a pseudoequa-
torial orientation. In compounds 7, 8, 12, 13, and 14, the methyl
group has a significant effect on the conformation since it
occupies a pseudoequatorial position. By changing the config-
uration at C-7 in compounds 7 and 12, and hence the orientation
of the methyl group, the conformation of ring B changes from
6E to E6. In compound 14, the hydroxyl group at C-5 is in a
pseudoaxial orientation, whereas the C-5 hydroxyl group of
compound 12 is in a pseudoequatorial orientation; thus, the
configuration of the carbon bearing the methyl group and hence
the orientation of the methyl group plays a major role in
determining the conformation of the B ring. Hence, compounds
TABLE 1. Vicinal Coupling Constants for Compounds 7-14 and
Their Proposed Conformations
compounds
vicinal
coupling
constant (Hz)
7
8
9
10
2.1
4.2
2.0
2.0
0.0
na
5.2
2.3
na
na
na
11
0.0
4.1
0.0
0.0
na
8.0
na
na
12
2.4
4.8
2.4
2.4
1.5
na
13
0.0
4.1
2.0
0.0
5.2
na
14
2.2
4.6
2.2
2.2
na
6.3
na
na
11.2
6.1
6.7
6.7
J1a,2
J1b,2
J2,3
4.8
4.8
4.8
3.8
3.8
5.9
2.0
4.0
2.0
0.0
8.0
8.0
0.0
4.3
0.0
0.0
4.3
9.9
J3,4
J4,5a
J4,5b
J5a,6a
J5a,6b
J5b,6a
J5b,6b
J6a,7
J6b,7
overlap overlap 8.6
overlap overlap 5.0
overlap overlap 8.6
overlap overlap 8.6
6.0
6.0
3.7
0
na
5.2
7.9
na
7.2
9.8
na
na
na
6.9
6.9
na
na
11.3 6.8
5.6 9.9
na
na
proposed
conformation
6E E2
E6 2E
4T5 2E 4T5 2E 4T5 2E 6E 2E E6 2E 6E 2E
6
7, 8, 12, 13, and 14 have overall conformations of E E2, E6
2E, 6E 2E, E6 2E, and 6E 2E, respectively. Both electrostatic and
steric effects control the conformations of compounds 7-14.
Thus, changing the configuration at C-7 or changing the C-7
substituent from a methyl group to an exo-methylene group has
a significant impact on the conformation of these compounds.
The ability to tailor the preferred conformations of these
compounds through the judicious choice of the type, location,
and stereochemistry of pendant functional groups could be of
significance in the design of molecules as candidate glycosidase
inhibitors.
FIGURE 2. Schematic representations of 6E E2, E6 2E, 6E 2E, and 4T5
Experimental Section
2E conformations.
General Methods. Optical rotations were measured at 23 °C.
1H and 13C NMR spectra were recorded with frequencies of 500
and 125 MHz, respectively. All assignments were confirmed with
the aid of two-dimensional 1H, 1H (gCOSY) and 1H, 13C (gHMQC)
experiments using standard Varian pulse programs. Processing of
the spectra was performed with MestRec software. 1D-NOESY
experiments were recorded at 295 K on a 500 MHz spectrometer.
For each 1D-NOESY spectrum, 512 scans were acquired with Q3
Gaussian Cascade pulse. A mixing time of 500 or 800 ms was used
in all the 1D-NOESY experiments. Matrix-assisted laser desorption
ionization time-of-flight (MALDI-TOF) mass spectra were obtained
using 2,5-dihydroxybenzoic acid as a matrix. Analytical thin-layer
chromatography (TLC) was performed on aluminum plates pre-
coated with silica gel 60F-254 as the adsorbent. The developed
plates were air-dried, exposed to UV light, and/or sprayed with a
H(1a)/H(3) correlation; hence, both H(1a) and H(3) are in
pseudoaxial orientations. Based on analysis of vicinal coupling
constants, we also propose that compounds 9-11 with a double
bond at C-7 have ring B in a twist conformation; hence,
compounds 9-11 have an overall conformation of 4T5 2E. This
conformation was further supported by 1D-NOESY experiments
which showed H(1a)/H(8b), H(3)/H(5a), H(6a)/H(8a), H(6b)/
H(8a), and H(3)/H(6a) correlations. From the analysis of vicinal
coupling constants and 1D-NOESY data, we propose that the
B ring of compounds 7, 12, and 14 has a 6E conformation. There
was a NOE correlation between H(5b)/H(7) for compounds 7
and 14 and there was no correlation between H(5a)/H(8) for
J. Org. Chem, Vol. 71, No. 8, 2006 2939

Kumar and Pinto
solution containing 1% Ce(SO4)2 and 1.5% molybdic acid in 10%
aqueous H2SO4, and heated. Column chromatography was per-
formed with silica gel 60 (230-400 mesh).
the product was dissolved in Et2O (20 mL). Allylmagnesium
bromide (1 M in Et2O, 2.5 mL, 2.5 mmol) was added dropwise,
and the mixture was stirred at ambient temperature under an N2
atmosphere for 16 h. The reaction was quenched with ice (5 mL),
and the mixture was diluted with Et2O (100 mL). The reaction
mixture was washed with H2O (2 × 50 mL) and brine (50 mL).
The organic layer was dried over anhydrous Na2SO4, filtered, and
concentrated. The crude product was purified by flash chromatog-
raphy [hexanes/EtOAc, 1:0 f 10:1] to give compound 22 as a
colorless oil (330 mg, 84%): [R]D +9.80 (c 1.02, CH2Cl2); 1H NMR
(CDCl3) δ 7.38-7.28 (m, 10H, Ar), 5.68 (dddd, 1H, J6a,7 ) J6b,7
) 6.6 Hz, J7,8b ) 17.0 Hz, J7,8a ) 10.2 Hz, H-7), 5.02 (dddd, 1H,
J6a,8b) J6b,8b ) J8a,8b ) 1.6 Hz, H-8b), 4.96 (dd, 1H, H-8a), 4.68
and 4.60 (2d, each 1H, Ja,b ) 11.7 Hz, CH2Ph), 4.59 and 4.55 (2d,
each 1H, Ja,b ) 11.9 Hz, CH2Ph), 4.08 (ddd, 1H, J1a,2 ) J1b,2 ) J2,3
) 5.9 Hz, H-2), 3.80 (dd, 1H, J3,4 ) 5.7 Hz, H-3), 3.23(ddd, 1H,
J4,5a ) 5.1 Hz, J4,5b ) 9.9 Hz, H-4), 3.17(dd, 1H, J1a,1b ) 10.9 Hz,
H-1a), 2.85 (dd, 1H, H-1b), 2.10 (m, 1H, H-6b), 2.05 (ddddd, 1H,
J5b,6a ) J6a,6b ) 7.3 Hz, J5a,6a ) 14.2 Hz, H-6a), 1.95 (dddd, 1H,
J5a,5b ) 6.5 Hz, H-5b), 1.62 (dddd, 1H, H-5a); 13C NMR (CDCl3)
δ 138.4, 138.2 (2Cipso), 137.9 (C-7), 128.7-128.0 (10CAr), 115.5
(C-8), 88.7 (C-3), 85.1 (C-2), 72.8, 72.2 (2 CH2Ph), 48.2 (C-4),
34.8 (C-5), 32.7 (C-6), 31.7 (C-1); MALDI-TOF MS m/e 355.30
(M+ + H), 377.28 (M+ + Na), 393.22 (M+ + K). Anal. Calcd for
C22H26O2S: C, 74.54; H, 7.39. Found: C, 74.68; H, 7.38.
