Expedious synthesis of polyhydroxylated selena and thia-heterocycles via Se and S-ring closure of α,ω-dibromoalditols

Article abstract of DOI:10.1016/j.tet.2004.01.061

The selena and thiaanhydro alditols (with xylo, ribo, D-arabino, erythro, D,L-threo and D-manno configuration) were easily and expeditiously synthesized in good to excellent yields by reaction of selenure and sulfur ions as binucleophiles with α,ω-dibromo

Full text of DOI:10.1016/j.tet.2004.01.061

Tetrahedron 60 (2004) 2889–2895
Expedious synthesis of polyhydroxylated selena and
thia-heterocycles via Se and S-ring closure of a,v-dibromoalditols
*
Mohammed Benazza, Sami Halila, Camille Viot, Alain Danquigny, Christele Pierru
`
and Gilles Demailly
´
Laboratoire des Glucides, CNRS FRE 2779, Universite de Picardie Jules Verne, 33 rue Saint-Leu F-80039 Amiens, France
Received 16 July 2003; revised 9 January 2004; accepted 14 January 2004
Abstract—The selena and thiaanhydro alditols (with xylo, ribo, D-arabino, erythro, D,L-threo and D-manno configuration) were easily and
expeditiously synthesized in good to excellent yields by reaction of selenure and sulfur ions as binucleophiles with a,v-dibromoalditols as
bis-electrophilic substrates. With the 1,6-dibromo-D-glucitol derivative as substrate, only the corresponding thiepane derivative was obtained
while the selenaheterocyclistation attempte led to complex mixture.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
in the ring is in a trivalent state (spirocycle-like), such as the
sulfimides,11 salacinol D and kotalanol E,12 which are
excellent glycosidase inhibitors. Although analogues with
more than six or seven membered rings (tetrahydrothio-
pyrane and thiepane) generally show weak glycosidase
inhibition activity,13 they are nevertheless excellent pre-
cursors for the thiacyclopentane ring through contraction of
the ring13,14 or for conduritol derivatives (from thiepane)15
which are glycosidase inhibitor and much used as
intermediates in the synthesis of inositol16 and amino-
cyclitol derivatives.17
It is well recognised that some diseases such as cancer,1 aids
and the neurodegenerative diseases (e.g. Parkinson and
Alzheimer)2 emerging from abnormally high production of
free radicals (oxydatif stress).3 This is attributed to
antioxydants deficiency (free radical scavengers) like
vitamins4 or of enzyme such selenodependent glutathione
peroxydase where the sulfur atoms of it’s cysteine moieties
were replaced by selenium atoms.5 This enzymatic
antioxydant catalysed the hydroperoxyde reduction
(reduced metabolite precursor of nossif HO free radical)
with concomitante oxydation of a biologically important
thiol, the glutathione which transformed in their disulfur.6
It was reported that a small organic molecules like Ebselen
A7 or the diphenyldiselenide B8 play an important part as
glutathione peroxydase mimics. More recently Schiesser
and co-workers reported the ten steps synthesis of C
(discribed in its perbenzylated xylo, ribo and D-arabino
configurations) which is an hydrosoluble antioxydant.9
In the thiaheterosugars analogues series where the oxygen
atom of the monosaccharide ring was replaced by sulfur
atom, cyclic tetrahydro thiophene is an important building
block of a large number of compounds that are very
interesting from the point of view of biological activity. In
particular it enters into the structures of nucleoside
analogues10 and certain compounds where the sulfur atom
The use of alditols as bielectrophilic substrates in hetero-
cyclisation reactions has been reported in the literature. It
has been shown, for instance, that the selenepane and
thiepane ring are obtained mainly from bis-epoxyhexitol
Keywords:
Alditols;
Dibromoalditols;
Thiaheterocycles;
Selenaheterocycles; Antioxydants; Biselectrophiles.
*
Corresponding author. Tel.: þ33-322827527; fax: þ33-322827560;
e-mail address: mohammed.benazza@u-picardie.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.061

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M. Benazza et al. / Tetrahedron 60 (2004) 2889–2895
such as D-mannitol always protected in the 3,4 positions.14b
However, this approach has limitations when applied to
other alditols.18 In our laboratory we have used alditols
bis-cyclic-sulfates as bielectrophilic intermediates. Poly-
hydroxylated tetrahydrothiophene, tetrahydropyrane and
thiepane derivatives have been isolated in good yields.19
Unfortunately, this approach is only applicable to free
tetritols and other partially protected alditols carrying only
four free hydroxyl groups. Although the alditols cyclic bis-
thionocarbonate derivatives formation take place efficiently
and directly from umprotected alditols, their use as bis-
electrophilic intermediates in thiaheterocyclisation often
encountered the endo-tet and exo-tet competition
(Scheme 1).20 To avoid this competition, the a,v-di-
bromoalditols seems to be a judicious alternative
(Scheme 2).
from 70 to 95% for a reaction time of 18 h for complete
disappearance of substrate.
It is interesting to emphasize that with brominated ribitol 11
and D-glucitol 21 (entries 4 and 7) non-negligible amount of
anhydro compounds were isolated (13 and 25, respectively).
