A straightforward and general strategy towards 1,5-dithio-1-enopyranosides

Article abstract of DOI:10.1002/ejoc.200800314

The synthesis of a new class of thiosugar derivatives, 1,5-dithio-1- enopyranosides, has been achieved in a two-step sequence from easily available aldofuranoses. In the first step, a carbohydrate-derived ketene dithioacetal was formed by Peterson olefination of an aldofuranose and a lithiated α-silyl thioacetal. In the second step, intramolecular nucleophilic substitution of an activated hydroxy group by a sulfur atom of the ketene dithioacetal function led to the target compounds in good yields. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800314

FULL PAPER
DOI: 10.1002/ejoc.200800314
A Straightforward and General Strategy Towards 1,5-Dithio-1-enopyranosides
Marie Buchotte,[a] Murielle Muzard,[a] and Richard Plantier-Royon*[a]
Keywords: Carbohydrates / Thiosugars / Ketene dithioacetal / Cyclization / Olefination
The synthesis of a new class of thiosugar derivatives, 1,5-
dithio-1-enopyranosides, has been achieved in a two-step se-
quence from easily available aldofuranoses. In the first step,
a carbohydrate-derived ketene dithioacetal was formed by
Peterson olefination of an aldofuranose and a lithiated α-silyl
thioacetal. In the second step, intramolecular nucleophilic
substitution of an activated hydroxy group by a sulfur atom
of the ketene dithioacetal function led to the target com-
pounds in good yields.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
A new class of glycosidase inhibitors, namely salacinol 2
and kotalanol 3 with inner-salt sulfonium–sulfate structures
(Figure 1), were recently isolated from the plant Salacia re-
ticulata, which is widespread in Sri Lanka and South In-
dia.[7] These sulfonium derivatives have been found to be
potent inhibitors of intestinal α-glucosidase. Many synthe-
ses of salacinol, its stereoisomers, selenium and nitrogen an-
alogues, as well as six-membered derivatives have been re-
ported.[8]
Six-membered analogues of salacinol generally possess
weak or no activity against glycosidases, but interestingly,
5-thio--glucal (4) was found to competitively inhibit α--
mannosidase and β--glucosidase.[9] Therefore, the presence
of the double bond could modify the geometry of the het-
erocycle and mimic the transition state involved in the enzy-
matic transformation.
Introduction
Thiosugars are carbohydrate analogues in which the in-
tracyclic oxygen is replaced by a sulfur atom, both in py-
ranoside and furanoside structures.[1] To date, except for 5-
thio--mannose, which was isolated in 1987 from marine
sponge Clathria pyramida,[2] thiosugars have not been found
in nature. Since the first synthesis of a 5-thio--hexopyr-
anose in 1961,[3] thiosugars have been obtained by the
transformation of natural monosaccharides.[4]
Owing to their interesting biological activities, these com-
pounds have recently attracted considerable interest from
chemists and biochemists.[5] In particular, 1,5-dithio--xylo-
pyranose-derived glycosides like 1 (Figure 1) have proved to
be orally active anti-thrombotic agents.[6]
Owing to their potential value as therapeutic agents,
thiosugars and their derivatives have become important tar-
gets and the search for original compounds remains a chal-
lenging topic. As a part of our research in the field of sugars
of biological interest, we have explored a general strategy
towards the synthesis of a new class of six-membered
thiosugars: 1,2-unsaturated 1,5-dithiopyranosides.
To the best of our knowledge, only two examples of un-
saturated 1,5-dithiopyranosides have been reported in lit-
erature. Gallagher and co-workers[10] reported the forma-
tion of a 1:1 mixture of the expected product and an azido
1,5-dithiopyranoside during the conversion of a primary to-
sylate obtained from the ketene dithioacetal derived from
2,3-O-isopropylidene--erythrose to the corresponding
azide (Scheme 1).
Figure 1. Selected thiosugars and derivatives of biological interest.
