New synthetic approach to enantiopure bicyclic sulfonium salts: Swainsonine analogues

Article abstract of DOI:10.1021/jo020511z

The enantioselective synthesis of bicyclic sulfonium salts 8 or 9, thioanalogues of swainsonine derivatives, is described. The synthetic strategy is based on a stereo- and regiospecific transannular cyclization reaction of nine-membered cyclic sulfides, mediated by Me₃SiI or carried out under acidic catalysis.

Full text of DOI:10.1021/jo020511z

New Syn th etic Ap p r oa ch to En a n tiop u r e
Bicyclic Su lfon iu m Sa lts: Sw a in son in e
An a logu es
Vanda Cere`,* Salvatore Pollicino, and Alfredo Ricci
Department of Organic Chemistry, “A. Mangini”-University
of Bologna, Viale Risorgimento 4, I-40136 Bologna, Italy
F IGURE 1.
cere@ms.fci.unibo.it
Received August 2, 2002
Abstr a ct: The enantioselective synthesis of bicyclic sulfo-
nium salts 8 or 9, thioanalogues of swainsonine derivatives,
is described. The synthetic strategy is based on a stereo- and
regiospecific transannular cyclization reaction of nine-
membered cyclic sulfides, mediated by Me3SiI or carried out
under acidic catalysis.
F IGURE 2.
moiety, such as a sulfonium ion in a bicyclic polyhydroxy-
lated system, is likely to increase its potency as a
glycosidase inhibitor since the charge separation would
mimic the putative oxonium ion transition state that is
generated during the carbohydrate hydrolysis by glycosi-
dases. Moreover these sulfur-based compounds exhibit
high water solubility and good stability, features of major
importance for their evaluation as glycosidase inhibitors.
Several years ago a bicyclic [3.3.0] sulfonium salt was
synthesized and tested as a glycosidase inhibitor by
Grierson (Figure 2, A).6
More recently Pinto et al.7 (Figure 2, B) described an
interesting bicyclic [4.3.0] sulfonium salt derivative that
can act as a mimic of castanospermine. All these authors
outlined, however, the scarcity of polyhydroxylated cyclic
sulfonium salts previously reported in the literature.8
Moreover, in the last years numerous synthetic and
biological studies related to Salacinol and Kotalanol,9
natural inner-sulfonium salts of therapeutic relevance
extracted from the Salacia Reticulata, have been reported
and successfully adopted in traditional Ayurvedic medi-
cine for the treatment of diabetes.
Glycosidase enzymes play an important role in the
biochemical processes,1 and their abnormal activity leads
to serious diseases. The compounds 1-deoxy-nojirimycin
(A), castanospermine (B), and swainsonine (C), depicted
in Figure 1, are among the most important therapeutic
agents used as glycosidase inhibitors.2
As piperidine analogues of glucopyranose, these com-
pounds inhibit several glucosidases and display antidia-
betic and antiviral activities, including activity against
HIV viruses.3 In addition their ability to reduce tumor
cell metastasis is well documented.4 Glycosidases and
their inhibitors have attracted the interest of many
groups of researchers. In particular the development of
new synthetic methods and the studies directed to
understand the role played by molecular shape and
charge on biological activity remain important problems
to be investigated.5
Many strategic routes for the synthesis of swainsonine
derivatives are reported in the literature but only a few
examples of analogous compounds in which the bridge-
head nitrogen atom is replaced by a sulfur atom have
been described so far. The increasing interest toward
these sulfonium salts stems from their ability to create
electrostatic interactions: the effect of a positively charged
All these findings prompted us to direct our efforts on
a new synthetic strategy aimed to synthesize a range of
bicyclic sulfonium salts, thioanalogues of the swainsonine
derivatives, which might constitute new therapeutic
targets.
Previous work from this laboratory has described the
transannular cyclization of medium-sized sulfurated
compounds under acidic conditions by interaction be-
(1) Dwek, R. A. Chem. Rev. 1996, 96, 683.
