D-Fructose-L-sorbose interconversions. Access to 5-thio-D-fructose and interaction with the D-fructose transporter, GLUT5

Article abstract of DOI:10.1016/S0008-6215(01)00153-7

Epimerisation and subsequent functionalization at C-5 of D-fructopyranose derivatives under Mitsunobu and Garegg's conditions provided efficient access to 5-thio-D-fructose (2) as well as to 5-azido-5-deoxy-1,2-O-isopropylidene-β-D-fructopyranose (19), a known precursor to 2,5-deoxy-2,5-imino-D-mannitol (3). The interaction of 2 with the D-fructose transporter GLUT5, was found to be weaker than that of D-fructose, a result that suggests involvement of the ring oxygen atom in the recognition of D-fructose by GLUT5.

Full text of DOI:10.1016/S0008-6215(01)00153-7

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Carbohydrate Research 333 (2001) 327–334
Note
D
-Fructose– -sorbose interconversions. Access to
L
5-thio-
D
-fructose and interaction with the
D-fructose
transporter, GLUT5
Arnaud Tatiboue¨t,a,* Myriam Lefoix,a Jonathan Nadolny,a Olivier R. Martin,a
Patrick Rollin,a Jing Yang,b Geoffrey D. Holmanb
aInstitut de Chimie Organique et Analytique, Uni6ersite´ d’Orle´ans, BP 6759, F-45067 Orleans, France
bDepartment of Biology and Biochemistry, Uni6ersity of Bath, Bath BA2 7AY, UK
Received 22 January 2001; received in revised form 17 May 2001; accepted 18 May 2001
Dedicated to Professor Gerard Descotes on the occasion of his retirement
Abstract
Epimerisation and subsequent functionalization at C-5 of
Garegg’s conditions provided efficient access to 5-thio- -fructose (2) as well as to 5-azido-5-deoxy-1,2-O-isopropyli-
dene-b- -fructopyranose (19), a known precursor to 2,5-deoxy-2,5-imino- -mannitol (3). The interaction of 2 with
the -fructose transporter GLUT5, was found to be weaker than that of -fructose, a result that suggests
-fructose by GLUT5. © 2001 Elsevier Science Ltd. All
D-fructopyranose derivatives under Mitsunobu and
D
D
D
D
D
involvement of the ring oxygen atom in the recognition of
rights reserved.
D
Keywords: GLUT5;
D-Fructose; L-Sorbose
The chemistry of
has not been as much developed as that of
-glucose even though it is one of the most
D
-fructose 1 (Scheme 1)
port in this note a straightforward method of
stereoselective functionalization of -fructose
with sulfur or nitrogen at C-5 and the subse-
quent cyclization process leading to 2 and to a
precursor of 3.
D
D
abundant simple sugars in nature and is indus-
trially produced.1 The objective of the studies
described here is primarily the development of
inhibitors of glycosidases and of
transporters.2 Specifically fructofuranose mim-
ics, 5-thio-
-fructose (2)3 and 2,5-dideoxy-
D
-fructose-
D
2,5-imino-
-mannitol (3)4 (Scheme 1) were
D
privileged targets within our project.5 We re-
* Corresponding author. Tel.: +33-23-8494854; fax: +33-
23-8417281.
E-mail address: arnaud.tatibouet@univ-orleans.fr (A. Tati-
boue¨t).
Scheme 1.
0008-6215/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(01)00153-7

328
A. Tatiboue¨t et al. / Carbohydrate Research 333 (2001) 327–334
Scheme 2.
respectively. Under Garegg’s conditions,9 the
5-deoxy-5-iodo- -sorbopyranose derivatives
11 and 12 were obtained in 90 and 69% yield
from 5 and 6, respectively. To our knowledge,
these are the first examples of conversion of
Our sequence started with established
procedures6 from 1,2;4,5-di-O-isopropylidene-
b- -fructopyranose involving protection of
L
D
the isolated hydroxyl group by benzoylation
followed by selective acidic hydrolysis to gen-
erate our starting material 4 in good yield.
The selective 4-O-acylation or silylation of 4
has been previously reported.6,7 4-O-Benzoyla-
tion was optimized and provided 5 in 85–90%
yield at low temperature (−65 °C) in a
CH2Cl2–pyridine mixture. Changing the O-
benzoyl protecting groups of 5 into benzyl
groups could be achieved by an efficient four-
step sequence (Scheme 2). A THP group was
first introduced at O-5 under standard condi-
tions in 98% yield. After methanolysis of the
benzoates (94% yield), benzylation of the free
hydroxyls was performed in 91% yield. Final
acid hydrolysis of the THP group gave 1,2-O-
D
-fructose to -sorbose derivatives by means
L
of Mitsunobu and Garegg’s conditions
(Scheme 2). These efficient procedures were
used to perform a second epimerization in
order to prepare 5-amino-5-deoxy- and 5-thio-
D
-fructopyranose derivatives.
