Short and efficient synthesis of polyhydroxylated tetrahydrothiophene, tetrahydrothiopyrane and thiepane from bielectrophilic erythro, threo, xylo, ribo, arabino, manno and gluco α,ω-dibromoalditol derivatives

Article abstract of DOI:10.1016/S0040-4039(01)00442-7

Polyhydroxylated tetrahydrothiophene, tetrahydrothiopyrane and thiepane rings have been readily obtained in excellent yields (78-95%) from thioheterocyclisation of the bielectrophilic peracetylated α,ω-dibrominated derivatives of tetritols (erythritol (1) and d,L-threitol (4)), pentitols (xylitol (7), ribitol (10) and D-arabinitol (14)) and hexitols (D-mannitol (17) and D-glucitol (20)), respectively. With 2,3,4,5-tetra-O-acetyl-1,6-dibromo-1,6-dideoxy-D-glucitol (21) as substrate, the unexpected 2,6-anhydro derivative 25 was obtained. This could be attributed to previous S⁼ regioselective nucleophilic attack at C-1 position followed by 1,2-transesterification and 2,6-O-heterocyclisation. The preferential attack at C-1 of the D-glucitol derivative 21 subsequently allowed a facile direct synthesis in good yields of 2,3,4,5,6-penta-O-acetyl-1-bromo-1-deoxy-D-glucitol (26), 2,3,4,5-tetra-O-acetyl-6-bromo-6-deoxy-1-thiobutyl-1-deoxy-D-glucitol (28) and 2,3,4,5-tetra-O-acetyl-6-bromo-6-deoxy-1-thiooctyl-1-deoxy-D-glucitol (28).

Full text of DOI:10.1016/S0040-4039(01)00442-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3307–3310
Short and efficient synthesis of polyhydroxylated
tetrahydrothiophene, tetrahydrothiopyrane and thiepane from
bielectrophilic erythro, threo, xylo, ribo, arabino, manno and
gluco a,v-dibromoalditol derivatives
Sami Halila, Mohammed Benazza* and Gilles Demailly*
Laboratoire des Glucides, Universite´ de Picardie Jules Verne, 33 rue Saint-Leu, F-80039 Amiens, France
Received 7 March 2001; revised 15 March 2001; accepted 16 March 2001
Abstract—Polyhydroxylated tetrahydrothiophene, tetrahydrothiopyrane and thiepane rings have been readily obtained in excellent
yields (78–95%) from thioheterocyclisation of the bielectrophilic peracetylated a,v-dibrominated derivatives of tetritols (erythritol
(1) and
respectively. With 2,3,4,5-tetra-O-acetyl-1,6-dibromo-1,6-dideoxy-
tive 25 was obtained. This could be attributed to previous S= regioselective nucleophilic attack at C-1 position followed by
1,2-transesterification and 2,6-O-heterocyclisation. The preferential attack at C-1 of the -glucitol derivative 21 subsequently
allowed a facile direct synthesis in good yields of 2,3,4,5,6-penta-O-acetyl-1-bromo-1-deoxy- -glucitol (26), 2,3,4,5-tetra-O-acetyl-
6-bromo-6-deoxy-1-thiobutyl-1-deoxy- -glucitol (28) and 2,3,4,5-tetra-O-acetyl-6-bromo-6-deoxy-1-thiooctyl-1-deoxy- -glucitol
D
,
L
-threitol (4)), pentitols (xylitol (7), ribitol (10) and
D
-arabinitol (14)) and hexitols (
D-mannitol (17) and D-glucitol (20)),
D
-glucitol (21) as substrate, the unexpected 2,6-anhydro deriva-
D
D
D
D
(28). © 2001 Elsevier Science Ltd. All rights reserved.
Tetrahydrothiophene is an important building block of
a large number of compounds that are very interesting
from the point of view of biological activity. In particu-
lar it enters into the structures of nucleoside analogues1
and certain compounds where the sulfur atom in the
ring is in a trivalent state (spirobicyclic-like), such as
the sulfimides,2 salicinol3a and kotalanol,3b which are
excellent glycosidase inhibitors. Although analo-
gues with more than six- or seven-membered rings
(tetrahydrothiopyrane and thiepane) generally show
weak glycosidase4 inhibition activity, they are never-
theless excellent precursors for the thiacyclopen-
tane ring through contraction of the ring4,5 or for
conduritol derivatives (from thiepane)6 which are
glycosidase inhibitors and much used as intermediates
in the synthesis of inositol7 and aminocyclitol deriva-
tives.8
The use of alditols as bielectrophilic substrates in thio-
heterocyclisations has been reported in the literature. It
has been shown that the thiepane ring is obtained
mainly from bis-epoxyhexitol such as
D-mannitol
always protected in the 3,4-positions.5b However, this
approach has limitations when applied to other aldi-
tols.9 In our laboratory we have recently used alditol
bis-cyclic-sulfates as bielectrophilic intermediates. Poly-
hydroxylated tetrahydrothiophene, tetrahydropyrane
and thiepane derivatives have been isolated in good
OAc
1) AcBr
1,4-dioxane
R.T
HO
OAc
HO
OH
Br
Br
Na2S, 9H2O
n
n
n
DMSO
R.T.
20-45 min
2) Ac2O/pyridine
n = 2 : Tetritols
n = 3 : Pentitols
n = 4 : Hexitols
S
Scheme 1.
Keywords: alditol; thioheterocyclisation; thiosugar; thiepane; thiophene; thiopyrane.
* Corresponding authors. Fax: +33(3)22827561; e-mail: mohammed.benazza@sc.u-picardie.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00442-7

