Peracetylated 1,6-dibromo-D-glucitol as efficient precursor of 1,6-diiodo and some mono-, disubstituted and heterocyclic D-glucitol derivatives

Article abstract of DOI:10.1016/S0008-6215(02)00421-4

2,3,4,5-Tetra-O-acetyl-1,6-dibromo-1,6-dideoxy-D-glucitol (1a) obtained from D-glucitol was easily transformed into the 1,6-diiodo derivative in excellent yield (97%) by reaction with an excess of sodium iodide in refluxing butanone in 2 h. When the reaction time was prolonged to 24 h and the crude product was acetylated, 1,2,3,4,5-penta-O-acetyl-6-deoxy-6-iodo-D-glucitol and D-glucitol hexaacetate were isolated in 50 and 26% yields, respectively. The monodehalogenation then took place regioselectively at C-1. This regioselectivity allowed the synthesis of some mono- and disubstituted derivatives of D-glucitol. Thus, the peracetylated derivatives of D-glucitol, 6-bromo, 6-bromo-1-S-butyl, 6-bromo-1-S-octyl, 6-S-butyl, 6-S-butyl-1-S-octyl, 1-S-butyl, 1,6-di-S-octyl and 6-S-phenyl were synthesised in good to excellent yields. With S⁼ as binucleophilic reagent, 1a gave mainly the thiepane derivative (75%) plus the 1-S-acetyl-2,6-anhydro-D-glucitol derivative as a by-product (10%).

Full text of DOI:10.1016/S0008-6215(02)00421-4

Carbohydrate Research 338 (2003) 177–182
www.elsevier.com/locate/carres
Note
Peracetylated 1,6-dibromo-
,6-diiodo and some mono-, disubstituted and heterocyclic
-glucitol derivatives
D-glucitol as efficient precursor of
1
D
Sami Halila, Mohammed Benazza,* Gilles Demailly
Laboratoire des Glucides, Uni6ersit e´ de Picardie Jules Verne, 33 rue Saint-Leu, F-80039 Amiens, France
Received 10 April 2002; received in revised form 10 October 2002; accepted 20 October 2002
Abstract
2
,3,4,5-Tetra-O-acetyl-1,6-dibromo-1,6-dideoxy-
iodo derivative in excellent yield (97%) by reaction with an excess of sodium iodide in refluxing butanone in 2 h. When the
reaction time was prolonged to 24 h and the crude product was acetylated, 1,2,3,4,5-penta-O-acetyl-6-deoxy-6-iodo- -glucitol and
-glucitol hexaacetate were isolated in 50 and 26% yields, respectively. The monodehalogenation then took place regioselectively
D-glucitol (1a) obtained from D-glucitol was easily transformed into the 1,6-di-
D
D
at C-1. This regioselectivity allowed the synthesis of some mono- and disubstituted derivatives of
D-glucitol. Thus, the
peracetylated derivatives of
D
-glucitol, 6-bromo, 6-bromo-1-S-butyl, 6-bromo-1-S-octyl, 6-S-butyl, 6-S-butyl-1-S-octyl, 1-S-butyl,
ꢀ
1,6-di-S-octyl and 6-S-phenyl were synthesised in good to excellent yields. With S as binucleophilic reagent, 1a gave mainly the
thiepane derivative (75%) plus the 1-S-acetyl-2,6-anhydro-
D
-glucitol derivative as a by-product (10%). © 2002 Elsevier Science
Ltd. All rights reserved.
Keywords: Alditol;
D-glucitol; Iodoglucitol; Dehalogenation; Thioalditols; Bromoglucitol; Thiepane
In this report, a short and efficient synthesis of
,6-dideoxy-1,6-diiodo- -glucitol is reported. This was
carried out by bromine–iodide exchange from 1,6-di-
bromo-1,6-dideoxy- -glucitol 1a to the 1,6-diiodo ana-
logue 4 (Scheme 1). The former was directly synthesised
derivative 15 previously obtained in four steps from
3
1
D
methyl a-
Of interest was the formation in excellent yield (97%)
of the target 1,6-dideoxy-1,6-diiodo- -glucitol deriva-
tive 4 when the reaction time was reduced to 2 h (Path
).
Compounds 2 and 3 are probably formed through
D-glucopyranoside.
D
D
1,2
from unprotected
The first synthetic attempt at the target 1,6-dideoxy-
,6-diiodo- -glucitol derivative was performed with a
D-glucitol 1.
2
1
D
hydrolysis of an acetoxonium ions intermediate, pre-
sumably from a transient diiodide 4 (Scheme 2 Path 1
and 2). Reaction of 1a unsurprisingly gave mainly 6
large excess of sodium iodide (NaI, 10 equiv) in
refluxed undistilled butanone during 24 h for complete
disappearance of 1a (Path 1). Two compounds were
isolated after acetylation: 1,2,3,4,5-penta-O-acetyl-6-de-
(
thiepane) with some 5 (2,6-anhydro-D-glucitol) within
4
the presence of a sulfide ion (Scheme 3). Such higher
reactivity at C-1 in 1a was also observed, leading to C-1
substitution with acetate and thiolate ions. Thus,
oxy-6-iodo-
D-glucitol (2) and
D-glucitol hexaacetate 3
in yields of 50 and 26%, respectively. No trace of the
1,6-diiodo derivative 4 was detected.
1
(
1
,2,3,4,5-penta-O-acetyl-6-bromo-6-deoxy-
7), 2,3,4,5-tetra-O-acetyl-6-bromo-1-S-butyl-6-deoxy-
-thio- -glucitol (8) and 2,3,4,5-tetra-O-acetyl-6-
bromo-6-deoxy-1-S-octyl-1-thio- -glucitol (10) were
D-glucitol
The identification of 2 was fully achieved by correla-
tion with literature. Thus, 2 gave by reaction with the
phenylthiolate ion the 6-S-phenyl-6-thio- -glucitol
D
D
D
obtained in reasonable yields (50%). Derivatives 7, 8
and 10 were respectively transformed into 6-S-butyl 12
and 6-S-phenyl 15 (identical to that obtained from 2 in
*
Corresponding author. Fax: +33-3-22827561
E-mail address: mohammed.benazza@sc.u-picardie.fr (M.
Benazza).
3
order to correlate with literature), 1-S-butyl 14 and
0
008-6215/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(02)00421-4