(2S,3S,4R,7R/S)-2,3-Dibenzyloxy-7-methyl-cis-1-thio-niabicyclo-
[3.3.0]octane triflate (23/24). A solution of trifluoromethane-
sulfonic acid (0.05 mL, 0.57 mmol) in CH2Cl2 (2 mL) was added
dropwise to a stirred solution of 22 (200 mg, 0.57 mmol) in CH2-
Cl2 (8 mL) at -5 °C under N2 atmosphere. The mixture was stirred
at -5 °C for 2 h and then concentrated. The crude product was
purified by flash chromatography [CH2Cl2/MeOH, 1:0 f 20:1] to
give a pale yellow oil (150 mg, 52%). Analysis by NMR showed
that the product was a mixture of two isomers (∼1:1) at the
stereogenic C-7 center. The stereochemistry was assigned with the
aid of a 1D-NOESY spectrum which showed a strong correlation
between H-1a and H-7 for compound 24 and no correlation for
compound 23.
1,4-Anhydro-5-O-trityl-4-thio-D-arabinitol (20). A mixture of
compound 19 (4.10 g, 27.3 mmol) and trityl chloride (12.90 g, 1.7
equiv) in pyridine (200 mL) was stirred at room temperature under
an N2 atmosphere for 40 h. The reaction mixture was concentrated,
and the crude product was purified by flash chromatography [CH2-
Cl2/MeOH, 1:0 f 20:1] to give compound 20 as white foam (8.70
g, 81%): [R]D +6.15 (c 0.65, CH2Cl2); 1H NMR (CDCl3) δ 7.46-
7.20 (m, 15H, Ar), 4.21 (ddd, 1H, J1a,2 ) 6.9 Hz, J1b,2 ) J2,3 ) 7.1
Hz, H-2), 3.81 (dd, 1H, J3,4 ) 6.8 Hz, H-3), 3.48-3.35 (m, 2H,
H-4, H-5a), 3.30 (dd, 1H, J4,5b ) J5a,5b ) 7.3 Hz, H-5b), 3.04 (dd,
1H, J1a,1b ) 10.6 Hz, H-1a), 2.69 (dd, 1H, H-1b); 13C NMR (CD2-
Cl2) δ 136.05 (3Cipso), 128.8-127.4 (15CAr), 87.5 (Ph3C), 81.7 (C-
3), 78.1 (C-2), 67.1 (C-5), 48.2 (C-4), 33.0 (C-1); MALDI-TOF
MS m/e 415.17 (M+ + Na), 431.20 (M+ + K). Anal. Calcd for
C24H24O3S: C, 73.44; H, 6.16. Found: C, 73.65; H, 6.30.
1,4-Anhydro-2,3-di-O-benzyl-4-thio-D-arabinitol (21). A mix-
ture of compound 20 (8.00 g, 20.5 mmol) and 60% NaH (2.70 g,
2.5 equiv) in DMF (250 mL) was stirred in an ice bath for 10 min.
A solution of benzyl bromide (7.0 mL, 2.2 equiv) in DMF (20 mL)
was added, and the solution was stirred in an ice bath for 90 min.
The reaction was quenched with ice-water (150 mL) and extracted
with Et2O (2 × 200 mL). The combined organic phase was washed
with brine (100 mL), dried (Na2SO4), and concentrated. The residue
was dissolved in 1:1 formic acid/Et2O solution (300 mL), and the
solution was stirred at room temperature for 90 min. The mixture
was diluted with Et2O (200 mL) and washed with H2O (2 × 100
mL), saturated aqueous NaHCO3 (2 × 100 mL), and brine (100
mL). The organic phase was dried over anhydrous Na2SO4, filtered,
and concentrated. The crude product was purified by flash chro-
matography [hexanes/EtOAc, 4:1 f 3:1] to give compound 21 as
a pale yellow oil (4.71 g, 70%).
Alternative Method for the Synthesis of 1,4-Anhydro-2,3-di-
O-benzyl-4-thio-D-arabinitol (21). Compound 18 (6.01 g, 14.3
mmol) in 1.5% H2SO4/Ac2O (30.0 mL) was stirred at room
temperature for 16 h and then partitioned between EtOAc (200 mL)
and H2O (100 mL). The organic layer was washed with H2O (100
mL) and saturated aqueous NaHCO3 (3 × 100 mL), followed by
brine (100 mL). The organic layer was dried over anhydrous Na2-
SO4 and concentrated. The crude product was diluted with MeOH
(150 mL), and 1 M NaOMe/MeOH solution was added until the
solution was basic. The mixture was stirred at room temperature
for 1 h and then neutralized with AcOH. The mixture was
concentrated and then partitioned between EtOAc (200 mL) and
H2O (100 mL). The organic phase was washed with H2O (100 mL)
and brine (100 mL). The organic layer was dried over anhydrous
Na2SO4, filtered, and concentrated. The crude product was purified
by flash chromatography [hexanes/EtOAc, 4:1 f 3:1] to give
compound 21 as a colorless oil (2.97 g, 63%): [R]D -9.67 (c, 1.14,
Data for the (2S,3S,4R,7R)-2,3-dibenzyloxy-7-methyl-cis-1-
thioniabicyclo[3.3.0]octane triflate (23): 1H NMR (CD3OD) δ
7.38-7.12 (m, 10H, Ar), 4.87 (dd, 1H, J4,5a ) 2.6 Hz, J4,5b ) 7.7
Hz, H-4), 4.60 and 4.48 (2d, each 1H, Ja,b ) 11.9 Hz, CH2Ph),
4.53 and 4.41 (2d, each 1H, Ja,b ) 12.2 Hz, CH2Ph), 4.32 (d, 1H,
J1b,2 ) 5.0 Hz, H-2), 4.19 (s, 1H, H-3), 4.15 (m, 1H, H-7), 3.60
(dd, 1H, J1a,1b ) 15.3 Hz, H-1b), 3.34 (d, 1H, H-1a), 2.46 (m, 1H,
H-6a), 2.38 (m, 1H, H-5a), 2.21 (m, 1H, H-5b), 2.05 (m, 1H, H-6b),
1.48 (d, 3H, H-8); 13C NMR (CD3OD) δ 136.4-136.1 (2Cipso),
129.1-128.3 (10CAr), 121.0 (q, 1C, JC,F ) 318.6 Hz, OTf), 87.2
(C-3), 83.5 (C-2), 72.2, 72.1 (2 CH2Ph), 70.5 (C-4), 61.8 (C-7),
40.3 (C-1), 38.9 (C-6), 31.7 (C-5), 15.1 (C-8).