(2) Elbein, A. D. Crit. Rew. Biochem. 1984, 16, 21. Fellows, L. E.
Pestic. Sci. 1986, 17, 602. Fellows, L. E.; Fleet, G. W. J . Natural
Products Isolation; Wagman, G. H., Cooper, R., Eds.; Elsevier: Am-
sterdam, The Netherlands, 1988; pp 539-559. Elbein, A. D.; Molyneux,
R. J . Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W.,
Ed.; Wiley: New York, 1987; Vol. 5, pp 1-54. Fleet, G. W. J .; Fellows,
L. E.; Winchester, B. Bioactive Compounds from Plants; Ciba Founda-
tion Symposium 154; Wiley: Chichester, UK, 1990; pp 112-125. Stutz,
A. E. Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond;
Wiley-VCH: New York, 1999.
(3) Karpas, A.; Fleet, G. W. J .; Dwek, R. A.; Fellows, L. E.; Tyms,
A. S.; Petursson, S.; Namgoong, S. K.; Ramsden, N. G.; J acob, G. S.;
Rademacher, T. W. Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 9229.
Montefiori, D. C.; Robinson, W. E.; Mitchell, W. M. Proc. Natl. Acad.
Sci. U.S.A. 1988, 85, 9248.
(4) Mohla, S.; White, S.; Grzegorzewski, K.; Nielsen, D.; Dunston,
G.; Dickson, L.; Cha, J . K.; Asseffa, A.; Olden, K. Anticancer Res. 1990,
10, 1515. Goss, P. E.; Baptiste, J .; Fernandes, B.; Baker, M.; Dennis,
J . W. Cancer Res. 1994, 54, 1450.
(5) Heightman, T. D.; Vasella A. T. Angew. Chem., Int. Ed. 1999,
38, 750.
(6) Siriwardena, A. H.; Chiaroni, A.; Riche, C.; El-Daher, S.;
Winchester, B.; Grierson, D. S. J . Chem. Soc., Chem. Commun. 1992,
1531.
(7) Svansson, L.; J ohnston B. D.; Gu, J . H.; Patrick, B.; Pinto B. M.
J . Am. Chem. Soc. 2000, 122, 10769.
(8) Urban, F. J .; Breitenbach, R.; Vincent, L. A. J . Org. Chem. 1990,
55, 3670. Matsuyama, H.; Nakamura, T.; Kamigata, N. J . Org. Chem.
1989, 54, 5218. Tani, K.; Otsuka, S.; Kido, M.; Miura, I. J . Am. Chem.
Soc. 1980, 102, 7394.
(9) Yoshikawa, M.; Murakami, T.; Shimada, H.; Matsuda, H.;
Yamahara, J .; Tanabe, G.; Muraoka, O. Tetrahedron Lett. 1997, 38,
8367. Yoshikawa, M.; Murakami, T.; Yashiro, K.; Matsuda, H. Chem.
Pharm. Bull. 1998, 46, 1339. Ghavami, A.; J ohnston, B. D.; Pinto, B.
M. J . Org. Chem. 2001, 66, 2312. Yuasa, H.; Takada, J .; Hashimoto,
H. Bioorg., Med. Chem. Lett. 2001, 11, 1137. Masayuki, M.; Morikawa,
T.; Matsuda, H.; Tanabe, G.; Muraoka, O. Bioorg., Med. Chem. 2002,
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10.1021/jo020511z CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/27/2003
J . Org. Chem. 2003, 68, 3311-3314
3311

the isopropylidene diene derivatives 2a ,b12 (Scheme 1;
compounds deriving from the L-configuration are noted
as a , and those deriving from the D-configuration are
noted as b) which were di-O-methylated under standard
conditions with NaH and CH3I, to give, in 98% yield,
3a ,b. Hydroxylation of the two double bonds by means
of BH3‚Me2S followed by treatment with alkaline hydro-
gen peroxide led to 4a ,b in 65% yield. The ditosyl
derivatives 5a ,b obtained from 4a ,b, using p-TsCl in
pyridine (95%), gave the thiacyclononane derivatives 6a ,b
(65%) by intramolecular cyclization with Na2S‚9H2O. The
thiacyclononane derivatives 7a ,b, obtained in 98% yield,
using 0.1 N H2SO4 for 30 min at 50 °C, were submitted
to Me3SiI-mediated11 transannular nucleophilic substitu-
tion leading in 90% yield to the bicyclic systems 8a ,b.
