Synthesis of 2-deoxy-2-thiophenylglucosyl azides through 1,2 thio migration of thiophenyl mannosides

Article abstract of DOI:10.1080/07328300500409150

2-Deoxy-2-thio glucosyl azides bearing or not bearing an azido group at the 6-position can be conveniently obtained through a 1,2-thio migration from thiophenyl mannoside derivatives. Copyright Taylor & Francis LLC.

Full text of DOI:10.1080/07328300500409150

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Synthesis of 2‐Deoxy‐2‐thiophenylglucosyl
Azides through 1,2 Thio Migration of
Thiophenyl Mannosides
Carmen Maiereanu a , Akira Kanai a , Jean‐Marc Weibel a & Patrick Pale a
a Laboratoire de synthèse et réactivité organique, associé au CNRS , Institut
Le Bel, Université L. Pasteur , Strasbourg, France
Published online: 02 Feb 2007.
To cite this article: Carmen Maiereanu , Akira Kanai , Jean‐Marc Weibel & Patrick Pale (2005) Synthesis
of 2‐Deoxy‐2‐thiophenylglucosyl Azides through 1,2 Thio Migration of Thiophenyl Mannosides, Journal of
Carbohydrate Chemistry, 24:8-9, 831-842, DOI: 10.1080/07328300500409150
To link to this article: http://dx.doi.org/10.1080/07328300500409150
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Journal of Carbohydrate Chemistry, 24:831–842, 2005
Copyright # Taylor & Francis LLC
ISSN: 0732-8303 print 1532-2327 online
DOI: 10.1080/07328300500409150
Synthesis of 2-Deoxy-2-
thiophenylglucosyl Azides
through 1,2 Thio Migration
of Thiophenyl Mannosides
Carmen Maiereanu, Akira Kanaiꢀ, Jean-Marc Weibel, and
Patrick Pale
`
´
´
´
Laboratoire de synthese et reactivite organique, associe au CNRS, Institut Le Bel,
´
Universite L. Pasteur, Strasbourg, France
2-Deoxy-2-thio glucosyl azides bearing or not bearing an azido group at the 6-position
can be conveniently obtained through a 1,2-thio migration from thiophenyl mannoside
derivatives.
Keywords Glucosyl azides, Thiophenyl mannosides, 1,2-Thio migration
INTRODUCTION
Carbohydrates play crucial roles in important biological recognition processes,
including bacterial and viral infections, cell adhesion in inflammation and
metastasis, differentiation, development, regulation, and other intercellular
communication and signal transduction events.[1,2] Since natural oligosacchar-
ides are easily degraded in vivo, development of biologically stable oligosac-
charide analogs is very important for studying such recognition processes
and for the elaboration of carbohydrate-based therapeutics and vaccines.[3]
In this context, we are investigating 6-amino-6-deoxyglycosides, glycosyl
amines, and the corresponding deoxy derivatives as building blocks for some
oligosaccharide mimics (Fig. 1).[4,5]
Received August 2005; accepted September 2005.
*
On leave from the Tokyo University of Science (RIKADAI), Faculty of Pharmaceutical
Sciences.
Address correspondence to Patrick Pale, Laboratoire de synthese et reactivite organi-
`
´
´
´
´
que, associe au CNRS, Institut Le Bel, Universite L. Pasteur, Strasbourg 67000,
France. Tel./Fax: þ33 390 241 517; E-mail: ppale@chimie.u-strasbg.fr
831

C. Maiereanu et al.
832
Figure 1: Oligosaccharides mimics based on glycosyl amines, 6-amino-6 deoxyglycosyl
amines and their corresponding 2-thio and 2-deoxy analogs.
In order to have convenient access to this family of compounds, we realized
that 2-deoxy-2-thio glycosyl azides, with or without an azido group at the 6
position, would offer a key entry to several series of derivatives. The azido
group can indeed be reduced to the amine, and the thio group can also be
reduced leading to the 2-deoxy series. A literature survey revealed that
6-amino-2,6-dideoxy-2-thioglycosyl azides are unknown and that even
2-deoxy-2-thioglycosyl azides surprisingly are almost unknown. A single
paper mentioned 2-deoxy-2-thioglucosyl azides in multicomponent reactions
leading to carbohydrate combinatorial libraries;[6] they were obtained as
mixtures through electrophilic addition of dibenzyl disulfide-antimony penta-
chloride to glucals in the presence of trimethylsilyl azide and alcohols.
