A highly efficient and stereocontrolled synthesis of 2-deoxy-1,5- thioanhydro-L-hexitols from D-glycals in a tandem nucleophilic displacement reaction

Article abstract of DOI:10.1002/ejoc.200600010

2-Deoxy-1,5-thioanhydro-L-hexitols have been synthesized in a concise sequence that includes: i) ring opening of glycals with aqueous mercury(II) acetate/sodium borohydride; ii) mesylation of the free hydroxy groups of the multifunctionalized open interme

Full text of DOI:10.1002/ejoc.200600010

FULL PAPER
DOI: 10.1002/ejoc.200600010
A Highly Efficient and Stereocontrolled Synthesis of 2-Deoxy-1,5-thioanhydro-
L
-hexitols from -Glycals in a Tandem Nucleophilic Displacement Reaction
D
Pietro Passacantilli,*[a] Clara Centore,[a] Elena Ciliberti,[a] Francesca Leonelli,[a] and
Giovanni Piancatelli*[a]
Keywords: Carbohydrates / Glycals / S-Heterocyclization
2-Deoxy-1,5-thioanhydro-
L
-hexitols have been synthesized
oxy-1,5-thioanhydro-
chemistry is shown to be useful for the synthesis of glycosyl
derivatives of 2-deoxy-1,5-thioanhydro- -hexitol, starting
from glycosyl glycals such as -lactal, -cellobial, -maltal,
-melibial and -gentiobial, thus avoiding the usually
D-xylo-hexitol. This straightforward
in a concise sequence that includes: i) ring opening of glycals
with aqueous mercury(II) acetate/sodium borohydride; ii) me-
sylation of the free hydroxy groups of the multifunctionalized
open intermediates; and iii) S-heterocyclization by treatment
with sodium sulfide. The thiosugar derivatives are obtained
L
D
D
D
D
D
lengthy glycosylation procedures.
with a 60–80% yield. Thus,
converted into the corresponding 2-deoxy-1,5-thioanhydro-
-hexitols, while -rhamnal gives 3,4-di-O-benzyl-2,6-dide-
D-glucal and D-galactal can be
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
L
L
recyclization protocol of suitably modified -sugar deriva-
tives.[9a–9c,12,15] The net retention of the (R)-stereogenic cen-
ter located at the 5-position during the introduction of the
sulfur functionality is usually achieved by double inversion
of the original (R)-hydroxycarbon center.[9c,12,15] The other
stereogenic centers present in the original sugars are left
unchanged. For example, 5-thio--glucopyranose is synthe-
sized from -glucopyranose.[16]
As part of our continuing exploitation of the reactivity
and usefulness of carbohydrate derivatives in organic syn-
thesis,[17] we describe here a new and expeditious strategy
for the synthesis of 2-deoxy-1,5-thioanhydro--hexitols that
allows access to these compounds in three steps, starting
from easily available -glycal derivatives. The versatility of
this methodology is demonstrated by its application in di-
saccharide chemistry.
Introduction
Thiosugars are carbohydrate analogues in which one or
more oxygen atoms are substituted by a sulfur atom both
in the pyranoside and furanoside structures.[1,2] In recent
years, these compounds have attracted considerable interest
from chemists and biochemists because of their biological
activity.[3] For example, both mono- and oligosaccharide
thiosugars have become increasingly important targets due
to their potential value as enzyme inhibitors[3f,4] and thera-
peutic agents, such as for diabetes,[3c] and for antiviral[5,6]
and antineoplastic[6,7] treatments. Of the several different
thiosugars described to date, only 5-thio--mannose has
been isolated some years ago from a marine sponge;[8] the
majority of the thiosugars are obtained by transformation
of natural sugars.[9] It is worth noting that a potent α-gluco-
sidase inhibitor with a unique thiosugar sulfonium sulfate
structure (a derivative of 1-deoxy-4-thioarabinofuranose)
has recently been isolated from the Ayurvedic traditional
To the best of our knowledge, there is no general and
flexible approach to prepare six-membered -configured
thiosugar derivatives in a small number of steps.
medicine Salacia reticulata in Sri Lanka and India.[10]
A
good inhibitory activity was found for a six-membered ring
analogue that is not naturally available.[11]
Results and Discussion
Furthermore, much attention has been focused on the
synthesis of 5-thiosugar-containing di- and oligosaccha-
rides, since the glycosidic bond of 5-thiosugars is known to
be resistant to enzymatic degradation by glycosidases.[12–14]
All the strategies described in the literature to obtain,
for instance, 5-thiohexopyranoses are based on a multi-step
reaction sequence, generally through a novel ring opening/
All the starting materials were prepared in one step from
O-benzyl derivatives of glycals and glycosyl glycals accord-
ing to our previously reported procedure[18] by treatment
with aqueous mercury() acetate/sodium borohydride in
one reaction flask and on a large scale (Scheme 1).
To test the efficiency of our strategy, we prepared enan-
tiomerically pure (2R,3R)-2,3-dibenzyloxypentane-1,5-diol
(2a) and the corresponding (2R,3S)-diastereoisomer 2b
from the per-O-benzylated -xylal 1a and the -arabinal 1b,
[a] Dipartimento di Chimica and Istituto di Chimica Biomolecol-
are del CNR – Sezione di Roma – Università “La Sapienza”,
Piazzale Aldo Moro 5, 00185 Rome, Italy
Eur. J. Org. Chem. 2006, 3097–3104
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P. Passacantilli, C. Centore, E. Ciliberti, F. Leonelli, G. Piancatelli
FULL PAPER
which contain good leaving groups for the following
domino process (nucleophilic displacement followed by S-
heterocyclization). In fact, the subsequent reaction with so-
dium sulfide in DMSO/methanol at 60 °C for six hours gave
the corresponding 3,4,6-tri-O-benzyl-2-deoxy-1,5-thioanhy-
dro--hexitols 7a and 7b directly in 60–65% yield
(Scheme 3). Their structure was completely in agreement
with the spectroscopic and analytical data (see Exp. Sect.).
Interestingly, (3R,4R,5S)-3,4-dibenzyloxyhexane-1,5-diol
(8), which was obtained from per-O-benzylated -rhamnal,
could be easily converted into 3,4-di-O-benzyl-2,6-dideoxy-
1,5-thioanhydro--xylo-hexitol (10) in 60% yield via the in-
termediate 9 (Scheme 4). The structure of 10 was deter-
mined from its spectroscopic data (see Exp. Sect.).
Scheme 1.
respectively (Scheme 1). The intermediates 2a and 2b have
a carbon skeleton with the protected required functionality
and free hydroxy groups for the introduction of the sulfur
atom in the right position to prepare 5-thiosugar deriva-
tives. Activation of the two primary alcohol groups as their
mesylates 3a,b, and subsequent cyclization by treatment
with sodium sulfide in DMSO at room temp. for six hours,
gave the corresponding 3,4-(dibenzyloxy)tetrahydrothiopyr-
ans 4a and 4b in 80% yield (Scheme 2). Their structure was
completely in agreement with spectroscopic and analytical
data (see Exp. Sect.).
Scheme 4.
Prompted by these findings, we decided it would be inter-
esting to exploit the reactivity of glycosyl glycals in order to
develop a short and efficient protocol for preparing glycosyl
derivatives of 2-deoxy-1,5-thioanhydro--hexitol. The suc-
cess of this strategy should render these compounds readily
accessible, thereby avoiding the usually lengthy glycosyla-
tion procedures. It is well known that in the synthesis of 5-
thiosugar-containing oligosaccharide the regio- and stere-
Scheme 2.
Stimulated by these results, we turned our attention to ospecific glycoside formation is the most important
exploring the reactivity of more densely functionalized step.[12,14] This step has been investigated by using different
(3R,4R,5R)-3,4,6-tribenzyloxyhexane-1,5-diol (5a) and the protocols, mainly a coupling reaction between thiosugars
corresponding (3R,4S,5R)-diastereoisomer 5b, which are and glycosyl acceptors and the use of a reaction promoter
available from the corresponding -glucal and -galactal, for the coupling, generally a Lewis acid or an enzyme.[12,14]
respectively, and are characterized by the presence of a sec- The yields vary from poor to good.[4a,19]
ondary and a primary alcohol. The free hydroxy groups
The enantiomerically pure 4-benzyloxyhexane-1,2,3,6-
were easily mesylated at room temperature in pyridine to tetraol derivatives 11a–e, with a sugar moiety located either
obtain the corresponding dimesyl derivatives 6a and 6b, at C1 or at C3, were easily prepared by the usual reaction
Scheme 3.