To avoid in iodide 8a ,b possible equilibration with a form
deriving from the five-membered ring-opening and dark-
ening after long-term storage, bicyclic systems bearing
nonnucleophilic counterions in the sulfonium salts were
taken into consideration as well. Accordingly compounds
9a ,b were obtained in good yields (90%) by treatment of
6a ,b with CF3COOH in CH3CN for 2 h at 90 °C (CF3-
SO3H and H2SO4 also can be used).
F IGURE 3. Retrosynthetic plan.
SCHEME 1a
Compounds 8 and 9, obtained in both enantiomeric
pure forms, can be considered di-O-methylated thia
mimics of swainsonine.
In conclusion we have developed a conceptually new
approach that should, at least in part, overcome the
difficulties often encountered in the synthesis of func-
tionalized thioswainsonine. A good asset of this method
that nicely complements the previously reported strate-
gies6,7 lies in the fact that by using the nine-membered
thiacyclo derivatives 6a ,b, the presence of a C2 axis and
the complete regio- and stereoselectivity of the transan-
nular substitution leads to a single configurationally
homogeneous product irrespective of the fact that the
sulfur atom would attack C5 or C6. Moreover, the reduced
number of steps and the easy availability of the starting
materials make this route highly practical and suitable
to be applied in a more general way to the synthesis of
new thionia derivatives as compounds with potential
interesting biological activities. An extensive study ongo-
ing in our laboratory is aimed at the synthesis of new
eight- and nine-membered polyhydroxylated sulfurated
cycles.
a
Reagents and conditions: (i) Dibal-H, Zn(CHdCH2)2, ref 12
(83%); (ii) NaH, MeI (98%); (iii) BH3‚Me2S, H2O2, NaOH (65%);
(iv) pTsCl, Py (95%); (v) Na2S‚9H2O (65%); (vi) 0.1 N H2SO4, 30
min, 50 °C (98%); (vii) Me3SiI (90%); (viii) CF3COOH in CH3CN,
2 h, 90°C (90%).
tween the S atom and a double bond.10 Further on we
have reported that a transannular nucleophilic substitu-
tion by a sulfur atom on a carbon bearing an hydroxy
group also can be achieved, under very mild conditions,
by means of the Me3SiI.11 With these results in hand,
we envisioned a simple new retrosynthetic plan to
synthesize a thio-swainsonine analogue by using as a key
step in the synthesis a stereo- and regiospecific transan-
nular cyclization of a suitable thiacyclononane derivative
(Figure 3).
To address this problem a suitable and straightforward
approach to a configurationally homogeneous cyclic sul-
fide 6 was needed (Scheme 1). Thus, starting from diethyl
L- and D-tartrate, enantiopure inexpensive and easily
available compounds from the natural pool, we obtained
Exp er im en ta l Section
All moisture-sensitive reactions were performed in flame-dried
glassware equipped with rubber septa under positive pressure
of dry nitrogen. Organic extracts were dried over CaSO4. Melting
points are uncorrected. Preparative flash chromatographic
experiments were performed with ICN Silica gel 230-400 mesh.