We thus designed and described here an alternative and more convenient
route to 2-deoxy-2-thio glucosyl azides bearing or not bearing an azido group
at the 6-position through a 1,2-migration of thio mannose derivatives (Sch. 1).
The rearrangement of thio derivatives through thiiranium intermediates is
a well-known process often used in organic chemistry.[7] This process has been
extended in carbohydrate chemistry and applied to the synthesis of 2-thioglyco-
sides,[8] 2-deoxyglycosides,[9–11] sugar 2-C-sulfonic acids,[12] and 1,2-thio-
linked disaccharides.[13] It has also been used in the total synthesis of
apoptolidin.[14] This rearrangement was also detected in various works as an
undesirable side reaction.[15–18]
Based on these precedents, we anticipated that a-thio mannosides bearing
an electron-withdrawing group at the 2-position should have the right geo-
metrical and electronic requirements for a facile 1-2-thio migration. In the
presence of an azide source, the thiiranium intermediate, which should be
formed, might be opened, leading to 2-deoxy-2-thioglucosyl azides (Sch. 1).
Scheme 1: Anticipated synthesis of 2-deoxy-2-thioglucosyl azides by 1,2-thio migration of
thio mannosides (R ¼ OPG, N3).

Synthesis of 2-Deoxy-2-thiophenylglucosyl
833
RESULTS AND DISCUSSION
To validate this route, we started from the known[19] a-D-thiophenyl manno-
side protected by the Ley acetal[20] at the 3, 4 position (1 in Sch. 2). Due to
this selective protecting group, the 2, 6-positions of the sugar remained free
but are easily distinguishable, the 6 being a primary hydroxyl group. Indeed,
selective silylation[21] with tri-isopropylsilyl chloride in the presence of imida-
zole provided exclusively the 6-silylated compound 2, which was then tosylated
at the 2-position with the Bouzide’s method,[22] giving 3 in excellent overall
yields. Alternatively, selective tosylation at the 6 position can be achieved
using Yoshida’s method[23] (4 in Sch. 2). The resulting primary tosylate was
then displaced by sodium azide, leading to the azido compound 5, which was
then mesylated and tosylated (6a–b), thus providing an entry to the
6-amino-6-deoxyglucosyl series.
The tosylated thiophenyl a-D-mannoside 3 was used as a model to find the
right conditions for the expected 1,2-thio migration. Treatment of 3 with
sodium azide in polar solvents such as DMF, MeCN, THF, etc., at various temp-
eratures led mostly to the recovery of the starting material if the temperature
did not reach 1008C. DMF proved to be the best solvent, but its effect seemed
mainly correlated with its boiling point. Indeed, nothing happened after 24 h
at 508C and only 15% of starting material was converted at 808C
(Table 1; entries 1–2), but at 1008C, 50% of the expected product 7 was
formed (entry 3). A better yield was obtained at 1308C but decomposition
started occurring (entry 4). The structure of 7 was easily deduced from
changes in NMR spectra. As expected, the signal corresponding to H2 was
Scheme 2: Synthesis of the starting materials.

C. Maiereanu et al.
834
Table 1: Formation of glucosyl azides upon treatment of a-thiophenyl mannosides
by NaN3 in DMF.
Temperature Time Ratio Yield
a
Entry
Glycosides
Products
(8C)
(h) a:b
(%) b
1
2
3
4
50
80
24 1:2.5
15 1:2.5
15 1:2.5
15 1:2.5
0
11
50
64
100
130
5
6
80
24
—
0c
46
130
15 1:2
7
8
130
130
15 2:1
45
76
24 2.5:1
9
130
15 1.2:1
62
aThe ratio was derived from integration of the H1 NMR anomeric signals of the crude mixture.
bYields of pure isolated product.
cStarting material recovered.