Data for the (2S,3S,4R,7S)-2,3-dibenzyloxy-7-methyl-cis-1-
thioniabicyclo[3.3.0]octane triflate (24): 1H NMR (CD3OD) δ
7.38-7.12 (m, 10H, Ar), 4.83 (dd, 1H, J4,5a ) J4,5b ) 8.8 Hz, H-4),
4.56 and 4.51 (2d, each 1H, Ja,b ) 11.7 Hz, CH2Ph), 4.46 (d, 1H,
J1b,2 ) 4.5 Hz, H-2), 4.55 and 4.42 (2d, each 1H, Ja,b ) 11.9 Hz,
1
CH2Cl2); H NMR (CDCl3) δ 7.39-7.24 (m, 10H, Ar), 4.69 and
4.63 (2d, each 1H, Ja,b ) 11.8 Hz, CH2Ph), 4.58 and 4.53 (2d,
each 1H, Ja,b ) 11.8 Hz, CH2Ph), 4.19 (ddd, 1H, J1a,2 ) J1b,2 ) J2,3
) 5.3 Hz, H-2), 4.04 (dd, 1H, J3,4 ) 4.8 Hz, H-3), 3.69 (dd, 1H,
J4,5a ) 5.3 Hz, J5a,5b ) 11.4 Hz, H-5a), 3.66 (dd, 1H, J4,5b ) 5.2
Hz, H-5b), 3.48(ddd, 1H, H-4), 3.04 (dd, 1H, J1a,1b ) 11.2 Hz,
H-1a), 2.86 (dd, 1H, H-1b); 13C NMR (CDCl3) δ 138.2, 137.9
(2Cipso), 128.8-128.0 (10CAr), 85.3 (C-3), 85.0 (C-2), 72.7, 72.1
(2 CH2Ph), 63.7 (C-5), 51.5 (C-4), 32.6 (C-1); MALDI-TOF MS
m/e 331.20 (M+ + H), 353.19 (M+ + Na), 369.17 (M+ + K). Anal.
Calcd for C19H22O3S: C, 69.06; H, 6.71. Found: C, 69.36; H, 6.65.
(2S,3S,4R)-2,3-Dibenzyloxy-4-(but-3-enyl)thiolane (22). Tri-
ethylamine (0.19 mL, 1.26 mmol), tosyl chloride (260 mg, 1.33
mmol), and 4-(dimethylamino)pyridine (20.0 mg, 0.13 mmol) were
added to a stirred solution of 21 (370 mg, 1.12 mmol) in CH2Cl2
(10 mL) at 0 °C under N2 atmosphere. The mixture was stirred at
0 °C for 2 h and then concentrated. The crude tosylated product
was purified by flash chromatography [hexanes/EtOAc, 6:1], and
CH2Ph), 4.30 (m, 1H, H-7), 4.25 (s, 1H, H-3), 3.66 (d, 1H, J1a,1b
)
15.0 Hz, H-1a), 3.60 (dd, 1H, H-1b), 2.50-2.39 (m, 2H, H-5a,
H-5b), 2.27-2.15 (m, 2H, H-6a, H-6b), 1.60 (d, 3H, H-8); 13C NMR
(CD3OD) δ 136.4-136.1 (2Cipso), 129.1-128.3 (10CAr), 121.0 (q,
1C, JC,F ) 318.6 Hz, OTf), 86.2 (C-3), 84.9 (C-2), 72.7, 72.2 (2
CH2Ph), 70.4 (C-4), 56.5 (C-7), 46.4 (C-1), 36.5 (C-6), 31.2 (C-
5), 17.6 (C-8).
For the mixture of 23 and 24: MALDI-TOF MS m/e 355.04
(M+ - OTf). Anal. Calcd for C23H27F3O5S2: C, 54.75; H, 5.39.
Found: C, 54.38; H, 5.55.
(2S,3S,4R,7R/S)-2,3-Dihydroxy-7-methyl-cis-1-thionia-bicyclo-
[3.3.0]octane Triflate (7/8). BCl3 gas was bubbled vigorously
through a solution of 23/24 (100 mg, 0.20 mmol) in CH2Cl2 (15
mL) at -78 °C under N2 atmosphere for 5 min. The mixture was
2940 J. Org. Chem., Vol. 71, No. 8, 2006

Synthesis and Conformational Analysis of Bicyclic Sulfonium Salts
stirred at -78 °C for 2 h, and a stream of dry air was blown
vigorously over the solution to remove excess BCl3. The reaction
was quenched with MeOH (5 mL), and the solvent was removed.
The residue was coevaporated with MeOH (2 × 5 mL), and the
crude product was washed with CH2Cl2 (2 × 2 mL) to give a yellow
oil (48.0 mg, 75%). Analysis by NMR showed that the product
was a mixture of two isomers (∼1:1) at the stereogenic C-7 center.
The stereochemistry was assigned with the aid of a 1D-NOESY
spectrum which showed a strong correlation between H-1a and H-7
for compound 8, whereas there was a correlation between H-1a
and H-8 for compound 7.
4.58 and 4.48 (2d, each 1H, Ja,b ) 11.9 Hz, CH2Ph), 4.48 and 4.40
(2d, each 1H, Ja,b ) 11.6 Hz, CH2Ph), 4.42 (d, 1H, J1b,2 ) 4.0 Hz,
H-2), 4.33 (s, 1H, H-3), 3.95 (dd, 1H, J1a,1b ) 14.8 Hz, H-1b),
3.78 (d, 1H, H-1a), 3.01 (ddddd, 1H, J5a,6a ) J5b,6a ) 8.0 Hz, J6a,6b
) 16.0 Hz, H-6a), 2.82 (ddddd, 1H, J5a,6b ) 5.6 Hz, J5b,6b ) 7.7
Hz, H-6b), 2.64 (dddd, 1H, J5a,5b ) 13.3 Hz, H-5b), 2.30 (dddd,
1H, H-5a); 13C NMR (CDCl3) δ 142.8 (C-7), 136.1, 135.8 (2Cipso),
128.8-128.0 (10CAr), 124.9 (C-8), 120.1 (q, 1C, JC,F ) 306.5 Hz,
OTf), 87.8 (C-3), 83.7 (C-2), 72.2, 72.0 (2 CH2Ph), 70.2 (C-4),
52.5 (C-1), 35.6 (C-6), 29.8 (C-5); MALDI-TOF MS m/e 353.06
(M+ - OTf). Anal. Calcd for C23H25F3O5S2: C, 54.97; H, 5.01.