1
78
S. Halila et al. / Carbohydrate Research 338 (2003) 177–182
Scheme 1. (i) AcBr, 1,4-dioxane, rt; (ii) NaI (10 equiv), refluxing undistilled butanone, 24 h; (iii) Ac O, pyridine; (iv) NaI (10
2
equiv), refluxing anhyd butanone, 48 h; (v) NaI (10 equiv), refluxing undistilled butanone, 2 h; (vi) PhSH, Me SO NaH, rt, 15 min.
2
13
6-S-butyl-1-S-octyl-
D-glucitol 13 in excellent yields.
relative to Me Si. All C NMR signals were assigned
4
This unexpected regioselective transformation then en-
abled us to synthesise the 1,6-di-S-alkyl derivative 13
with two different alkyl chains of different lengths.
through C,H-correlated spectra. TLC was performed
on Silica Gel 60 F254 230 mesh (E. Merck) and detec-
tion by the vanillin–H SO reagent. The silica gel used
2
4
Note that with an excess of thiolate ion in a Me SO–
THF mixture, the thioalkylation was reported to occur
indiscriminately at the two sites C-1 and C-6 to give the
in column chromatography was 35–70 v (Amicon).
Mass spectroscopy analyses were performed by the
‘Service d’Analyse de la Facult e´ de Pharmacie, Univer-
sit e´ de Reims. Elemental analyses were performed by
the ‘Service de Microanalyse du CNRS’, Universit e´ de
Reims.
2
disubstituted compounds 9 and 11 in excellent yields
2
(
Scheme 4).
1. Experimental
1
.2. General procedure of iodination
1.1. General methods
To 2,3,4,5-tetra-O-acetyl-1,6-dibromo-1,6-dideoxy-
D
-
1,2
Melting points were determined with a B u¨ chi 535 ap-
glucitol (1a, 10 mL) in 1 mmol undistilled butanone
(10 mL) was added NaI (10 equiv). The mixture was
refluxed until complete disappearance of the substrate.
The residue obtained after concentration was dissolved
1
13
paratus and are uncorrected. H and C NMR spectra
Tables 1–3) were recorded with a Bruker 300 WB
spectrometer; chemical shifts are reported in d (ppm)
(
Scheme 2.
Scheme 3.