For TLC precoated glass plates were used (Stratochrom SIF254
,
0.25 mm thick) and the spots were developed at 110 °C with an
aqueous solution of (NH4)6Mo7O24 (2.5%) and (NH4)4Ce(SO4)4
(1%) in 10% H2SO4 or 0.1 M KMnO4/1 M H2SO4 1/1. Yields are
1
for isolated compounds. Unless specified otherwise, H and 13C
NMR spectra were recorded at 300 and 75 MHz, respectively,
in CDCl3 as solvent. Chemical shifts are in ppm downfield of
TMS and signal multiplicities were established by DEPT experi-
ments. Signal assignments, if necessary, were elucidated by
decoupling 1H NMR. Optical rotations were measured at 589
nm. Infrared spectra were recorded on a FT IR spectrophotom-
eter. Mass spectra were recorded by using electron impact at
(10) Calderoni, C.; Cere`, V.; Pollicino, S.; Sandri, E.; Fava, A. J . Org.
Chem. 1980, 45, 2641. Cere`, V.; Paolucci, C.; Pollicino, S.; Sandri, E.;
Fava, A. J . Org. Chem. 1982, 47, 2861.
(11) Cere`, V.; Pollicino, S.; Fava, A. Tetrahedron 1996, 52, 5989.
Cere`, V.; Peri, F.; Pollicino, S. J . Org. Chem. 1997, 62, 8572.
3312 J . Org. Chem., Vol. 68, No. 8, 2003

70 eV (EIMS), or electron spray ionization (ESIMS). CH3CN was
distilled from CaH2 and pyridine from KOH. NaI was heated at
100 °C and 0.1 mmHg for 48 h. Light petroleum had bp 35-60
°C.
1097, 960, 872, 835, 813, 761, 735, 662 cm-1. (EIMS) m/e (rel
intensity): 586 (<1), 343 (8), 186 (12), 155 (23), 113 (24), 101
(48), 91 (70), 71 (100). Anal. Calcd for C27H38O10S2: C, 55.27; H,
6.53. Found: C, 55.21; H, 6.55.
(+)-(4S,5S)-4,5-Bis[(1S)-1-m et h oxy-2-p r op en yl]-2,2-d i-
m eth yl-1,3-d ioxola n e (3a ). The suspension of 1.0 g (22.3 mmol)
of 50% NaH, previously washed with light petroleum under N2,
was treated with 4.8 g (22.3 mmol) of (-)-(1S)-1-{(4S,5S)-5-[(1S)-
1-hydroxy-2-propenyl]-2,2-dimethyl-1,3-dioxolan-4-yl}-2-propen-
1-ol12 (2a ) dissolved in 180 mL of THF. After 10 min 2.8 mL
(44.6 mmol) of CH3I was added, and the reaction mixture was
stirred for 1 h. Then 1.0 g of 50% NaH and 2.8 mL of CH3I were
added again, using the same procedure. The residue, obtained
by evaporation of the solvent, was treated with 20 mL of H2O
and extracted three time with 30 mL of CH2Cl2. The evaporation
of the dried organic layer gave a crude product that was purified
by flash chromatography (SiO2-CH2Cl2/EtOAc 100/1) obtaining
(3R)-3-{(4R,5R)-5-[(1R)-3-(4-Meth ylben zen esu lfon a te)-1-
m eth oxyp r op yl]-2,2-d im eth yl-1,3-d ioxola n -4-yl}-3-m eth ox-
yp r op yl 4-Meth ylben zen esu lfon a te (5b). The title compound
was synthesized as described for the above-reported enantiomer
5a .