Mitsunobu conditions were applied to com-
pounds 9 and 10 to introduce nitrogen via a
phthalimido group and sulfur by way of a
dithiocarbamate functionality10 (Scheme 3). In
all cases, complete transformations occurred
but the products were contaminated with di-
ethyl hydrazodicarboxylate (DEADH2) even
after chromatography. Pure compounds could
be isolated from 10 after two further steps: (i)
the phthalimido group was removed with
ethylenediamine and the amino group thus
released was acetylated to give compound 13
in 83% overall yield; (ii) the dithiocarbamate
functionality was reduced with LAH into a
thiol that was then acetylated to 14 in 77%
overall yield.
isopropylidene-3,4-di-O-benzyl-b- -fructopy-
D
ranose (6) in nearly quantitative yield. This
sequence could be carried out on a multigram
scale without purification of the intermediates,
thus providing 6 in nearly 85% overall yield.
Epimerisation at C-5 in both compounds 5
and 6 was faced in order to prepare
L
-
sorbopyranose derivatives. Under standard
Mitsunobu conditions8 using chloroacetic acid
and p-nitrobenzoic acid, compounds 5 and 6
gave esters 7 and 8 in 76 and 90% yields,
respectively. Selective deprotection of the
chloroacetyl and nitrobenzoyl groups using
hydrazine acetate and Zemplen conditions, re-
Another method for the introduction of
nitrogen and sulfur was based on nucleophilic
displacements of iodine in 5-deoxy-5-iodo- -
L
sorbopyranose derivatives bearing either ben-
zoyl (11) or benzyl (12) protective groups.
Using potassium thioacetate in DMF, excel-
lent yields were obtained (93% for 14 and 95%
for 15). Sodium azide in DMF proved to be
spectively, gave the
L
-sorbopyranose deriva-
tives 9 and 10 in 70 and 94% yield

A. Tatiboue¨t et al. / Carbohydrate Research 333 (2001) 327–334
329
Scheme 3.
smoothly underwent acetolysis into 18 in 90%
yield. The anomers 18a and 18b could be
separated by chromatography (1:4 ratio).
NMR spectroscopy clearly showed that 18b
less efficient on the benzoate 11, in which case
only 50% of 16 was isolated. By changing the
solvent to Me2SO, however, a clean displace-
ment occurred and azides 16 and 17 were
obtained in very good yields (91 and 85%,
respectively).
The benzylated thioacetate 14 could thus be
reached either by way of the Mitsunobu reac-
tion or by the Garegg’s reaction. Both routes
were competitive in terms of yields, though
the Mitsunobu approach required three more
steps. The benzoylated thioacetate 15 was
reached more conveniently using the Garegg’s
reaction. No attempts were made to obtain
this product through a Mitsunobu approach
because of the multistep process required.
2
was in the usual C5 conformation whereas
5
18a was in a C2 conformation.
A standard transesterification process in
methanol then gave 5-thio- -fructose (2) in
D
nearly quantitative yield. Moreover, when a
transesterification of 16 was performed under
the same conditions, the well-known precursor
19 of 2,5-dideoxy-2,5-imino- -mannitol (3)
D
was prepared in very good yield.
In conclusion, we have further explored the
selective functionalization of
at C-5 and its epimerisation into
D
-fructopyranose
-sorbose
L
compounds using Mitsunobu and Garegg’s
methodologies. Advantage was taken of the
reactivity of the C-5 hydroxyl to provide a
All
D
-fructopyranose and
L
-sorbopyranose
2
derivatives 7–17 were shown to exist in a C5
conformation in solution. This was confirmed
by the magnitude of the J3,4 coupling con-
3
new efficient access to 5-thio-
D
-fructose (2) in
stant (8.5–10.7 Hz). The epimerisation pro-
eight steps from -fructose and in 20–25%
D
3
cess was monitored by the J4,5 values which
overall yield. Access to 19 was also efficient, in
seven steps and 25–30% overall yield.
ranged for
tween 3.4 and 4.7 Hz and for
D
-fructopyranose compounds be-
-sorbopyranose
L
Biological studies of 2 as a GLUT5 in-
hibitor were undertaken with CHO cell line in
which GLUT 5 transporter is expressed at
high levels.2 The substrate for the assays is a
derivatives between 9.4 and 10.0 Hz (Tables 1
and 2).