Found: C, 54.67; H, 5.29.
(2S,3S,4R)-2,3-Dihydroxy-7-methylene-cis-1-thionia-bicyclo-
[3.3.0]octane Triflate (9). BCl3 gas was bubbled vigorously through
a solution of 26 (55.0 mg, 0.11 mmol) in CH2Cl2 (10 mL) at -78
°C under N2 atmosphere for 5 min. The mixture was stirred at -78
°C for 2 h, and a stream of dry air was blown vigorously over the
solution to remove excess BCl3. The reaction was quenched with
MeOH (5 mL), and the solvent was removed. The residue was
coevaporated with MeOH (2 × 5 mL), and the crude product was
washed with CH2Cl2 (2 × 2 mL) to give compound 9 as an
amorphous solid (25.0 mg, 71%): [R]D +133.9 (c 0.91, MeOH);
1H NMR (CD3OD) 6.11 (ddd, 1H, J6a,8a ) J6b,8a ) J8a,8b ) 1.7 Hz,
H-8a), 6.03 (ddd, 1H, J6a,8b ) J6b,8b ) 1.9 Hz, H-8b), 4.72 (dd, 1H,
J4,5a ) 4.3 Hz, J4,5b ) 9.9 Hz, H-4), 4.59 (d, 1H, J1b,2 ) 4.3 Hz,
H-2), 4.52 (s, 1H, H-3), 4.08 (dd, 1H, J1a,1b ) 14.1 Hz, H-1b),
3.47 (d, 1H, H-1a), 3.38 (ddddd, 1H, J5a,6a ) J5b,6a ) 8.6 Hz, J6a,6b
) 16.0 Hz, H-6a), 2.89 (ddddd, 1H, J5a,6b ) 5.0 Hz, J5b,6b ) 8.6
Hz, H-6b), 2.55 (dddd, 1H, J5a,5b ) 12.9 Hz, H-5a), 2.42 (dddd,
1H, H-5b); 13C NMR (CD3OD) δ 144.6 (C-7), 123.4 (C-8), 120.6
(q, 1C, JC,F ) 315.9 Hz, OTf), 83.4 (C-3), 79.2 (C-2), 73.8 (C-4),
55.0 (C-1), 35.2 (C-6), 29.7 (C-5); MALDI-TOF MS m/e 173.24
(M+ - OTf). Anal. Calcd for C9H13F3O5S2: C, 33.54; H, 4.07.
Found: C, 33.23; H, 4.21.
(2S,3S,4R)-2,3-Dibenzyloxy-4-formaldehydethiolane-(27). A
solution of trifluoroacetic anhydride (0.7 mL, 9.3 mmol) in CH2-
Cl2 (5 mL) was added to a stirred solution of DMSO (1.2 mL,
17.2 mmol) in CH2Cl2 (12 mL) at -78 °C under N2 atmosphere
dropwise, and the mixture was stirred at -78 °C for 30 min. A
solution of 21 (0.70 g, 2.12 mmol) in CH2Cl2 (12 mL) was added
dropwise while maintaining the temperature below -78 °C, and
stirring was continued for 1.5 h. A solution of diisopropylethylamine
(2.0 mL, 11.0 mmol) in CH2Cl2 (12 mL) was added dropwise, and
the stirring was continued at -78 °C for an additional 2 h. The
reaction was quenched with aqueous HCl (0.5 M, 5 mL), and the
mixture was partitioned between Et2O (150 mL) and H2O (50 mL).
The Et2O layer was washed with H2O (50 mL) and brine (50 mL).
The organic phase was dried over anhydrous Na2SO4, filtered, and
concentrated. The crude product was purified by flash chromatog-
raphy [hexanes/EtOAc, 6:1] to give compound 27 as a pale yellow
oil (0.56 g, 81%): [R]D -3.5 (c 1.15, CH2Cl2); 1H NMR (CDCl3)
δ 9.44 (d, 1H, J4,5 ) 2.8 Hz, H-5), 7.36-7.25 (m, 10H, Ar), 4.66
and 4.57 (2d, each 1H, Ja,b ) 11.9 Hz, CH2Ph), 4.49 (s, 2H, CH2-
Ph), 4.44 (dd, 1H, J2,3 ) J3,4 ) 2.5 Hz, H-3), 4.23 (ddd, 1H, J1a,2
Data for (2S,3S,4R,7R)-2,3-Dihydroxy-7-methyl-cis-1-thionia-
bicyclo[3.3.0]octane triflate (7): 1H NMR (CD3OD) δ 4.41 (ddd,
1H, J1a,2 ) J1b,2 ) J2,3 ) 4.8 Hz, H-2), 4.29 (ddd, 1H, J3,4 ) J4,5a
) 3.8 Hz, J4,5b ) 5.9 Hz, H-4), 4.16 (dd, 1H, H-3), 4.01 (ddq, 1H,
J6a,7 ) J6b,7 ) 6.0 Hz J7,8 ) 6.9 Hz, H-7), 3.51 (dd, 1H, J1a,1b
)
14.0 Hz, H-1a), 3.18 (dd, 1H, H-1b), 2.46-1.88 (m, 4H, H-5a,
H-5b, H-6a, H-6b), 1.41 (d, 3H, H-8); 13C NMR (CD3OD) δ 119.8
(q, 1C, JC,F ) 315.4 Hz, OTf), 81.6 (C-3), 81.0 (C-2), 68.9 (C-4),
56.6 (C-7), 38.2 (C-1), 35.2 (C-6), 31.1 (C-5), 13.3 (C-8).
Data for (2S,3S,4R,7S)-2,3-Dihydroxy-7-methyl-cis-1-thionia-
bicyclo[3.3.0]octane triflate (8): 1H NMR (CD3OD) δ 4.59 (ddd,
1H, J1a,2 ) J2,3 ) 2.0 Hz, J1b,2 ) 4.0 Hz, H-2), 4.51 (dd, 1H, J4,5a
) J4,5b ) 8.0 Hz, H-4), 4.42 (d, 1H, H-3), 4.15 (ddq, 1H, J6a,7
)
J6b,7 ) J7,8 ) 6.9 Hz, H-7), 3.68 (dd, 1H, J1a,1b ) 14.5 Hz, H-1a),
3.48 (dd, 1H, H-1b), 2.46-1.88 (m, 4H, H-5a, H-5b, H-6a, H-6b),
1.44 (d, 3H, H-8); 13C NMR (CD3OD) δ 119.8 (q, 1C, JC,F ) 315.4
Hz, OTf), 79.7 (C-2), 76.4 (C-3), 71.8 (C-4), 61.5 (C-7), 46.4 (C-
1), 38.0 (C-5), 32.0 (C-6), 16.7 (C-8).
