Reactivity of per-O-acetylated 1-thioglycosides and glycosyl sulfones towards chromium(II) complexes in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2006.06.075

Anomeric carbon-sulfur bonds in 1-thioglycosides and glycosyl sulfones can be cleaved by chromium(II) complexes in water-DMF medium. Anomeric radicals as well as sugar-chromium(III) complex intermediates can be generated in these reactions, leading in some cases, to the exclusive formation of the corresponding glycals.

Full text of DOI:10.1016/j.tetlet.2006.06.075

Tetrahedron Letters 47 (2006) 6117–6120
Reactivity of per-O-acetylated 1-thioglycosides and glycosyl
sulfones towards chromium(II) complexes in aqueous medium
a,
a
b
c,
*
*
´
´
´
´
´
´
Karoly Micskei, Zsuzsa Juhasz, Zoran R. Ratkovic and Laszlo Somsak
aDepartment of Inorganic and Analytical Chemistry, Faculty of Natural Sciences, University of Debrecen, H-4010 Debrecen,
Egyetem te´r 1, PO Box 21, Hungary
bDepartment of Chemistry, Faculty of Sciences, University of Kragujevac, R. Domanovica 12, PO Box 60, 34000 Kragujevac,
Serbia and Montenegro
cDepartment of Organic Chemistry, Faculty of Natural Sciences, University of Debrecen H-4010 Debrecen, Egyetem te´r 1,
PO Box 20, Hungary
Received 10 April 2006; revised 7 June 2006; accepted 14 June 2006
Available online 7 July 2006
Abstract—Anomeric carbon–sulfur bonds in 1-thioglycosides and glycosyl sulfones can be cleaved by chromium(II) complexes in
water–DMF medium. Anomeric radicals as well as sugar–chromium(III) complex intermediates can be generated in these reactions,
leading in some cases, to the exclusive formation of the corresponding glycals.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The chemistry of the anomeric centre of carbohydrate
derivatives is characterized by the electrophilic nature
of this carbon.1 Umpolung of this reaction centre can
be achieved by the generation of glycosyl radicals2 or
–anions,3 and such transformations have also been
intensively investigated leading to elegant synthetic
methodologies and significant achievements in synthetic
carbohydrate and natural product chemistry.
glycosyl chlorides or bromides in water–DMF solvent
mixture,5b and the transformation could also be per-
formed in water.5c Nevertheless, the sensitivity of these
substrates towards hydrolysis as well as nucleophilic
substitution and elimination proved a disadvantage of
these reactions leading to the appearance of several
by-products. Therefore, hydrolytically more stable
monosaccharide derivatives were sought to achieve
higher selectivity under aqueous conditions. In this
initial letter, we disclose our initial results on the investi-
gation of the reactions between thioglycosides/glycosyl
sulfones and chromium(II) complexes in water–DMF.
With increasing social concerns towards pollution of the
environment, the quest for carrying out chemical trans-
formations under environmentally benign conditions
has been continuously growing. Among others, water
or aqueous conditions have been proposed for a large
array of organic reactions.4 However, most ‘classical’
methods used for the generation of glycosyl anions3
are incompatible with aqueous and even protic
conditions.
While the use of Cr(II) species for the reductive transfor-
mation of several functional groups (e.g., halogenides,
carbonyl and epoxides) under aprotic conditions6 has
become a very useful and popular synthetic method, to
the best of our knowledge, no chromium based reagents
have been applied as yet for the cleavage of C–S bonds.
Several thioglycosides/glycosyl sulfones were applied in
reactions with SmI2 to achieve the generation of glycosyl
radicals and/or –anions.3,7
Some years ago, we demonstrated that glycosyl-chro-
mium(III) species were remarkably stable under aque-
ous conditions.5a This method could be elaborated for
the preparation of pyranoid glycals from per-O-acylated
The thioglycosides and glycosyl sulfones studied in this
work are collected in Table 1. The most reactive
[CrII(EDTA)]2À complex was used9 for testing the reac-
tions with derivatives 1–11 (Table 2). The formation of
glycals 12–15 (Scheme 1) was an indication of the
*
Corresponding authors. Tel.: +36 52 512 900x22757; fax: +36 52 489
667 (K.M.); Tel.: +36 52 512 900x22348; fax: +36 52 453 836
(L.S.); e-mail addresses: kmicskei@delfin.unideb.hu; somsak@tigris.