[a] Institut de Chimie Moléculaire de Reims, CNRS UMR 6229,
Université de Reims Champagne-Ardenne, UFR Sciences,
Moulin de la Housse, B. P. 1039, 51687 Reims Cedex 2, France
Fax: +33-3-26913166
E-mail: richard.plantier-royon@univ-reims.fr
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Scheme 1.
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M. Buchotte, M. Muzard, R. Plantier-Royon
FULL PAPER
In the second example,[11] 1,5-dithiopyranosides were ob- Table 1. Synthesis of ketene dithioacetals 9–12.
tained from the condensation of 2,3-O-isopropylidene--
or --erythrose with methylthiomethyl p-tolyl sulfone, fol-
lowed by mesylation of two free hydroxy groups leading
to elimination and intramolecular cyclization (Scheme 2).
These two examples have proved the participation of one of
the sulfur atoms of the ketene dithioacetal function in the
cyclization step.
Scheme 2.
In this paper, we report a general strategy towards unsat-
urated 1,5-dithiopyranosides starting from carbohydrate-
derived ketene dithioacetals. The cyclization step was
studied, optimized and generalized for several ketene di-
thioacetals with various protecting groups.
Results and Discussion
In our study, the title thiosugar analogues were readily
synthesized from carbohydrate-derived ketene dithioacetals,
which are easily available from protected aldofuranoses.[12]
[a] Compound 10 was unstable to silica gel chromatography and
Condensation of the lithium derivative of bis(methyl-
sulfanyl)trimethylsilylmethane with the protected aldofur-
anoses 2,3-O-isopropylidene--erythrofuranose (5),[13] 2,3-
di-O-benzyl--threofuranose (6), the commercially available
2,3,5-tri-O-benzyl--arabinofuranose (7) and 2,3-O-isopro-
pylidene-5-O-trityl--ribofuranose (8)[13] afforded the inter-
mediate sugar-derived ketene dithioacetals 9–12 in good
yields (Table 1). Compound 6 was prepared from methyl
2,3-di-O-benzyl-5-O-trityl--arabinofuranoside[14] accord-
ing to the sequence depicted in Scheme 3.
was used without purification in the next step.
Scheme 3. Synthesis of the aldofuranose 6.
Ketene dithioacetals 9–12 were used immediately after
purification as they underwent spontaneous O-cyclization,
as described previously in the literature.[12b] Owing to its
instability, compound 10 was used without purification.
The next step of the reaction required the activation of
the free hydroxy group of the ketene dithioacetals 9–12 to
induce ring closure by intramolecular nucleophilic attack of
one of the sulfur atoms of the ketene dithioacetal function.
The first attempts were carried out with compound 11.
Under the experimental conditions described in the litera-
ture for a similar cyclization of dithioacetals (PPh3, I2, imid-
azole[15] or mesylation of the free hydroxy group[16]), the
starting material decomposed. Only traces of the target
compound 15 were obtained.
the intermediate sulfonium into 15 was assumed to be due
to the presence of an excess of pyridine as a nucleophile
is essential to remove the methyl group at the sulfur atom
(Scheme 4).
The use of a triflate as a more efficient leaving group was
then envisioned. Compound 11 was treated with trifluoro-
methanesulfonic anhydride (2 equiv.) in the presence of an
excess of pyridine (6 equiv.) at –20 °C. The corresponding
triflate was not isolated and, at room temperature, cycliza-
Scheme 4. Mechanism for the formation of the unsaturated 1,5-
dithiopyranoside 15.
The overall transformation was easily monitored by
tion occurred to afford the unsaturated 1,5-dithiopyrano- TLC, which showed the formation of the apolar triflate at
side 15 in 50% yield. The spontaneous transformation of –20 °C, its transformation into the polar sulfonium deriva-
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A Strategy Towards 1,5-Dithio-1-enopyranosides
tive at 0 °C and finally the formation of the expected unsat- Table 2. Synthesis of unsaturated 1,5-dithiopyranosides 13–16.
urated thiosugar at room temperature.
