Preparation of anhydro-thiohexofuranosides from methyl fructofuranosides via the thio-Mitsunobu reaction

Article abstract of DOI:10.1080/104265090508424

Methyl α-D-fructofuranoside was transformed regioselectively into the corresponding 6-S-thioacetate in one step by use of the thio-Mitsunobu reaction. Reaction of the trimesylate derived from this thioacetate with sodium hydrogen carbonate led to the thie

Full text of DOI:10.1080/104265090508424

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Preparation of Anhydro-
Thiohexofuranosides from
Methyl Fructofuranosides Via
the Thio-Mitsunobu Reaction
Kerstin Polchow a & Jürgen Voss a
a Institut für Organische Chemie der Universität
Hamburg, Martin-Luther-King-Platz 6 , D-20146,
Hamburg, Germany
Published online: 01 Feb 2007.
To cite this article: Kerstin Polchow & Jürgen Voss (2005) Preparation of Anhydro-
Thiohexofuranosides from Methyl Fructofuranosides Via the Thio-Mitsunobu Reaction ,
Phosphorus, Sulfur, and Silicon and the Related Elements, 180:7, 1755-1768, DOI:
10.1080/104265090508424
To link to this article: http://dx.doi.org/10.1080/104265090508424
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Phosphorus, Sulfur, and Silicon, 180:1755–1768, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090508424
Preparation of Anhydro-Thiohexofuranosides from
Methyl Fructofuranosides Via the Thio-Mitsunobu
Reaction1
Kerstin Polchow
¨
Jurgen Voss
Institut fu¨r Organische Chemie der Universita¨t Hamburg,
Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany
Methyl α-D-fructofuranoside was transformed regioselectively into the correspond-
ing 6-S-thioacetate in one step by use of the thio-Mitsunobu reaction. Reaction of
the trimesylate derived from this thioacetate with sodium hydrogen carbonate led to
the thietanosugar methyl 4,6-anhydro-1,3-di-O-mesyl-4-thio-α-D-tagatofuranoside.
Methyl β-D-fructofuranoside gave the corresponding 6-S-thioacetate and, with ex-
cess thioacetic acid, the 1-S,6-S-bis-thioacetate. Whereas this mono-thioacetate
did not yield a thietano derivative, the bis-thioacetate gave the bis-thietane
methyl 1,3:4,6-dianhydro-1,4-dithio-β-D-sorbofuranoside with sodium hydrogen
carbonate.
Keywords Cyclisation; intramolecular reaction; SN2; methyl fructofuranosides;
thietanosugars; thio-Mitsunobu reaction
We have very successfully applied the thio-Mitsunobu reaction for
the chemoselective preparation of 5-S-acetyl-5-thiopentofuranosides3–6
from the corresponding methyl pentofuranosides, the secondary hy-
droxy groups of which were mostly unprotected. Also, methyl D-
glucohexopyranoside has proved to be a suitable starting material for
the direct introduction of the acetylthio group into an aldohexose.7
The thio-Mitsunobu reaction of methyl ketosides has, however, not yet
been investigated. We have studied the reaction of methyl α-D- (2) and
Received June 22, 2004; in final form July 8, 2004.
This article was previously published in Phosphorus, Sulfur, and Silicon and the Re-
lated Elements 180(2) without figures. It is now reprinted here with figures. The publisher
apologizes for this error.
We thank the University of Hamburg and the Fonds der Chemischen Industrie for
financial support K. P. thanks the University of Hamburg for a Graduate Fellowship.
Address correspondence to Ju¨rgen Voss, Institut fu¨r Organische Chemie der Uni-
versita¨t Hamburg, Martin-Luther-King-Platz 6, D-20146 Hamburg, Germany. E-mail:
voss@chemie.uni-hamburg.de
1755

1756
K. Polchow and J. Voss
methyl β-D-fructofuranoside (3) with thioacetic acid in the presence
of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine. As in
the above mentioned cases, we were interested in the base-promoted
cleavage of the sugar thioacetates and concomitant intramolecular cy-
clization of the thiolates to thietano- or thiolanosugars.
RESULTS AND DISCUSSION
Methyl fructofuranosides are not as easily available as other methyl
glycosides, e.g. methyl glucopyranoside. Due to the fact that in solu-
tion fructose exists as a mixture of the two furanoid and the two pyra-
noid isomers, “simple derivatizations of D-fructose, such as glycosida-
tions . . . usually yield product mixtures of, at worst, all five tautomeric
forms, from which separation of the major component is cumbersome
and highly detrimental to the yields obtainable.”8 As recently as 1999
a novel synthesis of methyl fructofuranosides has been published.9 We
decided to prepare the desired starting compounds 2 and 3 by a two-step
procedure from D-fructose via its 1,2:4,5-di-O-isopropylidene derivative
1 (Scheme 1). Compound 1 can be prepared in large amounts,10 although
the percentage yield is only moderate. Acid-catalyzed methanolysis un-
der carefully optimized conditions transformed 1 into a mixture of 2, 3
and 4, which can be separated by column chromatography.*
O
OMe
HO
HO
O
OH
O
O
(1)
O
HO
+
HO
OH
OMe
OH
O
O
OH
OH
1
2
3
O
O
O
+
OH
OH
HO
4
SCHEME 1 (1): HCl, MeOH.
*The preparation of methyl fructofuranosides from 1 by use of I2 in methanol has been
described by W. A. Szarek, A. Zamojski, K. N. Tiwari, and E. R. Ison, Tetrahedron Lett.,
27, 3827 (1986), but the authors did not report the experimental details (amounts of 1
and of the reagents, separation of the anomers). Therefore, we explored and applied the
acid-catalyzed methanolysis of 1.