unideb.hu
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.075

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K. Micskei et al. / Tetrahedron Letters 47 (2006) 6117–6120
Table 2. Reduction of the C1–S bonds by the [CrII(EDTA)]2À complex
Table 1. The substrates investigated
Ra
Entry Substrate pH Reaction Productb Conversionc (%)
time (h)
OAc
O
1
1
2
3
4
5
6
7
8
1
2
6
9
6
5
4
6
6
6
6
6
6
6
6
6
6
48
18
18
18
18
36
36
2a + 34
48
5
12
12
12
12
12
12
12
12
12
12
12
13
13
14
15
N.r.
N.r.
N.r.
17
>95
>95
15
AcO
AcO
S
R
2
OAc
N
2
2
2
3
N
4
3
4
17
O
N
9
5
N.r.
>95
>95
>95
>95
82
10
11
12
13
14
15
6
4
7
5
S
8
36
36
36
36
OAc
O
9
O
S
10
11
5
AcO
AcO
R
80
O
OAc
a T = 60 ꢁC.
N
N
b 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hex-1-enitol (12),
3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-lyxo-hex-1-enitol (13), 3,4-
di-O-acetyl-1,5-anhydro-2-deoxy-D-threo-pent-1-enitol (14), 3,4-di-
O-acetyl-1,5-anhydro-2-deoxy-D-erythro-pent-1-enitol (15).
c Calculated from the 1H NMR spectra.
6
7
S
N
OAc
O
AcO
AcO
O
S
8
1
R
R
O
S
OAc
2
R
O
O
OAc
Cr(II)L
SO
R
n
N
S
9
-Cr(III)L
3
n = 0, 2
-RSO
R
n
OR
-OAc
1
1-11
N
O
2
3
Cr(II)L
-Cr(III)L
AcO
AcO
10
R
R
= CH OAc, R = H, R = OAc 12
2
O
1
2
3
OAc
= CH OAc, R = OAc, R = H 13
2
1
2
3
AcO
AcO
R
R
= R = H, R = OAc 14
O
O
S
SO
R
n
O
1
3
2
= R = H, R = OAc 15
N
11
O
OAc
OR
-RSO
-Cr(III)L
-OAc
a References: 1,8a 2,8b 3,8c 4,8c,e 5,8f 6,8g 8–11.8h
n
O
O
efficient formation of a glycosyl-chromium(III) interme-
diate.5a Phenyl thioglucoside 1 was not reactive (entry 1)
at the optimal pH for the formation of the
[CrII(EDTA)]2À complex.10 The reactions of 2-pyridyl
thioglucoside 2 exhibited an interesting pH dependence,
showing the highest reactivity under significantly acidic
conditions (entries 2–5). Since the concentration of the
reactive complex is essentially the same in the pH range
investigated,11 the differences must be due to proton-
ation of the pyridine ring. If unprotonated, this substitu-
ent has little potency for promoting the transformation
by stabilizing the postulated radical–anion intermediate,
but with a positive charge this capacity seems sufficient
for the reaction to occur. From the thioglucosides, 2-
benzoxazolyl derivative 3 showed much higher reactivity
as compared to its 2-benzothiazolyl counterpart 4
(entries 6–8), whilst the reaction of 10 corroborated
this finding (entry 14). In the glucosyl-sulfone series the
phenyl derivative 5 was again unreactive (entry 9), while
2-pyridyl and 2-benzothiazolyl compounds 6 and 7,
respectively, exhibited high reactivities (entries 10 and
11). Similarly, the D-galactosyl (8, 9) and D-arabinosyl
(11) derivatives (entries 12, 13, and 15) also showed
good reactivity.
Cr(II)L
Cr(III)L
-Cr(II)L
OR
OR
OAc
O
OAc
H2C=CHCN
CN
AcO
AcO
16
Scheme 1.