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3097–3104

Stereocontrolled Synthesis of 2-Deoxy-1,5-thioanhydro--hexitols
FULL PAPER
Scheme 5.
with aqueous mercury() acetate/sodium borohydride in
very high yields (ca. 90%) from per-O-benzylated -lactal,
-cellobial, -maltal, -melibial, and -gentiobial, respec-
tively (see Exp. Sect.).[17b]
The generation of the S-heterocyclized compounds 13a–
e in 70–75% yield proceeded smoothly following the above
protocol in a two-step sequence starting from 11a–e, namely
Experimental Section
General: 1H (200 MHz) and 13C NMR (50.3 MHz) spectra were
recorded with a Varian Gemini 200 spectrometer with CDCl3 as
the solvent and as the internal standard. IR spectra were recorded
on an IR Equinox 55 Bruker. HR mass spectra were recorded with
a Micromass Q-TOF micro Mass Spectrometer (Waters). Optical
rotations were measured using the sodium D-line on a DIP 370
formation of 2,6-di-O-mesylates 12a–e by reaction with Jasco digital polarimeter. Yields are given for products isolated af-
ter column chromatography that show a single spot by TLC and
no detectable impurities in the 1H NMR spectrum. All reactions
were performed under an inert atmosphere of N2 in flame-dried
glassware. All solvents and commercially available reagents were
used without purification, unless otherwise noted. All reactions
were monitored by TLC on Merck F-254 silica glass plates visual-
ized with UV/light and heat-gun treatment with 2  H2SO4 solu-
tion. Column chromatography was performed with Merck silica gel
60 (230–400 mesh).
methanesulfonyl chloride in pyridine and their subsequent
treatment with sodium sulfide in DMSO/CH3OH at 60 °C
for six hours (Scheme 5).
The outcome of the reaction clearly indicates that the
presence of a sugar derivative adjacent to the secondary
hydroxy group in 11a–e does not influence the intramolecu-
lar ring closure between the sulfide anion, first introduced
at C6 by a nucleophilic substitution by treatment with so-
dium sulfide, and the mesylate at C2 as leaving group. In
particular, the steric hindrance due to the presence of a per-
benzylated sugar unit close to the reaction center does not
affect the reactivity.
Preparation of Diols 2a,b, 5a,b, 8, and 11a–e. General Procedure:[18]
The appropriate per-O-benzyl derivative (1 equiv.) was dissolved in
THF (20 mL per mmol) and treated with a solution of Hg(OAc)2
(3 equiv.) in H2O (8 mL per mmol). The reaction mixture was then
stirred at room temp. until TLC (n-hexane/diethyl ether, 7:3)
showed the disappearance of the starting material (ca. 30 min.).
The reaction flask was then cooled with an ice bath and NaBH4
(60 equiv.) and MeOH (4 mL per mmol) were added. After stirring
for 1 h at 0 °C, the solvent was evaporated under reduced pressure
and the residue was dissolved in Et2O, washed in a separating fun-
nel with H2O (till neutral), then with brine, dried with anhydrous
Na2SO4, and the solvent removed. The crude product was then
purified by column chromatography.
Conclusion
In conclusion, we have demonstrated that glycals and
glycosyl glycals are attractive starting materials for the con-
struction of previously unknown -thiosugar analogues that
should be biologically important. It is worth noting that
our initial aim was to find simplified synthetic strategies
and to be guided by readily available starting materials in
conjunction with straightforward chemistry. This new strat-
egy shows high flexibility, particularly in disaccharide
chemistry, and avoids the extensive manipulations reported
for classical glycosylation sequences.
(2R,3R)-2,3-Bis(benzyloxy)pentane-1,5-diol (2a): This compound
was prepared from 1a (200 mg, 0.67 mmol) following the general
procedure described above. It was purified by column chromatog-
raphy (SiO2; n-hexane/EtOAc, 2:8) and obtained as a viscous oil
(196 mg, 92%). [α]D = +23.7 (c = 1.1, CHCl ). IR (CHCl ): ν =
˜
3
3
3500, 3100, 2950, 2900, 1600, 1500, 1372, 1278, 1120, 1076 cm–1.
1H NMR: δ = 7.31–7.25 (m, 10 H, Ph), 4.65 (d, J = 11 Hz, 1 H,
HA of CH2Ph), 4.61 (s, 2 H, CH2Ph), 4.51 (d, J = 11 Hz, 1 H, HB
of CH2Ph), 3.85–3.55 (m, 6 H, 1-HA, 1-HB, 2-H, 3-H, 5-HA, 5-HB),
Further extension of this strategy to the synthesis of
more complex thiosugars from trisaccharides is currently in
progress.
Eur. J. Org. Chem. 2006, 3097–3104
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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P. Passacantilli, C. Centore, E. Ciliberti, F. Leonelli, G. Piancatelli
(3R,4R,5R)-3,6-Bis(benzyloxy)-4-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzyl-β- -ga-
FULL PAPER
2.42 (s, 2 H, 2 OH), 2.22–1.80 (m, 2 H, 4-HA, 4-HB) ppm. 13C
D
NMR: δ = 138.0, 137.9 (Cq, Ph), 128.3, 127.9, 127.8 (Ph), 80.1, lactopyranosyl)hexane-1,5-diol (11a): This compound was prepared
77.6 (C-2, C-3), 72.8 (CH2Ph), 61.4, 59.8 (C-1, C-5), 32.6 (C-4) from perbenzylated -lactal (200 mg, 0.23 mmol) following the ge-
ppm. HRMS calcd. for C19H24O4 334.2018 [M + NH4]+; found
334.2010.
neral procedure described above. It was purified by column
chromatography (SiO2; n-hexane/EtOAc, 1:1) and obtained as a
viscous oil (187 mg, 92%). [α]D = –15.5 (c = 1.2, CHCl3). IR
(2R,3S)-2,3-Bis(benzyloxy)pentane-1,5-diol (2b): This compound
was prepared from 1b (200 mg, 0.67 mmol) following the general
procedure described above. It was purified by column chromatog-
raphy (SiO2; n-hexane/EtOAc, 2:8) and obtained as a viscous oil
(CHCl ): ν = 3500, 3120, 2950, 2930, 1650, 1500, 1470, 1378, 1275,
˜
3
1
1070 cm–1. H NMR: δ = 7.42–7.22 (m, 30 H, Ph), 5.20–4.58 (m,
13 H, 6 CH2Ph, 1Ј-H), 4.32–3.65 (m, 13 H, 1-HA, 1-HB, 3-H, 4-H,
5-H, 6-HA, 6-HB, 2Ј-H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB), 3.04 (br.
s, 2 H, 2 OH), 2.38–2.14 (m, 2 H, 2-HA, 2-HB) ppm. 13C NMR: δ
= 138.5, 138.2, 137.8, 137.6 (Cq, Ph), 128.3, 128.1, 128.0, 127.8,
127.7, 127.6, 127.5, 127.4 (Ph), 104.0 (C-1Ј), 82.3, 79.2, 78.2, 77.6,
77.1, 75.1, 73.6 (C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 74.4, 73.3,
73.2, 72.8, 72.3, 71.8, 70.8, 68.8 (C-6, C-6Ј, CH2Ph), 60.3 (C-1),
32.2 (C-2) ppm. HRMS calcd. for C54H60O10 886.4530
[M + NH4]+; found 886.4538.
(196 mg, 92%). [α]D = +12.3 (c = 1.4, CHCl ). IR (CHCl ): ν =
˜
3
3
3500, 3120, 2950, 2900, 1620, 1500, 1460, 1378, 1275, 1072 cm–1.