Under the same experimental conditions, ketene di-
thioacetal 9 led to a mixture of the expected thiosugar 13
and a by-product in a 1:1 ratio (Scheme 5). After careful
separation by flash chromatography over silica gel and spec-
troscopic studies, the structure of the thiosugar 17 was as-
signed to this by-product. The formation of compound 17
results from electrophilic substitution of the ethylenic pro-
ton of 1,5-dithiopyranoside 13 by the species generated
from the interaction of pyridine with trifluoromethanesul-
fonic anhydride.[17]
[a] Overall yield from the protected aldofuranose.
Scheme 5. Formation of the by-product 17 from the carbohydrate-
derived ketene dithioacetal 9.
This transformation was confirmed by the reaction of
1,5-dithiopyranoside 13 with a solution of the electrophilic
Scheme 6. Synthesis of sulfonium 18.
species, obtained by reaction of trifluoromethanesulfonic
anhydride and pyridine at 0 °C. Under these conditions,
Conclusions
compound 17 was quantitatively obtained. In order to
avoid this electrophilic substitution, pyridine substituted at
the 4-position was used instead of pyridine. Thus, in the
presence of 2 equiv. of trifluoromethanesulfonic anhydride
and 6 equiv. of 4-picoline (4-methylpyridine), the target 1,2-
unsaturated 1,5-dithiopyranosides 13–16 were obtained in
good yields (Table 2). The SN2 mechanism involved in the
cyclization step led to an inversion of configuration at C–
5, as confirmed by a NOE experiment on compound 16
(9.5% between H-4 and H-5).
Finally, in order to prove the mechanistic pathway of the
overall transformation, we attempted to isolate the interme-
diate sulfonium formed during the formation of 13 from 9
(Scheme 6).
By using 1.6 equiv. of 4-picoline and 1.2 equiv. of trifluo-
romethanesulfonic anhydride at 0 °C, the reaction effec-
tively stopped, according to TLC, at the sulfonium step.
However, purification of the sulfonium 18 by silica gel
chromatography proved to be tedious due to the presence
of the 4-methylpyridinium salt. Nevertheless, a small
amount of pure sulfonium 18, with trifluoromethanesulfon-
ate as the counter-ion, was isolated as a single diastereomer
and then fully characterized.
In this study we have developed a general and efficient
method for the synthesis of original 1,5-dithio-1-enopyr-
anosides from easily available protected aldofuranoses in a
two-step sequence in good yields. These compounds possess
a ketene dithioacetal function that allows the introduction
of various substituents at the 2-position of the heterocycle
by well-known electrophilic or radical reactions.[18] These
new thiosugars have potential as precursors of modified 5-
thiopyranosides as well as precursors of glycosidase inhibi-
tors and demand further investigation.
Experimental Section
General: All reactions were performed under argon. The solvents
were dried and distilled prior to use. THF was distilled from so-
dium benzophenone ketyl and dichloromethane from calcium hy-
dride. n-Butyllithium (2.5 ) was purchased from Acros Organics
and titrated in THF against menthol in the presence of ortho-phen-
anthroline. Merck silica gel F254 (0.2 mm) was used to prepare
TLC plates. Flash column chromatography was performed over sil-
ica gel (Merck 9385 Kieselgel 60, 40–63 µm). NMR spectra were
recorded with Bruker spectrometers (250 or 500 MHz for 1H, 63
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M. Buchotte, M. Muzard, R. Plantier-Royon
2-Deoxy-3,4-O-isopropylidene- -erythro-pent-1-enose Dimethyl Di-
FULL PAPER
or 125 MHz for 13C, as indicated). Chemical shifts are expressed in
parts per million (ppm) using TMS as the internal standard, coup-
ling constants are in Hz and splitting pattern abbreviations are as
follows: br broad, s singlet, d doublet, t triplet, q quartet, m mul-
tiplet. Optical rotations were determined at 20 °C with a Perkin–
Elmer Model 241 polarimeter. High-resolution mass spectra
(HRMS) were performed with Q-TOF Micro micromass positive
ESI (CV = 30 V) spectrometer.