The reactivity of the Cr(II) ion can be carefully regu-
lated by the coordinated ligand;5a,b therefore, the two
highly reactive sugar derivatives 3 and 7 were subjected
to reactions with less reactive chromium(II) complexes
(Table 3). With [CrII(OAc)2] (entries 1 and 2), the start-
ing materials were recovered (>90%). On increasing the
reactivity with ligands5b (MAL < GLY < IDA <
NTA < EDTA), the formation of the corresponding
glycal 12 could be detected (entries 3–10). Complete
conversions were reached when the [CrII(EDTA)]2À
complex was used (entries 11 and 12). In comparison
with 3, reduction of 7 with the less reactive [CrII(MAL)],

K. Micskei et al. / Tetrahedron Letters 47 (2006) 6117–6120
6119
Table 3. Reduction of C1–S bonds by chromium(II) complexes
The UV–visible spectra (Fig. 1) show the decomposition
of the organometallic bond resulting in the elimination
product.
Entry Complex CrIILa Substrate pHb Conversionc,d (%)
1
2
3
4
5
6
7
8
[CrII(OAc)2]
[CrII(MAL)]
[CrII(GLY)]+
[CrII(IDA)]
3
7
3
7
3
7
3
7
3
7
3
7
6.5
6.5
4.0
4.0
6.0
6.0
6.0
6.0
6.5
6.5
6.5
6.5
N.r.
N.r.
33
>95
92
>95
91
>95
73
In order to test the hypothesis of the intermediate radi-
cal (Scheme 1), the reaction of 7 was performed in the
presence of acrylonitrile.12 Analysis of the reaction mix-
ture indicated the formation of C-glucosyl derivative
1613 as a product of radical coupling.
9
[CrII(NTA)]À
[CrII(EDTA)]2À
In this work, we have demonstrated that hydrolytically
stable anomeric C–S bonds can be cleaved by
chromium(II) complexes to produce a glycosyl radical
suitable for coupling as well as a C(1)–Cr(III) organo-
metallic bond featuring a carbanionic anomeric centre.
10
11
12
>95
>90
>95
a L: malonic acid (MAL); glycine (GLY); iminodiacetic acid (IDA);
nitrilotriacetic acid (NTA); ethylenediaminetetra-acetic acid
(EDTA).
b Reaction time was 18 h in all reactions.
c Calculated from the 1H NMR spectra.
Acknowledgements
d Product:
3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-arabino-hex-1-
enitol (12).
Financial support is acknowledged from the Hungarian
Scientific Research Fund (Grant OTKA, No. T46942).
[CrII(GLY)]+, [CrII(IDA)], and [CrII(NTA)]À complexes
was also suitable, indicating that the 2-benzothiazolyl
sulfonyl moiety makes cleavage of the C–S bond espe-
cially easy. (Unfortunately, all efforts so far made
towards the preparation of the sulfonyl counterpart of
3 failed because of the extreme lability of that
compound.)
References and notes
1. Collins, P. M.; Ferrier, R. J. Monosaccharides—Their
Chemistry and Their Roles in Natural Products; John Wiley
& Sons: Chichester, 1995.
2. Praly, J.-P. Adv. Carbohydr. Chem. Biochem. 2001, 56, 65–
151.
We suggest that radical formation is the first step in C–S
bond breaking (Scheme 1) with the cleavage of a sulfide
or sulfinate from the possible intermediate radical anion.
The structure of the aglycon (R) has a strong bearing on
the electron acceptor capacity of the substrates. The 2-
benzoxazolyl moiety was found to be the most effective
for thioglycosides and the 2-benzothiazolyl moiety for
glycosyl sulfones. The radical may equilibrate with a
glycosyl-Cr(III) intermediate which then decomposes
to give glycals 12–15.
´
3. Somsak, L. Chem. Rev. 2001, 101, 81–135.
´
4. (a) Lubineau, A.; Auge, J.; Queneau, Y. Synthesis 1994,
741–760; (b) Scherrmann, M. C.; Lubineau, A. Actualite
Chimique 2003, 72–76; (c) Lubineau, A.; Auge, J. Water as
solvent in organic synthesis. Modern Solvents in Organic
Synthesis, 1999; pp 1–39; (d) Lubineau, A. Chem. Ind.
1996, 123–126.
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5. (a) Kovacs, G.; Gyarmati, J.; Somsak, L.; Micskei, K.