In both cases the formation of these O-heterocyclic
compounds could be explained by an initial attack at one
of the primary sites by Sv, followed by transesterification
and O-heterocyclisation leading to those anhydro
derivatives.
For compound 13, 13C NMR shows both an intra-cyclic
secondary carbon atom at 70.82 ppm and another extra-
cyclic at 30.9 ppm, plus a signal at 190 ppm shift for
thioacetate group. In 1H NMR, the coupling constant
J2,3¼5.4 Hz is in agreement with a 1,4-anhydroribitol
structure.23
In the case of the anhydro-D-glucitol derivative 25, the
sequence of coupling constantes J2,3¼3.48 Hz,
J3,4¼10.96 Hz and J4,5¼0 Hz favours a 2,6-anhydro-D-
glucitol structure. Mechanistically, this requires an
initial regioselective attack on the primary C-1 site of
disymetrique dibrominated D-glucitol derivative 21
(Scheme 3) followed by competition between S-cyclisation
(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 2,6-anhydro-D-glucitol
derivatives 25.24
Scheme 1. n¼0 or 1; n0¼2, 3 or 4; n00¼2 or 3.
Scheme 2. (i) AcBr, 1,4-dioxane, rt, 16 h; (ii) Ac2O, pyridine; (iii) Na2S,
DMSO; (iv) Se, NaBH4, H2O, DMSO, rt, 5 min.
To corroborate this higher reactivity of C-1 compared with
C-6 in the derivative 1,6-dibromo-D-glucitol 21, we
attempted regioselective nucleophilic substitution using
mononucleophiles such as acetate ion (AcO2) and the
alkylthiolate anions (n-C4H9S2 and n-C8H17S2) (Scheme
4).24 In both cases we confirmed the high reactivity of C-1
leading respectively to 1,2,3,4,5-penta-O-acetyl-6-bromo-6-
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 (30) in reasonable yields (50%). Derivatives 26, 28
and 30 were respectively transformed into the derivatives
6-thiobutyl, 1-thiobutyl and 6-thiobutyl-1-thiooctyl-D-
glucitol 27, 29 and 31 in excellent yields. This regio-
selective functional transformation then enabled us to
synthesise the derivative 1,6-dithioalkyl 31 with two alkyl
chains of differing lengths. Note that with an excess of
thiolate in the DMSO–THF mixture, the thioalkylation
takes place indiscriminately at the two sites C-1 and C-6 to
give the disubstituted compound 32.24
Herein we report a general, short and efficient synthesis
affording polyhydroxylated tetrahydroseleno/thiophene,
tetrahydroseleno/thiopyrane and selene/thiepane rings
from peracetylated a,v-dibromo-a,v-dideoxyalditols with
erythro, D,L-threo, xylo, ribo, D-arabino, D-manno and
D-gluco configurations. The latter are obtained directly by
bromination of the corresponding alditols.21
2. Results and discussion
In the synthesis of thiaheterocycles from bis-electrophilic
alditols derivatives, solvents such as EtOH,13 MeOH22 or a
mixture of acetone–H2O were used.19 In the latter case,
under mild conditions (rt, 15 min), we showed that cyclic
tetritol bis-sulfates reacting with Na2S, 9H2O leads to
corresponding thiacyclopentane derivatives in good yields.
Initially, applying these conditions, 2,3,4-tri-O-acetyl-1,5-
dibromo-1,5-dideoxyxylitol (8) (Table 1, entry 3) lead, 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 heterocyclisation product.
Finally, while investigating the influence of the nature of the
solvent on thioheterocyclisation, we were able, using
DMSO as solvent, to isolate thioheterocyclic compounds
in very good yields without subsequent acetylation and in
particularly mild conditions (20–45 min, only 1.5 mmol of
Na2S–9H2O instead of 5 mmol in acetone–H2O). Further-
more, in the case of ribitol (entry 4) and D-glucitol (entry 7)
we noted any amounts of the corresponding anhydro
derivatives 13 and 25.
Under the same conditions, the S-cyclisation of a,v-
dibromoalditol derivatives 2, 5, 11, 15, 18 and 21 followed
by acetylation leads to tetrahydrothiophene rings 3 and 6
(entries 1 and 2), tetrahydrothiopyrane 12 and 16 (entries 4
and 5) and thiepane 19 and 23 (entries 6 and 7) in yields
The above conditions in DMSO could not be applied

M. Benazza et al. / Tetrahedron 60 (2004) 2889–2895
2891
´
(Laboratoire de Bioorganique, Universite de Reims
Champagne Ardenne’).
directly to selenaheterocyclisation since Na2Se must be
synthesized firstly from metallic selenium and NaBH4 as
reducing reagent in aqueous medium.13 After some
attempts, we showed that reaction of peracetylated a,v-
dibromoalditols derivatives in DMSO with a colorless
solution obtained by addition of NaBH4 to a suspension of
Se in water, gave in less than 10 min the corresponding
selenaheterocycles derivatives in good to excellent yields
(Table, entries 1–6). Thus, the tetrahydroselenophene 33
(erythro, 93%) and 34 (D,L-threo, 98%), the tetrahydro-
selenopyrane 35 (xylo, 80%), 36 (ribo, 70%), 37 (D-arabino,
95%) and manoselenepane 38 (70%) were efficiently
obtained. The high rate of Se-heterocyclisation could be
attributed to both higher nucleophilicity of Sev (compara-
tively to Sv) and to the temperature enhancement
(approximately 40 8C) when NaBH4 was added to Se.