(-)-(3a S,4S,10S,10a S)-4,10-Dim et h oxy-2,2-d im et h yloc-
ta h yd r oth ion in o[5,6-d ][1,3]d ioxole (6a ). To 100 mL of ab-
solute EtOH, bubbled at reflux with N2 for 10 min, was added
637 mg (2.65 mmol) of Na2S‚9H2O. In this solution was slowly
added dropwise and under reflux 518 mg (0.89 mmol) of 5a
dissolved in 80 mL of absolute EtOH. The reaction mixture was
successively refluxed for 48 h and then evaporated. The residue
was finally treated with 10 mL of H2O and extracted with CH2-
Cl2. The evaporation of the dried organic layer gave a crude
product that was purified by flash chromatography (SiO2-light
petroleum/Et2O; 2/1.6) obtaining 159 mg (65%) of 6a as a white
solid, mp 84-85 °C. 1H NMR: δ 4.53 (br s, 2H), 3.59 (m, 2H),
3.38 (s, 6H), 2.76 (m, 2H), 2.50 (m, 2H), 1.98 (m, 4H), 1.40 (s,
1
5.4 g (98%) of the title compound 3a as a colorless oil. H NMR:
δ 5.85-5.63 (m, 2H), 5.48-5.16 (m, 4H), 3.90 (m, 2H), 3.59 (d,
2H, J ) 7.49 Hz), 3.27 (s, 6H), 1.33 (s, 6H). 13C NMR: δ 134.3,
26
120.2, 83.9, 80.0, 56.6, 27.0. [R]D +10.1 (CHCl3, c 1.020). IR
(neat): 2986, 2937, 2894, 2823, 1643, 1458, 1424, 1380, 1370,
1242, 1216, 1168, 1092, 1001, 928, 894, 863 cm-1. (EIMS) m/e
(rel intensity): 242 (<1), 227 (11), 171 (19), 113 (64), 85 (48), 71
(100). Anal. Calcd for C13H22O4: C, 64.44; H, 9.15. Found: C,
64.60; H, 9.10.
20
6H).13C NMR: δ 107.9, 79.5, 76.9, 58.5, 30.9, 28.7, 27.1. [R]D
-12.2 (CHCl3, c 1.081). IR (KBr) 2982, 2930, 2863, 2827, 1458,
1447, 1373, 1359, 1244, 1214, 1167, 1108, 1089, 1052, 850 cm-1
.
(EIMS) m/e (rel intensity): 276(4), 261 (21), 218 (18), 203 (16),
117 (18), 85 (41), 72 (100). Anal. Calcd for C13H24O4S: C, 56.49;
H, 8.75. Found: C, 56.40; H, 8.73.
(-)-(4R,5R)-4,5-Bis[(1R)-1-m et h oxy-2-p r op en yl]-2,2-d i-
m eth yl-1,3-d ioxola n e (3b). The application of the above-
described procedure, starting from the diethyl D-tartrate, led to
(+)-(3a R,4R,10R,10a R)-4,10-Dim eth oxy-2,2-d im eth yloc-
ta h yd r oth ion in o[5,6-d ][1,3]d ioxole (6b). The title compound
was obtained with use of the same procedure adopted for the
26
the enantiopure compound 3b. [R]D -10.2 (CHCl3, c 1.130).
(-)-(3S)-3-{(4S,5S)-5-[(1S)-3-h yd r oxy-1-m eth oxyp r op yl]-
2,2-d im eth yl-1,3-d ioxola n -4-yl}-3-m eth oxy-1-p r op a n ol (4a ).
To 242 mg (1 mmol) of 3a , dissolved in 5 mL of n-hexane and
cooled at 0-5 °C, was added 78 µL (0.83 mmol) of BH3‚Me2S
maintaining the temperature at 5 °C. To the reaction mixture,
stirred for 3 h at room temperature, was added 2 mL of EtOH
and 0.6 mL of 3 N NaOH. After the solution was cooled at 0-5
°C, 270 µL of 30% H2O2 was added dropwise without exceeding
the internal temperature of 35 °C. The mixture was refluxed
for 3 h then, after cooling, was poured into 1 mL of cold brine.
The aqueous phase was extracted three time with 10 mL of CH2-
Cl2 and the combined organic layers were dried on MgSO4,
filtered ,and evaporated to dryness to give 180 mg (65%) of 4a .
The crude product could be used without further purification.
A sample was purified by flash chromatography (SiO2-Et2O/
MeOH 9/1) to afford the analitically pure title compound as a
white oil. 1H NMR: δ 3.97 (m, 2H), 3.73 (t, 4H, J ) 5.86 Hz),
3.45 (m, 2H), 3.40 (s, 6H), 2.92 (br s, 2H), 1.81 (m, 4H), 1.35 (s,
20
synthesis of 6a . [R]D +12.2 (CHCl3, c 1.077).