1H NMR: δ = 7.31–7.25 (m, 10 H, Ph), 4.64 (d, J = 12 Hz, 1 H,
HA of CH2Ph), 4.59 (s, 2 H, CH2Ph), 4.53 (d, J = 12 Hz, 1 H, HB
of CH2Ph), 3.75–3.50 (m, 6 H, 1-HA, 1-HB, 2-H, 3-H, 5-HA, 5-HB),
2.31 (s, 2 H, 2 OH), 2.22–1.84 (m, 2 H, 4-HA, 4-HB) ppm. 13C
NMR: δ = 138.1, 137.9 (Cq, Ph), 128.3, 127.8, 127.7 (Ph), 78.2,
77.6 (C-2, C-3), 72.8 (CH2Ph), 61.2, 59.9 (C-1, C-5), 32.4 (C-4)
ppm. HRMS calcd. for C19H24O4 334.2018 [M + NH4]+; found
334.2022.
(3R,4R,5R)-3,6-Bis(benzyloxy)-4-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzyl-β-D-glu-
copyranosyl)hexane-1,5-diol (11b): This compound was prepared
from perbenzylated -cellobial (200 mg, 0.23 mmol) following the
general procedure described above. It was purified by column
chromatography (SiO2; n-hexane/EtOAc, 6:4) and obtained as a
viscous oil (187 mg, 92%). [α]D = +21.6 (c = 1.2, CHCl3). IR
(3R,4R,5R)-3,4,6-Tris(benzyloxy)hexane-1,5-diol (5a): This com-
pound was prepared from perbenzylated -glucal (200 mg,
0.48 mmol) following the general procedure described above. It was
purified by column chromatography (SiO2; n-hexane/EtOAc, 1:1)
and obtained as a viscous oil (192 mg, 92%). [α]D = +22.8 (c = 1.1,
(CHCl ): ν = 3500, 3150, 3000, 2900, 1650, 1500, 1450, 1378, 1268,
˜
3
1
1072 cm–1. H NMR: δ = 7.40–7.20 (m, 30 H, Ph), 5.00–4.40 (m,
CHCl ). IR (CHCl ): ν = 3500, 3250, 2940, 2900, 1600, 1510, 1460,
˜
3
3
13 H, 6 CH2Ph, 1Ј-H), 4.18–3.35 (m, 13 H, 1-HA, 1-HB, 3-H, 4-H,
5-H, 6-HA, 6-HB, 2Ј-H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB), 2.58 (br.
s, 2 H, 2 OH), 2.25–1.85 (m, 2 H, 2-HA, 2-HB) ppm. 13C NMR: δ
= 139.1, 138.9, 138.7, 138.6, 138.5, 138.3 (Cq, Ph), 128.9, 128.8,
128.7, 128.5, 128.4, 128.3, 128.2, 128.1 (Ph), 104.1 (C-1Ј), 85.3,
82.7, 78.4, 74.9, 71.3 (C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 75.4,
73.9, 73.8, 72.8, 71.4, 69.5 (C-6, C-6Ј, CH2Ph), 60.8 (C-1), 32.9 (C-
2) ppm. HRMS calcd. for C54H60O10 886.4530 [M + NH4]+; found
886.4540.
1368, 1270, 1077 cm–1. 1H NMR: δ = 7.45–7.30 (m, 15 H, Ph),
4.70–4.50 (m, 6 H, 3 CH2Ph), 4.10–3.85 (m, 2 H, 4-H, 5-H), 3.75–
3.62 (m, 5 H, 1-HA, 1-HB, 3-H, 6-HA, 6-HB), 2.60 (br. s, 2 H, 2
OH), 1.90–1.85 (m, 2 H, 2-HA, 2-HB) ppm. 13C NMR: δ = 138.0,
137.9, 137.6 (Cq Ph), 128.4, 128.3, 128.1, 127.9, 127.8, 127.7, 127.6
(Ph), 77.9, 77.2 (C-3, C-4), 73.5, 73.4, 72.6, 70.7 (C-6, CH2Ph),
70.3 (C-5), 59.3 (C-1), 32.5 (C-2) ppm. HRMS calcd. for C27H32O5
454.2593 [M + NH4]+; found 454.2588.
(3R,4S,5R)-3,4,6-Tris(benzyloxy)hexane-1,5-diol (5b): This com-
pound was prepared from perbenzylated -galactal (200 mg,
0.48 mmol) following the general procedure described above. It was
purified by column chromatography (SiO2; n-hexane/EtOAc, 1:1)
and obtained as a viscous oil (192 mg, 92%). [α]D = –5.0 (c = 1.3,
(3R,4R,5R)-3,6-Bis(benzyloxy)-4-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzyl-α-D-glu-
copyranosyl)hexane-1,5-diol (11c): This compound was prepared
from perbenzylated -maltal (200 mg, 0.23 mmol) following the ge-
neral procedure described above. It was purified by column
chromatography (SiO2; n-hexane/EtOAc, 6:4) and obtained as a
viscous oil (187 mg, 92%). [α]D = +42.6 (c = 1.1, CHCl3). IR
CHCl ). IR (CHCl ): ν = 3500, 3120, 2950, 2900, 1600, 1520, 1460,
˜
3
3
1378, 1278 cm–1. 1H NMR: δ = 7.42–7.20 (m, 15 H, Ph), 5.40–4.20
(m, 7 H, 3 CH2Ph, 4-H), 4.18–3.70 (m, 6 H, 1-HA, 1-HB, 5-H, 3-
H, 6-HA, 6-HB), 2.73 (br. s, 2 H, 2 OH), 2.54–2.13 (m, 2 H, 2-HA,
2-HB) ppm. 13C NMR: δ = 137.9, 137.8 (Cq, Ph), 128.4, 128.3,
128.0, 127.9, 127.7, 127.6 (Ph), 79.2, 78.1 (C-3, C-4), 73.9, 73.3,
72.4, 70.9 (C-6, CH2Ph), 69.9 (C-5), 59.7 (C-1), 33.2 (C-2) ppm.
HRMS calcd. for C27H32O5 454.2593 [M + NH4]+; found 454.2583.
(CHCl ): ν = 3500, 3100, 2950, 2900, 1600, 1500, 1460, 1378, 1278,
˜
3
1072 cm–1. H NMR: δ = 7.50–7.15 (m, 30 H, Ph), 5.25–4.62 (m,
1
13 H, 6 CH2Ph, 1Ј-H), 4.45–3.50 (m, 13 H, 1-HA, 1-HB, 3-H, 4-H,
5-H, 6-HA, 6-HB, 2Ј-H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB), 3.05 (br.
s, 2 H, 2 OH), 2.40–2.25 (m, 2 H, 2-HA, 2-HB) ppm. 13C NMR: δ
= 138.5, 138.2, 138.1, 137.7, 137.6, 137.4 (Cq, Ph), 128.4, 128.2,
128.0, 127.9, 127.7, 127.5, 127.4 (Ph), 97.9 (C-1Ј), 81.5, 79.1, 77.3,
76.9, 72.8, 70.7 (C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 77.2, 75.9,
75.1, 74.5, 73.2, 73.0, 71.8, 67.8 (C-6, C-6Ј, CH2Ph), 59.3 (C-1),
32.4 (C-2) ppm. HRMS calcd. for C54H60O10 886.4530
[M + NH4]+; found 886.4535.