Farther more we had verify that the addition of the DMSO
solution of a,v-dibromoalditols substrates to the cooled
solution of Se and NaBH4 (to 14 8C) increased the reaction
temperature of the mixture to 30 8C. Thus both Na2Se
formation and subsequente heterocyclisation were exo-
thermal. We could note also that the peracetylated a,v-
dibromoalditols don’t undertake any deacetylation reaction
although the temperature enhancement and the basicity of
the medium.
3.2. Synthesis of thiahetrocycles 3, 6, 9, 12, 16, 19 and 23
General procedure. To a solution of peracetylated a,v-
dibromoalditols (1 mmol)21 in DMSO (5 mL), was added
Na2S, 9H2O (1.5 mmol) and the mixture was stirred at rt for
the time indicated in table. The extraction was realised with
CH2Cl2 (30 mL) and H2O (2£30 mL). The organic layer
was concentrated and the products was purified by
chromatography on silica gel and mixture of Hexan–
EtOAc as eluent.
3.2.1. 2,3-Di-O-acetyl-1,4-dideoxy-1,4-thioerythritol (3).
186.7 mg, 92% yield as colorless syrup; Rf 0.44 (6:2,
Hexan–EtOAc); 1H NMR, (CDCl3) d 2.77 (dd, 2H, J1a,1b
¼
J4a,4b¼11.1 Hz, J1a,2¼J4a,3¼5.4 Hz, H1a,4a), 3.95 (dd, 2H,
J1b,2¼J4b,3¼5.6 Hz, H1b,4b), 5.21 (m, H2,3); 1.98 (s, 6H,
CH3); 13C NMR, d 31 (C1vC4), 74.3 (C2vC3), 21.1 (CH3),
170.2 (CO). Anal. calcd for C8H12O4S: C, 47.04; H, 5.92; O,
31.33; S, 15.70. Found: C, 47.24; H, 6.11.
3.2.2. 2,3-Di-O-acetyl-1,4-dideoxy-1,4-thio-D,L-threitol
(6). 193 mg, 95% yield; white solid: mp 43–45 8C; Rf
1
0.47 (6:2, Hexan–EtOAc); H NMR, (CDCl3) d 2.70 (dd,
In conclusion, this work has led to the short and efficient
synthesis in excellent yields of polyhydroxylated tetra-
hydrothio/selenophene, tetrahydrothio/selenopyrane and
thie/selenepane derivatives in various configurations via
dibrominated alditol derivatives that are readily prepared
from the corresponding alditols. In addition we have shown
a higher reaction rate at the primary C-1 compared with the
C-6 site of the 2,3,4,5-tetra-O-acetyl-1,6-dibromo-D-
glucitol (21). This opens the way to numerous derivatives
of D-glucitol with various functional groups, as well as to a
rare sugar, gulose.25 Finally, it is of interest to emphasise
that this strategie from pentitols led to high overal yields in
selenaheterocyclic pentitols 35 (xylo), 36 (ribo) and 37
(D-arabino) comparatively to those obtained in the ten steps
strategies reported in the literature.9
2H, J1a,1b¼J4a,4b¼12.2 Hz, J1a,2¼J4a,3¼1.3 Hz, H1a,4a),
3.17 (dd, 2H, J1b,2¼J4b,3¼4.0 Hz, H1b,4b), 5.22 (m, 2H,
H2,3); 2.1 (s, 6H, CH3); 13C NMR, d 34 (C1vC4), 77.9
(C2vC3), 21.2 (CH3), 170.0 (CO). Anal. calcd for
C8H12O4S: C, 47.04; H, 5.92; O, 31.33; S, 15.70. Found:
C, 47.32; H, 6.01.
3.2.3. 2,3,4-Tri-O-acetyl-1,5-dideoxy-1,5-thioxylitol (9).
248.7 mg, 90% yield; white solid: mp 120–122 8C; Rf 0.39
1
(5:2, Hexan–EtOAc); H NMR (CDCl3), d 2.53 (m, 2H,
J1a,1b¼J5a,5b¼13.9 Hz, J1a,2¼J5a,4¼6.4 Hz, H1a,5a), 2.74 (m,
J1b,2¼J5b,4¼1.8 Hz, H1ab5b), 4.93 (m, 3H, H2,3,4), 1.96 (s,
6H, CH3), 1.99 (s, 3H, CH3); 13C NMR, d 30.6 (C1,5), 72.7
(C2,4), 73.7 (C3), 20.7 (CH3), 169.7 (CO). Anal. calcd for
C11H16O6S: C, 47.82; H, 5.84; O, 34.74; S, 11.61. Found: C,
47.93; H, 6.12.
3.2.4. 2,3,4-Tri-O-acetyl-1,5-dideoxy-1,5-thioribitol (12).