Thiethanosugars
1757
The thio-Mitsunobu reaction of methyl α-D-fructofuranoside (2) with
each 1.3 equivalents of thioacetic acid, triphenylphosphine and di-
isopropyl azodicarboxylate (DIAD) for a prolonged reaction time of
72 h led to the 6-thioacetate 5 as the only product. It was ob-
tained with 39% yield after purification by column chromatography
(Scheme 2).
AcS
OH
O
(1)
HO
2
OMe
OH
5
SAc
SAc
AcS
HO
O
O
HO
HO
OMe
OMe
OH
OH
6
7
SCHEME 2 (1): AcSH, DIAD, Ph3P, THF.
The isomeric 1-thioacetate 6 or the 1,6-bis-thioacetate 7 could not
be detected. Although the expected NMR spectra of 5 and 6 should
be very similar, we were able to prove the structure of the product
1
to be 5 by its H- and 13C-NMR spectra. Each two signals of the two
CH2 groups present in the molecule are detected at 3.02/3.26 ppm and
3.55/3.64 ppm. On account of their chemical shifts, the first two signals
are to be assigned to a CH2-SAc11 group and the second two signals
to a CH2-OH group.12 Since the signals at 3.02 ppm and 3.26 ppm
appear as two dublets of dublets with a geminal coupling of 2J =
3
3
13.7 Hz and vicinal couplings of J = 7.3 Hz and J = 4.4 Hz, they
are due to H-6 and H-6ꢀ, whereas the signals at 3.55 ppm and 3.64
ppm, which appear as two dublets with only a geminal coupling of 2J =
12.1 Hz, must be due to H-1 and H-1ꢀ. The reverse assignment of the
coupling patterns to the signals would be valid for the isomer 6. This

1758
K. Polchow and J. Voss
assignment was corroborated by 1H-1H-COSY and 1H-13C-COSY exper-
iments. It was in agreement with the structures of the follow-up prod-
ucts, in particular with that of 9, the NMR spectrum of which was more
straightforward.
Mesylation of 5 in pyridine as solvent afforded the trimesylate 8
in nearly quantitative yield. Due to the electron-withdrawing and the
anisotropy effect of the mesylate groups, the respective 1H NMR signals
of 8 are shifted downfield to δ = 4.34 (H-1), 4.66 (H-1ꢀ), 5.17 (H-3) and
5.10 (H-4) as compared with δ = 3.55 (H-1), 3.64 (H-1ꢀ), 4.04 (H-3) and
3.75 (H-4) in 5. In the last step of the reaction sequence, 8 was treated
with sodium hydrogen carbonate in refluxing 2-methoxyethanol con-
taining 5% water. The best result was achieved with 1.5 equivalents of
the base after a reaction time of 11 h. Under these conditions a total
yield of 48% of the 4,6-anhydro-4-thiofuranoside 9 together with 5% of
the disulfide 10 was obtained. The structure of 9 is obvious from its 1H
NMR spectrum. The two dublets at 4.45 and 4.69 ppm with a geminal
coupling constant of 2J = 11.1 Hz are unequivocally due to H-1 and H-1ꢀ,
whereas the two dublets of dublets at 2.97 and 3.40 ppm with geminal
(2J = 10.3 Hz) and vicinal (3J = 3.4/4.3 Hz) coupling constants must
be assigned to H-6 and H-6ꢀ. Due to the incorporation of C-4 into a thi-
etane ring, its 13C NMR signal is shifted to δ = 46.0 ppm as compared
with δ ≈ 80 ppm in related open chained compounds such as 8. Since
the intramolecular nucleophilic attack of the thiolate occurs under in-
version on C-4, 9 belongs to the D-tagatose series. If more base and a
shorter reaction time were applied a mixture of 18% 9 and 22% 10 and
the epoxydisulfide 11 (9%) was obtained (Scheme 3), from which pure
10 and 11 could be separated.
OMs
AcS
O
(2)
(1)
MsO
5
OMe
OMs
8
S
S
OMs
O
OMs
O
OMs
+
O
MsO
S
+
MsO
OMe
OMe
OMe
OMs
10
O
2
2
9
11
SCHEME 3 (1): MsCl, pyridine; (2): NaHCO3, 2-methoxyethanol.

Thiethanosugars
1759
The 1H NMR signals of H-3 and H-4 in 10 appear at δ > 5 ppm as in
the case of 8. The epoxide protons H-3 and H-4 in 11 exhibit a typical
coupling constant of 2.9 Hz and the 13C NMR signals of C-3 and C-4 are
shifted from δ ≈ 80 ppm to δ = 57.5 ppm and 58.3 ppm. The disulfides
10 and 11 are only formed during the work-up procedure by oxidation of
the intermediate thiolate anions, as we have shown by monitoring with
thin layer chromatography. The formation of the epoxydisulfide 11 can
be explained by a base-catalyzed splitting of the mesylate at C-4 and
intramolecular nucleophilic substitution of the second mesylate on C-3
as leaving group by the alkoxide on C-4 under inversion. The resulting
11 exhibits, therefore, the D-psico-configuration.
The reaction of methyl β-D-fructofuranoside (3) with each 1.27 equiv-
alents of triphenylphosphine, DIAD, and thioacetic acid also gave 32%
of the 6-thioacetate 12 as the only product (Scheme 4). A reaction time
of 72 h at room temperature was necessary. In this case, pyridine had to
be used as solvent since the solubility of 3 in tetrahydrofuran is too low.
The structural elucidation of 12 was achieved by NMR spectroscopy
OMe
AcS
O
(1)
3
HO
OH
OH
(2)
12
OMe
AcS
OMe
O
HO
O
HO
HO
SAc
SAc
OH
OH
13
SCHEME 4 (1): 1.27 equiv. AcSH, DIAD, Ph3P, pyridine; (2): 3.0 equiv. AcSH,
DIAD, Ph3P, pyridine.