(3R,4R,5S)-3,4-Bis(benzyloxy)hexane-1,5-diol (8): This compound
was prepared from perbenzylated -rhamnal (200 mg, 0.64 mmol)
following the general procedure described above. It was purified by
column chromatography (SiO2; n-hexane/EtOAc, 1:1) and obtained
as a viscous oil (197 mg, 92%). [α]D = –26.5 (c = 1.2, CHCl3). IR
(3R,4R,5R)-3,4-Bis(benzyloxy)-6-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzyl-α-D-ga-
(CHCl ): ν = 3500, 3100, 2950, 2840, 1600, 1500, 1460, 1378, 1260, lactopyranosyl)hexane-1,5-diol (11d): This compound was prepared
˜
3
1070 cm–1. 1H NMR: δ = 7.42–7.20 (m, 10 H, Ph), 4.88 (d, J =
11 Hz, 1 H, HA of CH2Ph), 4.82 (s, 2 H, CH2Ph), 4.76 (d, J = general procedure described above. It was purified by column
11 Hz, 1 H, HB of CH2Ph), 4.28–3.62 (m, 5 H, 1-HA, 1-HB, 3-H, chromatography (SiO2; n-hexane/EtOAc, 6:4) and obtained as a
4-H, 5-H), 3.02 (br. s, 2 H, 2 OH), 2.22–1.98 (m, 2 H, 2-HA, 2-HB), viscous oil (187 mg, 92%). [α]D = +48.0 (c = 1.1, CHCl3). IR
1.68 (d, J = 5 Hz, 3 H, CH3) ppm. 13C NMR: δ = 137.8, 137.4 (Cq,
(CHCl ): ν = 3500, 3200, 2950, 2850, 1650, 1500, 1480, 1370, 1278,
Ph), 128.4, 128.3, 128.1, 128.0, 127.9, 127.8 (Ph), 81.4, 77.6 (C-3, 1082 cm–1. H NMR: δ = 7.45–7.20 (m, 30 H, Ph), 5.20–4.38 (m,
from perbenzylated -melibial (200 mg, 0.23 mmol) following the
˜
3
1
C-4), 73.6, 72.6 (CH2Ph), 67.4 (C-5), 59.7 (C-1), 32.6 (C-2), 19.6
(C-6) ppm. HRMS calcd. for C20H26O4 348.2175 [M + NH4]+;
found 348.2170.
13 H, 6 CH2Ph, 1Ј-H), 4.18–3.51 (m, 13 H, 1-HA, 1-HB, 3-H, 4-H,
5-H, 6-HA, 6-HB, 2Ј-H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB), 2.82 (br.
s, 2 H, 2 OH), 1.88–1.80 (m, 2 H, 2-HA, 2-HB) ppm. 13C NMR: δ
3100
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3097–3104

Stereocontrolled Synthesis of 2-Deoxy-1,5-thioanhydro--hexitols
FULL PAPER
= 138.5, 138.2, 138.1, 138.0, 137.8 (Cq, Ph), 128.3, 128.1, 128.0,
127.9, 127.7, 127.6, 127.4, 127.3 (Ph), 98.8 (C-1Ј), 79.7, 78.8, 77.3,
76.4, 74.8, 70.3, 69.6 (C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 74.6,
73.8, 73.6, 73.3, 72.8, 72.7, 70.2, 68.8 (C-6, C-6Ј, CH2Ph), 59.7 (C-
4a: [α]D = –9.5 (c = 1.4, CHCl ). IR (CHCl ): ν = 3050, 3010, 2950,
˜
3 3
2900, 1650, 1500, 1450, 1350, 1050, 1010 cm–1. 1H NMR: δ = 7.31–
7.15 (m, 10 H, Ph), 4.82–4.66 (m, 4 H, 2 CH2Ph), 3.72–3.68 (m, 1
H, 4-H); 3.60–3.48 (m, 1 H, 3-H); 3.30–3.15 (m, 2 H, 2-H), 2.85–
1), 33.4 (C-2) ppm. HRMS calcd. for C54H60O10 886.4530 [M + 2.45 (m, 4 H, 5-HA, 5-HB, 6-HA, 6-HB) ppm. 13C NMR: δ = 138.6,
NH4]+; found 886.4539.
138.4 (Cq, Ph), 128.3, 127.6, 127.5, 127.4 (Ph), 79.5, 79.3 (C-3, C-
4), 72.3, 72.1 (CH2Ph), 32.8, 30.7, 26.1 (C-2, C-5, C-6) ppm.
HRMS calcd. for C19H22O2S 332.1684 [M + NH4]+; found
332.1680.
(3R,4R,5R)-3,4-Bis(benzyloxy)-6-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzyl-β-D-glu-
copyranosyl)hexane-1,5-diol (11e): This compound was prepared
from perbenzylated -gentiobial[17b] (200 mg, 0.23 mmol) following
the general procedure described above. It was purified by column
chromatography (SiO2; n-hexane/EtOAc, 6:4) and obtained as a
viscous oil (187 mg, 92%). [α]D = +24.0 (c = 1.8, CHCl3). IR
(3S,4S)-3,4-Bis(benzyloxy)tetrahydrothiopyran (4b): This com-
pound was prepared from 2b (196 mg, 0.62 mmol) following the
general procedure described above. It was purified by column
(CHCl ): ν = 3500, 3140, 2950, 2850, 1640, 1500, 1460, 1360, 1275, chromatography (SiO2; n-hexane/EtOAc, 9:1) and obtained as a
˜
3
1077 cm–1. H NMR: δ = 7.45–7.20 (m, 30 H, Ph), 5.10–4.38 (m,
viscous oil (148 mg, 0.47 mmol, 80%). The intermediate dimesylate
1
13 H, 6 CH2Ph, 1Ј-H), 4.18–3.51 (m, 13 H, 1-HA, 1-HB, 3-H, 4-H, compound 3b was purified by column chromatography (SiO2; n-
5-H, 6-HA, 6-HB, 2Ј-H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB), 2.70 (br. hexane/EtOAc, 1:1) and obtained as a viscous oil (278 mg,
s, 2 H, 2 OH), 1.90–1.80 (m, 2 H, 2-HA, 2-HB) ppm. 13C NMR: δ
= 138.5, 138.2, 138.1, 138.0, 137.9 (Cq, Ph), 128.3, 128.2, 128.0,
127.8, 127.7, 127.5, 126.6 (Ph), 102.3 (C-1Ј), 82.7, 79.7, 78.8, 77.3,
74.8, 70.3, 69.6 (C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 74.6, 73.8,
73.6, 73.4, 72.9, 72.5, 70.1, 69.0 (C-6, C-6Ј, CH2Ph), 59.7 (C-1),
33.2 (C-2) ppm. HRMS calcd. for C54H60O10 886.4530
[M + NH4]+; found 886.4537.
0.59 mmol, 95%).
3b: [α]D = +7.4 (c = 1.2, CHCl ). IR (CHCl ): ν = 3250, 3000,
˜
3
3
2930, 1600, 1510, 1460, 1368, 1270, 1077 cm–1. 1H NMR: δ = 7.40–
7.20 (m, 10 H, Ph), 4.85–4.45 (m, 6 H, 2-H, 3-H, 2 CH2Ph), 4.30–
4.25 (m, 2 H, 1-HA, 1-HB), 4.10–3.70 (m, 2 H, 5-HA, 5-HB), 3.18
(s, 3 H, CH3SO2), 3.16 (s, 3 H, CH3SO2), 2.10–1.83 (m, 2 H, 4-HA,
4-HB) ppm. 13C NMR: δ = 137.4, 137.3 (Cq, Ph), 128.4, 128.0,
127.9 (Ph), 77.1, 74.2 (C-2, C-3) 73.2, 72.9 (CH2Ph), 68.8, 67.0 (C-
1, C-5), 37.4, 37.2 (CH3SO2), 29.4 (C-4) ppm. HRMS calcd. for
C21H28O8S2 490.1569 [M + NH4]+; found 490.1576.
General Procedure for the Preparation of Compounds 4a,b, 7a,b, 10,
and 13a–e: CH3SO2Cl (2.4 equiv.) was added at 0 °C to a stirred
solution of the appropriate linear diol (1 equiv.) in dry pyridine
(4.5 mL per mmol). The reaction mixture was stirred at room temp.
until the TLC (n-hexane/EtOAc, 1:1) showed the disappearance of
the starting material (about 1 h) and then diluted with EtOAc
(200 mL per mmol), washed in a separating funnel with 6  HCl
(12 mL per mmol), saturated aqueous NaHCO3 (until basic), H2O
(until neutral), brine (20 mL per mmol), dried with anhydrous
Na2SO4, and the solvent removed under reduced pressure. The resi-
due was then purified by column chromatography to give the dime-
sylate as a viscous oil (95% yield). The latter compound was dis-
solved in dry DMSO (4.8 mL per mmol) (a 2:1 DMSO/MeOH mix-
ture was used for compounds 7a,b, 10, and 13a–e) and treated at
room temp. with Na2S·9H2O (3 equiv.). The reaction mixture was
stirred at room temp. (compounds 7a,b, 10 and 13a–e require a
temperature of 60 °C) until the TLC (n-hexane/EtOAc, 8:2) showed
the disappearance of the starting material (about 6 h) and then di-
luted with Et2O (200 mL per mmol), washed in a separating funnel
with H2O (until neutral), brine (20 mL per mmol), dried with anhy-
drous Na2SO4, and the solvent removed under reduced pressure.