shifted from 4.88 ppm in 3 to 3.27 ppm in 7a (2.97 in 7b) and its multiplicity
changed from a massif in 3 to a doublet of doublet in 7, clearly reflecting
profound modifications in the atomic environment of this proton and in its
stereochemistry. Similarly, the signal of the anomeric proton H1 was
shielded, especially for the b-anomer of 7 (5.55 ppm in 3, 5.38 in 7a, and
4.58 ppm in 7b). The multiplicity was also different: Appearing as a broad
singlet in 3, the anomeric proton in 7 is a doublet with typical constant
either for axial-equatorial coupling in 7a (J ¼ 4.0 Hz) or for axial-axial
coupling in 7b (J ¼ 9.5 Hz).
It is worth noting that the a/b ratio did not change whatever the conditions
in this series of experiments, and that it was in favor of the b isomer as
expected from nucleophilic opening of a thiiranium intermediate (see Sch. 1).
Further control experiments showed that this ratio did not change either

Synthesis of 2-Deoxy-2-thiophenylglucosyl
835
upon prolonged heating. These results are thus in agreement with the inter-
mediate formation of a thiiranium species.
During preliminary experiments to form 4 using standard tosylation pro-
cedures, we obtained mixtures of products, among which the mannoside mono-
tosylated at position 2 (8) was isolated (,15%). This analog of 3 bearing a free
hydroxyl group at position 6 (8) was also submitted to the above-mentioned
conditions (Table 1, entries 5–6). Although disaccharide formation could be a
competitive process via a nucleophilic attack of the free 6-alcohol to the thiira-
nium intermediate, the corresponding thioglucosyl azide 9 was cleanly
obtained but in moderate yields. Here again, a higher temperature was
required (entry 6 vs. 5) and the a/b ratio observed was similar to the one
obtained from the 6-protected 3 (entry 6 vs. 3, 4). Interestingly enough, no dis-
accharide can be detected, reflecting the better nucleophilicity of the azide ion
over the hydroxyl group. Compound 9 exhibited NMR data similar to 7 with H1
appearing as a doublet at 5.38 ppm (J ¼ 4.0 Hz) in 7a and 4.61 ppm (J ¼ 9.6 Hz)
in 7b and with H2 as a doublet of doublet at 3.30 ppm (J ¼ 4.0, 11.3 Hz) in 7a
and 2.98 ppm (J ¼ 9.6, 11.2 Hz) in 7b.
With the conditions in hand for the expected 1,2-thio migration and azida-
tion, we started investigating the azido mannosides 6a–b. Both gave the
expected rearranged product 10 in good yields (Table 1, entries 7–9). The
azido mesylated compound 6a proved to be less reactive than its tosylated
counterpart 6b. Indeed, heating 6a at 1308C for 1 day was required to get a
satisfactory yield (entry 8 vs. 7), while heating overnight was enough for 6b
(entry 9). The new product formed 10 exhibited NMR spectra very similar
to 7 and 9 and was also a mixture of anomers (H1: doublet at 5.41 ppm
(J ¼ 4.2 Hz) in 10a and 4.59 ppm (J ¼ 9.6 Hz) in 10b; H2: doublet of
doublet at 3.29 ppm (J ¼ 4.2, 11.5 Hz) in 10a and 3.00 ppm (J ¼ 9.6,
10.8 Hz) in 10b).
Surprisingly, the anomeric ratio of the azidoglucosyl azide so formed
10 was in favor of the a isomer when starting from the mesyl derivative 6a,
but did not show any significant preference for one anomer or the other
when starting from the tosyl derivatives 6b. Such differences obviously
reflect some isomerization of the thiiranium intermediate to a thia-carbenium
intermediate, but the role of the leaving group in this process is unclear
(Sch. 3).
Scheme 3: Isomerization of the thiiranium intermediate, leading to an a/b mixture of
products.

C. Maiereanu et al.
836
CONCLUSION
This work demonstrated that concomitant 1,2-thio migration and azidation of
a-thiophenyl mannosides can be achieved and offer a convenient synthesis of
various glucosyl azides, substituted or not. The compounds so obtained could
then be reduced to the corresponding glycosyl amines and to their 2-deoxy
derivatives. Such compounds may find broad applications as building blocks
and tools in glycoscience. Progress in this area is under way.