1760
K. Polchow and J. Voss
with the same argumentation as for the α-anomer 5. The two dublets
(2J = 11.7 Hz) at 3.52 and 3.61 ppm belong to the protons of the 1-
CH2OH group, whereas the two dublets of dublets (2J = 13.8 Hz, 3J =
7.5/4.7 Hz) at 3.06 and 3.29 ppm must be assigned to the 6-CH2SAc
1
1
group in agreement with the H,1H-COSY and H,13C-COSY results.
When each of the three equivalents of the reagents were applied in the
thio-Mitsunobu reaction of 3 a 27% yield of the 1,6-bis-thioacetate 13
was obtained (Scheme 4).
The mesylation of 12 afforded a quantitative yield of the trimesylate
14. Typical chemical shifts of δ > 5 ppm are observed for H-3 and H-4 in
OMe
AcS
O
OMe
O
S
(2)
(1)
MsO
MsO
12
OMs
OMs
MsO
MsO
15
14
2
(2)
O
OMe
MsO
S
OMs
16
AcS
O
OMe
(1)
(2)
MsO
13
SAc
MsO
17
O
OMe
MeS
O
OMe
S
+
S
MsO
S
19
18
SCHEME 5 (1): MsCl, pyridine (2): NaHCO3, 2-methoxyethanol.

Thiethanosugars
1761
the mesylates 14 and 15. The nucleophile promoted thioacetate cleav-
age of 14 and cyclization of the thiolate to form 16 was not successful.
After a reaction time of 11 h with 1.5 equivalents of sodium hydrogen
carbonate, only a trace (1.4%) of the disulfide 15 could be isolated by col-
umn chromatography from the dark brown reaction mixture (Scheme
5). The reason for the different behavior of the α-anomer 8 and the β-
anomer 14 might be electronic or steric repulsion between the attacking
thiolate group and the glycosidic methoxy group of 14.
Although it was not possible to remove the triphenylphosphine oxide
from 13 completely by chromatography, 13 was mesylated and the re-
sulting dimesylate 17 [91% yield; δ (H-3/H-4) = 5.15/5.18] was reacted
for 18 h with an excess of 20 equivalents of sodium hydrogen carbonate.
Column chromatography of the mixture afforded two products: 60% of
the desired 1,3:4,6-dianhydro-1,4-dithio-β-D-sorbofuranoside (18) and
11% of a byproduct which, according to its NMR spectra, exhibits the
structure of the 1,3-anhydro-6-S-methyl-1,6-dithio-D-psico derivative
19 (Scheme 5). The 13C NMR signals of the thietane carbon atoms C-3
(56.1 ppm) and C-4 (49.1 ppm) in 18 and C-3 (50.8 ppm) in 19 exhibit the
typical shift to lower values (cf. 9). The formation of 19, in particular, the
origin of the S-methyl group, can be explained only by a participation
of the solvent 2-methoxyethanol.
CONCLUSIONS
Our study has shown that the methyl fructofuranosides 2 and 3, as ex-
pected, react chemoselectively with thioacetic acid under the Mitsunobu
conditions. A primary hydroxy group is transformed into a thioacetate
whereas the less reactive secondary hydroxy groups are not attacked.
The reaction is, moreover, also regioselective. Only the 6-S-thioacetates
5 and 12 but not the 1-S-thioacetates are formed (if not a substantial ex-
cess of reagents is applied, which leads to the 1-S,6-S-bis-thioacetate 13
in case of the β anomer 3). The low reactivity of a hydroxy group in the
1-position in SN2 reactions as compared with the 6-position is a result
of the pronounced steric hindrance. It carries three substituents in the
β-position (neopentyl effect) and, in the first step of the Mitsunobu re-
action, triphenylphosphane has to be transferred from an exceptionally
bulky phosphonium cation to the hydroxy group.13
Base-promoted cleavage and concomitant intramolecular cycliza-
tion of the mesylated thioacetates 8 and 17 leads to the thietano-
ketofuranosides 9, 18, and 19. In striking contrast with these successful
reactions and the positive results in the aldohexopyranoside series,2,7
our strong efforts to prepare suitable thioacetates and cyclic thioanhy-
drides in the fructopyranoside series were in vain,2 although we were