L
thioacetal (9): Following the general procedure, nBuLi (11.3 mL,
13.94 mmol), bis(methylsulfanyl)trimethylsilylmethane (2.41 g,
12.69 mmol), 60% NaH (305 mg, 7.62 mmol) and 5 (1.02 g,
6.35 mmol) yielded 9 as a yellow oil (1.38 g, 87%). [α]2D0 = –149.0
(c = 2.3, CHCl3). 1H NMR (250 MHz, CDCl3): δ = 5.72 (d, J =
8.1 Hz, 1 H, 2-H), 5.35 (dd, J = 6.8, J = 8.1 Hz, 1 H, 3-H), 4.28
(dt, J = 4.4, J = 6.8 Hz, 1 H, 4-H), 3.52 (m, 2 H, 5-H), 2.34 (s, 3
H, SCH3), 2.30 (s, 3 H, SCH3), 1.50 [s, 3 H, C(CH3)], 1.40 [s, 3 H,
C(CH3)] ppm. 13C NMR (63 MHz, [D6]acetone): δ = 139.0 (C-1),
128.6 (C-2), 109.6 [C(CH3)2], 80.5 (C-4), 76.7 (C-3), 62.9 (C-5), 28.9
and 26.3 [2 C, C(CH3)2], 18.1 and 17.3 (SCH3) ppm. MS (ESI): m/z
= 273.0 [M + Na]+, 523.1 [2M + Na]+. HRMS (ESI): calcd. for
C10H18O3NaS2 [M + Na]+ 273.0595; found 273.0600.
2,3-Di-O-benzyl-D-threofuranose (6): Water (1 mL) and 37% hydro-
chloric acid (1 mL) were added to a solution of methyl 2,3-di-O-
benzyl-5-O-trityl--arabinofuranoside (0.96 g, 1.64 mmol) in diox-
ane (8.1 mL). The temperature was raised to 80 °C and the reaction
was stirred overnight. A saturated aqueous NaHCO3 solution was
then added and the aqueous phase was extracted with dichloro-
methane (3ϫ20 mL). The combined organic layers were dried with
Na2SO4 and concentrated in vacuo. The crude product was purified
by flash chromatography over silica gel (petroleum ether/EtOAc,
4:6) to give the pure 2,3-di-O-benzyl--arabinofuranose in 58%
yield (314.8 mg, 0.95 mmol).
3,4,6-Tri-O-benzyl-2-deoxy-D-arabino-hex-1-enose Dimethyl Di-
thioacetal (11): Following the general procedure, nBuLi (2.97 mL,
5.34 mmol), bis(methylsulfanyl)trimethylsilylmethane (918 mg,
5.09 mmol), 60% NaH (122 mg, 3.05 mmol) and
7 (1.07 g,
2.55 mmol) yielded 11 as a yellow oil (1.05 g, 81%). [α]2D0 = –49.6
1
(c = 1.0, CHCl3). H NMR (250 MHz, CDCl3): δ = 7.31–7.25 (m,
NaBH4 (322 mg, 8.51 mmol) was added portionwise over 1 h to a
solution of 2,3-di-O-benzyl--arabinofuranose (1.12 g, 3.41 mmol)
in methanol (6.4 mL) at 0 °C. The mixture was stirred for 1 h at
0 °C and then the temperature was allowed to rise to room temp.
and stirred for 2 h. The solvent was evaporated in vacuo and the
crude product was used in the next step without further purifica-
tion.