EXPERIMENTAL
General
Reactions were monitored by TLC on silica gel MERCK DC Alufolien
Kieselgel 60 PF254 with detection by UV absorption (254 nm). All moisture-
sensitive reactions were carried out under an atmosphere of argon in oven-
dried glassware. Solvents were freshly distilled; THF was distilled from
Na/benzophenone; C6H6, MeCN, and CH2Cl2 were distilled from CaH2.
Column chromatographies were performed with Merck silica gel (0.040–
0.063 mesh). Yields were based on isolated products. 1H and 13C
NMR spectra were recorded on a Bruker AC-300 spectrometer. For 1H
NMR, TMS was used as internal standard; for 13C NMR, the solvent peak
at 77.00 ppm (CDCl3) was used. IR spectra were recorded on a spectrafile
IRTM Plus MIDAC spectrophotometer. Mass Spectra were recorded on a
Bruker Daltonis Data Analysis 3.1 mass spectrometer. Specific rota-
tions were measured at 589 nm with an ADP 220 Bellingham-Stanley
polarimeter or a Perkin Elmer 241 polarimeter. Melting points were deter-
mined on a Bibby Sterilin Stuart Scientific melting point apparatus and are
uncorrected.
Phenyl 6-O-triisopropylsilyl-3,4-O-(20,30-dimethoxybutane-
20,30-diyl)-1-thio-a-D-mannopyranoside (2)
A solution of diol 1[19] (0.04 g, 0.104 mmol), triisopropylsilylchloride
(0.034 mL, 0.156 mmol), and imidazole (0.011 g, 0.156 mmol) in DMF (1 mL)
was stirred for 7 h at rt. After quenching with water, the mixture was extracted
three times with EtOAc. The combined organic layers were then washed with
brine and dried over Na2SO4. The solvent was evaporated in vacuo and the
resulting crude solid was grossly purified by column chromatography (cyclo-
hexane/EtOAc, 4/1), leading to a white solid (0.059 g; quantitative yield),
which was directly engaged in the next step.

Synthesis of 2-Deoxy-2-thiophenylglucosyl
837
Phenyl 6-O-triisopropylsilyl-3,4-O-(20,30-dimethoxybutane-
20,30-diyl)-2-O-toluenesulfonyl-1-thio-a-D-
mannopyranoside (3)
A suspension of 2, silver oxide (0.104 g, 0.448 mmol), potassium iodide
(0.074 g, 0.448 mmol), and p-toluenesulfonyl chloride (TsCl) (0.085 g,
0.448 mmol) in CH2Cl2 was refluxed for 11 h, then cooled down to rt. The
mixture was filtered with Celite. The residue was evaporated in vacuo and
then purified by column chromatography (cyclohexane/EtOAc, 4/1), yielding
a colorless oil (0.062 g, 79% yield). [a]2D4 þ113.1 (c 1.23, CHCl3). 1H NMR:
7.83 (d, J ¼ 8.3, 2H, Ph), 7.44–7.46 (m, 2H, Ph), 7.27–7.29 (m, 3H, Ph), 5.55
(br.s, 1H, H1), 4.88 (m, 1H, H2), 4.15 (br.dt, J ¼ 3.4 and 10.1 Hz, 1H, H5), 4.04
(dd, J ¼ 10.0 and 10.2 Hz, 1H, H4), 3.95 (dd, J ¼ 3.0 and 10.0 Hz, 1H, H3),
3.90–3.91 (m, 2H, H6), 3.20 (s, 3H, OCH3), 3.14 (s, 3H, OCH3), 2.42 (s, 3H,
PhCH3), 1.25 (s, 3H, CH3), 1.07 (s, 3H, Me), 1.03 (s, 21H, TIPS). 13C NMR:
144.3, 133.9, 133.7, 131.7, 129.3, 129.0, 128.2, 127.6, 100.1, 99.6, 86.8, 78.6,
72.9, 66.7, 62.7, 61.6, 21.6, 17.9, 17.8, 17.7, 17.4, 12.3, 11.9. IR (KBr): 3017,
2944, 2867, 1597, 1463, 1370, 1112, 921, 756. HR-MS: calcd for
C34H52O9NaSiS2 ([M þ Na]þ): 719.2714. Found: 719.2734.