1762
K. Polchow and J. Voss
successful in the L-sorbofuranoside as well as the L-sorbopyranoside
series.2
EXPERIMENTAL
General Procedure
Corrected melting points were determined on an Electrothermal ap-
paratus. Optical rotations were measured on a Perkin Elmer 341 po-
larimeter. Thin layer chromatography (TLC) was performed on Al foils
coated with SiO2 F254 (Merck, Darmstadt, Germany ). The spots were
detected by the extinction of the fluorescence, or, after spraying with
20% H2SO4 in EtOH, by heating. Column chromatography (CC) was
performed on Kieselgel 60 F, 0.063–0.200 mm (Merck, Darmstadt,
Germany). Eluents were distilled prior to use. IR (KBr pellets or films)
spectra were measured on an ATI Mattson Instruments Genesis Series
FT-IR spectrometer. NMR spectra were measured on a Bruker AMX
400 spectrometer at 400 MHz for 1H and at 101 MHz for 13C. Chemical
shifts δ (ppm) are related to SiMe4 which was used as internal standard
in CDCl3. Spectra measured in acetone-d6 were calibrated to δ(1H) =
2.09 ppm of the CD2H signal and δ(13C) = 30.56 ppm of the CD3 signal
and subsequently related to SiMe4. Spectra measured in D2O were cali-
brated to δ(1H) = 4.75 ppm of the HOD signal and δ (13C) was calculated
from the resonance frequency of the deuterium lock signal. In order to
1
enhance the resolution, the H NMR spectra were recalculated from
the FID by use of the program WinNMR 5.1 (Bruker). In most cases,
unequivocal assignments of the signals were achieved by performing
1
1H-1H-COSY-, H-13C-COSY-, DEPT-135- or PENDANT experiments.
Solvents were purified and dried by standard laboratory procedures,14
THF was kept over KOH for several days and subsequently refluxed and
distilled over metallic potassium. Thioacetic acid (Merck, Darmstadt,
Germany) was purified by four times distillation at low temperature in
a vacuum.
1,2:4,5-Di-O-isopropylidene-β-D-fructopyranose (1) was prepared ac-
1
cording to Brady.10 M.p. 119◦C (lit.: 119◦C). IR: ν 3460 (OH) cm−1. H
NMR (CDCl3): δ 1.37 (s, 3 H, CH3), 1.44 (s, 3 H, CH3), 1.51 (s, 3 H, CH3),
1.53 (s, 3 H, CH3), 3.66 (d, 1 H, H-3), 3.98 (d, 1 H, H-1), 4.01 (d, 1 H,
H-6), 4.12 (dd, 1 H, H-6ꢀ), 4.15 (d, 1 H, H-4), 4.18 (d, 1 H, H-1ꢀ), 4.21 (ddd,
2
3
3
3
ꢀ
1 H, H-5); JH-1,H1 8.8 Hz, JH-3,H-4 6.9 Hz, JH-4,H-5 5.9 Hz, JH-5,H-6
0.7 Hz, JH-5,H-6 2.6 Hz, 2 J
(CH3), 26.3 (CH3), 26.4 (CH3), 28.0 (CH3), 60.7 (C-6), 70.4 (C-3), 72.3
13.4 Hz. 13C NMR (CDCl3): δ 26.0
3
ꢀ
ꢀ
H-6,H-6
(C-1), 73.4 (C-5), 77.3 (C-4), 104.6 (C-2), 109.4 (CMe2), 111.9 (CMe2).

Thiethanosugars
1763
The 1H NMR and 13C NMR spectra were in agreement with literature
data.15
Methyl α-D-fructofuranoside (2), methyl β-D-fructofuranoside
(3), and 1,2-O-isopropylidene-β-D-fructopyranose (4)
A 0.02% methanolic HCl solution was prepared from acetyl chloride
(0.08 mL) and methanol (260 mL). After 30 min, 1 (5.00 g, 19.2 mmol)
was added and the mixture was stirred at 20◦C for 16 h. The solu-
tion was neutralized with triethyl amine and evaporated to dryness.
Repeated CC (EtOAc/EtOH 3:1) of the residue gave the 4 fractions
F1–F4.
F1: recovered 1 (0.48 g, 1.84 mmol, 10%).
F2: 4 (1.76 g, 7.99 mmol, 42%). IR: ν 3402 (OH) cm−1. 1H NMR (D2O):
δ 1.28 (s, 3 H, CH3), 1.36 (s, 3 H, CH3), 3.56 (dd, 1H, H-6), 3.61 (d,
1 H, H-3), 3.67 (dd, 1 H, H-4), 3.83 (dd, 1 H, H-6ꢀ), 3.85-3.87 (m, 2
2
3
H, H-1, H-5), 4.03 (d, 1 H, H-1ꢀ); J
9.3 Hz, JH-3,H-4 10.1 Hz,
ꢀ
H-1,H1
3JH-4,H-5 3.1 Hz, 3 J
1.8 Hz, 3 J
1.2 Hz, 2 J
12.6 Hz.
ꢀ
ꢀ
H-5,H-6
H-5,H-6
H-6,H-6
13C NMR (D2O): δ 25.3 (CH3), 26.5 (CH3), 64.5 (C-6), 67.4 (C-3), 69.3
(C-5), 70.7 (C-4), 71.0 (C-1), 106.2 (C-2), 113.1 (CMe2). The 1H NMR
and 13C NMR spectra were in agreement with literature data.16
1
F3: 2 (0.56 g, 2.88 mmol, 15%). H NMR (D2O): δ 3.30 (s, 3 H, OCH3),
3.65 (d, 1 H, H-1), 3.67 (dd, 1 H, H-6), 3.77 (d, 1 H, H-1ꢀ), 3.80 (dd,
1 H, H-6ꢀ), 3.92–3.95 (m, 2 H, H-4, H-5), 4.08 (d, 1 H, H-3); J
2
ꢀ
H-1,H1
10.9 Hz, 3 J
3.0 Hz, 3 J
5.6 Hz, 3 J
1.4 Hz, 2 J
H-5,H-6 H-6,H-6
ꢀ
ꢀ
H-3,H-4
H-5,H-6
12.2 Hz. 13C NMR (D2O): δ 48.6 (OCH3), 58.1 (C-1), 61.6 (C-6), 77.8
(C-4), 80.4 (C-3), 83.7 (C-5), 108.7 (C-2). The 1H NMR and 13C NMR
spectra were in agreement with literature data.17
1
F4: 3 (0.98 g, 5.05 mmol, 26%). H NMR (D2O): δ 3.37 (s, 3 H, OCH3),
3.69 (d, 1 H, H-1), 3.69 (dd, 1 H, H-6), 3.77 (d, 1 H, H-1ꢀ), 3.84 (dd,
1 H, H-6ꢀ), 3.90 (dvt, 1 H, H-5), 4.10 (vt, 1 H, H-4), 4.21 (d, 1 H,
H-3); 2 J
12.2 Hz, 3 J
8.0 Hz, 3 J
7.5 Hz, 3 J
ꢀ
H-1,H1
H-3,H-4
H-4,H-5 H-5,H-6
7.2 Hz, 3 J
3.2 Hz, 2 J
12.2 Hz. 13C NMR (D2O): δ 49.3
ꢀ
ꢀ
H-5,H-6
H-6,H-6
(OCH3), 60.1 (C-1), 63.0 (C-6), 75.4 (C-4), 77.2 (C-3), 81.6 (C-5), 104.2
(C-2). The H NMR and 13C NMR spectra were in agreement with
1
literature data.17
Methyl 6-S-acetyl-6-thio-α-D-fructofuranoside (5)
Compound 2 (540 mg, 2.78 mmol) was dissolved in THF (10 mL) at
0 ◦C under N2. Purified thioacetic acid (0.25 mL, 3.51 mmol) was added.
This solution was added to a suspension of triphenylphosphine (TPP,
0.91g 3.47 mmol) and diisopropyl azodicarboxylate (DIAD, 0.68 mL,