3308
S. Halila et al. / Tetrahedron Letters 42 (2001) 3307–3310
yields.10 However, we have shown that this approach is
only applicable to free tetritols and other partially
protected alditols carrying only four free hydroxyl
groups.
Table 1. Regioselective thioheterocyclisation of a,v-dibromoalditols derivatives (1 mmol) using sodium sulfide nonahydrate
as binucleophilic reagent. Solvent effect on the isolated yields
Isolated yields (%) with
DMSO as solventb
Isolated yields (%) with
acetone-H2O as solventa
Yield (%)**
α,ω-dibromoalditols
Substrates
Isolated thioheterocyclic
products
Entry
derivatives (Yield (%))*
Yield (%)
Time
P = Ac
P = Ac
OHOH
OP Br
S
92
20 min
1
2
93
95
OHOH
Br OP
OP
OP
Erythritol (1)
2 (85)
3
OHOH
S
OP Br
PO
95
"
OHOH
D,L-Threitol (4)
Br OP
OP
(
)-
5 (86)
(
)-
6
OHOHOH
Br OP Br
S
S
3
4
87
78
30 min
90
70
20
OP
OP
PO
PO
OHOH
PO
OP OP
xylitol (7)
8 (70)
9
OHOHOH
Br OP Br
OP
"
OHOH
Ribitol (10)
OP OP
11 (68)
12
+
SP
O
0
OP OP
(
)-
13
OHOHOH
Br OP Br
OP
S
1
2
5
6
86
82
75
83
"
5
PO
4
PO
OHOH
OP OP
3
D-arabinitol (14)
15 (73)
16
PO
OP
OHOHOH
Br OP OP
PO
OP
88
85
45 min
OHOH
OP OP Br
18 (60)
OH
S
19
D-mannitol (17)
PO
PO
OP
OP
OH
OHOH
OP Br
OP
"
7
S
23
+
OH
OHOH
Br
OP OP
21 (50)
D-glucitol (20)
OP
O
3
2
5
6
0
PO
10
PO
OP
4
1
25 (2,6-anhydro)
*Isolated yields from the corresponding alditols; **Isolated yields from α,ω-dibromoalditols derivatives and after acetylation of crude product;
a 5 mmol of Na2S, 9H2O, 18 h; b 1.5 mmol of Na2S, 9H2O