Phenyl 3,4-O-(20,30-dimethoxybutane-20,30-diyl)-6-O-
toluenesulfonyl-1-thio-a-D-mannopyranoside (4)
To a stirred solution of 1 (1.878 g, 4.86 mmol) in acetonitrile (50 mL) was
added TsCl (1.85 g, 9.72 mmol) and TMEDA (1.5 mL, 9.72 mmol). The mixture
was then stirred at 1.5 h at rt, poured into ice water, and then extracted with
methylene chloride. The organic layer was dried (MgSO4) and evaporated
under vacuum. The residue was chromatographied on silica gel using
EtOAc/cyclohexane 3/2 as eluent giving 4 (2.556 g, 2.63 mmol; 97%). [a]D25
þ216.6 (c 2.19, CHCl3). IR (neat): 3465, 3015, 2951, 2835, 1638, 1599, 1366,
1177, 755. 1H NMR (300 MHz, CDCl3): 7.7 (d, J ¼ 8.1 Hz, 2H, Har), 7.41–
7.37 (m, 2H, Har), 7.30–7.24 (m, 5H, Har), 5.37 (br.s, 1H, H1), 4.40 (m, 1H,
H5), 4.26–4.01(m, 4H, H2, H3, H4, H6), 3.94 (dd, J ¼ 2.8 and 11.1 Hz, 1H, H6),
3.29 (s, 3H, -OCH3), 3.22 (s, 3H, -OCH3), 2.49 (d, J ¼ 1.8 Hz, 1H, -OH), 2.41
(s, 3H, -PhCH3), 1.31 (s, 3H, CH3), 1.29 (s, 3H, CH3). 13C NMR (75 MHz,
CDCl3): 144.5 (1C, Cq), 133.4 (1C, Cq), 132.7 (1C, Cq), 131.7 (1C, CHar),
129.5 (1C, CHar), 128.9 (1C, CHar), 127.9 (1C, CHar), 127.5 (1C, CHar),
100.4 (1C, Cq), 100.0 (1C, Cq), 87.9 (1C, C1), 70.8 (1C), 69.2 (1C), 68.6 (1C),
67.6 (1C), 62.9 (1C), 48.1 (1C, -OCH3), 48.0 (1C, -OCH3), 21.5 (PhMe), 17.6
(1C, -CH3), 17.5 (1C, -CH3). HR-MS: calcd for C25H32O9NaS2 ([M þ Na]þ):
563.1379. Found: 563.1393.

C. Maiereanu et al.
838
Phenyl 6-azido-6-deoxy-3,4-O-(20,30-dimethoxybutane-20,30-
diyl)-1-thio-a-D-mannopyranoside (5)
To a solution of 4 (125 mg, 0.23 mmol) in DMF (3 mL) was added at rt
sodium azide (45 mg, 0.69 mmol). The resulting mixture was heated at 808C
for 40 h. The mixture was then poured in ice water and extracted three times
with EtOAc. The organic solvent was dried (MgSO4) and evaporated under
vacuum. The residue was chromatographied on silica gel with EtOAc/cyclo-
hexane 1/2 as eluent giving 5 (93 mg, 0.22 mmol ; 98%). [a]2D5 þ249 (c 1.62,
CHCl3). IR (neat): 3447, 2993, 2948, 2833, 2100, 1583, 1480, 1376, 1281,
1140, 1049, 753. 1H NMR (300 MHz, CDCl3): 7.48–7.44 (m, 2H, Har),
7.30 ¼ 7.21 (m, 3H, Har), 5.53 (d, J ¼ 0.5 Hz, 1H, H1), 4.40 (m, 1H, H5), 4.20
(m, 1H, H2), 4.05 (dd, J ¼ 9.8 and 10.1 Hz, 1H, H4), 3.96 (dd, J ¼ 2.8
and 10.1 Hz, 1H, H3), 3.44 (s, 1H, OH), 3.42–3.36 (m, 2H, H6), 3.27 (s, 3H,
-OCH3), 3.19 (s, 3H, -OCH3), 2.49 (d, J ¼ 1.8 Hz, 1H, -OH), 2.41 (s, 3H,
-PhCH3), 1.32 (s, 3H, CH3), 1.27 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3):
133.6 (1C, Cq), 131.6 (2C, CHar), 129 (2C, CHar), 127.5 (1C, CHar), 100.4
(1C, Cq), 100.0 (1C, Cq), 88.1 (1C, C1), 71.0 (1C), 70.9 (1C), 68.7 (1C), 64.3
(1C), 50.6 (1C, C6), 48.1 (1C, -OCH3), 47.9 (1C, -OCH3), 17.7 (1C, -CH3), 17.5
(1C, -CH3). HR-MS: calcd for C18H25O6NaS ([M þ Na]þ): 434.1356. Found:
434.1359.