1764
K. Polchow and J. Voss
3.45 mmol) in THF (10 mL) at 0◦C. The reaction mixture was left at
room temp. for 72 h. The solvent was removed in a vacuum and the
residue was purified by CC (EtOAc/petroleum ether/EtOH 3:5:1) to yield
5 (266 mg, 1.11 mmol, 40%) as a pale yellow syrup. [α]2D0: +87.7 (c 1.0,
1
acetone). IR: ν 3450 (OH), 1687 (C O) cm−1. H NMR (acetone-d6): δ
2.30 (s, 3 H, COCH3), 3.02 (dd, 1 H, H-6), 3.24 (s, 3 H, OCH3), 3.26
(dd, 1 H, H-6ꢀ), 3.55 (d, 1 H, H-1), 3.64 (d, 1 H, H-1ꢀ), 3.75 (dd, 1 H,
H-4), 3.83 (ddd, 1 H, H-5), 4.04 (vt, 1 H, H-3), 4.32 (d, 1 H, OH-4),
ꢀ
4.55 (d, 1 H, OH-3); 2 J
12.1 Hz, 3 J
4.0 Hz, 3 J
H-4,H-5
6.4 Hz,
4.8 Hz,
H-1,H-1
H-3,H-4
3
2
3
3 J
7.4 Hz, J
4.4 Hz, J
13.7 Hz, J
ꢀ
ꢀ
H-5,H-6
H-5,H-6
H-6,H-6 H-3,OH-3
3 JH-4,OH-4 6.6 Hz. 13C NMR (acetone-d6): δ 30.4 (COCH3), 32.2 (C-6), 48.7
(OCH3), 60.4 (C-1), 81.95, 81.98 (C-4, C-5), 83.5 (C-3), 108.6 (C-2), 195.2
(COCH3).
Methyl 6-S-acetyl-1,3,4-tri-O-mesyl-6-thio-α-D-
fructofuranoside (8)
Compound 5 (156 mg, 0.62 mmol) was dissolved in dry pyridine
(20 mL). Methanesulfonyl chloride (0.20 mL, 2.57 mmol) was added
at 0◦C. The mixture was stirred overnight at 20◦C. After evaporation
to dryness the crude product was purified by CC (EtOH) to yield 8
(0.294 mg, quant.) as a light yellow syrup. IR: ν 1689 (C O), 1356 (SO2),
1179 (SO2) cm−1. 1H NMR (acetone-d6): δ 2.40 (s, 3 H, COCH3), 3.31 (s,
3 H, SO2CH3), 3.37 (s, 3 H, SO2CH3), 3.40 (dd, 1 H, H-6), 3.44 (s, 3 H,
SO2CH3), 3.45 (s, 3 H, OCH3), 3.52 (dd, 1 H, H-6ꢀ), 4.34 (d, 1 H, H-1),
4.44 (ddd, 1 H, H-5), 4.66 (d, 1 H, H-1ꢀ), 5.10 (dd, 1 H, H-4), 5.17 (d, 1
ꢀ
H, H-3); 2 J
11.1 Hz, 3 J
1.5 Hz, 3 J
4.4 Hz, 3 J
H-1,H-1
H-3,H-4
H-4,H-5 H-5,H-6
6.0 Hz, 3 J
5.3 Hz, 2 J
14.2 Hz. 13C NMR (acetone-d6): δ 30.5
ꢀ
ꢀ
H-5,H-6
H-6,H-6
(COCH3), 30.9 (C-6), 37.5 (SO2CH3), 38.4 (SO2CH3), 38.6 (SO2CH3),
49.2 (OCH3), 63.8 (C-1), 83.0 (C-5), 84.8 (C-4), 85.2 (C-3), 106.7 (C-2),
195.1 (COCH3).
Methyl 4,6-Anhydro-1,3-di-O-mesyl-4-thio-α-D-
tagatofuranoside (9)
A solution of 8 (437 mg, 0.91 mmol) in a 19:1 mixture (v/v) of 2-
methoxyethanol and H2O (60 mL, satd. with N2 for 30 min) was refluxed
with NaHCO3 (110 mg, 1.31 mmol) for 11 h. The solvent was evaporated
to dryness and the residue was fractionated by CC (EtOAc/petroleum
ether 1:1).
F1: 9 (56 mg, 0.16 mmol, 18%), light yellow syrup. IR: ν 1357 (MeSO3),
1174 (MeSO3) cm−1. 1H NMR (acetone-d6): δ 2.97 (ddd, 1 H, H-6), 3.23
(s, 3 H, SO2CH3), 3.24 (s, 3 H, SO2CH3), 3.28 (s, 3 H, OCH3), 3.40 (dd,