S. Halila et al. / Carbohydrate Research 338 (2003) 177–182
179

1
80
S. Halila et al. / Carbohydrate Research 338 (2003) 177–182
Scheme 4. (i) AcONa (3 equiv), 60 °C, 5 h, Me SO; (ii) C H SH (1.2 equiv), NaH (1.1 equiv) Me SO, rt, 15 min; (iii) C H SH
2
4
9
2
4
9
(
1.2 equiv), NaH (1.1 equiv), Me SO-THF (1:1), rt, 15 min; (iv) AcONa (3 equiv), 60 °C, 24 h, Me SO; (v) C H SH (1.2 equiv),
2
2
8
1
7
NaH (1.1 equiv), Me SO, rt, 15 min; (vi) C H SH (2.2 equiv), NaH (2.4 equiv), Me SO-THF (1:1), rt, 15 min; (vii) PhSH (1.2
2
4
9
2
equiv), NaH (1.2 equiv), Me SO-THF (1:1), rt, 15 min; (viii) C H SH (2.2 equiv), NaH (2.4 equiv), Me SO-THF, rt, 15 min.
2
8
17
2
Table 2
Coupling constants (Hz) for peracetylated
D
-glucitol derivatives (in CDCl3)
Compd
J1,1%
J1,2
J1%,2
J2,3
J3,4
J4,5
J5,6%
J5,6
J6,6%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
a
–
4.6
5.9
6.1
–
6.2
7.2
5.8
6.9
5.5
6.9
4.9
6.1
–
4.6
3.8
4.0
–
3.3
3.9
3.8
5.2
4.8
5.2
4.7
3.9
–
7.8
6.8
6.3
7.0
3.5
1.4
–
6.1
6.2
6.1
6.1
–
3.5
3.8
4.1
3.4
11.0
8.1
–
4.1
5.2
4.1
5.2
–
7.3
6.3
6.7
7.0
0
3.7
3.9
3.7
–
4.7
4.6
3.8
3.6
6.9
3.6
6.9
5.1
–
4.8
5.9
5.3
6.5
1.8
7.4
6.3
6.2
7.2
6.2
7.1
7.5
–
11.6
11.3
12.4
11.3
10.7
15.4
11.5
11.6
14.0
11.6
14.3
14.3
–
12.2
12.1
–
14.5
14.6
12.2
14.2
16.0
14.2
14.2
12.0
–
6.0
–
6.7
6.9
6.7
6.4
–
5.2
6.8
5.9
6
0
1
2
3
4
5
5
5.2
5.7
6.3
6.4
5.2
4.4
4.1
4.0
14.2
12.1
12
6.9
6
6
5.4
4
4
3.3
4.5
4.5
5.4
7.3
7.2
12.4
14.4
14.4
i
i
3
From ref.
in CH Cl and the solution was washed with saturated
1.2.2. 2,3,4,5-Tetra-O-acetyl-1,6-dideoxy-1,6-diiodo-D-
2
2
aq Na S O . The crude product was chromatographed
glucitol (4). Obtained from 1a (450 mg) following the
2
2
3
on silica gel with 3:1 hexane–AcOEt as eluent.
.2.1. 1,2,3,4,5-Penta-O-acetyl-6-deoxy-6-iodo- -glucitol
2) and 1,2,3,4,5,6-hexa-O-acetyl- -glucitol (3). Follow-
ing the general procedure, 1a (600 mg) was allowed to
react with NaI during 24 h. The following products
were isolated after acetylation: 2, Yield 318 mg (50%);
general procedure after stirring during only 2 h. Yield
5
25 mg (97%); Syrup; R 0.58 in 5:3 hexane–EtOAc.
f
1
(
D
Anal. Calcd for C H O I : C, 29.49; H, 3.54; I, 44.52.
14
20 8 2
D
Found: C, 29.40; H, 3.55.
1.2.3. 3,4,5-Tri-O-acetyl-1-S-acetyl-2,6-anhydro-1-thio-
Syrup; R 0.46 in 5:3 hexane–EtOAc. Anal. Calcd for
D
-glucitol (5) and 2,3,4,5-Tetra-O-acetyl-1,6-thioanhy-
dro- -glucitol (6). To 1 mmol of 1a (476 mg) in 30 mL
of 15:1 acetone–water, was added Na S·9H O (5
f
C H O I: C, 38.25; H, 4.58; O, 31.87; I, 25.30.
D
1
6
23 10
Found: C, 38.31; H, 4.60. 3, Yield 142 mg (26%%); Mp
7.9–98.7; R 0.31 in 5:3 hexane–EtOAc. Anal. Calcd
2
2
9
equiv). The mixture was vigourously stirred for 1 night
at rt. After concentration and subsequent acetylation,
the crude product was chromatographed on silica gel
f
for C H O : C, 49.77; H, 6.03; O, 44.20. Found: C,
1
8
26 12
49.74; H, 6.20.