The residue was then purified by column chromatography.
4b: [α]D = –8.5 (c = 1.3, CHCl ). IR (CHCl ): ν = 3050, 3000, 2950,
˜
3
3
2850, 1640, 1500, 1480, 1350, 1050, 1010 cm–1. 1H NMR: δ = 7.33–
7.20 (m, 10 H, Ph), 4.80–4.70 (m, 4 H, 2 CH2Ph), 3.70–3.65 (m, 1
H, 4-H), 3.60–3.45 (m, 1 H, 3-H), 3.28–3.15 (m, 2 H, 2-H), 2.85–
2.45 (m, 4 H, 5-HA, 5-HB, 6-HA, 6-HB) ppm. 13C NMR: δ = 138.6,
138.4 (Cq, Ph), 128.3, 128.2, 127.8, 127.5, (Ph), 79.5, 77.2 (C-3, C-
4), 72.3, 72.1 (CH2Ph), 32.6, 30.5, 23.1 (C-2, C-5, C-6) ppm.
HRMS calcd. for C19H22O2S 332.1684 [M + NH4]+; found
332.1679.
3,4,6-Tri-O-benzyl-2-deoxy-1,5-thioanhydro-
L
-xylo-hexitol
(7a):
This compound was prepared from 5a (192 mg, 0.44 mmol) follow-
ing the general procedure described above. It was purified by col-
umn chromatography (SiO2; n-hexane/EtOAc, 9:1) and obtained as
a viscous oil (107 mg, 0.25 mmol, 60%). The intermediate dimesyl-
ate compound 6a was purified by column chromatography (SiO2;
n-hexane/EtOAc, 7:3) and obtained as a viscous oil (247 mg,
0.42 mmol, 95%).
6a: [α]D = +12.7 (c = 1.2, CHCl ). IR (CHCl ): ν = 3250, 2970,
˜
3
3
2900, 1650, 1510, 1460, 1368, 1270, 1077 cm–1. 1H NMR: δ = 7.34–
7.21 (m, 15 H, Ph), 5.28–5.20 (m, 1 H, 5-H), 5.07–4.71 (m, 6 H, 3
CH2Ph), 4.52–4.31 (m, 2 H, 3-H, 4-H), 4.21–3.94 (m, 4 H, 1-HA,
1-HB, 6-HA, 6-HB), 3.24 (s, 3 H, CH3SO2), 3.13 (s, 3 H, CH3SO2),
2.45–2.13 (m, 2 H, 2-HA, 2-HB) ppm. 13C NMR: δ = 137.5, 137.3
137.2 (Cq, Ph), 128.4, 128.2, 128.0 127.8, 127.7 (Ph), 82.4, 79.5,
75.0 (C-3, C-4, C-5), 74.1 73.3, 72.9, 68.8, 66.4 (C-1, C-6, CH2Ph),
38.3, 37.0 (CH3SO2), 30.4 (C-2) ppm. HRMS calcd. for
C29H36O9S2 610.2144 [M + NH4]+; found 610.2148.
(3S,4R)-3,4-Bis(benzyloxy)tetrahydrothiopyran (4a): This com-
pound was prepared from 2a (196 mg, 0.62 mmol) following the
general procedure described above. It was purified by column
chromatography (SiO2; n-hexane/EtOAc, 9:1) and obtained as a
viscous oil (148 mg, 0.47 mmol, 80%). The intermediate dimesylate
compound 3a was purified by column chromatography (SiO2; n-
hexane/EtOAc, 1:1) and obtained as a viscous oil (278 mg,
0.59 mmol, 95%).
3a: [α]D = +12.3 (c = 1.2, CHCl ). IR (CHCl ): ν = 3250, 2940,
˜
3
3
2900, 1600, 1510, 1460, 1368, 1270, 1100 cm–1. 1H NMR: δ = 7.41– 7a: [α]D = –58.8 (c = 1.4, CHCl ). IR (CHCl ): ν = 3050, 3010,
˜
3
3
1
7.15 (m, 10 H, Ph), 4.85–4.45 (m, 6 H, 2-H, 3-H, 2 CH2Ph), 4.35–
4.25 (m, 2 H, 1-HA, 1-HB); 4.00–3.80 (m, 2 H, 5-HA, 5-HB); 3.21 = 7.38–7.20 (m, 15 H, Ph), 4.83 (s, 2 H, CH2Ph), 4.75 (s, 4 H, 2
2960, 2910, 1620, 1510, 1460, 1350, 1060, 1020 cm–1. H NMR: δ
(s, 3 H, CH3SO2), 3.18 (s, 3 H, CH3SO2), 2.21–1.83 (m, 2 H, 4-HA,
CH2Ph), 4.04–3.76 (m, 5 H, 1-HA, 1-HB, 3-H, 4-H, 5-H), 3.25–3.12
4-HB) ppm. 13C NMR: δ = 137.4, 137.3 (Cq, Ph), 128.4, 128.0 (Ph), (m, 1 H, 6-HA), 2.73–2.62 (m, 1 H, 6-HB), 2.52–2.16 (m, 2 H, 2-
76.8, 73.9 (C-2, C-3), 73.0, 72.9 (CH2Ph), 68.7, 66.5 (C-1, C-5), HA, 2-HB) ppm. 13C NMR: δ = 138.5, 138.3, 138.2 (Cq, Ph), 128.3,
37.2, 37.1 (CH3SO2), 29.6 (C-4) ppm. HRMS calcd. for
C21H28O8S2 490.1569 [M + NH4]+; found 490.1560.
128.0, 127.6, 127.5, 127.4 (Ph), 74.6, 73.5 (C-3, C-4), 73.0, 72.7,
71.3, 69.4 (CH2Ph, C-6), 40.9 (C-5), 28.1, 22.6 (C-2, C-1) ppm.
Eur. J. Org. Chem. 2006, 3097–3104
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3101

P. Passacantilli, C. Centore, E. Ciliberti, F. Leonelli, G. Piancatelli
FULL PAPER
HRMS calcd. for C27H30O3S 452.2259 [M + NH4]+; found
452.2265.
was prepared from 11a (187 mg, 0.22 mmol) following the general
procedure described above. It was purified by column chromatog-
raphy (SiO2; n-hexane/EtOAc, 9:1) and obtained as a viscous oil
(133 mg, 0.15 mmol, 75%). The intermediate dimesylate compound
12a was purified by column chromatography (SiO2; n-hexane/
EtOAc, 7:3) and obtained as a viscous oil (210 mg, 0.21 mmol,
95%).
3,4,6-Tri-O-benzyl-2-deoxy-1,5-thioanhydro-L-ribo-hexitol
(7b):
This compound was prepared from 5b (192 mg, 0.44 mmol) follow-
ing the general procedure described above. It was purified by col-
umn chromatography (SiO2; n-hexane/EtOAc, 9:1) and obtained as
a viscous oil (107 mg, 0.25 mmol, 60%). The intermediate dimesyl-
ate compound 6b was purified by column chromatography (SiO2;
n-hexane/EtOAc, 7:3) and obtained as a viscous oil (247 mg,
0.42 mmol, 95%).