(-)-(4S,5R,6R,7S)-4,7-Dim eth oxy-5,6-th ion a n ed iol (7a ).
To 276 mg (1 mmol) of 6a , dissolved in 3.5 mL of CH3CN, was
added 2 mL of 0.1 N H2SO4. The reaction mixture was stirred
at 50 °C for 30 min, neutralized with Na2CO3, and evaporated.
The residue extracted with CH2Cl2 gave 231 mg (98%) of crude
7a , which was purified by flash chromatography (SiO2-CH2Cl2/
CH3OH 30/0.5) obtaining a colorless oil. 1H NMR (CD3OD): δ
4.22 (br s, 2H), 3.60 (m, 2H), 3.40 (s, 6H), 2.82 (m, 2H), 2.43 (m,
2H), 2.07 (m, 4H). 13C NMR (CD3OD): δ 83.8, 73.4, 58.0, 33.4,
29.6. [R]D20 - 45.0 (CH3OH, c 1.185). IR (neat): 3432, 2930, 2819,
2539, 1451, 1370, 1263, 1093, 938, 798 cm-1. (EIMS) m/e (rel
intensity): 218 (17), 187 (37), 146 (16), 115 (12), 87 (22), 72 (100),
71 (75). Anal. Calcd for C10H20O4S: C, 50.82; H, 8.53. Found:
C, 50.75; H, 8.55.
(+)-(4R,5S,6S,7R)-4,7-Dim eth oxy-5,6-th ion a n ed iol (7b).
20
This compound was obtained analogously to 7a . [R]D + 44.9
20
6H). 13C NMR: δ 110.2, 81.1, 79.6, 60.0, 58.4, 32.9, 27.5. [R]D
(CH3OH, c 1.164).
- 46.5 (CHCl3; c 1.381). IR (neat): 3417, 2974, 2930, 2827, 1650,
1454, 1373, 1252, 1215, 1167, 1078, 890, 865, 806 cm-1. (EIMS)
m/e (rel intensity): 189 (7), 157 (10), 131 (100), 113 (18), 99 (23),
89 (52), 85 (13), 71 (28), 59 (54). Anal. Calcd for C13H26O6: C,
56.10; H, 9.42. Found: C, 56.22; H, 9.39.
Syn t h esis
of
t h e
Bicyclic
Su lfon iu m
Sa lt s
(1S,7S,8S,8a S)-8-Hyd r oxy-1,7-d im eth oxyocta h yd r oth ien o-
[1,2-a ]th iop yr a n iu m Iod id e (8a ). To 236 mg (1 mmol) of 7a
dissolved in 2 mL of dry CH3CN was added 165 mg (1,1 mmol)
of dried NaI, followed by dropwise addition of 140 µL (1.1 mmol)
of freshly distilled Me3SiI. The mixture was refluxed for 2 h and
after cooling to room temperature, a few drops of aqueous 10%
NH4Cl was added. The organic layer, obtained by extraction with
CH2Cl2, was sequentially washed with 5 mL of aqueous 20%
Na2S2O3 and brine. The evaporation of the dried organic layer
gave 311 mg (90%) of the title compound (8a ) as a pale yellow
oil that darkened on standing.1H NMR (CD3OD): δ 4.62 (m, 1H),
4.55 (m, 1H), 4.04 (m, 1H), 3.95-3.52 (m, 3H), 3.44 (s, 3H), 3.40
(s, 3H), 3.35 (m, 2H), 2.83 (dd, 1H, J ) 7.16, 14.86 Hz), 2.15 (m,
3H). 13C NMR ((CD3)2CO): δ 85.0, 77.3, 66.4, 65.6, 57.5, 57.0,
44.6, 41.7, 33.1, 22.8. ES+ MS 219, ES-MS 127. Anal. Calcd for
10H19IO3S: C, 34.69; H, 5.53. Found: C, 34.75; H, 5.55.