215.3 mg, 78% yield; white solid: mp 89–91 8C; Rf 0.36
(5:2, Hexan–EtOAc); H NMR (CDCl3), d 2.45 (dd, 2H,
3. Experimental
1
3.1. General methods
J1a,1b¼J5a,5b¼12.1 Hz, J1a,2¼J5a,4¼12.1 Hz, H1a,5a), 2.80 (t,
2H, J1b,2¼J5b,4¼4.2 Hz, H1b5b), 5.01 (m, 2H, H2,4), 5.55 (s,
1H, H3), 1.96 (s, 6H, CH3), 2.15 (s, CH3); 13C NMR d 25.1
(C1,5), 70.9 (C2,4), 69.2 (C3), 20.8 (CH3), 169.5, 169.7 (CO).
Anal. calcd for C11H16O6S: C, 47.82; H, 5.84; O, 34.74; S,
11.61. Found: C, 48.01; H, 5.98.
Melting points were determined with a Buchi 535 apparatus
and are uncorrected. 1H and 13C NMR spectra were
recorded in CDCl3 on Bruker 300 WB spectrometer;
chemical shifts are reported in d (ppm) relative to Me4Si.
Coupling constants, assigned by double irradiation, are in
Hz. All 13C NMR signals were assigned though C,H-
correlated spectra with hsqc.grad experiment. TLC was
performed on silica Gel 60 F254 230 mesh (E. Merck) with
hexane–EtOAc as eluent, and zones were detected by
vanillin-H2SO4 reagent. The silica gel used in column
chromatography was 35–70 m (Amicon). Optical rotations
were determined with Jasco Dip 370 electronic micro-
polarimeter (10 cm cell) for compounds 37 and 38, and
Perkin–Elmer instruments, model 343 polarimeter (1 mL
cell) for compounds 16 and, 19 and 23. Elemental analyses
were performed by the ‘Service de Microanalyse du CNRS
3.2.5. 2,3-Di-O-acetyl-5-S-acetyl-1,4-anhydro-5-thio-D,L-
ribitol (13). Obtained when the acetone/H2O mixture was
used solvent in the thiaheterocyclisation reaction (Table 1,
entry 4). 55.3 mg, 20% yield; colorless syrup; Rf 0.28 (5:2,
Hexan–EtOAc); 1H NMR (CDCl3), d 3.76 (dd, 1H,
J1a,1b¼10.4 Hz, J1a,2¼3.4 Hz, H1a), 4.22 (dd, 1H,
J1b,2¼5.1 Hz, H1b), 5.13 (ddd, 1H, J2,3¼7.3 Hz, H2), 4.06
(dd, 1H, J3,4¼5.4 Hz, H3), 5.28 (dd, 1H, J4,5a¼6.0 Hz,
J4,5b¼24.4 Hz, H4), 5.01 (dd, 1H, J5a,5b¼14.1 Hz, H5a), 3
(dd, 1H, H5b), 2.02 (s, 3H, CH3), 2.04 (s, 3H, CH3 (Ac)),

Table 1. Regioselective thia and selenaheterocyclisation of peracetylated a,v-dibromoalditols derivatives using sodium sulfide and sodium selenide
Entry
Substrates
a,v-Dibromoalditols
derivatives (yield (%))a
Isolated thiaheterocyclic
products
Isolated yields (%) in
conditions with acetone–
H2O as solventb
Isolated yields (%) in conditions with
DMSO as solventc
Isolated selenahyeterocyclic products
after 5 min of reaction time in
DMSO/H2O as solvent
Yield (%)d
93
Time (h)
18
Yield (%) Time (min)
92
Time (min)
20
Yield (%)
Time (min)
1
,10
Erythritol (1)
D,L-Threitol (4)
Xylitol (7)
2 (85)
5 (86)
8 (70)
11 (68)
3
6
33 (93)
2
3
4
95
90e
70
18
18
18
18
95
87
78
0
20
30
30
30
,10
,10
,10
,10
34 (98)
35 (80)
9
Ribitol (10)
12
20
36 (70)
13
16
19
5
6
86
82
18
18
83
88
30
45
,10
,10
D-Arabinitol (14)
15 (73)
37 (95)
D-Mannitol (17)
18 (60)
38 (70)

M. Benazza et al. / Tetrahedron 60 (2004) 2889–2895
2893
Scheme 3. (i) Na2S, 9H2O, Acetone–H2O (15:1), rt, 18 h.
Scheme 4. R¼OAc; (i) AcONa (3 equiv.), 60 8C, 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 8C, 24 h, DMSO; (v) C8H17SH (1.2 equiv.), NaH (1.1 equiv.),
DMSO, TA, 15 min; (vi) C4H9SH (2.2 equiv.), NaH (2.4 equiv.) DMSO-
THF (1:1), rt, 15 min.
2.33 (s, 3H, CH3 (SAc)); 13C NMR d 70.8 (C1), 78.0 (C2),
73.5 (C3), 71.2 (C4), 30.9 (C5), 20.5 (CH3 (OAc)) 30.4 (CH3
(SAc)), 169.8 (CO, (Ac)), 194.7 (CO (SAc)). Anal. calcd for
C11H16O6S: C, 47.82; H, 5.84; O, 34.74; S, 11.61. Found: C,
48.07; H, 5.88.