15 H, 3ϫAr), 5.83 (d, J = 8.8 Hz, 1 H, 2-H), 4.95 (dd, J = 3.6, J
= 8.8 Hz, 1 H, 3-H), 4.65–4.36 (m, 7 H, 5-H, 3ϫCH2Ph), 4.06–
3.97 (m, 1 H, 5-H), 3.63–3.58 (m, 3 H, 4-H, 6-H), 2.93 (d, J =
5.6 Hz, 1 H, OH), 2.27 (s, 3 H, SCH3), 2.24 (s, 3 H, SCH3) ppm.
13C NMR (63 MHz, CDCl3): δ = 138.3 (C-1), 138.0 (Cipso, Ar),
128.4–127.6 (15 CAr, C-2), 80.7 (C-4), 76.4 (C-3), 73.9, 73.4 and
71.2 (CH2Ph), 70.8 (C-6), 70.5 (C-5), 17.0 and 16.4 (SCH3) ppm.
MS (ESI): m/z = 517.1 [M + Li]+, 533.1 [M + Na]+, 549.1 [M +
K]+. HRMS (ESI): calcd. for C29H34O4NaS2 [M + Na]+ 533.1796;
found 533.1784.
NaIO4 (2.92 g, 13.64 mmol) was added portionwise to a solution
of the previous product in tert-butyl alcohol/water (3:2, 5.6 mL/
3.8 mL). The resulting mixture was stirred for 24 h. Saturated aque-
ous NaHCO3 was then added, the solution was filtered and the
solid washed with dichloromethane. The aqueous phase was ex-
tracted with dichloromethane (3ϫ20 mL). The combined organic
layers were dried with Na2SO4 and concentrated in vacuo. The
crude product was purified by flash chromatography over silica gel
(petroleum ether/EtOAc, 8:2) to give 2,3-di-O-benzyl--threofur-
anose (6) in 65% yield over two steps (682 mg, 2.27 mmol).
2-Deoxy-3,4-O-isopropylidene-6-O-trityl-D-ribo-hex-1-enose
Di-
methyl Dithioacetal (12): Following the general procedure, nBuLi
(1.92 mL, 3.54 mmol), bis(methylsulfanyl)trimethylsilylmethane
(660 mg, 3.66 mmol), 60% NaH (88 mg, 2.20 mmol) and
8
(791 mg, 1.83 mmol) yielded 12 as a white foam (517 mg, 56%).
1
[α]2D0 = +51.9 (c = 0.9, CHCl3). H NMR (250 MHz, CDCl3): δ =
7.50–7.34 (m, 5 H, Ar), 7.26 (m, 10 H, 2ϫAr), 5.76 (d, J = 8.8 Hz,
1 H, 2-H), 5.42 (dd, J = 6.2, J = 8.8 Hz, 1 H, 3-H), 4.18 (dd, J =
6.2, J = 8.2 Hz, 1 H, 4-H), 4.68–3.77 (m, 1 H, 5-H), 3.32 (d, J =
4.7 Hz, 2 H, 6-H), 2.34 (s, 3 H, SCH3), 2.29 (s, 3 H, SCH3), 1.36
[s, 6 H, 2ϫC(CH3)] ppm. 13C NMR (63 MHz, CDCl3): δ = 144.0
(Cipso, Ar), 139.1 (C-1), 128.8–127.1 (15 CAr), 126.0 (C-2), 108.8
[C(CH3)2], 87.0 [C(Ar)3], 78.2 (C-4), 75.8 (C-3), 69.8 (C-5), 65.2 (C-
6), 28.0 and 25.7 [C(CH3)2], 17.4 and 16.7 (SCH3) ppm. HRMS
(ESI): calcd. for C30H34O4NaS2 [M + Na]+ 545.1796; found
545.1799.