12a: [α]D = +7.0 (c = 1.2, CHCl ). IR (CHCl ): ν = 3250, 2940,
˜
3
3
2900, 1600, 1510, 1460, 1368, 1290, 1077 cm–1. 1H NMR: δ = 7.44–
7.18 (m, 30 H, Ph), 5.03–4.15 (m, 16 H, 1-HA, 1-HB, 5-H, 1Ј-H, 6
CH2Ph), 3.98–3.52 (m, 10 H, 3-H, 4-H, 6-HA, 6-HB, 2Ј-H, 3Ј-H,
4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB), 2.92 (s, 3 H, CH3SO2), 2.72 (s, 3 H,
CH3SO2), 2.32–2.05 (m, 2 H, 2-HA, 2-HB) ppm. 13C NMR: δ =
138.5, 138.4, 138.1, 137.7, 137.6, 137.5 (Cq, Ph), 128.4, 128.3, 128.1
127.8, 127.7, 127.6, 127.5, 127.4 (Ph), 102.9 (C-1Ј), 82.4, 82.2, 79.0,
77.7, 74.9, 73.8, 73.3 (C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 74.9,
74.8, 73.2, 72.8, 72.0, 68.9, 68.4, 66.9 (C-1, C-6, C-6Ј, CH2Ph), 38.4,
36.9 (CH3SO2), 29.4 (C-2) ppm. HRMS calcd. for C56H64O14S2
1042.4081 [M + NH4]+; found 1042.4075.
6b: [α]D = +24.7 (c = 1.3, CHCl ). IR (CHCl ): ν = 3250, 2940,
˜
3
3
2900, 1660, 1510, 1460, 1370, 1270, 1077 cm–1. 1H NMR: δ = 7.42–
7.25 (m, 15 H, Ph), 5.12–4.55 (m, 10 H, 1-HA, 1-HB, 4-H, 5-H, 3
CH2Ph), 4.28–3.96 (m, 3 H, 3-H, 6-HA, 6-HB), 3.18 (s, 3 H,
CH3SO2), 3.12 (s, 3 H, CH3SO2); 2.42–2.20 (m, 2 H, 2-HA, 2-HB)
ppm. 13C NMR: δ = 137.6, 137.4 137.1 (Cq, Ph), 128.3, 128.0, 127.9
127.8 (Ph), 80.9, 77.8, 74.9 (C-3, C-4, C-5), 74.0 73.1, 71.7, 68.8,
66.4 (C-1, C-6, CH2Ph), 38.0, 36.7 (CH3SO2), 29.8 (C-2) ppm.
HRMS calcd. for C29H36O9S2 610.2144 [M + NH4]+; found
610.2138.
13a: [α]D = –26.4 (c = 1.3, CHCl ). IR (CHCl ): ν = 3050, 3000,
˜
3
3
7b: [α]D = –79.5 (c = 1.4, CHCl ). IR (CHCl ): ν = 3050, 3000,
˜
1
2940, 2900, 1600, 1520, 1450, 1350, 1050, 1010 cm–1. H NMR: δ
= 7.42–7.18 (m, 30 H, Ph), 5.10–4.32 (m, 13 H, 1Ј-H, 6 CH2Ph),
4.02–3.38 (m, 11 H, 3-H, 4-H, 5-H, 2Ј-H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA,
6Ј-HB, 6-HA, 6-HB), 3.09–1.98 (m, 4 H, 1-HA, 1-HB, 2-HA, 2-HB)
ppm. 13C NMR: δ = 138.7, 138.5, 138.4, 138.0, 137.7 (Cq, Ph),
128.3, 128.2, 128.1, 127.7, 127.6, 127.3, 127.2 (Ph), 104.8 (C-1Ј),
82.1, 79.1, 74.5, 73.6, 73.3, 72.8 (C-3, C-4, C-2Ј, C-3Ј, C-4Ј, C-5Ј),
74.9, 74.5, 73.4, 73.2, 72.6, 70.7, 68.9, 68.7 (C-6, C-6Ј, CH2Ph),
40.3 (C-5), 26.6, 22.5 (C-1, C-2) ppm. HRMS calcd. for C54H58O8S
884.4196 [M + NH4]+; found 884.4190.
3
3
1
2950, 2900, 1610, 1500, 1450, 1350, 1050, 1010 cm–1. H NMR: δ
= 7.40–7.21 (m, 15 H, Ph), 4.91–4.68 (m, 7 H, 4-H, 3 CH2Ph),
4.12–3.85 (m, 4 H, 3-H, 5-H, 6-HA, 6-HB), 3.38–3.20 (m, 1 H, 1-
HA), 2.70–2.45 (m, 2 H, 2-HA, 2-HB), 2.10–1.92 (m, 1 H, 1-HB)
ppm. 13C NMR: δ = 138.8, 138.3, 138.1 (Cq, Ph), 128.2, 127.8,
127.7, 127.5, 127.4 (Ph), 79.8, 73.0 (C-3, C-4), 73.2, 71.8, 71.3, 69.3
(CH2Ph, C-6), 41.1 (C-5), 31.9, 22.7 (C-1, C-2) ppm. HRMS calcd.
for C27H30O3S 452.2259 [M + NH4]+; found 452.2265.
3,4-Di-O-benzyl-2,6-dideoxy-1,5-thioanhydro-D-xylo-hexitol
(10):
This compound was prepared from 8 (197 mg, 0.60 mmol) follow-
ing the general procedure described above. It was purified by col-
umn chromatography (SiO2; n-hexane/EtOAc, 9:1) and obtained as
a viscous oil (121 mg, 0.37 mmol, 60%). The intermediate dimesyl-
ate compound 9 was purified by column chromatography (SiO2; n-
hexane/EtOAc, 6:4) and obtained as a viscous oil (275 mg,
0.57 mmol, 95%).
3,6-Di-O-benzyl-4-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzyl-β-
D-glucopyranosyl)-
2-deoxy-1,5-thioanhydro- -xylo-hexitol (13b): This compound was
L
prepared from 11b (187 mg, 0.22 mmol) following the general pro-
cedure described above. It was purified by column chromatography
(SiO2; n-hexane/EtOAc, 9:1) and obtained as a viscous oil (124 mg,
0.14 mmol, 70%). The intermediate dimesylate compound 12b was
purified by column chromatography (SiO2; n-hexane/EtOAc, 7:3)
and obtained as a viscous oil (210 mg, 0.21 mmol, 95%).
9: [α]D = –22.1 (c = 1.2, CHCl ). IR (CHCl ): ν = 3250, 2940, 2900,
˜
3
3
1
1600, 1510, 1460, 1368, 1270, 1077 cm–1. H NMR: δ = 7.45–7.32
(m, 10 H, Ph), 5.28–5.18 (m, 1 H, 5-H), 5.02 (d, J = 11 Hz, 1 H,
HA of CH2Ph), 4.88 (d, J = 12 Hz, 1 H, HAЈ of CH2Ph), 4.86 (d,
J = 11 Hz, 1 H, HB of CH2Ph), 4.76 (d, J = 12 Hz, 1 H, HBЈ of
CH2Ph), 4.45–4.40 (m, 2 H, 3-H, 4-H), 4.12–3.84 (m, 2 H, 1-HA,
1-HB), 3.18 (s, 3 H, CH3SO2), 3.16 (s, 3 H, CH3SO2), 2.40–2.08 (m,
2 H, 2-HA, 2-HB), 1.78 (d, J = 6.5 Hz, 3 H, CH3) ppm. 13C NMR:
δ = 137.6 (Cq, Ph), 128.4, 128.1, 128.0 127.9 (Ph), 81.0, 79.1, 75.0
(C-3, C-4, C-5), 74.1 73.1 (CH2Ph), 66.5 (C-1), 38.5, 37.1
(CH3SO2), 30.6 (C-2), 16.7 (CH3) ppm. HRMS calcd. for
C22H30O8S2 504.1726 [M + NH4]+; found 504.1720.