The procedures described are efficient path-
ways to thio- and amino- functionalization at
tracer concentration (1 mM) of [14C-U]-
-
D
C-5 of
these results, the synthesis of 5-thio-
(2) was performed. The thioacetate 15
D
-fructose. As a first development of
fructose. First results showed a weak inhibi-
tion constant of 96 mM. This indicates that
the affinity is at least six-times lower than for
D
-fructose

330
A. Tatiboue¨t et al. / Carbohydrate Research 333 (2001) 327–334
Table 1
1H NMR chemical shifts (l in ppm) and coupling constants (J in Hz) for 1,2-O-isopropylidene
D-fructopyranose- and
L
-sorbopyranose derivatives
H-1a
H-1b
H-3
H-4
H-5
H-6a
H-6b
specific protons C(CH3)2
6
3.93 (d)
J1a,1b 12.6
3.97 (d)
3.77(d)
J3,4 9.4
3.95 (dd)
3.4
5.93 (dd)
J4,5 9.8
4.04 (ddd)
J5,6a 1.7
3.80 (dd)
J6a,6b 13.0
3.96–4.12
3.93 (dd)
J5,6b 1.5
3.96–4.12
n.d. a
2.4 (OH, s)
1.43
1.49
1.42
1.54
7
3.96–4.12 3.96–4.12 5.51 (d)
5.33 (ddd)
n.d. a
n.d. a
J3,4 9.8
J5,6a 6.4, J5,6b n.d. a
10.4
3.89 (d)
J1a,1b 8.7
3.97 (d)
5.54 (d)
J3,4 9.4
4.14 (dd)
J4,5 9.4
5.56 (dd)
J4,5 10.0
5.24 (ddd)
J5,6a 10.6
3.83–4.14
n.d. a
3.77 (dd)
3.91 (dd)
J5,6b 6.2
1.48
1.51
1.43
1.54
1.44
1.50
1.41
1.54
1.45
1.50
1.47
1.42
J6a,6b 10.9
3.83–4.14
n.d. a
9
3.83–4.14 3.83–4.14 5.47 (d)
3.83–4.14 3.7 (OH, d)
n.d. a
n.d. a
3.91 (d)
J3,4 9.8
n.d. a
JOH,5 4.9
10 3.87 (d)
J1a,1b 8.5
11 3.99 (d)
J1a,1b 9.4
12 3.81 (d)
J1a,1b 8.5
13 3.87 (d)
J1a,1b 9.5
3.39 (d)
3.69–3.77 3.69–3.77
3.69–3.77
3.69–3.77 2.05 (OH, s)
J3,4 9.00 n.d. a
n.d. a
4.16–4.34
n.d. a
n.d. a
5.40 (d)
J3,4 9.7
3.38 (d)
n.d. a
3.53 (d)
J3,4 9.8
5.96 (dd)
3.94–4.1
n.d. a
4.16–4.34
J4,5 10.05 n.d. a
n.d. a
3.89 (d)
J3,4 8.5
3.96 (d)
3.79–4.11 3.79–4.11
3.79–4.11
3.79–4.11
n.d. a
3.98 (dd)
n.d. a
n.d. a
4.6 (m)
n.d. a
4.01 (dd)
J4,5 4.7
3.70 (dd)
J6a,6b 12.1
J5,6a 1.8
2.00 (COCH3)
6.53
(NHCOCH3, d)
JNH,5 8.31
J5,6b 1.9
14 3.87 (d)
J1a,1b 8.5
3.92 (d)
4.00 (d)
3.38 (d)
J3,4 9.8
4.18 (dd)
J4,5 4.7
4.35 (m)
4.49 (m)
3.69 (dd)
J6a,6b 12.4
J5,6a 1.9
3.85 (dd)
J6a,6b 12.2
J5,6a 1.3
4.24 (dd)
J5,6b 2.2
2.39 (COCH3)
1.42
1.46
15 4.07 (d)
J1a,1b 9.4
5.60 (d)
J3,4 10.7 J4,5 4.7
5.88 (dd)
4.53 (dd)
J5,6b 2.2
2.24 (COCH3)
1.43
1.53
16 4.02 (d)
9.4
17 3.92 (d)
8.5
4.10 (d)
3.94 (d)
5.87 (d)
J3,4 10.4 J4,5 3.4
3.77 (d)
9.6
5.78 (dd)
4.31 (ddd)
J5,6a 1.7
3.91 (m)
3.88 (dd)
J6a,6b 12.6
3.65 (dd)
J6a,6b 12.8
J5,6a 1.1
4.24 (dd)
J5,6b 1.7
3.90 (dd)
J5,6b 1.7
1.43
1.53
1.42
1.46
4.05 (dd)
3.7
a n.d., not determined.