1
Oil, yield 65% (over two steps). H NMR (250 MHz, CDCl3): δ =
7.33–7.25 (m, 12 H, Ar), 5.43 (dd, J = 8.4, J = 4.1 Hz, 0.4 H, 1β-
H), 5.32 (d, J = 9.6 Hz, 0.6 H, 1α-H), 4.64–4.48 (m, 4 H, CH2Ph),
4.20–4.06 (m, 2.6 H, 3-H, 2ϫ4α-H, 4β-H), 3.99–3.94 (m, 1 H, 2-
H), 3.85–3.79 (m, 0.4 H, 4β-H) ppm. 13C NMR (63 MHz, CDCl3):
δ = 137.7, 137.5, 137.2 and 137.0 (Ar), 128.8–127.9 (10 CAr), 101.2
(C-1α), 96.7 (C-1β), 85.3 (C-2β), 82.3 (C-2α), 81.4 (C-3β), 81.2 (C-
3α), 73.1, 72.1, 71.8 (CH2Ph), 71.7 (CH2Ph and C-4α), 69.3 (C-
4β) ppm. MS (ESI): m/z = 523.1 [M + Na]+. HRMS (ESI): calcd.
for C18H20O4Na [M + Na]+ 323.1266; found 323.1259.
General Procedure for the Synthesis of 1,2-Unsaturated-1,5-Dithio-
pyranosides 13–16: 4-Picoline (3.6 equiv. for 9 and 10, 6 equiv. for
11 and 12) was added to a solution of ketene dithioacetal 9–12
(1 equiv.) in dichloromethane (10 mLmmol–1). The mixture was co-
oled to –20 °C and trifluoromethanesulfonic anhydride was added
dropwise (1.2 equiv. for 9 and 10, 2 equiv. for 11 and 12). The re-
sulting mixture was stirred for 15 min at –20 °C and then warmed
up to 0 °C and stirred for 1 h. The mixture was stirred overnight
and the temperature was allowed to rise to room temp. Dichloro-
methane was evaporated in vacuo. The crude product was purified
by flash chromatography over silica gel (petroleum ether/EtOAc,
8:2) to give the pure cyclized thiosugars.
General Procedure for the Preparation of Ketene Dithioacetals 9–12:
A solution of nBuLi in hexane (2.1 equiv.) was added dropwise to
a solution of bis(methylsulfanyl)trimethylsilylmethane (2 equiv.) in
anhydrous THF (2 mL per mmol) at –30 °C. The resulting mixture
was stirred for 2 h at –30 °C and was then cooled to –78 °C. Simul-
taneously, a solution of the protected sugar (1 equiv.) in anhydrous
THF (1.2 mLmmol–1) was added dropwise to a suspension of 60%
NaH (1.2 equiv.) in anhydrous THF (2 mLmmol–1) at 0 °C. After
2 h, the silyl reagent solution was slowly added to the sugar solu-
tion and the mixture was stirred overnight, the temperature being
allowed to rise to room temp. Saturated aqueous NH4Cl was then
added and the aqueous phase was extracted with Et2O (2ϫ15 mL).
The combined organic layers were dried with MgSO4 and concen-
trated in vacuo. The crude product was purified by flash
chromatography over silica gel (petroleum ether/EtOAc, 75:25) to
afford the pure ketene dithioacetals.