Phenyl 6-azido-6-deoxy-3,4-O-(20,30-dimethoxybutane-20,30-
diyl)-2-O-methylsulfonyl-1-thio-a-D-mannopyranoside
(6a)
To a stirred solution of alcohol 5 (112 mg, 0.27 mmol) in CH2Cl2 (3 mL) was
added MsCl (0.33 mL, 3.99 mmol) and triethylamine (0.57 mL, 4.1 mmol). The
mixture was stirred for 1 day and then quenched with ice water. The water
layer was extracted with dichloromethane. The organic layers were dried
(MgSO4) filtrated and the solvent evaporated in vacuo. The product was
purified by flash chromatography, using cyclohexane/EtOAc 3/1 as eluent
giving 6a (112 mg, 0.23 mmol; 84%). [a]2D5 þ162.5 (c 2.00, CHCl3). IR (neat):
2994, 2948, 2835, 2101, 1583, 1364, 1177, 1142, 1109, 923. 1H NMR
(300 MHz, CDCl3): 7.50–7.46 (m, 2H, Har), 7.35–7.29 (m, 3H, Har), 5.58
(d, J ¼ 1.0 Hz, 1H, H1), 5.09 (dd, J ¼ 1.5 and 2.7 Hz, 1H, H2), 4.38 (m, 1H,
H5), 4.11 (dd, J ¼ 2.7 and 10.3 Hz, 1H, H3), 3.99 (dd, J ¼ 10.0 and 10.3 Hz,
1H, H4), 3.55–3.40 (m, 2H, H6), 3.31 (s, 3H), 3.24 (s, 3H), 3.16 (s, 3H), 1.29
(s, 6H, CH3). 13C NMR (75 MHz, CDCl3): 132.5 (1C, Cq), 132.2 (2C, CHar),
129.3 (2C, CHar), 128.3 (1C, CHar), 100.5 (1C, Cq), 100.0 (1C, Cq), 87.5 (1C,
C1), 79.4 (1C), 71.3 (1C), 67.0 (1C), 64.1 (1C), 50.4 (1C, C6), 48.4 (1C, -OCH3),
48.2 (1C, -OCH3), 39.0 (1C, -SO2CH3), 17.6 (1C, -CH3), 17.5 (1C, -CH3). HR-
MS: calcd for C19H27O8NaS2 ([M þ Na]þ): 512.1131. Found: 512.1107.