12b: [α]D = +9.3 (c = 1.1, CHCl ). IR (CHCl ): ν = 3250, 2940,
˜
3
3
2900, 1600, 1510, 1460, 1368, 1270, 1077 cm–1. 1H NMR: δ = 7.43–
7.20 (m, 30 H, Ph), 5.04–4.20 (m, 16 H, 1-HA, 1-HB, 5-H, 1Ј-H, 6
CH2Ph), 3.98–3.88 (m, 10 H, 3-H, 4-H, 6-HA, 6-HB, 2Ј-H, 3Ј-H,
4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB), 2.92 (s, 3 H, CH3SO2), 2.86 (s, 3 H,
CH3SO2), 2.32–2.05 (m, 2 H, 2-HA, 2-HB) ppm. 13C NMR: δ =
138.4, 138.2, 138.0, 137.9, 137.7, 137.4 (Cq, Ph), 128.3, 128.1, 127.8,
127.7, 127.6, 127.5 (Ph), 102.4 (C-1Ј), 84.6, 82.2, 82.0, 77.1, 77.0,
74.6 (C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 75.6, 74.84, 74.80, 73.2,
72.9, 72.0, 68.7, 66.8 (C-1, C-6, C-6Ј, CH2Ph), 38.5, 37.0 (CH3SO2),
29.3 (C-2) ppm. HRMS calcd. for C56H64O14S2 1042.4081 [M +
NH4]+; found 1042.4088.
10: [α]D = +37.8 (c = 1.2, CHCl ). IR (CHCl ): ν = 3050, 3000,
˜
3
3
1
2940, 2890, 1600, 1500, 1450, 1360, 1050, 1015 cm–1. H NMR: δ
= 7.45–7.25 (m, 10 H, Ph), 4.92 (d, J = 11 Hz, 1 H, HA of CH2Ph),
4.90 (d, J = 11 Hz, 1 H, HAЈ of CH2Ph), 4.79 (d, J = 11 Hz, 1 H,
HB of CH2Ph), 4.76 (d, J = 11 Hz, 1 H, HBЈ of CH2Ph), 3.91–3.49
(m, 3 H, 3-H, 4-H, 5-H), 3.20–2.60 (m, 2 H, 1-HA, 1-HB), 2.45–
2.12 (m, 2 H, 2-HA, 2-HB), 1.49 (d, J = 6.5 Hz, 3 H, CH3) ppm.
13C NMR: δ = 138.6, 138.4 (Cq, Ph), 128.3, 128.0, 127.6, 127.5,
127.4 (Ph), 78.6, 74.0 (C-2, C-3), 72.6, 71.5 (CH2Ph), 35.8 (C-5),
28.6, 22.5 (C-1, C-2), 16.5 (CH3) ppm. HRMS calcd. for
C20H24O2S 346.1841 [M + NH4]+; found 346.1849.
13b: [α]D = –16.2 (c = 1.4, CHCl ). IR (CHCl ): ν = 3040, 3010,
˜
3
3
2950, 2900, 1600, 1500, 1450, 1350, 1100, 1010 cm–1. H NMR: δ
= 7.44–7.20 (m, 30 H, Ph), 5.28–4.36 (m, 13 H, 1Ј-H, 6 CH2Ph),
4.10–3.30 (m, 11 H, 3-H, 4-H, 5-H, 6-HA, 6-HB, 2Ј-H, 3Ј-H, 4Ј-H,
5Ј-H, 6Ј-HA, 6Ј-HB), 3.21–3.16 (m, 1 H, 1-HA), 2.42–2.00 (m, 3 H,
1-HB, 2-HA, 2-HB) ppm. 13C NMR: δ = 138.7, 138.6, 138.1, 138.0
(Cq, Ph), 128.3, 128.2, 128.1, 127.9, 127.7, 127.6, 127.5, 127.4, 127.3
(Ph), 104.4 (C-1Ј), 84.6, 82.0, 77.7, 74.8, 74.7 (C-3, C-4, C-2Ј, C-
3Ј, C-4Ј, C-5Ј), 75.6, 74.8, 74.6, 73.4, 72.7, 70.9, 69.9, 68.8 (C-6, C-
6Ј, CH2Ph), 40.1 (C-5), 26.5, 22.4 (C-1, C-2) ppm. HRMS calcd.
for C54H58O8S 884.4196 [M + NH4]+; found 884.4189.
1
3,6-Di-O-benzyl-4-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzyl-β-
D-galactopyranos-
yl)-2-deoxy-1,5-thioanhydro- -xylo-hexitol (13a): This compound
L
3102
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3097–3104

Stereocontrolled Synthesis of 2-Deoxy-1,5-thioanhydro--hexitols
FULL PAPER
3,6-Di-O-benzyl-4-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzyl-α-
D
-glucopyranosyl)-
CH2Ph), 41.0 (C-5), 29.9, 23.1 (C-1, C-2) ppm. HRMS calcd. for
C54H58O8S 884.4196 [M + NH4]+; found 884.4199.
2-deoxy-1,5-thioanhydro- -xylo-hexitol (13c): This compound was
L
prepared from 11c (187 mg, 0.22 mmol) following the general pro-
cedure described above. It was purified by column chromatography
(SiO2; n-hexane/EtOAc, 9:1) and obtained as a viscous oil (124 mg,
0.14 mmol, 70%). The intermediate dimesylate compound 12c was
purified by column chromatography (SiO2; n-hexane/EtOAc, 7:3)
and obtained as a viscous oil (210 mg, 0.21 mmol, 95%).
3,4-Di-O-benzyl-6-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzyl-β-
D-glucopyranosyl)-
2-deoxy-1,5-thioanhydro- -xylo-hexitol (13e): This compound was
L
prepared from 11e (187 mg, 0.22 mmol) following the general pro-
cedure described above. It was purified by column chromatography
(SiO2; n-hexane/EtOAc, 9:1) and obtained as a viscous oil (124 mg,
0.14 mmol, 70%). The intermediate dimesylate compound 12e was
purified by column chromatography (SiO2; n-hexane/EtOAc, 7:3)
and obtained as a viscous oil (210 mg, 0.21 mmol, 95%).
12c: [α]D = +45.0 (c = 1.3, CHCl ). IR (CHCl ): ν = 2940, 2900,
˜
3
3
1
1600, 1510, 1460, 1368, 1270, 1077 cm–1. H NMR: δ = 7.42–7.22
(m, 30 H, Ph), 5.13–4.18 (m, 16 H, 1-HA, 1-HB, 5-H, 1Ј-H, 6
CH2Ph), 4.04–3.58 (m, 10 H, 3-H, 4-H, 6-HA, 6-HB, 2Ј-H, 3Ј-H,
4Ј-H, 5Ј-H, 6Ј-HA, 6Ј-HB), 2.98 (s, 3 H, CH3SO2), 2.82 (s, 3 H,
CH3SO2), 2.36–1.76 (m, 2 H, 2-HA, 2-HB) ppm. 13C NMR: δ =
138.5, 138.0, 137.8, 137.3 (Cq, Ph), 128.4, 128.2, 128.1, 127.9, 127.7
(Ph), 96.7 (C-1Ј), 82.1, 81.6, 79.3, 77.4, 77.2, 76.5, 73.7 (C-3, C-4,
C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 75.4, 75.0, 73.2, 72.4, 71.0, 68.9, 67.9,
66.5 (C-1, C-6, C-6Ј, CH2Ph), 38.2, 36.8 (CH3SO2), 30.0 (C-2) ppm.
HRMS calcd. for C56H64O14S2 1042.4081 [M + NH4]+; found
1042.4090.
12e: [α]D = +13.4 (c = 1.2, CHCl ). IR (CHCl ): ν = 3250, 2950,
˜
3
3
2930, 1600, 1510, 1460, 1368, 1270, 1077 cm–1. 1H NMR: δ = 7.42–
7.23 (m, 30 H, Ph), 5.00–4.38 (m, 14 H, 5-H, 1Ј-H, 6 CH2Ph), 4.22–
3.68 (m, 12 H, 1-HA, 1-HB, 3-H, 4-H, 6-HA, 6-HB, 2Ј-H, 3Ј-H, 4Ј-
H, 5Ј-H, 6Ј-HA, 6Ј-HB), 2.86 (s, 3 H, CH3SO2), 2.80 (s, 3 H,
CH3SO2), 2.12–1.80 (m, 2 H, 2-HA, 2-HB) ppm. 13C NMR: δ =
138.4, 138.3, 137.5, 137.4, 137.1 (Cq, Ph), 128.5, 128.3, 128.0, 127.9,
127.7, 127.4 (Ph), 102.5 (C-1Ј), 81.7, 79.9, 78.4, 77.4, 75.1, 73.3,
69.6 (C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 74.8, 74.6, 73.3, 72.8,
72.2, 69.8, 68.9, 66.5, 65.9 (C-1, C-6, C-6Ј, CH2Ph), 38.2, 37.4
(CH3SO2), 29.2 (C-2) ppm. HRMS calcd. for C56H64O14S2
1042.4081 [M + NH4]+; found 1042.4089.