For the mixture of 7 and 8: MALDI-TOF MS m/e 175.24 (M+
- OTf). Anal. Calcd for C9H15F3O5S2: C, 33.33; H, 4.66. Found:
C, 33.01; H, 4.58.
(2S,3S,4R,7R)-2,3-Dibenzyloxy-7-bromomethyl-cis-1-thio-
niabicyclo[3.3.0]octane Triflate (25). Br2 (61.0 µL, 1.20 mmol)
was added dropwise to a stirred solution of 22 (420 mg, 1.19 mmol)
in CH2Cl2 (10 mL) at 0 °C under N2. The mixture was stirred at 0
°C for 2 h, and then silver triflate (310 mg, 1.20 mmol) was added.
Stirring was continued at 0 °C for an additional 2 h, and the mixture
was concentrated. The crude product was purified by flash
chromatography [CH2Cl2/MeOH, 1:0 a` 20:1] to give a colorless
oil (520 mg, 75%) as a 4:1 mixture of diastereomers. The major
component of the mixture was assigned to be the diastereomer with
the R configuration at C-7 on the basis of analysis of a 1D-NOESY
spectrum which showed a correlation between H-1a and H-8.
Data for the major isomer (25): 1H NMR (CD2Cl2) δ 7.42-
7.24 (m, 10H, Ar), 5.02 (dd, 1H, J4,5a ) J4,5b ) 8.7 Hz, H-4), 4.70
and 4.63 (2d, each 1H, Ja,b ) 11.9 Hz, CH2Ph), 4.64 (d, 1H, J1b,2
) 4.3 Hz, H-2), 4.62 and 4.56 (2d, each 1H, Ja,b ) 11.7 Hz, CH2-
Ph), 4.59 (m, 1H, H-7), 4.42 (s, 1H, H-3), 4.08 (d, 1H, J1a,1b
)
15.2 Hz, H-1a), 4.04 (dd, 1H, J8a,8b ) 11.5 Hz, J7,8a ) 4.9 Hz,
H-8a), 3.97 (dd, 1H, J7,8b ) 7.8 Hz, H-8b), 3.83 (dd, 1H, H-1b),
2.72 (m, 1H, H-5a), 2.61 (m, 1H, H-5b), 2.55 (m, 1H, H-6a), 2.43
(m, 1H, H-6b); 13C NMR (CD2Cl2) δ 126.8, 126.6 (2Cipso), 119.1-
118.3 (10CAr), 111.1 (q, 1C, JC,F ) 306.1 Hz, OTf), 75.9 (C-3),
75.4 (C-2), 63.0, 62.3 (2 CH2Ph), 61.3 (C-4), 58.4 (C-7), 37.7 (C-
1), 26.3 (C-6), 21.8 (C-5), 20.5 (C-8).
) J1b,2 ) 3.2 Hz, H-2), 3.80 (dd, 1H, H-4), 3.16 (dd, 1H, J1a,1b
)
11.4 Hz, H-1a), 3.00 (dd, 1H, H-1b); 13C NMR (CDCl3) δ 198.4
(C-5), 137.4, 137.4 (2Cipso), 128.8-128.0 (10CAr), 85.6 (C-3), 83.4
(C-2), 72.3, 71.5 (2 CH2Ph), 58.5 (C-4), 34.7 (C-1); MALDI-TOF
MS m/e 329.15 (M+ + H), 351.13 (M+ + Na), 367.09 (M+ + K).
Anal. Calcd for C19H20O3S: C, 69.48; H, 6.14. Found: C, 69.61;
H, 6.26.
For the mixture of diastereomers: MALDI-TOF MS m/e 435.13,
433.13 (M+ - OTf), 353.22 (M+ - (OTf, HBr)). Anal. Calcd for
C23H26Br1F3O5S2: C, 47.34; H, 4.49. Found: C, 47.66; H, 4.36.
(2S,3S,4R)-2,3-Dibenzyloxy-7-methylene-cis-1-thionia-bicyclo-
[3.3.0]octane Triflate (26). Silver oxide (126 mg, 0.61 mmol) was
added to a stirred solution of 25 (320 mg, 0.55 mmol) in H2O/
THF (1:1, 10 mL). The mixture was stirred at ambient temperature
for 20 h and concentrated. The crude product was purified by flash
chromatography [CH2Cl2/MeOH, 1:0 f 20:1] to give compound
26 as a colorless oil (254 mg, 92%): [R]D +50.2 (c 1.08, CH2Cl2);
1H NMR (CDCl3) δ 7.31-7.09 (m, 10H, Ar), 6.24 (ddd, 1H, J6a,8a
(2S,3S,4R,1′S/R)-2,3-Dibenzyloxy-4-(1′-hydroxybut-3′-enyl)-
thiolane (28/29). Allylmagnesium bromide (1 M in Et2O, 1.4 mL,
1.4 mmol) was added to a stirred solution of 27 (230 mg, 0.70
mmol) in anhydrous Et2O (5 mL) under N2 atmosphere at 0 °C
dropwise, and the mixture was stirred at ambient temperature for
16 h. The reaction was quenched with ice (5 mL), and the mixture
was diluted with Et2O (100 mL). The reaction mixture was washed
with H2O (2 × 50 mL) and brine (50 mL). The organic layer was
) J6b,8a ) J8a,8b ) 1.9 Hz, H-8a), 5.83 (ddd, 1H, J6a,8b ) J6b,8b
)
1.9 Hz, H-8b), 4.99 (dd, 1H, J4,5a ) 4.6 Hz, J4,5b ) 10.1 Hz, H-4),
J. Org. Chem, Vol. 71, No. 8, 2006 2941

Kumar and Pinto
dried over anhydrous Na2SO4, filtered, and concentrated. Analysis
by NMR showed that the crude product was present as 1:2 mixture
of diastereomers 28 and 29, respectively. The crude product was
purified by flash chromatography [CH2Cl2/MeOH, 1:0 f 49:1] to
give 28 (133 mg, 51%) and 29 (78 mg, 30%).