Synthesis of 2-Deoxy-2-thiophenylglucosyl
839
Phenyl 6-azido-6-deoxy-3,4-O-(20,30-dimethoxybutane-20,30-
diyl)-2-O-toluenesulfonyl-1-thio-a-D-mannopyranoside
(6b)
To a stirred solution of alcohol 5 (49 mg, 0.12 mmol) in CH2Cl2 (2 mL) was
added Ag2O (110 mg, 0.48 mmol), TsCl (91 mg, 0.48 mmol), and KI (79 mg,
0.48 mmol). The mixture was refluxed for 48 h. After cooling at rt, the
mixture was filtered and a large excess of TMEDA was added. After stirring
for 10 min, the solvent was evaporated in vacuo. The product was purified by
flash chromatography, using cyclohexane/EtOAc 4/1 as eluent giving 6b
(65 mg, 0.11 mmol; 96%). IR (neat): 3060, 2993, 2952, 2835, 2101, 1738, 1597,
1
1444, 1370, 918. H NMR (300 MHz, CDCl3): 7.84–7.80 (m, J ¼ 8.3 Hz, 2H,
Har), 7.47–7.34 (m, 2H, Har), 7.34–7.25 (m, 5H, Har), 5.57 (d, J ¼ 1.0 Hz,
1H, H1), 4.86 (dd, J ¼ 1.4 and 2.4 Hz, 1H, H2), 4.29 (m, 1H, H5), 3.94–3.90
(m, 2H, H3 and H4), 4.28 (dd, J ¼ 2.6 and 13.2 Hz, 1H, H6), 4.19 (dd, J ¼ 6.4
and 13.2 Hz, 1H, H6), 3.18 (s, 3H, -OCH3), 3.11 (s, 3H, -OCH3), 2.02 (s, 3H, -
C6H4-CH3), 1.22 (s, 3H, CH3), 1.04 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3):
144.6 (1C, Cq), 133.6 (1C, Cq), 132.7 (1C, Cq), 132.1, 129.4, 129.3, 128.3, and
128.2 (CHar), 100.2 (1C, Cq), 99.8 (1C, Cq), 87.2 (1C, C1), 78.5 (1C), 71.3
(1C), 66.3 (1C), 64.1 (1C), 50.5 (1C, C6), 48.0 (2C, -OCH3), 21.6 (1C, Ar-Me),
17.6 (1C, -CH3), 17.3 (1C, -CH3). HR-MS: calcd for C25H31O8NaS2
([M þ Na]þ): 588.1444. Found 588.1401.
Procedure for 1,2-Thio Migration/Azidation
.
To a solution of thiophenyl a-D-mannoside (1 eq.) in DMF (0.05 M) was
added at rt sodium azide (3 eq). The resulting mixture was heated at 1308C
for several hours until disappearance of the starting material as judged
from TLC. The mixture was then poured in ice water and extracted
three times with CH2Cl2. The combined organic layers were washed with
water are brine, dried over MgSO4, and concentrated in vacuum. The
residue was chromatographied on silica gel with EtOAc/cyclohexane 7/1
as eluent.
2-Deoxy-6-O-triisopropylsilyl-3,4-O-(20,30-dimethoxybutane-
20,30-diyl)-2-thiophenyl-D-mannopyranosyl azide (7)
1
(Mixture a/b) H NMR (300 MHz, CDCl3): 7.60–7.53 (m, 2H, Har), 7.29–
7.24 (m, 3H, Har), 5.38 (d, J ¼ 4.0 Hz, 1H, H1 minor), 4.58 (d, J ¼ 9.5 Hz, 1H,
H1 major), 3.95–3.89 (m, two H6 major; H3, H4, H5, and H6 minor), 3.82 (dd,
J ¼ 9.6 and 9.9 Hz, 1H, H4 major), 3.67 (dd, J ¼ 9.6 and 11.4 Hz, 1H, H3
major), 3.48 (ddd, J ¼ 2.2, 3.1 and 9.5 Hz, 1H, H5 major), 3.38 (s, 3H, -OCH3
major), 3.35 (s, 3H, -OCH3 minor), 3,27 (dd, J ¼ 4.0 and 11.2 Hz, 1H, H2

C. Maiereanu et al.
840
minor), 3.28 (s, 3H, -OCH3 major), 3.26 (s, 3H, -OCH3 minor), 2,97 (dd, J ¼ 9.5
and 11.4 Hz, 1H, H2 major), 1.35 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.05 (s, 21H,
TIPS).
2-Deoxy-3,4-O-(20,30-dimethoxybutane-20,30-diyl)-2-
thiophenyl-D-mannopyranosyl azide (9)
1
(Mixture a/b) H NMR (300 MHz, CDCl3): 7.60–7.52 (m, 2H, Har), 7.29–
7.24 (m, 3H, Har), 5.38 (d, J ¼ 4.0 Hz, 1H, H1 minor), 4.61 (d, J ¼ 9.6 Hz, 1H,
H1 major), 4.05–3,68 (m, H6, H4, and H3 of both anomers, H5 minor), 3.55
(m, 1H, H5 major), 3.38 (s, 3H, -OCH3 major), 3.35 (s, 3H, -OCH3 minor),
3.30 (dd, J ¼ 4.0 and 11.3 Hz, 1H, H2 minor), 3.26 (s, 3H, -OCH3), 2.98 (dd,
J ¼ 9.6 and 11.2 Hz, 1H, H2 major), 1.34 (s, 3H, CH3 major), 1.31 (s, 3H, CH3
minor), 1.30 (s, 6H, CH3 major and minor).