3.2.6. 2,3,4-Tri-O-acetyl-1,5-dideoxy-1,5-thio-D-ara-
binitol (16). 229.1 mg, 83% yield; [a]D¼220.4 (c 3.3;
CHCl3); Rf 0.42 (5:2, Hexan–EtOAc); 1H NMR (CDCl3), d
2.54 (dd, 1H, J1a,1b¼14 Hz, J1a,2¼7.7 Hz, H1a), 2.83 (dd,
1H, J1b,2¼2.2 Hz, H1b), 5.08 (ddd, 1H, J2,3¼8.1 Hz, H2),
4.89 (dd, 1H, J3,4¼2.6 Hz, H3), 5.28 (dd, 1H, J4,5a¼7.2 Hz,
J4,5b¼2.6 Hz, H4), 2.62 (dd, 1H, J5a,5b¼14 Hz, H5a), 2.75
(dd, 1H, H5b), 1.98 (s, 3H, CH3), 1.97 (s, 3H, CH3), 1.99 (s,
3H, CH3), 2.15 (s, CH3); 13C NMR d 28.7 (C1), 68.9 (C2),
70.3 (C3), 68.8 (C4), 28.6 (C5), 20.8 (CH3), 169.5, 169.7,
169.9 (CO). Anal. calcd for C11H16O6S: C, 47.82; H, 5.84;
O, 34.74; S, 11.61. Found: C, 48.18; H, 6.22.

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M. Benazza et al. / Tetrahedron 60 (2004) 2889–2895
3.2.7. 2,3,4,5-Tetra-O-acetyl-1,6-dideoxy-1,6-thio-D-
mannitol (19). 307.2 mg, 88% yield; white solid: mp 93–
95 8C; [a]D¼2157 (c 3.7; CHCl3); Rf 0.42 (5:3, Hexan–
3.3.1. 2,3-Di-O-acetyl-1,4-dideoxy-1,4-selenoerythritol
(33). 70.5 mg, 93% yield as yellow syrup; Rf 0.52 (5:2,
Hexan–EtOAc); 1H NMR, (CDCl3) d 2.92 (dd, 2H, J1a,1b
¼
EtOAc); 1H NMR (CDCl3), d 2.79 (dd, 2H, J1a,1b
¼
J4a,4b¼10.3 Hz, J1a,2¼J4a,3¼5.9 Hz, H1a,4a), 3.11 (dd, 2H,
J1b,2¼J4b,3¼5.6 Hz, H1b,4b), 5.42 (m, H2,3); 2.04 (s, 6H,
CH3); 13C NMR, d 21.9 (C1vC4), 75.9 (C2vC3), 21.4
(CH3), 170.6 (CO). Anal. calcd for C8H12O4Se: C, 38.26; H,
4.82; O, 25.48; Se, 31.44. Found: C, 38.43; H, 4.85.
J6a,6b¼14.6 Hz, J1a,2¼J6a,5¼7.0 Hz, H1a,6a), 2.83 (dd, 2H,
J1b,2¼J6b,5¼4.5 Hz, H1b,6b), 5.28 (m, 2H, J2,3¼J4,5¼0.8 Hz,
H2,5), 5.28 (m, 2H, H3,4),1.96 (s, 6H, CH3), 1.99 (s, 6H,
CH3); 13C NMR, d 30.9 (C1,6), 70.2 (C2,5), 70.9 (C3,4), 20.6
(CH3), 169.3, 169.7 (CO). Anal. calcd for C14H20O8S: C,
48.27; H, 5.79; O, 36.74; S, 9.20. Found: C, 48.32; H, 6.05.
3.3.2. 2,3-Di-O-acetyl-1,4-dideoxy-1,4-seleno-D,L-threitol
(34). 74.3 mg, 98% yield; yellow syrup; Rf 0.55 (5:2,
3.2.8. 2,3,4,5-Tetra-O-acetyl-1,6-dideoxy-1,6-thio-D-
glucitol (23). 296.7 mg; [a]D¼20.2 (c 1.6; CHCl3); 85%
yield; white solid: mp 76–78 8C; Rf 0.26 (5:3, Hexan–
Hexan–EtOAc); 1H NMR, (CDCl3) d 2.93 (dd, 2H, J1a,1b
¼
J4a,4b¼11.0 Hz, J1a,2¼J4a,3¼2.4 Hz, H1a,4a), 3.20 (dd, 2H,
J1b,2¼J4b,3¼4.0 Hz, H1b,4b), 5.33 (m, 2H, H2,3); 2.05 (s, 6H,
CH3); 13C NMR, d 24.80 (C1vC4), 78.5 (C2vC3), 21.4
(CH3), 170.2 (CO). Anal. calcd for C8H12O4Se: C, 38.26; H,
4.82; O, 25.48; Se, 31.44. Found: C, 38.75; H, 5.01.