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Tetrahedron Lett. 1996, 37, 1293–1296; (b) Kovacs, G.;
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Toth, K.; Dinya, Z.; Somsak, L.; Micskei, K. Tetrahedron
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1999, 55, 5253–5264; (c) Kovacs, G.; Micskei, K.; Somsak,
L. Carbohydr. Res. 2001, 336, 225–228.
6. Reviews: (a) Wessjohann, L. A.; Scheid, G. Synthesis 1999,
1.2
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1–36; (b) Furstner, A. Chem. Rev. 1999, 99, 991–1045; (c)
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Hodgson, D. M. J. Organomet. Chem. 1994, 476, 1–5; (d)
Cintas, P. Synthesis 1992, 248–257.
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7. (a) Pouilly, P.; Chenede, A.; Mallet, J.-M.; Sinay, P.
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Tetrahedron Lett. 1992, 33, 8065–8068; (b) Skrydstrup, T.;
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1965, 98, 3515–3519; (d) Zinner, H.; Peseke, K. Chem. Ber.
1965, 98, 3508–3514; NMR data: (e) Khodair, A. I.; Al-
Masoudi, N. A.; Gesson, J.-P. Nucleosides, Nucleotides,
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Figure 1. Typical kinetic curve5a recorded at 320 nm demonstrating
elimination of the organochromium(III) intermediate in the reaction of
9. Typical procedure for the preparation of glycals: EDTA
(1.265 g, 3.4 mmol, 6 equiv) was dissolved in a mixture of
water (30 ml) and DMF (30 ml), and stirred under argon.
[CrII(EDTA)]2À and
7
([CrII] = 5 mM, [EDTA] = 7.4 mM, [7] =
0.5 mM, pH = 5, H2O/DMF = 1/1, t = 25 ꢁC in 1.00 cm cell).

6120
K. Micskei et al. / Tetrahedron Letters 47 (2006) 6117–6120
sure. The resulting residue was examined by TLC (eluent:
A calculated amount of an aq KOH solution (2.4446 M,
1.25 ml) was added to this solution to obtain pH ꢀ 6.
After the solution had cleared (30 min), [Cr(CH3COO)2Æ
H2O] (0.540 g, 2.83 mmol, 5 equiv) was added in one
portion. Formation of the complex was indicated by a
change of colour. The solution of thioglycoside 3 (0.273 g,
0.56 mmol, 1 equiv) in DMF (5 ml) was added to the
mixture and stirred at room temperature for 18 h. (For
glycosyl-sulfones the reaction time was 5 h.)
1
ether/hexane = 6/4) and H NMR.
´
10. Micskei, K.; Debreczeni, F.; Nagypal, I. J. Chem. Soc.,
Dalton Trans. 1983, 1335–1338.
11. The experimental conditions for pH dependence measure-
ments were the same as above9 except for the amounts of
KOH, which were: 6.25–4.0–2.0–0 ml (entries 2–5, Table
2), and the amount of the ligand EDTA was 8.15 mmol
(3.035 g) in all cases.
Work-up for thioglycosides: Saturated NH4Cl solution
(50 ml) was added to the reaction mixture. This solution
was extracted with ether (6 · 20 ml), the organic layer was
washed with water (4 · 10 ml), and dried over Na2SO4.
The solvent was removed under reduced pressure. The
resulting residue was examined by TLC (eluent: ether/
hexane = 6/4) and 1H NMR. The products had NMR
characteristics identical with those of authentic samples.
Work-up for glycosyl-sulfones: Saturated NH4Cl solution
(50 ml) was added to the reaction mixture. This solution
was extracted with chloroform (6 · 20 ml), the organic
layer was washed with water (4 · 10 ml), and dried over
Na2SO4. The solvent was removed under reduced pres-
12. Typical procedure for generation of the C(1)–C bond:
[CrII(EDTA)]2À complex was generated in situ in H2O/
DMF = 1/1 as above. A solution of glycosyl-sulfone
(0.265 g, 0.56 mmol, 1 equiv), in DMF (5 ml) was added
to the mixture. After 15 min, acrylonitrile (2 ml, 0.03 mol,
60 equiv) was added to the reaction mixture in one
portion. The reaction was stirred at room temperature
for 18 h followed by work-up a similar described above.
The resulting residue was examined by TLC (eluent: ether/
1
hexane = 6/4) and H NMR, which show the presence of
1613 in ꢀ40% yield.
13. Gotanda, K.; Matsugi, M.; Suemura, M.; Ohira, C.; Sano,
A.; Oka, M.; Kita, Y. Tetrahedron 1999, 55, 10315–10324.