S. Halila et al. / Tetrahedron Letters 42 (2001) 3307–3310
3309
Herein, we report a general, short and efficient synthe-
sis affording polyhydroxylated tetrahydrothiophene,
tetrahydrothiopyrane and thiepane rings from peracety-
lated a,v-dibromoalditols with the erythro, threo, xylo,
ribo, arabino, manno and gluco configurations (Scheme
1). The latter are obtained directly by bromination of
the corresponding alditols.11
to 95% for a reaction time of 18 h for complete
disappearance of substrate.
It is interesting to emphasise that with brominated
ribitol 11 and
D
-glucitol 21 (entries 4 and 7) non-negli-
gible amounts of anhydro compounds were isolated. In
both cases the formation of these O-heterocyclic com-
pounds could be explained by an initial attack at one of
the primary sites by S=, followed by transesterification
and O-heterocyclisation leading to anhydro derivatives
13 and 25 after acetylation.
In the synthesis of thioheterocycles from bielectrophilic
alditols derivatives, solvents such as EtOH,4 MeOH12
or a mixture of acetone–H2O were used.10 In the latter
case, under mild conditions (rt, 15 min), cyclic tetritol
bis-sulfates reacting with Na2S, 9H2O lead to the corre-
sponding thiacyclopentane derivatives in good yields.
Initially, applying these conditions 2,3,4-tri-O-acetyl-
1,5-dibromo-1,5-dideoxyxylitol (8) (Table 1) led, after
flash chromatography, to the xylotetrahydrothiopyrane
derivative 9 in only 37% yield. When this reaction is
followed by acetylation of the reaction mixture, the
yield of compound 9 reaches 90% (entry 3). This is
explained by the concomitant deacetylation of the hete-
rocyclisation product.
For compound 13, 13C NMR shows both an intra-
cyclic secondary carbon atom at 70.82 ppm and
another extra-cyclic at 30.90 ppm, plus a signal at 190
1
ppm shift for the thioacetate group. In H NMR, the
coupling constant J2,3=5.4 Hz is in agreement with a
1,4-anhydroribitol structure.13
In the case of the derivative of anhydro-
the sequence of coupling constants J2,3=3.48 Hz, J3,4
10.96 Hz and J4,5=0 Hz favours a 2,6-anhydro- -gluci-
D
-glucitol 25,
=
D
tol structure. Mechanistically, this requires an initial
regioselective attack on the primary C-1 site of the
Under the same conditions, thiocyclisation of a,v-
dibromoalditol derivatives 2, 5, 11, 15, 18 and 21
followed by acetylation leads to the tetra-
hydrothiophenes 3 and 6 (entries 1 and 2), tetra-
hydrothiopyranes 12 and 16 (entries 4 and 5) and
thiepanes 19 and 23 (entries 6 and 7) in yields from 70
disymmetric dibrominated
D
-glucitol derivative 21
(Scheme 2) followed by competition between S-cyclisa-
tion (path-a) leading to thiepane 23 and a 1,2-trans-
esterification (path-b) leading to 2-hydroxy compound
24. A subsequent O-heterocyclisation at 2,6 leads to
OP
OP
OP
O
PO
SP
2,6-O-cyclisation
PO
Br
SP
OP OH
25 (2,6-anhydro)
24
(path-b) Trans-esterification
PO
PO
OP
OP
OP
(a)
OP
OP Br
OP
(path-a)
2
1
4
i
S-
6
5
3
1,6-S-cyclisation
(b)
Br
OP OP
21
OP O
Br
Me
S
23
C
22
O
P = Ac
Scheme 2. (i) Na2S, 9H2O, acetone–H2O (15:1), rt, 18 h.
OP
OP OP
OP
OP
OP
OP
OP
OP
OP
SC8H17
iii
OP SC8H17
v
50%
ii
i
50%
90%
85%
C4H9S
Br
Br
C4H9S
OP OP
OP OP
OP OP
OP OP
26
27
30
31
21
OP
OP SC4H9
OP SC4H9
OP SC4H9
OP
iv
vi
iii
50%
70%
93%
Br
OP
OP OP
28
OP OP
29
C4H9S
OP OP
32
P = Ac
Scheme 3. (i) AcONa (3 equiv.), 60°C, 5 h, DMSO; (ii) C4H9SH (1.2 equiv.), NaH (1.1 equiv.), DMSO, rt, 15 min; (iii) C4H9SH
(1.2 equiv.), NaH (1.1 equiv.), DMSO–THF (1:1), rt, 15 min; (iv) AcONa (3 equiv.), 60°C, 24 h, DMSO; (v) C8H17SH (1.2 equiv.),
NaH (1.1 equiv.), DMSO, T.A., 15 min; (vi) C4H9SH (2.2 equiv.), NaH (2.4 equiv.), DMSO–THF (1:1), rt, 15 min.

3310
S. Halila et al. / Tetrahedron Letters 42 (2001) 3307–3310
Acknowledgements
2,6-anhydro- -glucitol derivatives 25. To corroborate
D
this higher reactivity of C-1 compared with C-6 in the
derivative 1,6-dibromo- -glucitol 21, we attempted
D
The authors thank the Conseil Re´gional de Picardie for
its financial support.
regioselective nucleophilic substitution using mononucleo-
philes such as the acetate ion (AcO−) and the alkylthio-
late anions (n-C4H9S− and n-C8H17S−) (Scheme 3). In
both cases we confirmed the high reactivity of C-1
leading, respectively, to 1,2,3,4,5-penta-O-acetyl-6-
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