was continued at 0 °C for an additional 2 h, and the mixture was
filtered. The filtrate was concentrated, and the residue was dissolved
in H2O/THF (1:1, 5 mL). Silver oxide (43 mg, 0.22 mmol) was
added, and the mixture was stirred at ambient temperature for 16
h and concentrated. The crude product was purified by flash
chromatography [CH2Cl2/MeOH, 1:0 f 10:1] to give compound
31 as a pale yellow oil (68 mg, 72%). The stereochemistry at C-5
was assigned with the aid of a 1D-NOESY spectrum which showed
a strong correlation between H-3 and H-5: [R]D +101.3 (c 0.8,
CH2Cl2); 1H NMR (CD2Cl2): δ 7.31-7.14 (m, 10H, Ar), 6.15 (dd,
1H, J6a,8a ) J8a,8b ) 2.7 Hz, H-8a), 5.96 (dd, 1H, J6a,8b ) 2.7 Hz,
H-8b), 5.03 (d, 1H, J5,OH ) 3.6 Hz, OH), 4.80 (bs, 2H, H-4, H-5),
4.63 and 4.49 (2d, each 1H, Ja,b ) 11.6 Hz, CH2Ph), 4.56 (s, 1H,
H-3), 4.41 (s, 2H, CH2Ph), 4.38 (d, 1H, J1b,2 ) 4.7 Hz, H-2), 3.84
(dd, 1H, J1a,1b ) 14.7 Hz, H-1b), 3.59 (d, 1H, H-1a), 3.33 (dddd,
1H, J6a,6b ) 16.0 Hz, H-6a), 2.79 (bd, 1H, H-6b); 13C NMR (CD2-
Cl2) δ 141.5 (C-7), 136.5, 135.9 (2Cipso), 129.0-128.4 (10CAr),
127.5 (C-8), 120.9 (q, 1C, JC,F ) 318.4 Hz, OTf), 86.2 (C-3), 83.9
(C-2), 80.4 (C-4), 75.2 (C-5), 72.7, 72.6 (2 CH2Ph), 52.5 (C-1),
43.1 (C-6); MALDI-TOF MS m/e 369.36 (M+ - OTf). Anal. Calcd
for C23H25F3O6S2: C, 53.27; H, 4.86. Found: C, 53.31; H, 4.72.
(2S,3S,4R,5R)-2,3,5-Trihydroxy-7-methylene-cis-1-thionia-
bicyclo[3.3.0]octane Triflate (10). BCl3 gas was bubbled vigor-
ously through a solution of 30 (102 mg, 0.20 mmol) in CH2Cl2 (10
mL) at -78 °C under N2 atmosphere for 4 min. The mixture was
stirred at -78 °C for 1.5 h, and a stream of dry air was blown
vigorously over the solution to remove excess BCl3. The reaction
was quenched with MeOH (5 mL), and the solvent was removed.
The residue was coevaporated with MeOH (2 × 5 mL), and the
crude product was washed with CH2Cl2 (2 × 2 mL) to give
compound 10 as a colorless oil (55 mg, 83%): [R]D +169.1 (c
Data for the major diastereomer (28): [R]D -12.0 (c 1.0, CH2-
1
Cl2); H NMR (CDCl3) δ 7.38-7.27 (m, 10H, Ar), 5.81 (dddd,
1H, J6b,7 ) 6.9 Hz, J6a,7 ) 7.3 Hz, J7,8a ) 10.2 Hz, J7,8b ) 17.0 Hz,
H-7), 5.11 (dddd, 1H, J6a,8b) J6b,8b ) J8a,8b ) 1.8 Hz, H-8b), 5.09
(dddd, 1H, J6a,8a) J6b,8a ) 1.1 Hz H-8a), 4.78 and 4.63 (2d, each
1H, Ja,b ) 11.6 Hz, CH2Ph), 4.60 and 4.58 (2d, each 1H, Ja,b
)
11.8 Hz, CH2Ph), 4.18 (ddd, 1H, J1a,2 ) J1b,2 ) J2,3 ) 5.6 Hz,
H-2), 4.11 (dd, 1H, J3,4 ) 5.5 Hz, H-3), 3.83 (ddd, 1H, J4,5 ) 2.8
Hz, J5,6b ) 5.9 Hz, J5,6a ) 7.4 Hz, H-5), 3.49 (dd, 1H, H-4), 3.02
(dd, 1H, J1a,1b ) 11.1 Hz, H-1a), 2.83 (dd, 1H, H-1b), 2.24 (ddddd,
1H, J6a,6b ) 14.1 Hz, H-6a), 2.12 (ddddd, 1H, H-6a); 13C NMR
(CDCl3) δ 138.2, 137.7 (2Cipso), 134.5 (C-7), 128.8-128.0 (10CAr),
118.1 (C-8), 86.0 (C-3), 84.5 (C-2), 73.1, 72.2 (2 CH2Ph), 70.2
(C-5), 54.9 (C-4), 41.6 (C-6), 31.9 (C-1); MALDI-TOF MS m/e
371.17 (M+ + H), 393.19 (M+ + Na), 409.16 (M+ + K). Anal.
Calcd for C22H26O3S: C, 71.32; H, 7.07. Found: C, 71.59; H, 7.21.
Data for the minor diastereomer (29): [R]D -25.0 (c 1.0, CH2-
1
Cl2); H NMR (CDCl3): δ 7.39-7.28 (m, 10H, Ar), 5.83 (dddd,
1H, J6b,7 ) 6.8 Hz, J6a,7 ) 7.7 Hz, J7,8a ) 9.6 Hz, J7,8b ) 17.5 Hz,
H-7), 5.13 (dddd, 1H, J6a,8b) J6b,8b ) J8a,8b ) 1.5 Hz, H-8b), 5.11
(dddd, 1H, J6a,8a) J6b,8a ) 1.5 Hz H-8a), 4.71 and 4.65 (2d, each
1H, Ja,b ) 11.7 Hz, CH2Ph), 4.59 and 4.56 (2d, each 1H, Ja,b
)
11.9 Hz, CH2Ph), 4.30 (dd, 1H, J2,3 ) J3,4 ) 4.1 Hz, H-3), 4.22
(ddd, 1H, J1a,2 ) J1b,2 ) 4.7 Hz, H-2), 3.77 (ddd, 1H, J4,5 ) J5,6b
) 7.6 Hz, J5,6a ) 4.0 Hz, H-5), 3.36 (dd, 1H, H-4), 3.08 (dd, 1H,
J1a,1b ) 11.2 Hz, H-1a), 2.90 (dd, 1H, H-1b), 2.45 (m, 1H, H-6a),
2.19 (ddddd, 1H, H-6a); 13C NMR (CDCl3) δ 138.1, 134.6 (2Cipso),
134.5 (C-7), 128.8-128.0 (10CAr), 118.6 (C-8), 85.0 (C-3), 84.9
(C-2), 73.0 (C-5), 72.2, 71.8 (2 CH2Ph), 54.3 (C-4), 40.3 (C-6),
33.4 (C-1); MALDI-TOF MS m/e 371.12 (M+ + H), 393.14 (M+
+ Na). Anal. Calcd for C22H26O3S: C, 71.32; H, 7.07. Found: C,
71.57; H, 6.89.