Thiethanosugars
1765
1 H, H-6ꢀ), 4.31 (vt, 1 H, H-4), 4.45 (d, 1 H, H-1), 4.69 (d, 1 H, H-1ꢀ),
4.97 (d, 1 H, H-3), 5.16 (dvt, 1 H, H-5); 2 J
11.1 Hz, 3 J
3.2 Hz, J
ꢀ
H-1,H-1
H-3,H-4
3
4
3
3
ꢀ
6.5 Hz, J
6.5 Hz, J
0.7 Hz, J
H-4,H-5
H-6,H-6
H-4,H-6
H-5,H-6 H-5,H-6
6.4 Hz, 2 J
10.3 Hz. 13C NMR (acetone-d6): δ 30.6 (C-6), 37.5
ꢀ
(SO2CH3), 38.5 (SO2CH3), 46.0 (C-4), 49.2 (OCH3), 64.6 (C-1), 81.7
(C-5), 83.6 (C-3), 108.6 (C-2).
F2: 9 (94 mg, 0.27 mmol, 30%) + 10 (18.5 mg, 0.021 mmol, 5%)
Bis(Methyl 6-deoxy-1,3,4-tri-O-mesyl-α-D-fructofuranosid-6-yl)
disulfide (10) and bis(methyl 3,4-anhydro-6-deoxy-1-O-
mesyl-α-D-psicofuranosid-6-yl) disulfide (11)
A solution of 8 (294 mg, 0.62 mmol) and NaHCO3 (100 mg, 1.19 mmol)
was refluxed (4 h) and worked up as described for 9.
F1: 11 (31 mg, 0.057 mmol, 9%), light yellow syrup. 1H NMR (acetone-
d6): δ 2.64 (dd, 1 H, H-6), 2.71 (dd, 1 H, H-6ꢀ), 3.19 (s, 3 H, SO2CH3),
3.35 (s, 3H, OCH3), 3.80 (d, 1 H, H-3), 4.02 (d, 1 H, H-4), 4.10 (d, 1
ꢀ
H, H-1), 4.31 (ddd, 1 H, H-5), 4.40 (dd, 1 H, H-1ꢀ); 2 J
11.0 Hz,
7.8 Hz,
H-1,H-1
4 J
0.7 Hz, 3 J
2.9 Hz, 3 J
0.8 Hz, 3 J
H-1,H-4
H-5,H-6
H-3,H-4
H-6,H-6
H-4,H-5 H-5,H-6
3 J
6.2 Hz, 2 J
13.6 Hz. 13C NMR (acetone-d6): δ 34.2 (C-
ꢀ
ꢀ
6), 37.4 (SO2CH3), 49.8 (OCH3), 57.5 (C-3), 58.3 (C-4), 66.2 (C-1), 79.1
(C-5), 104.4 (C-2).
F2: 9 (38 mg, 0.11 mmol, 18%) + 10 (20 mg, 0.023 mmol, 4%).
F3: 10 (97 mg, 0.11 mmol, 18%), light yellow syrup. 1H NMR (acetone-
d6): δ 2.88 (dd, 1 H, H-6), 3.00 (dd, 1 H, H-6ꢀ), 3.09 (s, 3 H, OCH3),
3.22 (s, 3 H, SO2CH3), 3.34 (s, 3 H, SO2CH3), 3.39 (s, 3 H, SO2CH3),
4.27 (d, 1 H, H-1), 4.40 (dvt, 1 H, H-5), 4.58 (d, 1 H, H-1ꢀ), 5.12 (d,
ꢀ
1 H, H-3), 5.19 (ddd, 1 H, H-4); 2 J
11.1 Hz, 3 J
6.4 Hz, J
H-5,H-6 H-5,H-6
1.8 Hz,
4.6 Hz,
H-1,H-1
H-3,H-4
4
3
3
3 J
4.8 Hz, J
0.7 Hz, J
ꢀ
H-4,H-5
H-6,H-6
H-4,H-6
2 J
14.5 Hz. 13C NMR (acetone-d6): δ 35.9 (C-6), 37.6 (SO2CH3),
ꢀ
38.6 (SO2CH3), 38.7 (SO2CH3), 49.2 (OCH3), 64.0 (C-1), 84.1 (C-5),
84.9 (C-4), 85.4 (C-3), 106.5 (C-2).
Methyl 6-S-acetyl-6-thio-β-D-fructofuranoside (12)
Compound 12 was prepared and purified as described for 5 from a
solution of 3 (0.85 g, 4.38 mmol) in pyridine (10 mL), thioacetic acid
(0.40 ml, 5.60 mmol) and a solution of TPP (1.46 g, 5.57 mmol) and
DIAD (1.10 ml, 5.60 mmol) in THF (10 mL). Yield 0.359 g (1.06 mmol,
1
32%), pale yellow syrup. IR: ν 3408 (OH), 1697 (C O) cm−1. H NMR
(acetone-d6): δ 2.33 (s, 3 H, COCH3), 3.06 (dd, 1 H, H-6), 3.289 (dd, 1
H, H-6ꢀ), 3.290 (s, 3 H, OCH3), 3.52 (d, 1 H, H-1), 3.61 (d, 1 H, H-1ꢀ),
3.78 (ddd, 1 H, H-5), 3.96 (dd, 1 H, H-4), 4.11 (d, 1 H, H-3); 2 J
ꢀ
H-1,H-1
11.7 Hz, 3 J
7.3 Hz, 3 J
6.7 Hz, 3 J
7.5 Hz, 3 J
ꢀ
H-3,H-4
H-4,H-5
H-5,H-6 H-5,H-6