S. Halila et al. / Carbohydrate Research 338 (2003) 177–182
181

1
82
S. Halila et al. / Carbohydrate Research 338 (2003) 177–182
2
2
with 4:1 hexane–EtOAc as eluent. The following prod-
Syrup; Yield 313 mg (90%); [a] +2.6 (c 1.4, CHCl3);
f
D
ucts were isolated: 5, Yield 35 mg (10%); Syrup; R 0.38
R
0.60 in 5:3 hexane–EtOAc. Anal. Calcd for
f
in 5:3 hexane–EtOAc. Anal. Calcd for C H O S: C,
C H O S: C, 51.71; H, 6.94; S, 6.90. Found: C, 51.87;
20 32 10
14
20
8
48.26; H, 5.79; S, 9.20. Found: C, 48.72; H, 5.93. 6,
H, 7.08.
Yield 262 mg (75%); Mp 76–78 °C; R 0.26 in 5:3
f
hexane–EtOAc. Anal. Calcd for C H O S: C, 48.26;
H, 5.79; O, 36.78; S, 9.20. Found: C, 48.33; H, 5.79.
14
20
8
1.3.4.
dithio-
2,3,4,5-Tetra-O-acetyl-6-S-butyl-1-S-octyl-1,6-
D-glucitol (13). Obtained from 10 (220 mg, 0.41
mmol), n-C H SH (0.05 mL, 1.2 equiv, 0.41 mmol), 5
4
9
1
.2.4. 1,2,3,4,5-Penta-O-acetyl-6-bromo-6-deoxy- -glu-
D
mL of Me SO and NaH (18 mg, 0.45 mmol, 1.1 equiv).
2
citol (7). To 400 mg (0.84 mmol) of 1a in 5 mL anhyd
Chromatography used 7:1 hexane–EtOAc as eluent.
Me SO was added AcONa (210 mg 3 equiv; 2.52
Syrup; Yield 190 mg (85%); R 0.62 in 7:3 hexane–
2
f
mmol). The mixture was stirred for 3 h at 60 °C under
argon atmosphere. The crude product obtained after
concentration was treated with brine (10 mL) and
EtOAc. Anal. Calcd for C H O S : C, 56.70; H, 8.42;
S, 11.64. Found: C, 56.97; H, 8.70.
26
46
8 2
extracted with 10 mL Et O. The aq layer was washed
2
1.3.5. 2,3,4,5,6-Penta-O-acetyl-1-S-butyl-1-thio-D-gluci-
tol (14). To a solution of 0.24 g (0.49 mmol) of 8 in 2.5
twice with 10 mL Et O and the organic layers were
2
combined together and dried (Na SO ). The crude
2
4
mL of Me SO, was added 3 equiv (120 mg; 1.47 mmol)
2
product obtained after concentration was chro-
of AcONa. The mixture was stirred during 24 h at
matographed on silica gel with 7:3 hexane–EtOAc.
6
0 °C. The solution was subsequently extracted by 10
2
5
Syrup; Yield 192 mg (50%); [a] +12.5 (c 3.6, CHCl3);
D
mL of diethylether and 10 mL of brine. The aq layer
was washed twice with 10 mL of diethylether. The
organic layers were collected and dried on Na SO .
R
f
0.55 in 1:1 hexane–EtOAc. Anal. Calcd for
C H O Br: C, 42.20; H, 5.09; Br, 17.55. Found: C,
1
6
23 10
2
4
42.44; H, 5.25.
After filtration and concentration, the crude product