1
0.9, MeOH); H NMR (CD3OD) δ 6.29 (dd, 1H, J6b,8a ) 1.2 Hz,
J6a,8a ) 2.7 Hz, H-8a), 6.16 (dd, 1H, J6b,8b ) 2.3 Hz, J6a,8b ) 2.7
Hz, H-8b), 4.87 (dd, 1H, J5,6b ) 2.3 Hz, J5,6a ) 5.2 Hz, H-5), 4.60
(dd, 1H, J2,3 ) J3,4 ) 2.0 Hz, H-3), 4.56 (ddd, 1H, J1a,2 ) 2.1 Hz,
J1b,2 ) 4.2 Hz, H-2), 4.13 (bs, 1H, H-4), 4.10 (dd, 1H, J1a,1b
)
14.1 Hz, H-1b), 3.70 (dddd, 1H, J6a,6b ) 16.2 Hz, H-6a), 3.55 (dd,
1H, H-1a), 2.87 (dddd, 1H, H-6b); 13C NMR (CD3OD) δ 142.2
(C-7), 125.9 (C-8), 120.6 (q, 1C, JC,F ) 316.5 Hz, OTf), 81.4 (C-
2), 81.0 (C-4), 78.8 (C-3), 74.2 (C-5), 54.2 (C-1), 42.9 (C-6);
MALDI-TOF MS m/e 189.24 (M+ - OTf). Anal. Calcd for
C9H13F3O6S2: C, 31.95; H, 3.87. Found: C, 31.75; H, 3.91.
(2S,3S,4R,5S)-2,3,5-Trihydroxy-7-methylene-cis-1-thionia-
bicyclo[3.3.0]octane Triflate (11). BCl3 gas was bubbled vigor-
ously through a solution of 31 (80 mg, 0.15 mmol) in CH2Cl2 (10
mL) at -78 °C under N2 atmosphere for 4 min. The mixture was
stirred at -78 °C for 2 h, and a stream of dry air was blown
vigorously over the solution to remove excess BCl3. The reaction
was quenched with MeOH (5 mL), and the solvent was removed.
The residue was coevaporated with MeOH (2 × 5 mL), and the
crude product was washed with CH2Cl2 (2 × 2 mL) to give
(2S,3S,4R,5S)-2,3-Dibenzyloxy-5-hydroxy-7-methylene-cis-1-
thioniabicyclo[3.3.0]octane Triflate (30). Br2 (11.4 µL, 0.21 mmol)
was added to a stirred solution of 28 (78 mg, 0.21 mmol) in CH2-
Cl2 (6 mL) at 0 °C under N2. The mixture was stirred at 0 °C for
1.5 h, and then silver triflate (65 mg, 0.21 mmol) was added. Stirring
was continued at 0 °C for an additional 2 h, and the mixture was
filtered. The filtrate was concentrated and then dissolved in H2O/
THF (1:1, 5 mL). Silver oxide (48 mg, 0.25 mmol) was added,
and the mixture was stirred at ambient temperature for 16 h and
concentrated. The crude product was purified by flash chromatog-
raphy [CH2Cl2/MeOH, 1:0 a` 10:1] to give compound 30 as a pale
yellow oil (81 mg, 77%). The stereochemistry at C-5 was assigned
with the aid of a 1D-NOESY spectrum which showed no correlation
between H-3 and H-5: [R]D +47.0 (c 1.1, CH2Cl2); 1H NMR (CD2-
Cl2): δ 7.38-7.21 (m, 10H, Ar), 6.14 (dd, 1H, J6a,8a ) J8a,8b ) 2.4
Hz, H-8a), 6.03 (dd, 1H, J6a,8b ) 2.4 Hz, H-8b), 5.16 (s, 1H, H-3),
5.11 (d, 1H, J5,OH ) 5.4 Hz, OH), 5.02 (d, 1H, J4,5 ) 8.5 Hz, H-4),
4.98 (m, 1H, H-5), 4.75 and 4.60 (2d, each 1H, Ja,b ) 11.6 Hz,
CH2Ph), 4.68 and 4.43 (2d, each 1H, Ja,b ) 11.3 Hz, CH2Ph), 4.49
(d, 1H, J1b,2 ) 4.5 Hz, H-2), 4.08 (dd, 1H, J1a,1b ) 14.5 Hz, H-1b),
3.70 (d, 1H, H-1a), 3.32 (dddd, 1H, J6a,6b ) 16.1 Hz, H-6a), 3.04
(dd, 1H, H-6b); 13C NMR (CD2Cl2) δ 136.8, 136.7 (2Cipso), 135.9
(C-7), 128.9-128.6 (10CAr), 128.7 (C-8), 120.9 (q, 1C, JC,F ) 318.1
Hz, OTf), 83.9 (C-3), 83.8 (C-2), 72.6, 72.5 (2 CH2Ph), 72.2 (C-
5), 71.0 (C-4), 54.4 (C-1), 40.0 (C-6); MALDI-TOF MS m/e 369.26
(M+ - OTf). Anal. Calcd for C23H25F3O6S2: C, 53.27; H, 4.86.
Found: C, 53.19; H, 4.76.
compound 11 as a colorless oil (42 mg, 81%): [R]D +203.8 (c
1
0.8, MeOH); H NMR (CD3OD) δ 6.18 (dd, 1H, J6b,8a ) J6a,8a
)
2.9 Hz, H-8a), 6.11 (bs, 1H, H-8b), 4.97 (s, 1H, H-3), 4.79 (ddd,
1H, J5,6b ) 7.2 Hz, J4,5 ) 8.0 Hz, J5,6a ) 9.8 Hz, H-5), 4.60 (d,
1H, J1b,2 ) 4.1 Hz, H-2), 4.58 (d, 1H, H-4), 4.14 (dd, 1H, J1a,1b
)
14.1 Hz, H-1b), 3.59 (dd, 1H, H-1a), 3.47 (dddd, 1H, J6a,6b ) 15.6
Hz, H-6a), 3.05 (dd, 1H, H-6b); 13C NMR (CD3OD) δ 138.4 (C-
7), 125.9 (C-8), 120.6 (q, 1C, JC,F ) 316.1 Hz, OTf), 79.4 (C-3),
79.1 (C-4), 73.2 (C-2), 71.4 (C-5), 55.2 (C-1), 40.3 (C-6); MALDI-
TOF MS m/e 189.12 (M+ - OTf). Anal. Calcd for C9H13F3O6S2:
C, 31.95; H, 3.87. Found: C, 31.66; H, 3.83.