1
EtOAc); H NMR (CDCl3) (arbitrary numeration), d 2.69
(dd, 1H, J1a,1b¼14.6 Hz, J1a,2¼7.2 Hz, H1a), 2.84 (dd, 1H,
J1b,2¼3.9 Hz, H1b), 5.33 (ddd, 1H, J2,3¼1.4 Hz, H2), 5.15
(dd, 1H, J3,4¼8.1 Hz, H3), 5.49 (dd, 1H, J4,5¼6 Hz, H4),
5.04 (ddd, 1H, J5,6a¼7.4 Hz, J5,6b¼4.6 Hz, H5), 2.74 (dd,
1H, J1a,1b¼15.4 Hz, H6a), 2.88 (dd, 1H, H6b),1.95 (s, 3H,
CH3), 1.98 (s, 3H, CH3), 1.99 (s, 3H, CH3), 2.02 (s,3H,
CH3); 13C NMR d 33.1 (C1,6), 71.3 (C2), 70.8 (C3), 70.6
(C4), 75.2 (C5), 20.6, 20.8 (CH3), 169.0, 169.1, 169.5, 169.8
(CO). Anal. calcd for C14H20O8S: C, 48.27; H, 5.79; O,
36.74; S, 9.20. Found: C, 48.63; H, 5.92.
3.3.3. 2,3,4-Tri-O-acetyl-1,5-dideoxy-1,5-selenoxylitol
(35). 64 mg, 80% yield; red solid: mp 110–112 8C; Rf
0.46 (5:2, Hexan–EtOAc); 1H NMR (CDCl3), d 2.64 (d, 2H,
J1a,1b¼J5a,5b¼12.1 Hz, J1a,2¼J5a,4¼0 Hz, H1a,5a), 2.72 (dd,
J1b,2¼J5b,4¼4.8 Hz, H1ab5b), 5.07 (m, 2H, H2,4), 4.95 (d, H3,
1.96 (s, 6H, CH3), 1.99 (s, 3H, CH3); 13C NMR, d 21.4
(C1,5), 74.1 (C2,4), 74.3 (C3), 20.9, 21.2 (CH3), 169.9, 170.1
(CO). Anal. calcd for C11H16O6Se: C, 40.88; H, 4.99; O,
29.70; Se, 24.43. Found: C, 40.93; H, 5.12.
3.2.9. 3,4,5-Tri-O-acetyl-1-S-acetyl-2,6-anhydro-1-thio-
D-glucitol (25). Obtained when the acetone/H2O mixture
was used solvent in the thiaheterocyclisation reaction
(Table 1, entry 7). 34.8 mg, 10% yield; Yelow syrup; Rf
0.38 (5:3, Hexan–EtOAc); 1H NMR (CDCl3), d 3 (dd, 1H,
J1a,1b¼14.5 Hz, J1a,2¼6.2 Hz, H1a), 3.52 (dd, 1H,
J1b,2¼3.3 Hz, H1b), 5.13 (ddd, 1H, J2,3¼3.5 Hz, H2), 4.06
(dd, 1H, J3,4¼11 Hz, H3), 5.38 (dd, 1H, J4,5¼0 Hz, H4), 5.01
(ddd, 1H, J5,6a¼1.8 Hz, J5,6b¼4.7 Hz, H5), 3.76 (dd, 1H,
J1a,1b¼10.7 Hz, H6a), 4.22 (dd, 1H, H6b), 1.93 (s, 3H, CH3),
2.01 (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.29 (s,3H, CH3
(SAc)); 13C NMR d 72.3 (C1), 67.8 (C2), 79.4 (C3), 74.5
(C4), 77.3 (C5), 30.8 (C6), 20.7 (CH3 (Ac)), 30.4 (CH3
(SAc)), 169.3, 169.6 (CO (OAc)), 194.5 (CH3 (SAc)). Anal.
calcd for C14H20O8S: C, 48.27; H, 5.79; O, 36.74; S, 9.20.
Found: C, 48.54; H, 5.83.
3.3.4. 2,3,4-Tri-O-acetyl-1,5-dideoxy-1,5-selenoribitol
(36). 56 mg, 70% yield; pink solid: mp 128–130 8C; Rf
1
0.46 (5:2, Hexan–EtOAc); H NMR (CDCl3), d 2.45 (dd,
2H, J1a,1b¼J5a,5b¼11.7 Hz, J1a,2¼J5a,4¼4.1 Hz, H1a,5a),
2.97 (t, 2H, J1b,2¼J5b,4¼11.7 Hz, H1b5b), 5.15 (m, 2H,
H2,4), 5.53 (s, 1H, H3), 2.01 (s, 6H, CH3), 2.19 (s, 3H, CH3);
13C NMR d 16.2 (C1,5), 72.7 (C2,4), 70.1 (C3), 21.2 (CH3),
170.2, 169.9 (CO). Anal. calcd for C11H16O6Se: C, 40.88;
H, 4.99; O, 29.70; Se, 24.43. Found: C, 41.04; H, 5.23.