was chromatographed with 4:1 hexane–EtOAc. Syrup;
1.3. General procedure for thioetherification
Yield 161 mg (70%); R 0.60 in 3:2 hexane–EtOAc.
f
Anal. Calcd for C H O S: C, 51.71; H, 6.94; S, 6.90.
Found: C, 51.93; H, 7.10.
20
32 10
To a solution of 1a (1 mmol 476 mg) in Me SO (5 mL),
2
was added alkanethiol (n-C H2n+1SH) or phenylthiol
n
−
3
(
1
1.2×10 mol, 1.2 equiv) and sodium hydride (46 mg;
.1 equiv 1.1 mmol). The mixture was stirred 15 min at
1
.3.6. 1,2,3,4,5-Penta-O-acetyl-6-S-phenyl-6-thio-D-glu-
citol (15). Obtained following the thioetherification gen-
eral procedure from 7 (and from 2a, 400 mg) and PhSH
rt under argon atmosphere and extracted with 10 mL of
brine and 10 mL Et O. The aq layer was washed twice
2
(
2.2 equiv), NaH (2.4 equiv), 10 mL of 1:1 Me SO–
2
with 10 mL Et O. The organic layers were collected and
2
THF, rt, 15 min. Syrup; Yield 384 mg (90%); R 0.27 in
f
dried on Na SO . After filtration and concentration, the
2
4
7
:3 hexane–EtOAc. Anal. Calcd for C H O S: C,
22 28 10
crude product was chromatographed on silica gel with
5
4.54; H, 5.82; S, 6.62. Found: C, 54.75; H, 5.88.
7:1 hexane–EtOAc.
1
.3.1.
2,3,4,5-Tetra-O-acetyl-6-bromo-1-S-butyl-6-de-
-glucitol (8). Syrup; Yield 243 mg (50%);
a] +12.5 (c +3, 1.5 CHCl ); R 0.48 in 7:3 hexane–
Acknowledgements
oxy-1-thio-
[
D
2
6
D
3
f
The authors thank the Conseil R e´ gional de Picardie
for its financial support.
EtOAc. Anal. Calcd for C H O BrS: C, 44.54; H,
6
18
29
8
.02; Br, 16.46; S, 6.61. Found: C, 44.79; H, 6.11.
1
.3.2. 2,3,4,5-Tetra-O-acetyl-6-bromo-6-deoxy-1-S-oc-
References
tyl-1-thio-
D
-glucitol (10). Syrup; Yield 271 mg (50%);
2
1
[
a] +2.7 (c 2, CHCl ); R 0.47 in 7:3 hexane–EtOAc.
D
3
f
1
. El Anzi, A.; Benazza, M.; Fr e´ chou, C.; Demailly, G.
Tetrahedron Lett. 1993, 34, 3741–3744.
Anal. Calcd for C H O BrS: C, 48.79; H, 6.89; Br,
22
37
8
14.76; S, 5.92. Found: C, 48.96; H, 6.91.
2. Crombez-Robert, C.; Benazza, M.; Fr e´ chou, C.; Demailly,
G. Carbohydr. Res. 1997, 303, 359–365.
3
. Santoyo Gonz a´ lez, F.; Baer, H. H. Carbohydr. Res. 1990,
02, 33–47.
1.3.3. 1,2,3,4,5-Penta-O-acetyl-6-S-butyl-6-thio-D-gluci-
2
tol (12). Obtained from 7 (340 mg) and 1.2 equiv of
C H SH, 1.1 equiv of NaH, 7 mL Me SO, rt, 15 min.
4. Halila, S.; Benazza, M.; Demailly, G. Tetrahedron Lett.
2001, 42, 3307–3310.
4
9
2