(2S,3S,4R,5R,7R/S)-2,3,5-Trihydroxy-7-methyl-cis-1-thionia-
bicyclo[3.3.0]octane Triflate (12/13). Pd/C (10 mg) was added to
a stirred solution of 10 (38 mg, 0.11 mmol) in MeOH (5 mL). The
mixture was stirred under H2 pressure (100 psi) for 5 h, filtered
though Celite, and concentrated. The residue was washed with CH2-
Cl2 (2 × 2 mL) to give a pale yellow oil (27 mg, 71%). Analysis
by NMR showed that the product was a mixture of two isomers
(2S,3S,4R,5R)-2,3-Dibenzyloxy-5-hydroxy-7-methylene-cis-1-
thioniabicyclo[3.3.0]octane Triflate (31). Br2 (10.2 µL, 0.19 mmol)
was added to a stirred solution of 29 (70 mg, 0.19 mmol) in CH2-
Cl2 (6 mL) at 0 °C under N2. The mixture was stirred at 0 °C for
1.5 h, and then silver triflate (58 mg, 0.19 mmol) was added. Stirring
2942 J. Org. Chem., Vol. 71, No. 8, 2006

Synthesis and Conformational Analysis of Bicyclic Sulfonium Salts
(∼3:2) at the stereogenic C-7 center. The stereochemistry was
assigned with the aid of NOESY spectrum which showed a strong
correlation between H-1a and H-8 for compound 12, whereas
compound 13 showed a correlation between H-1a and H-7.
Data for the major diastereomer (12): 1H NMR (CD3OD) δ 4.99
(ddd, 1H, J4,5 ) J5,6a ) 5.2 Hz, J5,6b ) 7.9 Hz, H-5), 4.66 (dd, 1H,
J2,3 ) 2.0 Hz, J1b,2 ) 4.1 Hz, H-2), 4.62 (bs, 1H, H-3), 4.31 (d,
1H, H-4), 4.28 (m, 1H, H-7), 3.80 (dd, 1H, J1a,1b ) 14.4 Hz, H-1b),
3.68 (d, 1H, H-1a), 2.80 (ddd, 1H, J6a,6b ) 13.8 Hz, H-6a), 2.11
(ddd, 1H, H-6b), 1.68 (d, 3H, H-8); 13C NMR (CD3OD) δ 120.6
(q, 1C, JC,F ) 253.0 Hz, OTf), 81.0 (C-3), 80.4 (C-2), 79.9 (C-4),
75.4 (C-5), 57.6 (C-7), 48.6 (C-1), 44.4 (C-6), 17.6 (C-8).
Data for the minor diastereomer (13): 1H NMR (CD3OD) δ 4.77
Data for the major diastereomer (14): 1H NMR (CD3OD) δ 4.78
(dd, 1H, J2,3 ) J3,4 ) 2.2 Hz, H-3), 4.70 (ddd, 1H, J4,5 ) 6.3 Hz,
J5,6b ) 8.3 Hz, J5,6a ) 11.2 Hz, H-5), 4.54 (ddd, 1H, J1a,2 ) 2.2
Hz, J1b,2 ) 4.6 Hz, H-2), 4.35 (dd, 1H, H-4), 4.08 (ddt, 1H, J6b,7
)
J7,8 ) 6.7 Hz, J7,8 ) 12.9 Hz, H-3), 3.76 (dd, 1H, J1a,1b ) 14.6 Hz,
H-1b), 3.51 (dd, 1H, H-1a), 2.61 (ddd, 1H, J6a,6b ) 12.4 Hz, H-6a),
2.43 (dd, 1H, H-6b), 1.56 (d, 3H, H-8); 13C NMR (CD3OD) δ 120.6
(q, 1C, JC,F ) 316.3 Hz, OTf), 79.0 (C-3), 77.9 (C-2), 73.2 (C-5),
71.2 (C-4), 48.8 (C-7), 41.5 (C-1), 40.0 (C-6), 13.2 (C-8); MALDI-
TOF MS m/e 191.14 (M+ - OTf). Anal. Calcd for C9H15F3O6S2:
C, 31.76; H, 4.44. Found: C, 31.43; H, 4.68.
Conclusions
(dd, 1H, J4,5 ) 1.5 Hz, J5,6b ) 3.7 Hz, H-5), 4.51 (ddd, 1H, J1a,2
J2,3 ) 2.4 Hz, J1b,2 ) 4.8 Hz, H-2), 4.46 (m, 1H, H-7), 4.40 (dd,
1H, J3,4 ) 4.8 Hz, H-3), 4.28 (dd, 1H, H-4), 3.71 (dd, 1H, J1a,1b
)
The syntheses of the bicyclic sulfonium analogues (7-14)
related to australine have been achieved starting from a common
precursor 21. The conformational preferences of these com-
pounds based on vicinal proton coupling constants and NOE
data have been proposed. We note that there is significant
conformational change when changing an exo-methylene group
to a methyl group. We also note that the hydroxyl groups at
C-2 and C-3 prefer to occupy pseudoaxial positions. Both
electrostatic effects and steric effects govern the conformational
preferences of these compounds. The activities of these com-
pounds as glycosidase inhibitors will be the subject of future
investigations.
)
14.5 Hz, H-1b), 3.44 (d, 1H, H-1a), 2.73 (ddd, 1H, J6a,6b ) 14.2
Hz, H-6a), 2.34 (dd, 1H, H-6b), 1.61 (d, 3H, H-8); 13C NMR (CD3-
OD) δ 120.6 (q, 1C, JC,F ) 316.3 Hz, OTf), 80.6 (C-3), 80.6 (C-
4), 79.8 (C-2), 76.1 (C-5), 53.4 (C-7), 43.1 (C-6), 40.6 (C-1), 13.0
(C-8).
For the mixture of 12 and 13: MALDI-TOF MS m/e 191.26
(M+ - OTf). Anal. Calcd for C9H15F3O6S2: C, 31.76; H, 4.44.
Found: C, 31.69; H, 4.62.
(2S,3S,4R,5S,7R)-2,3,5-Trihydroxy-7-methyl-cis-1-thionia-
bicyclo[3.3.0]octane Triflate (14). Pd/C (12 mg) was added to a
stirred solution of 11 (45 mg, 0.13 mmol) in MeOH (6 mL). The
mixture was stirred under H2 pressure (100 psi) for 4 h, filtered
though Celite, and concentrated. The residue was washed with CH2-
Cl2 (2 × 2 mL) to give a pale yellow oil (35 mg, 77%). Analysis
by NMR showed that the product was a mixture of two isomers
(∼4:1) at the stereogenic C-7 center. The major component of the
mixture was assigned to be the diastereomer with the R configu-
ration at C-7 on the basis of a 1D-NOESY spectrum, which showed
a correlation between H-1a and H-8.
Acknowledgment. We thank Dr. B. D. Johnston for helpful
discussions. We also thank the Natural Sciences and Engineering
Research Council of Canada for financial support and the
Michael Smith Foundation for Health Research for a trainee
fellowship (to N.S.K.). The cover shows a photo from the
National Tropical Botanical Garden by Peter S. Goltra.
JO051560P
J. Org. Chem, Vol. 71, No. 8, 2006 2943