Methyl 2-Deoxy-3,4-O-isopropylidene-1,5-dithio-L-erythro-pent-1-
enopyranoside (13): Following the general procedure, 9 (490 mg,
1.96 mmol), 4-picoline (690 µL, 7.06 mmol) and trifluoromethane-
sulfonic anhydride (390 µL, 2.35 mmol) yielded 13 as a white solid
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A Strategy Towards 1,5-Dithio-1-enopyranosides
(413 mg, 95%). M.p. 62 °C, [α]2D0 = –249.0 (c = 0.9, CHCl3). 1H
NMR (250 MHz, CDCl3): δ = 5.98 (d, J = 4.2 Hz, 1 H, 2-H), 4.49
H, 5-H), 2.38 (s, 3 H, SCH3), 1.42 [s, 3 H, C(CH3)], 1.30 [s, 3 H,
C(CH3)] ppm. 13C NMR (63 MHz, CDCl3): δ = 131.8 (C-1), 122.4
(dd, J = 4.2, J = 5.7 Hz, 1 H, 3-H), 4.27 (ddd, J = 4.7, J = 5.7, J and 120.9 (C-8 and C-9), 117.2 (C-2), 112.2 and 111.1 (C-7 and C-
= 10.8 Hz, 1 H, 4-H), 2.79 (dd, J = 4.7, J = 12.4 Hz, 1 H, 5-H), 10), 107.8 [C(CH3)2], 73.4 (C-4), 71.8 (C-3), 36.6 (C-6), 31.5 (C-5),
2.70 (dd, J = 10.8, J = 12.4 Hz, 1 H, 5Ј-H), 2.37 (s, 3 H, SCH3), 28.5 and 25.4 [C(CH3)2], 17.1 (SCH3) ppm. MS (ESI): m/z = 296.1
1.47 [s, 3 H, C(CH3)], 1.38 [s, 3 H, C(CH3)] ppm. 13C NMR
[M – SO2CF3 + H]+. HRMS (ESI): calcd. for C14H18NO2S2 [M +
(63 MHz, CDCl3): δ = 138.1 (C-1), 116.8 (C-2), 107.4 [C(CH3)2], H]+ 296.0779; found 296.0783.
73.3 (C-4), 71.1 (C-3), 31.1 (C-5), 28.3 and 25.5 [2 C, C(CH3)2],
Methyl
2-Deoxy-3,4-O-isopropylidene-5-[methylepisulfonium]-1-
-erythro-pent-1-enopyranoside Trifluoromethanesulfonate Salt
16.5 (SCH3) ppm. MS (ESI): m/z = 219.0 [M + H]+, 241.0 [M +
Na]+, 257.0 [M + K]+. HRMS (ESI): calcd. for C9H14O2S2K [M +
K]+ 257.0072; found 257.0063.
thio-L
(18): 4-Picoline (150 µL, 1.55 mmol) was added to a solution of
ketene dithioacetal 9 (243 mg, 0.97 mmol) in dichloromethane
(12.2 mL). The mixture was cooled to –20 °C and trifluorometh-
anesulfonic anhydride was added dropwise (190 µL, 1.17 mmol).
The resulting mixture was stirred for 15 min at –20 °C and then
warmed up to 0 °C and stirred for 1 h. The crude product was
purified by flash chromatography over silica gel (dichloromethane/
methanol, 14:1). As described above, a small amount of pure sulfo-
nium 18 was isolated for characterization. Oil, [α]2D0 = +32.5 (c =
1.3, MeOH). 1H NMR (250 MHz, CD3OD): δ = 6.82 (d, J =
4.2 Hz, 1 H, 2-H), 4.91–4.81 (m, 2 H, 3-H and 4-H), 4.25 (dd, J =
12.9, J = 5.3 Hz, 1 H, 5-H), 3.99 (dd, J = 12.9, J = 2.0 Hz, 1 H,
5Ј-H), 3.22 (s, 3 H, S+CH3), 2.57 (s, 3 H, SCH3), 1.42 [s, 6 H,
C(CH3)2] ppm. 13C NMR (63 MHz, CD3OD): δ = 139.3 (C-2),
124.3 (C-1), 111.9 [C(CH3)2], 71.6 (C-3), 68.8 (C-4), 42.7 (C-5), 27.7
and 26.1 [2 C, C(CH3)2], 25.6 (S+CH3), 18.5 (SCH3) ppm. HRMS
(ESI): calcd. for C10H17O2S2 [M]+ 233.0670; found 233.0678.