(1R ,7R ,8R ,8a R )-8-H y d r o x y -1,7-d i m e t h o x y o c t a h y -
d r oth ien o[1,2-a ]th iop yr a n iu m Iod id e (8b). 8b was synthe-
sized with use of the same procedure adopted for 8a .
(+)-(1S ,7S ,8S ,8a S )-8-H yd r oxy-1,7-d im e t h oxyoct a h y-
d r oth ien o[1,2-a ]th iop yr a n iu m Tr iflu or oa ceta te (9a ). To
236 mg (1 mmol) of 6a dissolved in 2 mL of CH3CN was added
200 µL of CF3COOH to obtain 9a . The reaction mixture was
heated at 50 °C for 2 h then directly evaporated to gave a crude
(+)-(3R)-3-{(4R,5R)-5-[(1R)-3-Hydr oxy-1-m eth oxypr opyl]-
2,2-d im eth yl-1,3-d ioxola n -4-yl}-3-m eth oxy-1-p r op a n ol (4b).
The title compound was obtained, analogously to 4a , from 3b.
20
[R]D +46.4 (CHCl3; c 1.272).
(3S)-3-{(4S,5S)-5-[(1S)-3-(4-m eth ylben zen esu lfon a te)-1-
m et h oxyp r op yl]-2,2-d im et h yl-1,3-d ioxola n -4-yl}-3-m et h -
oxyp r op yl 4-m eth ylben zen esu lfon a te (5a ). To 259 mg
(0.93 mmol) of 4a , dissolved in 2 mL of dry pyridine and cooled
at 0 °C, was added 530 mg (2.78 mmol) of p-toluenesulfonyl
chloride. After 14 h at 5 °C the solution was poured into 3 mL
of H2O and extracted with CH2Cl2. By evaporation of the dried
organic layer 516 mg (95%) of 5a was obtained as a white oil
and used without further purification. 1H NMR: δ 7.75 (d, 4H),
7.30 (d, 4H), 4.15 (m, 4H), 3.77 (m, 2H), 3.28 (m, 2H), 3.30 (s,
6H), 2.40 (s, 6H), 1.86 (m, 4H), 1.28 (s, 6H). 13C NMR: δ 145.3,
133.5, 130.4, 128.4, 112.0, 79.6, 78.5, 67.7, 58.7, 30.3, 27.4, 22.1.
IR (neat): 3063, 2982, 2827, 1922, 1805, 1598, 1454, 1359, 1174,
C
(12) J orgensen, M.; Iversen, E. H.; Paulsen, A. L.; Madsen, R. J .
Org. Chem. 2001, 66, 4630.
J . Org. Chem, Vol. 68, No. 8, 2003 3313

product that was purified by dissolution in CH2Cl2 and precipi-
tation with light petroleum obtaining 299 mg (90%) of 9a as a
colorless viscous oil. 1H NMR and13C NMR are identical with
bicyclic compound was obtained analogously to 9a . [R]D20 -17.8
(CH3OH, c 1.433).
20
those reported for 8a . [R]D +17.9 (CH3OH, c 1.635). IR
(Nujol): 3417, 2546, 1701, 1133, 990. ES+ MS 219, ES-MS 113.
Anal. Calcd for C12H19F3O5S: C, 43.37; H, 5.76. Found: C, 43.40;
H, 5.78.
Ack n ow led gm en t. This work has been supported
by the National Project “Stereoselezione in Chimica
Organica. Metodologie ed Applicazioni, 2002-2003”.
(-)-(1R ,7R ,8R ,8a R )-8-H yd r oxy-1,7-d im e t h oxyoct a h y-
d r oth ien o[1,2-a ]th iop yr a n iu m tr iflu or oa ceta te (9b). This
J O020511Z
3314 J . Org. Chem., Vol. 68, No. 8, 2003