3.3.5. 2,3,4-Tri-O-acetyl-1,5-dideoxy-1,5-seleno-D-ara-
binitol (37). 76 mg, 95% yield; yellow syrup;
[a]2D2¼284.8 (c 1.2, CH2Cl2); Rf 0.37 (5:2, Hexan–
1
EtOAc); H NMR (CDCl3), d 2.86–2.94 (m, 2H, H1a,1b),
5.27 (ddd, 1H, J2,3¼7.5 Hz, H2), 4.99 (dd, 1H, J3,4¼2.8 Hz,
H3), 5.43 (m, 1H, J4,5a¼7.3 Hz, J4,5b¼3.1 Hz, H4), 2.67 (dd,
1H, J5a,5b¼13.2 Hz, H5a), 2.70 (dd, 1H, H5b), 1.98 (s, 3H,
CH3), 1.97 (s, 3H, CH3), 1.99 (s, 3H, CH3), 2.11 (s, 9H,
CH3); 13C NMR d 19.2 (C1), 69.7 (C2), 71.0 (C3), 69.8 (C4),
19.5 (C5), 20.4, 21.3, 21.2 (CH3), 170.4, 170.2, 171.0 (CO).
Anal. calcd for C11H16O6Se: C, 40.88; H, 4.99; O, 29.70; Se,
24.43. Found: C, 40.73; H, 5.02.
3.3. Synthesis of selenahetrocycles 33, 34, 35, 36, 37 and
38
General procedure. To a freshly colorless solution obtained
from addition of NaBH4 in H2O to a suspension of Se in
H2O, was added a solution of peracetylated a,v-dibromo-
alditols21 in DMSO (Table 2). The mixture was stirred for
,10 min. The extraction was realised with CH2Cl2 (20 mL)
and H2O (2£20 mL). The organic layer was concentrated
and the products was purified by chromatography on silica
gel and mixture of Hexan–EtOAc as eluant.
3.3.6. 2,3,4,5-Tetra-O-acetyl-1,6-dideoxy-1,6-seleno-D-
mannitol (38). 58 mg, 70% yield; white solid: mp
93–95 8C; [a]2D2¼221.0 (c 0.55, CH2Cl2); Rf 0.42 (5:3,
Table 2. Selenaheterocyclisation conditions of peracetylated a, v-dibromoalditol derivatives
a,v-Dibromoalditol
M (g mol21
)
m (g)
N (mol)
Se
NaBH4
m (mg)
VH2O (mL)
VDMSO (mL)
m (mg)
equiv.
equiv.
Tetritol
Pentitol
Hexitol
332
404
476
0.100
0.100
0.100
0.3£1023
0.25£1023
0.2£1023
71
59
50
3
3
3
68
56
48
6
6
6
2£290 mL
2£230 mL
2£200 mL
1.10 mL
930 mL
790

M. Benazza et al. / Tetrahedron 60 (2004) 2889–2895
2895
Hexan–EtOAc); 1H NMR (CDCl3), d 2.79 (dd, 2H, J1a,1b
¼
Pharmacol. 1984, 33, 3247–3250. (d) Parnham, M. J. Adv.
Exp. Med. Biol. 1990, 264, 193–197.
J6a,6b¼14.6 Hz, J1a,2¼J6a,5¼7.0 Hz, H1a,6a), 2.83 (dd, 2H,
J1b,2¼J6b,5¼4.5 Hz, H1b,6b), 5.28 (m, 2H, J2,3¼J4,5¼0.8 Hz,
H2,5), 5.28 (m, 2H, H3,4),1.96 (s, 6H, CH3), 1.99 (s, 6H,
CH3); 13C NMR, d 30.9 (C1,6), 70.2 (C2,5), 70.9 (C3,4), 20.6
(CH3), 169.3, 169.7 (CO). Anal. calcd for C14H20O8Se: C,
42.54; H, 5.10; O, 32.38; Se, 19.98. Found: C, 42.72; H,
5.55.
8. (a) Wilson, S. R.; Zucker, P. R. C.; Spector, A. J. Am. Chem.
Soc. 1989, 111, 5936–5939. (b) Maciel, E. N.; Bolzman, R. C.;
Braga, A. L.; Rocha, J. B. J. Biochem. Mol. Toxicol. 2000, 14,
310–319.
9. Lucas, M. A.; Nguyen, O. T. K.; Schiesser, C. H.; Zheng, S. L.
Tetrahedron 2000, 56, 3995–4000.
10. (a) Selwood, D. V.; Carter, K.; Young, R. J.; Jandu, K. S.
Biorg. Med. Chem. Lett. 1996, 8, 991–994. (b) Tber, B.;
Fahmi, N. D.; Ronco, G.; Villa, P.; Ewing, D. F.; Mackenzi, G.
Carbohydr. Res. 1995, 267, 2203–2216.
Acknowledgements
´
The authors thank the Counsel regional de Picardie & le
Fonds Social Europeen for their financial support.
11. Yuasa, H.; Kajimoto, T.; Wong, C. H. Tetrahedron Lett. 1994,
35, 8243–8246.
´
12. (a) Yoshikawa, M.; Murakami, T.; Shimada, H.; Matsuda, H.;
Yamahara, J.; Tanabe, G.; Muraoka, O. Tetrahedron Lett.
1997, 38, 8367–8370. (b) Yoshikawa, M.; Murakami, T.;
Yashiro, K.; Matsuda, H. Chem. Pharm. Bull. 1998, 46,
1339–1340. (c) Ghavami, A.; Johnston, B. D.; Pinto, B. M.
J. Org. Chem. 2001, 66, 2312–2317.
References and notes
1. Sun, Y. Free Radical Biol. Med. 1990, 8, 583–599.
2. (a) Montine, K. S.; Milatovic, D.; Doherty, M.; Morrow, J. D.;
Montine, T. J. Curr. Neuropharmacol. 2003, 1, 125–134.