1766
K. Polchow and J. Voss
4.7 Hz, 2 J
13.8 Hz. 13C NMR (acetone-d6): δ 30.5 (COCH3), 33.5
ꢀ
H-6,H-6
(C-6), 49.4 (OCH3), 61.6 (C-1), 79.1 (C-3), 80.3 (C-4), 81.3 (C-5), 105.3
(C-2), 195.1 (COCH3).
Methyl 1,6-di-S-acetyl-1,6-dithio-β-D-fructofuranoside (13)
Compound 13 was prepared and purified as described for 12 from 3
(402 mg, 2.07 mmol), thioacetic acid (0.40 mL, 5.60 mmol), TPP (1.62 g,
6.17 mmol) and DIAD (1.21 g, 6.15 mmol). Yield 810 mg (0.55 mmol,
taking into account a small content of TPP, 27%), pale yellow syrup.
1
IR: ν 3051 (OH), 1689 (C O) cm−1. H NMR (CDCl3): δ 2.31 (s, 3 H,
COCH3), 2.33 (s, 3 H, COCH3), 3.13 (dd, 1 H, H-6), 3.23 (dd, 1 H, H-6ꢀ),
3.32 (m, 5 H, H-1, H-1ꢀ, OCH3), 3.92 (dvt, 1 H, H-5), 3.97 (d, 1 H, H-3),
4.00 (dd, 1 H, H-4); 2 J
14.4 Hz, 3 JH-3,H-4 7.3 Hz, 3 JH-4,H-5 6.9 Hz,
ꢀ
H-1,HH-1
3 J
6.9 Hz, 3 J
4.9 Hz, 2 J
13.9 Hz. 13C NMR (CDCl3):
ꢀ
ꢀ
H-5,H-6
H-5,H-6
H-6,H-6
δ 30.4 (COCH3), 30.5 (COCH3), 31.3 (C-1), 32.8 (C-6), 48.9 (OCH3),
79.0 (C-5), 79.9 (C-4), 80.2 (C-3), 103.5 (C-2), 195.0 (COCH3), 195.3
(COCH3).
Methyl 6-S-acetyl-1,3,4-tri-O-mesyl-6-thio-β-D-
fructofuranoside (14)
Compound 12 (359 mg, 1.42 mmol) was dissolved in dry pyridine
(10 mL). Methanesulfonyl chloride (0.70 mL, 8.98 mmol) was added
at 0◦C and the reaction mixture was stirred overnight at 20◦C. After
evaporation to dryness the crude product was purified by CC (EtOAc)
to yield 14 (700 mg, 1.40 mmol, 99%) as a light yellow syrup. IR: ν 1695
1
(C O), 1358 (SO2), 1176 (SO2) cm−1. H NMR (acetone-d6): δ 2.37 (s,
3 H, COCH3), 3.18 (dd, 1 H, H-6), 3.20 (s, 3 H, SO2CH3), 3.29 (s, 3 H,
SO2CH3), 3.32 (s, 3 H, SO2CH3), 3.44 (s, 3 H, OCH3), 3.56 (dd, 1 H,
H-6ꢀ), 4.28 (ddd, 1 H, H-5), 4.39 (d, 1 H, H-1), 4.44 (d, 1 H, H-1ꢀ), 5.19
ꢀ
(dd, 1 H, H-4), 5.33 (d, 1 H, H-3); 2 J
11.0 Hz, 3 J
7.0 Hz,
H-3,H-4
H-1,H-1
3 J
6.6 Hz, 3 J
8.0 Hz, 3 J
4.3 Hz, 2 J
14.3 Hz.
H-6,H-6
ꢀ
ꢀ
H-4,H-5
H-5,H-6
H-5,H-6
13C NMR (acetone-d6): δ 30.5 (COCH3), 32.1 (C-6), 37.5 (SO2CH3), 38.89
(SO2CH3), 38.94 (SO2CH3), 50.6 (OCH3), 67.5 (C-1), 78.6 (C-5), 81.4 (C-
3), 83.2 (C-4), 102.3 (C-2), 194.6 (COCH3).
Bis(methyl 6-deoxy-1,3,4-tri-O-mesyl-β-D-fructofuranosid-6-yl)
disulfide (15)
A solution of 14 (670 mg, 1.38 mmol) in a 19:1 (v/v) mixture of 2-
methoxyethanol and H2O (134 mL, saturated with N2 for 30 min) was
refluxed under N2 with NaHCO3 (170 mg, 2.02 mmol) for 11 h. The
solvent was removed with a rotatory evaporator. The residue was ex-
tracted with EtOAc. After evaporation to dryness and purification by