Methyl 3,4-Di-O-benzyl-2-deoxy-1,5-dithio-D-threo-pent-1-enopyr-
anoside (14): Following the general procedure, 10 (1.64 mmol), 4-
picoline (620 µL, 6.38 mmol) and trifluoromethanesulfonic anhy-
dride (350 µL, 2.13 mmol) yielded 14 as a yellow oil (270 mg, 46%
over two steps). [α]2D0 = –164.5 (c = 0.9, CHCl3). 1H NMR
(500 MHz, CDCl3): δ = 7.28 (m, 10 H, 2ϫAr), 5.82 (d, J = 4.4 Hz,
1 H, 2-H), 4.68 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.60 (s, 2 H, CH2Ph),
4.58 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.01 (ddd, J = 0.6, J = 4.4, J
= 5.0 Hz, 1 H, 3-H), 3.95 (ddd, J = 2.4, J = 5.0, J = 7.3 Hz, 1 H,
4-H), 3.07 (dd, J = 2.4, J = 13.3 Hz, 1 H, 5-H), 3.00 (ddd, J = 0.6,
J = 7.3, J = 13.3 Hz, 1 H, 5Ј-H), 2.34 (s, 3 H, SCH3) ppm. 13C
NMR (126 MHz, CDCl3): δ = 138.5 and 138.1 (2 Cipso, Ar), 135.1
(C-1), 128.7–128.0 (10 CAr), 118.7 (C-2), 75.0 (C-3), 73.2 (C-4), 71.6
and 71.4 (2ϫCH2Ph), 29.4 (C-5), 17.1 (SCH3) ppm. MS (ESI): m/z
= 381.1 [M + Na]+, 397.1 [M + K]+. HRMS (ESI): calcd. for
C20H22O2NaS2 [M + Na]+ 381.0959; found 381.0963.
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra for all new compounds.
Methyl 3,4,6-Tri-O-benzyl-2-deoxy-1,5-dithio-L-arabino-pent-1-eno-
pyranoside (15): Following the general procedure, 11 (273 mg,
0.54 mmol), 4-picoline (350 µL, 3.56 mmol) and trifluoromethane-
sulfonic anhydride (200 µL, 2.13 mmol) yielded 15 as a yellow oil
(222 mg, 86%). [α]2D0 = –143.0 (c = 1.0, CHCl3). 1H NMR
(250 MHz): δ = 7.23–7.17 (m, 15 H, 3ϫAr), 5.79 (dd, J = 0.7, J =
4.4 Hz, 1 H, 2-H), 4.60–4.38 (m, 6 H, 3ϫCH2Ph), 3.86–3.84 (m, 2
H, 3-H and 4-H), 3.65 (dd, J = 5.9, J = 8.8 Hz, 1 H, 6Ј-H), 3.59
(ddd, J = 2.0, J = 5.9, J = 7.3 Hz, 1 H, 5-H), 3.53 (dd, J = 7.3, J
= 8.8 Hz, 1 H, 6-H), 2.28 (s, 3 H, SCH3) ppm. 13C NMR (63 MHz,
CDCl3): δ = 138.2, 137.8 and 137.7 (3Cipso, Ar), 134.8 (C-1), 128.3–
127.6 (15 CAr), 117.4 (C-2), 73.0 (CH2Ph), 72.6 (C-4), 72.0 (C-3),
71.9 and 70.9 (2ϫCH2Ph), 68.3 (C-6), 43.0 (C-5), 16.8
(SCH3) ppm. MS (ESI): m/z = 501.4 [M + Na]+. HRMS (ESI):
calcd. for C28H30O3NaS2 [M + Na]+ 501.1534; found 501.1528.
Acknowledgments
The authors thank the Conseil Régional Champagne-Ardenne for
a doctoral fellowship (M. B.), and M. Gruit and V. Kikelj (under-
graduate students) for their participation in this work.
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www.eurjoc.org
3533

M. Buchotte, M. Muzard, R. Plantier-Royon
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Received: March 25, 2008
Published Online: June 3, 2008
3534
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3529–3534