Table 2
13C NMR chemical shifts (l in ppm) for 1,2-O-isopropylidene
D
-fructopyranose- and L-sorbopyranose derivatives
C-1
C-2
C-3
C-4
C-5
C-6
C(CH3)2
Specific carbons
6
7
8
71.7
71.6
71.5
105.6
104.0
105.1
74.5
69.4
78.3
80.1
71.6
81.3
67.1
71.1
72.8
62.9
60.0
59.9
26.1, 26.9, 111.9
26.2, 26.6, 113.0
26.2, 27.2, 112.5
CH2Ph 72.1, 75.3
COCH2Cl 40.5, 165.8
CH2Ph 75.5, 75.6
OCOPh 163.8
CꢀNO2 150.6
9
10
11
12
13
71.8
71.5
71.8
71.6
71.9
104.0
105.3
104.6
105.8
105.3
69.0
78.4
71.0
80.4
75.0
76.9
84.2
74.3
84.0
78.1
69.9
70.2
22.0
26.8
47.5
63.5
62.9
65.9
65.9
62.6
26.3, 26.7, 112.7
26.3, 27.2, 112.2
26.1, 26.7, 112.8
26.2, 27.2, 112.5
26.3, 27.1, 112.4
CH2Ph 2×75.4
CH2Ph 75.4, 75.7
CH2Ph 71.4, 75.4
COCH3 23.5, 170.5
CH2Ph 71.6, 75.3
COCH3 31.0, 195.1
COCH3 30.5, 193.5
14
71.9
105.6
76.4
78.1
45.5
63.7
26.1, 27.1, 112.3
15
16
17
71.9
71.8
71.8
104.7
104.7
105.7
68.4
67.2
75.0
69.9
71.7
80.0
45.5
60.2
60.1
63.8
62.1
61.8
26.1, 26.5, 112.5
26.2, 26.5, 112.5
26.1, 27.0, 112.2

A. Tatiboue¨t et al. / Carbohydrate Research 333 (2001) 327–334
331
D
-fructose.2 Therefore, a single change of oxy-
29.5 mmol) was added dropwise. After
overnight stirring, careful methanolysis (10
mL) was then effected. The mixture was di-
luted in water (100 mL) and extracted with
EtOAc (3×150 mL). The combined organic
fractions were washed with water (3×50 mL),
satd NaCl (50 mL), then dried over MgSO4
and evaporated to dryness. The crude mixture
was treated, in the last deprotection step, with
AcOH (30 mL)–water (7.5 mL) for 1 day.
After extraction with EtOAc–water, alcalini-
sation with aq K2CO3, drying of the organic
solution over MgSO4 and evaporation of the
solvent, 6 (4.5 g, 84%) was purified by flash
chromatography using 7:3 petroleum ether–
EtOAc: [h]2D0 −90° (c 1.1, CHCl3); IR (NaCl)
w 3460 (br, OH); ISMS(+): m/z 418 [M+
NH4]+, 423 [M+Na]+. Anal. Calcd for
C23H28O6: C, 68.98; H, 7.05. Found: C, 68.92;
H, 7.00.
gen into sulfur atom in the ring markedly
changes the interaction with the GLUT5 bind-
ing site. This result demonstrates that the ring
oxygen of
GLUT5 binding.
D
-fructofuranose is involved in
1. Experimental
General methods.—Melting points were de-
termined on a Bu¨chi 510 apparatus and are
uncorrected. H and 13C NMR spectra were
1
recorded in CDCl3 with Me4Si as internal
standard; for other solvents, the residual peak
was used as internal standard. Whenever ap-
propriate, signal assignments were deduced by
DEPT, COSY and HETCOR NMR experi-
ments. Specific rotations were measured at
20 °C using a Perkin–Elmer 141 polarimeter.
Low resolution mass spectra (MS) were
recorded by the ICOA Analytical Service on a
Perkin–Elmer SCIEX API 300 (ion spray).
Elemental analysis was performed by the mi-
croanalytical service at the University of Bath
and by the analytical service of the CNRS,
Vernaison. Analytical TLC was carried out on
precoated Silica Gel 60F-254 plates (E.
Merck) and spots were detected by UV light
(254 nm) and by spraying with a 5% H2SO4
ethanolic solution followed by heating.
Column chromatography was performed on
Silica Gel SI 60 (43–60 mm) (E. Merck).