6-Azido-2,6-dideoxy-3,4-O-(20,30-dimethoxybutane-20,30-
diyl)-2-thiophenyl-a-D-mannopyranosyl azide (10a)
[a]2D4 þ268 (c 0.51, CHCl3). IR (neat): 2993, 2948, 2833, 2107, 1440,
1379, and 1136. 1H NMR (300 MHz, CDCl3): 7.55 (m, 2H, Har), 7.29
(m, 3H, Har), 5.41 (d, J ¼ 4.2 Hz, 1H, H1), 4.09 (m, 1H, H5), 3.92 (dd,
J ¼ 9.6 and 11.5 Hz, 1H, H3), 3.71 (dd, J ¼ 9.6 and 9.8 Hz, 1H, H4), 3.58
(dd, J ¼ 2.5 and 13.3 Hz, 1H, H6), 3.40 (dd, J ¼ 4.8 and 13.3 Hz, 1H, H6),
3.35 (s, 3H, -OCH3), 3.29 (dd, J ¼ 4.2 and 11.5 Hz, 1H, H2), 3.26 (s, 3H,
-OCH3), 1.31 (s, 3H, CH3), 1.29 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3):
133.9 (1C, Cq ar), 132.7 (2C, CHar), 128.9 (2C, CHar), 127.7 (1C, CHar),
100.2 (1C, Cq), 100.1 (1C, Cq), 90.1 (1C, C1), 71.3 (1C, C5), 68.2 (1C, C3),
68.1 (1C, C4), 51.7 (1C, C2), 50.1 (1C, C6), 48.2 (1C, -OCH3), 48.1
(1C, -OCH3), 17.6 (1C, -CH3), 17.5 (1C, -CH3). HR-MS: calcd for
C18H24N6O5NaS ([M þ Na]þ): 459.1426. Found: 459.1413.
6-Azido-2,6-dideoxy-3,4-O-(20,30-dimethoxybutane-20,30-
diyl)-2-thiophenyl-b-D-mannopyranosyl azide (10b)
[a]2D4 þ116 (c 0.52, CHCl3). IR (neat): 2995, 2948, 2836, 2116, 1441, 1376,
1
and 1136. H NMR (300 MHz, CDCl3): 7.58 (m, 2H, Har), 7.28 (m, 3H, Har),
4.59 (d, J ¼ 9.6 Hz, 1H, H1), 3.64 (m, 4H, H3, H4, H5, H6), 3.37 (m, 1H, H6),
3.38 (s, 3H, -OCH3), 3.26 (s, 3H, -OCH3), 3.00 (dd, J ¼ 9.6 and 10.8 Hz, 1H,
H2), 1.34 (s, 3H, CH3), 1.29 (s, 3H, CH3). 13C NMR (75 MHz, CDCl3): 133.6
(1C, Cq ar), 133.2 (2C, CHar), 128.9 (2C, CHar), 127.8 (1C, CHar), 100.4 (1C,
Cq), 99.9 (1C, Cq), 91.5 (1C, C1), 75.4 (1C, C3), 70.5 (1C, C4), 67.8 (1C, C5),
53.5 (1C, C2), 50.2 (1C, C6), 48.4 (1C, -OCH3), 48.1 (1C, -OCH3), 17.6

Synthesis of 2-Deoxy-2-thiophenylglucosyl
841
(1C, -CH3), 17.5 (1C, -CH3). HR-MS: calcd for C18H24N6O5NaS ([M þ Na]þ):
459.1426. Found: 459.1445.
ACKNOWLEDGMENT
The authors thank the CNRS for financial support. C.M. thanks the ANRS for
financial support; A.K. thanks the Science University of Tokyo for fellowship.
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