13c: [α]D = +16.0 (c = 1.3, CHCl ). IR (CHCl ): ν = 3050, 3000,
˜
3
3
1
2950, 2900, 1610, 1500, 1450, 1350, 1050, 1010 cm–1. H NMR: δ
= 7.42–7.18 (m, 30 H, Ph), 4.98–4.38 (m, 13 H, 1Ј-H, 6 CH2Ph),
4.03–3.45 (m, 11 H, 4-H, 5-H, 6-HA, 6-HB, 3-H, 2Ј-H, 3Ј-H, 4Ј-H,
5Ј-H, 6Ј-HA, 6Ј-HB), 2.45–2.18 (m, 2 H, 1-HA, 1-HB) 1.96–1.70 (m,
2 H, 2-HA, 2-HB) ppm. 13C NMR: δ = 138.6, 138.3, 138.1, 138.0,
137.7 (Cq, Ph), 128.2, 127.8, 127.6, 127.5, 127.4, 127.1 (Ph), 97.8
(C-1Ј), 81.7, 79.9, 77.6, 71.1 (C-3, C-4, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 75.5,
75.0, 73.4, 73.2, 72.9, 70.8, 69.8, 68.2 (C-6, C-6Ј, CH2Ph), 41.1 (C-
5), 27.5, 22.6 (C-1, C-2) ppm. HRMS calcd. for C54H58O8S
884.4196 [M + NH4]+; found 884.4192.
13e: [α]D = +5.3 (c = 1.4, CHCl ). IR (CHCl ): ν = 3050, 3000,
˜
3
3
2970, 2930, 1650, 1500, 1450, 1350, 1050, 1010 cm–1. H NMR: δ
= 7.45–7.25 (m, 30 H, Ph), 5.20–4.60 (m, 13 H, 1Ј-H, 6 CH2Ph),
4.25–3.70 (m, 11 H, 3-H, 4-H, 5-H, 2Ј-H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-HA,
6Ј-HB, 6-HA, 6-HB), 3.10–2.74 (m, 2 H, 1-HA, 1-HB), 2.54–2.06 (m,
2 H, 2-HA, 2-HB) ppm. 13C NMR: δ = 138.7, 138.6, 138.5, 138.0
(Cq, Ph), 128.2, 128.1, 127.9, 127.8, 127.5, 127.4 (Ph), 102.2 (C-1Ј),
81.7, 78.7, 76.4, 74.9, 74.5, 69.5 (C-3, C-4, C-2Ј, C-3Ј, C-4Ј, C-5Ј),
74.7, 74.2, 72.8, 76.6, 71.6, 70.1, 68.9, 68.1 (C-6, C-6Ј, CH2Ph),
41.2 (C-5), 29.9, 23.1 (C-1, C-2) ppm. HRMS calcd. for C54H58O8S
884.4196 [M + NH4]+; found 884.4213.
1
3,4-Di-O-benzyl-6-(2Ј,3Ј,4Ј,6Ј-tetra-O-benzyl-α-
D-galactopyranos-
yl)-2-deoxy-1,5-thioanhydro- -xylo-hexitol (13d): This compound
L
was prepared from 11d (187 mg, 0.22 mmol) following the general
procedure described above. It was purified by column chromatog-
raphy (SiO2; n-hexane/EtOAc, 9:1) and obtained as a viscous oil
(124 mg, 0.14 mmol, 70%). The intermediate dimesylate compound
12d was purified by column chromatography (SiO2; n-hexane/
EtOAc, 7:3) and obtained as a viscous oil (210 mg, 0.21 mmol,
95%).
Acknowledgments
Financial support from the University “La Sapienza” of Rome is
gratefully acknowledged.
[1] H. Driguez, in Glycoscience: Synthesis of Substrate Analogs and
Mimetics (Eds.: H. Driguez, J. Thiem), Springer, Berlin, 1997,
pp. 86–116.
[2] S. Mehta, B. M. Pinto, in Modern Methods in Carbohydrate
Synthesis (Eds.: S. H. Khan, R. A. O’Neill), Harwood Aca-
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[3] For the biological activity, see, for instance: a) D. J. Hoffman,
R. L. Whistler, Biochemistry 1968, 7, 4479–4483; b) R. L. Whis-
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12d: [α]D = +27.4 (c = 1.2, CHCl ). IR (CHCl ): ν = 3250, 2940,
˜
3
3
2900, 1600, 1510, 1460, 1368, 1270, 1100 cm–1. 1H NMR: δ = 7.42–
7.23 (m, 30 H, Ph), 5.02–4.38 (m, 14 H, 5-H, 1Ј-H, 6 CH2Ph), 4.22–
3.68 (m, 12 H, 1-HA, 1-HB, 3-H, 4-H, 6-HA, 6-HB, 2Ј-H, 3Ј-H, 4Ј-
H, 5Ј-H, 6Ј-HA, 6Ј-HB), 2.86 (s, 3 H, CH3SO2), 2.82 (s, 3 H,
CH3SO2), 2.12–1.82 (m, 2 H, 2-HA, 2-HB) ppm. 13C NMR: δ =
138.4, 138.3, 137.5, 137.4, 137.3 (Cq, Ph), 128.4, 128.3, 128.1, 127.9,
127.7, 127.5, 127.4 (Ph), 97.5 (C-1Ј), 81.7, 79.9, 78.2, 77.1, 75.1,
73.3, 69.7 (C-3, C-4, C-5, C-2Ј, C-3Ј, C-4Ј, C-5Ј), 74.7, 74.5, 73.3,
72.8, 72.2, 69.8, 68.9, 66.4, 65.7 (C-1, C-6, C-6Ј, CH2Ph), 38.2,
37.0 (CH3SO2), 30.4 (C-2) ppm. HRMS calcd. for C56H64O14S2
1042.4081 [M + NH4]+; found 1042.4090.
13d: [α]D = +7.4 (c = 1.4, CHCl ). IR (CHCl ): ν = 3050, 3000,
˜
3
3
1
2950, 2900, 1610, 1500, 1450, 1350, 1050, 1010 cm–1. H NMR: δ
= 7.45–7.25 (m, 30 H, Ph), 5.22–4.61 (m, 13 H, 1Ј-H, 6 CH2Ph),
4.28–3.72 (m, 11 H, 3-H, 4-H, 5-H, 6-HA, 6-HB, 2Ј-H, 3Ј-H, 4Ј-H,
5Ј-H, 6Ј-HA, 6Ј-HB), 3.08–2.72 (m, 2 H, 1-HA, 1-HB), 2.54–2.06
(m, 2 H, 2-HA, 2-HB) ppm. 13C NMR: δ = 138.8, 138.7, 138.5,
138.0 (Cq, Ph), 128.2, 128.1, 127.9, 127.8, 127.7, 127.5, 127.4 (Ph),
98.2 (C-1Ј), 78.7, 77.1, 76.4, 74.9, 74.5, 69.5 (C-3, C-4, C-2Ј, C-3Ј,
C-4Ј, C-5Ј), 74.7, 73.3, 72.8, 72.6, 71.6, 68.9, 68.0 (C-6, C-6Ј,
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Eur. J. Org. Chem. 2006, 3097–3104
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3103

P. Passacantilli, C. Centore, E. Ciliberti, F. Leonelli, G. Piancatelli
FULL PAPER
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Received: January 5, 2006
Published Online: May 22, 2006
[13] O. Tsuruta, H. Yuasa, H. Hashimoto, K. Sujino, A. Otter, H.
Li, M. M. Palcic, J. Org. Chem. 2003, 68, 6400–6406.
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3097–3104