3,4-Di-O-benzoyl-5-O-chloroacetyl-1,2-O-
isopropylidene-i- -sorbopyranose (7).—To a
L
cooled (ice-salt bath) solution containing 5
(1.9 g, 4.44 mmol), triphenylphosphine (3 g,
11.4 mmol) and chloroacetic acid (1.05 g, 11.1
mmol) in dry toluene (20 mL), DEAD (2 mL,
12.7 mmol) was slowly added. The solution
was stirred at 60 °C overnight. After evapora-
tion of the solvent, colorless crystals of 7, (1.7
g, 76%) were obtained by silica-gel column
chromatography using 8.5:1.5 petroleum
ether–EtOAc: mp: 88–90 °C; [h]2D0 −139° (c
1.04, CHCl3); IR (NaCl) w 1770 and 1731
cm−1 (esters); ISMS(+): m/z 522 [M+NH4]+,
524 [M+NH4]+, 527 [M+Na]+, 529 [M+
Na]+. Anal. Calcd for C25H25ClO9: C, 59.47;
H, 4.99. Found: C, 59.12; H, 5.09.
3,4-Di-O-benzyl-1,2-O-isopropylidene-i-
fructopyranose (6).—To a solution of 3,4-di-
O-benzoyl-1,2-O-isopropylidene-b- -fructopy-
D
-
D
ranose (5)6 (5.7 g, 13.3 mmol) and dihydropy-
ran (8 mL, 87.7 mmol) in dry CH2Cl2 was
added camphorsulfonic acid (0.05 g, 0.21
mmol). The mixture was left under Ar at rt for
2 h. After alcalinisation with triethylamine,
the solvent was removed by evaporation. The
crude product was dissolved in dry MeOH (30
mL) and then Na (0.03 g, 1.3 mmol) was
added to the solution, which was stirred
overnight. The solution was made neutral with
DOWEX 50X, and the solvent removed by
evaporation. The residue was dissolved in
DMF (30 mL) and after cooling in an ice-salt
bath, NaH (60%, 2.3 g, 57.5 mmol) was
added. After 20 min stirring, BnBr (3.5 mL,
3,4-Di-O-benzyl-1,2-O-isopropylidene-5-O-
p-nitrobenzoyl-i- -sorbopyranose (8).—Same
L
conditions as those applied to 5 for 6 (1.245 g,
3.11 mmol), with some modifications: the re-
action was carried out at rt with p-nitroben-
zoic acid and the chromatography was
performed with 9:1 petroleum ether–EtOAc. 8
(1.17 g, 94%) was obtained as pale yellow
crystals: mp 94–95 °C; [h]2D0 +53° (c 1.09,
CHCl3); IR (NaCl) w 1731 cm−1 (esters);
ISMS(+): m/z 567 [M+NH4]+, 572 [M+
Na]+. Anal. Calcd for C30H31NO9: C, 65.56;
H, 5.69. Found: C, 65.84; H, 5.70.
3,4-Di-O-benzoyl-1,2-O-isopropylidene-i-
L
-
sorbopyranose (9).—To a solution of 7 (0.927

332
A. Tatiboue¨t et al. / Carbohydrate Research 333 (2001) 327–334
g, 1.84 mmol) in MeOH (30 mL) hydrazine
acetate (0.18 g, 1.95 mmol) was added. The
mixture was stirred at rt until completion.
After evaporation of the solvent, 9 (0.51 g,
65%) was purified by chromatography using
petroleum ether–EtOAc (4:1): mp 150–
151 °C; [h]2D0 −161° (c 1.17, CHCl3); IR
(NaCl) w 3468 (br, OH), 1729 cm−1 (esters);
ISMS(+): m/z 446 [M+NH4]+, 451 [M+
Na]+. Anal. Calcd for C23H24O8: C, 64.48; H,
5.65. Found: C, 64.42; H, 5.61.
fected using 4:1 petroleum ether–EtOAc. The
phthalimido compound contaminated with
DIADH2 was deprotected in EtOH (50 mL)
with ethylenediamine (0.95 mL, 14.2 mmol)
and overnight reflux, then purified after evap-
oration by chromatography using a mixture
45:4:1 EtOAc–MeOH–water. The crude
amine was directly acetylated using pyridine (3
mL) and Ac2O (3 mL), yielding 13 (0.915 g,
83%) over three steps without further purifica-
tion: [h]2D0 −81° (c 1, CHCl3); IR (NaCl) w
3,4-Di-O-benzyl-1,2-O-isopropylidene-i-
L
-
3293 (br, NH), 1651 cm−1 (amide); ISMS(+)
:
sorbopyranose (10).—The ester 8 (1.533 g, 2.8
mmol) was deacylated using standard Zem-
plen conditions. After completion of the reac-
tion, the solvent was removed. The crude
mixture was purified by flash chromatography
using 4:1 petroleum ether–EtOAc yielding 10
(1.05 g, 94%): mp 79–80 °C; [h]2D0 −32° (c
1.08, CHCl3); IR (NaCl) w 3449 cm−1 (br,
OH); ISMS(+): m/z 418 [M+NH4]+, 423
[M+Na]+. Anal. Calcd for C23H28O6: C,
68.98; H, 7.05. Found: C, 68.93; H, 7.11.