Thiethanosugars
1767
CC (EtOAc/petroleum ether 1:1), 15 (15 mg, 1.4%) was obtained as a
1
colorless oil. IR: ν 3452 (OH), 1355 (SO2), 1176 (SO2) cm−1. H NMR
(acetone-d6): δ 2.81 (dd, 1 H, H-6ꢀ), 2.95 (dd, 1 H, H-6), 3.11 (s, 3 H,
SO2CH3), 3.18 (s, 3 H, SO2CH3), 3.19 (s, 3 H, SO2CH3), 3.44 (s, 3 H,
OCH3), 4.28 (ddd, 1 H, H-5), 4.34 (s, 2 H, H-1, H-1ꢀ), 5.27 (dd, 1 H, H-4),
5.30 (d, 1 H, H-3); 3 J
6.2 Hz, 3 J
5.6 Hz, 3 J
6.9 Hz,
H-3,H-4
H-4,H-5
H-5,H-6
3 J
5.6 Hz, 2 J
14.2 Hz. 13C NMR (acetone-d6): δ 37.3 (C-6),
ꢀ
ꢀ
H-5,H-6
H-6,H-6
38.1 (SO2CH3), 39.4 (2· SO2CH3), 50.7 (OCH3), 66.5 (C-1), 79.1 (C-5),
80.7 (C-3), 82.8 (C-4), 101.9 (C-2).
Methyl 1,6-Di-S-acetyl-3,4-di-O-mesyl-1,6-dithio-β-D-
fructofuranoside (17)
Compound 17 was prepared and purified as described for 8 from 13
(720 mg, slightly contaminated with TPP, 0.50 mmol) and methane-
sulfonyl chloride (0.90 mL, 11.6 mmol). After a reaction time of 12 h at
20◦C, workup as for 8 and CC 14 (762 mg, 0.31 mmol, 91%) was obtained
as a light yellow syrup. IR: ν 1693 (C O), 1358 (SO2), 1182 (SO2) cm−1
.
1H NMR (acetone-d6): δ 2.36 (s, 3 H, COCH3), 2.38 (s, 3 H, COCH3), 2.83
(s, 3 H, SO2CH3), 3.08 (dd, 1 H, H-6), 3.20 (s, 3 H, SO2CH3), 3.31 (d, 1 H,
H-1), 3.39 (s, 3 H, OCH3), 3.48 (m, 2 H, H-1ꢀ, H-6ꢀ), 4.20 (ddd, 1 H, H-5),
ꢀ
5.15 (d, 1 H, H-3), 5.18 (dd, 1 H, H-4); 2 J
14.5 Hz, 3 JH-3,H-4 6.8 Hz,
H-1,H-1
H-5,H-6
3 JH-4,H-5 5.4 Hz, 3 JH-5,H-6 8.1 Hz, 3 J
4.7 Hz, 2 J
14.2 Hz. 13
C
ꢀ
ꢀ
H-6,H-6
NMR (acetone-d6): δ 30.2 (C-1), 30.4 (COCH3), 30.5 (COCH3), 32.0 (C-6),
39.1 (SO2CH3), 39.5 (SO2CH3), 49.7 (OCH3), 78.2 (C-5), 81.0 (C-3/C-4),
82.9 (C-3/C-4), 103.9 (C-2), 193.8 (COCH3), 194.5 (COCH3).
Methyl 1,3:4,6-dianhydro-1,4-dithio-β-D-sorbofuranoside (18)
and methyl 1,3-anhydro-4-O-mesyl-6-S-methyl-1,6-dithio-β-D-
psicofuranoside (19)
Compound 17 (300 mg, 0.12 mmol) and NaHCO3 (200 mg, 2.38 mmol)
were refluxed under N2 in a 19:1 (v/v) mixture of 2-methoxyethanol
and H2O (200 mL, saturated with N2 for 30 min) for 18 h. The solvents
were removed in a vacuum. The residue was extracted with EtOAc
and the extract was evaporated to dryness. The product mixture was
fractionated by CC (EtOAc/petroleum ether 1:1).
F1: 18 (13.6 mg, 0.070 mmol, 60%), light yellow oil. 1H NMR (CDCl3): δ
3.16 (dd, 1 H, H-6), 3.18 (d, 1 H, H-1), 3.46-3.50 (m, 2 H, H-1ꢀ, H-6ꢀ),
3.50 (s, 3 H, OCH3), 4.01 (d, 1 H, H-4), 4.19 (s, 1 H, H-3), 5.48 (dvt, 1
H, H-5); 2 J
9.3 Hz, 3 J
6.3 Hz, 3 J
2.9 Hz, 3 J
ꢀ
ꢀ
H-1,H-1
H-4,H-5
H-5,H-6 H-5,H-6
6.3 Hz, 2 J
10.4 Hz. 13C NMR (CDCl3): δ 32.0 (C-6), 36.4 (C-1),
ꢀ
H-6,H-6
49.1 (C-4), 50.1 (OCH3), 56.1 (C-3), 84.0 (C-5), 114.6 (C-2).

1768
K. Polchow and J. Voss
F2: 19 (3.8 mg, 0.013 mmol, 11%), light yellow oil. IR: ν 1377 (SO2), 1117
(SO2) cm−1. 1H NMR (CDCl3): δ 2.23 (s, 3 H, SCH3), 2.84 (dd, 1 H, H-
6), 3.05 (dd, 1 H, H-6’), 3.08 (s, 3 H, SO2CH3), 3.28 (d, 1 H, H-1), 3.29
(s, 3 H, OCH3), 3.54 (d, 1 H, H-1ꢀ), 4.35 (d, 1 H, H-3), 4.73 (ddd, 1 H,
ꢀ
H-5), 5.08 (dd, 1 H, H-4); 2 J
10.1 Hz, 3 JH-3,H-4 6.4 Hz, 3 J
H-4,H-5
H-1,H-1
7.4 Hz, 3 JH-5,H-6 4.1 Hz, 3 J
5.4 Hz, 2 J
14.5 Hz. 13C NMR
ꢀ
ꢀ
H-5,H-6
H-6,H-6
(CDCl3): δ 17.2 (SCH3), 35.3 (C-6), 37.6 (C-1), 38.4 (SO2CH3), 49.8
(OCH3), 50.8 (C-3), 78.3 (C-4), 79.8 (C-5), 107.6 (C-2).
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