(b) Bouvard, S.; Faure, P.; Roucard, C.; Favier, A.; Halimi, S.
Free Rad. Res. 2002, 36, 1017–1022. (c) Warner, H. R. Free
Rad. Biol. Med. 1994, 17, 249–258. (d) Adams, J. D., Jr.;
Odunze, I. N. Free Rad. Biol. Med. 1991, 10, 161–169.
(e) Sies, H. Am. J. Med. 1991, 9(suppl 3C), 3C-31S–3C-38S.
(f) Bautista, A. P. Free Rad Biol Med 2001, 31, 1527–1532.
3. Klotz, L. O.; Kroncke, K. D.; Buchczyk, D. P.; Sies, H. J Nutr.
2003, 133(5S-1), 1448S–1451S.
13. Le Merrer, Y.; Fuzier, M.; Dosbaa, I.; Foglietti, M. J.;
Depezay, J. C. Tetrahedron 1997, 53, 16731–16746.
`
14. (a) Cere, V.; Peri, F.; Pollicino, S. J. Org. Chem. 1997, 62,
8572–8574. (b) Fuzier, M.; Le Merrer, Y.; Depezay, J. C.
Tetrahedron Lett. 1995, 36, 6443–6446.
`
15. (a) Cere, V.; Peri, F.; Pollicino, S.; Ricci, A. Synlett 1998,
`
1197–1198. (b) Cere, V.; Peri, F.; Pollicino, S.; Ricci, A.
Tetrahedron Lett. 1997, 38, 7797–7800.
16. (a) Hudlicky, T.; Price, J. D.; Rulin, F.; Tsunoda, T. J. Am.
Chem. Soc. 1990, 112, 9439–9440. (b) Ley, S. V.; Sternfeld,
F. Tetrahedron Lett. 1988, 29, 5305–5308.
17. Legler, G. Adv. Carbohydr. Chem. Biochem. 1990, 48,
319–384.
4. (a) Lairon, D.; Bertrais, S.; Vincent, S.; Arnault, N.; Galan, P.;
Boutron, M. C.; Hercberg, S. Proc. Nutr. Soc. 2003, 62,
11–15. (b) Voirin, J.; Deschrevel, G.; Guincestre, J. Y.;
´
Foucault, P.; Bureau, F.; Duhamel, J. F. Ann. Pediatr. 1990,
37, 377–379. (c) Courtiere, A.; Cotte, J. M.; Pignol, F.; Jadot,
18. Altenbach, H. J.; Merhof, G. F. Tetrahedron: Asymmetry 1996,
7, 3087–3090.
`
19. Glac¸on, V.; Benazza, M.; Beaupere, D.; Demailly, G.
´
G. Therapie 1989, 44, 13–17.
5. (a) Flohe, L.; Gunzler, W. A.; Schock, H. H. FEBS lett. 1973,
32, 132–134. (b) Rotruck, J. T.; Pope, A. L.; Ganther, H. E.;
Swanson, A. B.; Hafman, D. G.; Hoesta, W. G. Science 1973,
179, 558–560. (c) Ursini, F.; Maorino, M.; Valente, M.; Ferri,
K.; Gregolin, C. Biochem. Biophys. Acta 1982, 710, 197–211.
(d) Behn, D.; Kyriakopoulos, A. Biochem. Biophys. Res.
Commun. 1990, 173, 1143–1149. (e) Rock, A.; Forchammer,
J. H.; Leinfelder, W.; Sawers, G.; Vepreck, B.; Zinnia, F. Mol.
Microbiol. 1991, 5, 515–520.
Tetrahedron Lett. 2000, 41, 5053–5056.
20. Halila, S.; Benazza, M.; Demailly, G. Tetrahedron Lett. 2002,
43, 815–818.
´
21. Robert, C. C.; Benazza, M.; Frechou, C.; Demailly, G.
Carbohydr. Res. 1997, 303, 359–365.
22. Calvo-Flores, F. G.; Garcia-Mendoza, P.; Hernandez-Mateo,
F.; Isac-Garcia, J.; Santoyo-Gonzalez, F. J. Org. Chem. 1997,
62, 3944–3961.
6. Engman, L.; Stern, D.; Cotgreave, A. I.; Andersson, C. M.
J. Am. Chem. Soc. 1992, 114, 9737–9743.
23. Benazza, M.; Masoui, M.; Uzan, R.; Demailly, G. Carbohydr.
Res. 1995, 275, 421–431.
7. (a) Mueller, A.; Cadenas, E.; Graf, P.; Sies, H. Biochem.
Pharmacol. 1984, 33, 3235–3239. (b) Wendel, A.; Fausel, M.;
Safayhi, H.; Tiegs, G.; Otter, R. Biochem. Pharmacol. 1984,
33, 3241–3245. (c) Parnham, M. J.; Kindt, S. Biochem.
24. Halila, S.; Benazza, M.; Demailly, G. Carbohydr. Res. 2003,
338, 177–182.
´
25. Gonzalez, F. S.; Baer, H. Carbohydr. Res. 1990, 202, 33–47.