3,4-Di-O-benzoyl-5-deoxy-5-iodo-1,2-O-iso-
m/z 443 [M+NH4]+. Anal. Calcd for
C25H31O6N: C, 68.01; H, 7.08 Found: C,
67.78; H, 7.13.
5-S-Acetyl-3,4-di-O-benzyl-1,2-O-isopropy-
lidene - 5 - thio - i -
D
- fructopyranose (14).—
Method A: The same protocol as for 7, using
precursor 10 (0.4 g, 1 mmol). The dithiocarba-
mate contaminated with DIADH2 was diluted
with Et2O (20 mL) and LAH (0.098 g, 2.6
mmol) was added portionwise. The solution
was stirred at rt for 48 h. The workup was
effected by the addition of ice and acidifica-
tion to pH 1 with HCl 2 M, then extracted
twice with EtOAc. The organic layers were
collected, washed with water until neutral and
dried over MgSO4. After evaporation, the
crude thiol was diluted with pyridine (5 mL)
and Ac2O (2 mL). After 24 h stirring at rt, the
solvents were removed by coevaporation with
toluene, and 14 crystallized in EtOH–water
mixture (0.356 g, 77%): mp 79–81 °C; [h]D20
−89° (c 1.09, CHCl3); IR (NaCl) w 1691
cm−1 (thioester); ISMS(+): m/z 476 [M+
NH4]+, 481 [M+Na]+. Anal. Calcd for
C25H30O6S: C, 65.48; H, 6.59. Found: C,
65.67; H, 6.65.
propylidene-i- -sorbopyranose (11).—Com-
L
pound 5 (1 g, 2.33 mmol), triphenylphosphine
(1.9 g, 7.25 mmol), imidazole (0.5 g, 7.35
mmol) and iodine (1.25 g, 4.84 mmol) were
dissolved in dry toluene (35 mL). The mixture
was maintained at 60 °C for 5 days, then
evaporated and purified by flash column chro-
matography, 9:1 petroleum ether–EtOAc
yielding 11 (1.15 g, 91%): mp 152–153 °C;
[h]2D0 −102° (c 1.02, CHCl3); IR (NaCl) w
1731 cm−1 (esters); ISMS(+): m/z 556 [M+
NH4]+, 561 [M+Na]+. Anal. Calcd for
C23H23IO7: C, 51.32; H, 4.31. Found: C, 51.71;
H, 4.35.
3,4-Di-O-benzyl-5-O-deoxy-5-iodo-1,2-O-
Method B: Compound 12 (0.07 g, 0.14
mmol) diluted in DMF (2 mL) was mixed
with AcSK (0.05 g, 0.51 mmol). The solution
was heated at 100 °C for 2 h. After dilution in
AcOEt, the organic phase was washed with
water (four times) and brine. The organic
layer was further dried over MgSO4 and de-
colorized with activated carbon. After filtra-
tion on a short Celite® pad, evaporation of the
solvent yielded pure 14 (0.061 g, 93%).
isopropylidene - i -
L
- sorbopyranose (12).—
Compound 6 (0.12 g, 0.3 mmol) gave 12 (0.1
g, 66%) under the same conditions as those
applied for 11: mp 85–87 °C; [h]2D0 +17° (c
1.05, CHCl3); ISMS(+): m/z 528 [M+NH4]+,
533 [M+Na]+. Anal. Calcd for C23H27IO5: C,
54.13; H, 5.33. Found: C, 54.37; H, 5.34.
5-Acetamido-3,4-di-O-benzyl-5-deoxy-1,2-
O-isopropylidene-i- -fructopyranose (13).—
D
Same protocol as for 7, using precursor 10
(1 g, 2.5 mmol), but the reaction was carried
out at rt overnight and purification was ef-
5-S-Acetyl-3,4-di-O-benzoyl-1,2-O-isopropy-
lidene-5-thio-i- -fructopyranose (15).—The
D
iodinated-derivative 11 (0.54 g, 1 mmol) was

A. Tatiboue¨t et al. / Carbohydrate Research 333 (2001) 327–334
333
diluted with DMF (4 mL) under Ar. Potas-
sium thioacetate (0.3 g, 3 mmol) was added to
the solution before heating to 100 °C for 90
min. After completion, the mixture was
poured in AcOEt then washed successively
with water (four times) and brine. After being
dried over MgSO4, decolorized with activated
carbon and filtrated over Celite® pad, the
mixture was evaporated to give 15 (0.435 g) of
good purity. Recrystallization in petroleum–
ether–Et2O gave pure 15 (0.35 g, 72%): mp
136–138 °C; [h]2D0 −141° (c 1.1, CHCl3); IR
(NaCl) w 1695 (thioester), 1738 cm−1 (esters);
ISMS(+): m/z 504.5 [M+NH4]+. Anal. Calcd
for C25H26O8S: C, 61.72; H, 5.39. Found: C,
61.45; H, 5.27.
92%). The crude compounds 18a, 18b (0.260
g) were separated on silica gel with CH2Cl2 as
eluent yielding 18a (0.058 g) as a syrup and
18b (0.2 g) which spontaneously crystallized:
1
18a: [h]2D0 +21° (c 1, CHCl3); H NMR (250
MHz, CDCl3): l 8.07–8.18 (m, 4 H, Harom),
7.60–7.63 (m, 4 H, Harom), 7.47–7.54 (m, 4 H,
H
arom), 5.84 (d, 1 H, H-3), 5.39 (dd, 1 H, J3,4
3.2 Hz, H-4), 4.85 (d, 1 H, H-1b), 4.42 (d, 1
H, J1a,1b 12.1 Hz, H-1a), 4.39 (ddd, 1 H, J4,5
3.2 Hz, H-5), 4.20 (dd, 1 H, J5,6b 11.9 Hz,
4
H-6b), 3.97 (ddd, 1 H, J6a,4 1.1, J6a,5 5.3, J6a,6b
11.3 Hz, H-6a), 2.32 (s, 3 H, SCOCH3), 1.96
(s, 3 H, CH3), 1.83 (s, 3 H, CH3); 13C NMR
(62.5 MHz, CDCl3): l 193.1 (SCO), 170.0,
168.4, 164.6, 164.2, 134.0, 133.9, 130.2, 129.9,
129.3, 128.9, 128.8, 128.7, 100.7 (C-2), 69.0
(C-4), 65.2 (C-3), 62.1 (C-1), 60.5 (C-6), 38.2
(C-5), 30.7 (SCOCH3), 21.8 (CH3), 20.7 (CH3);
ISMS(+): m/z 548 [M+NH4]+, 553 [M+
Na]+. Anal. Calcd for C26H28O8S: C, 58.86;
H, 4.94. Found: C, 59.03; H, 5.12. 18b: mp
5-Azido-3,4-di-O-benzoyl-5-deoxy-1,2-O-iso-
propylidene-i-
D
-fructopyranose
(16).—The
iodo derivative 11 (0.28 g, 0.52 mmol) was
dissolved in Me2SO (2 mL) and sodium azide
(0.345 g, 5.3 mmol) was added. The solution
was heated to 100 °C for 3 h, then poured into
AcOEt. The organic solution was washed with
water (three times), brine and dried over
MgSO4. After a short filtration over a silica
gel pad and evaporation to dryness, 16 (0.215
145–148 °C, [h]2D0 −108° (c 1, CHCl3); H
1
NMR (250 MHz, CDCl3): l 7.88–7.98 (m, 4
H, Harom), 7.46–7.55 (m, 4 H, Harom), 7.32–
7.42 (m, 4 H, Harom), 5.85 (dd, 1 H, J4,5 3.6
Hz, H-4), 5.79 (d, 1 H, J3,4 10.3 Hz, H-3), 4.80
(d, 1 H, H-1b), 4.57 (d, 1 H, J1a,1b 11.9 Hz,
H-1a), 4.53 (m, 1 H, H-5), 4.35 (dd, 1 H, J5,6b
2.3 Hz, H-6b), 4.02 (dd, 1 H, J6a,5 1.8, J6a,6b
12.8 Hz, H-6a), 2.29 (s, 3 H, SCOCH3), 2.25
(s, 3 H, CH3), 1.99 (s, 3 H, CH3); 13C NMR
(100 MHz, CDCl3): l 193.5 (SCO), 169.9,
168.1, 165.5, 165.3, 132.6, 132.4, 129.8, 129.7,
129.1, 129.0, 128.6, 128.5, 102.6 (C-2), 69.1
(C-4), 68.6 (C-3), 65.1 (C-6), 63.3 (C-1), 45.0
(C-5), 31.7 (SCOCH3), 21.7 (CH3), 20.6 (CH3);
ISMS(+): m/z 548 [M+NH4]+, 553 [M+
Na]+. Anal. Calcd for C26H28O8S: C, 58.86;
H, 4.94. Found: C, 59.15; H, 4.90.
g, 91%) was isolated: mp 84–86 °C; [h]D20
−
115° (c 1.15, CHCl3); IR (NaCl) w 2101 cm−1
(azide), 1729 cm−1 (ester); ISMS(+): m/z 471
[M+NH4]+. Anal. Calcd for C23H23N3O7: C,
60.92; H, 5.11. Found: C, 61.24; H, 5.23.
5-Azido-3,4-di-O-benzyl-5-deoxy-1,2-O-iso-
propylidene-i- -fructopyranose (17).—Same
D
conditions as those applied to 16 for 12 (0.134
g, 0.26 mmol) for 4 days at 90 °C. After usual
workup, 17 (0.094 g, 85%) was obtained: [h]D20
−87° (c 1, CHCl3); IR (NaCl) w 2107 (azide);
ISMS(+): m/z 443 [M+NH4]+, 448 [M+
Na]+. Anal. Calcd for C23H27N3O5: C, 64.93;
H, 6.40. Found: C, 65.03; H, 6.45.
5-S-Acetyl-3,4-di-O-benzoyl-1,2-di-O-acetyl-
5-Thio- -fructofuranose (2).—Compound
D
5-thio-
D
-fructopyranose (18a, 18b).—Under
18 (0.3 g, 0.567 mmol) was diluted in MeOH
and treated with sodium methoxide (0.6
mmol) at rt for 3 h. 2 (0.108 g, 97%) was
isolated after purification on silica gel (20:4:1
EtOAc–MeOH–water): [h]2D0 −7° (c 1.1,
MeOH), lit.3 −4° (c 0.72, MeOH). Anal.
Calcd for C6H12O5S: C, 36.73; H, 6.16.
Found: C, 37.01; H, 6.05.
Ar 15 (0.48 g, 1 mmol) was dissolved in Ac2O
(2.5 mL) and cooled (ice-salt bath) to −
10 °C. BF3·Et2O (0.1 mL) was added slowly.
After 90 min, the solution was diluted with
EtOAc, washed twice with ice cold water and
satd NaHCO3 then brine. The organic phase
was dried over MgSO4, evaporated under re-
duced pressure, and purified on silica gel (4:1
petroleum ether–EtOAc,) yielding 18 (0.485 g,
5-Azido-5-deoxy-1,2-O-isopropylidene-i-
D
-
fructopyranose (19).—Compound 16 (0.1 g,

334
A. Tatiboue¨t et al. / Carbohydrate Research 333 (2001) 327–334
2. Tatiboue¨t, A.; Yang, J.; Morin, C.; Holman, G. D.
Bioorg. Med. Chem. 2000, 8, 1825–1833.
3. Chmielewski, M.; Whistler, R. L. J. Org. Chem. 1975, 40,
639–643.
4. Simmonds, M. S. J.; Kite, G. C.; Porter, E. A. In
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0.22 mmol) was deacylated in MeOH (3 mL)
under Ar, using Zemplen conditions at rt
overnight. After completion of the reaction,
SiO2 was added to the solution and MeOH
removed under reduced pressure. Compound
19 (0.05 g, 92%) was purified by column chro-
matography (3:2 petroleum ether–EtOAc):
mp 113–114 °C, lit.11 114 °C.
6. Lichtenthaler, F. W.; Doleschal, W.; Hahn, S. Liebigs
Ann. Chem. 1985, 2454–2464.
7. Takagi, Y.; Lim, G. -J.; Tsuchiya, T.; Umezawa, S. J.
Chem. Soc., Perkin Trans. 1 1992, 657–658.
8. (a) Hughes, D. L. Org. Prep. Proc. Int. 1996, 28, 127–
164;
(b) Persky, R.; Albeck, A. J. Org. Chem. 2000, 65,
3775–3780.
9. (a) Garegg, P. J.; Samuelsson, B. Chem. Commun. 1979,
979–980;
Acknowledgements
The authors thank the MENRT, the CNRS
and the Medical Research Council (UK) for
financial support.
(b) Vaino, A. R.; Szarek, W. A. Ad6. Carbohydr. Chem.
Biochem. 2001, 56, 9–63.
10. Rollin, P. Tetrahedron Lett. 1986, 27, 4169–4170.
11. Hung, R. R.; Straub, J. A.; Whitesides, G. M. J. Org.
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