Methyltrioxorhenium catalyzed domino epoxidation-nucleophilic ring opening of glycals

Article abstract of DOI:10.1016/S0040-4039(03)01386-8

The use of catalytic methylrhenium trioxide (MTO) and urea hydrogen peroxide in room temperature ionic liquid for the hydroxyglycosylation with glycals in a domino fashion is reported. Excellent conversions and good selectivities for the epoxidation reaction were observed. Application to the synthesis of glycosylphosphates, good glycosyl donors, has been studied.

Full text of DOI:10.1016/S0040-4039(03)01386-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5589–5592
Methyltrioxorhenium catalyzed domino epoxidation-nucleophilic
ring opening of glycals
Gianluca Soldaini, Francesca Cardona and Andrea Goti*
Dipartimento di Chimica Organica ‘‘Ugo Schiff’’, Polo Scientifico, Universita` di Firenze, via della Lastruccia 13,
I-50019 Sesto Fiorentino, Firenze, Italy
Received 15 April 2003; revised 15 April 2003; accepted 3 June 2003
Abstract—The use of catalytic methylrhenium trioxide (MTO) and urea hydrogen peroxide in room temperature ionic liquid for
the hydroxyglycosylation with glycals in a domino fashion is reported. Excellent conversions and good selectivities for the
epoxidation reaction were observed. Application to the synthesis of glycosylphosphates, good glycosyl donors, has been studied.
© 2003 Elsevier Ltd. All rights reserved.
Cell surface glycoconjugates are involved in many cell–
cell recognition events connected to inflammation,
immune response, cancer and viral infections.1 In this
respect, glycals 1 have recently found a wide applica-
tion as synthetic building blocks in the construction of
various glycoconjugates.2 Direct epoxidation with gly-
cals furnishes 1,2-anhydrosugars 2, that behave as good
glycosyl donors. In turn, 1,2-anhydrosugars 2 can be
easily employed for the installation at C-1 of functional
groups that impart glycosyl donor character to the
anomeric carbon atom, such as azide, amine, fluoride,
phenylthiol, etc.3
hydroxyglycosylation with glycals that employs a
reagent combination of Tf2O and diphenylsulfoxide has
been described.9
During the last years, we have been involved in the
study of new convenient, practical, and environmen-
tally friendly oxidation procedures, addressed in partic-
ular to the oxidation of nitrogen containing
compounds.10 During these studies, we have focused on
the use of methylrhenium trioxide (CH3ReO3, MTO),11
as the catalyst for the oxidation of secondary amines to
nitrones by using as the stoichiometric oxidant the
complex urea–H2O2 (UHP),10c,12 which simplifies the
work-up procedures and allows the use of non-aqueous
solvents and safe reagents.
Methyltrioxorhenium has emerged in the last decade, in
combination with hydrogen peroxide as the stoichio-
metric oxidant, as an important catalyst for the oxida-
tion of many classes of substrates, among which the
most important and studied reactions were epoxidation
of olefins.13 To our knowledge, however, no example of
use of MTO as catalyst for the oxidation of enol ethers
has been reported, apart from the oxidation of silyl
enol ethers to a-hydroxy and a-silyloxy ketones.14
The epoxidation of glycals 1 to 2 is not a trivial task,
due also to the sensitive nature of 2, particularly in
acidic media. This transformation is usually performed
using dimethyldioxirane (DMDO);4 other reagents have
been proposed, namely methyl(trifluoromethyl)-
dioxirane,5 MCPBA/KF,6 or perfluoro-cis-2,3-dialkyl-
oxaziridines,7 but always as stoichiometric oxidants. No
general catalytic oxidation procedure has been reported
so far for this type of transformation.8 Recently, a C-2
We decided to test methyltrioxorhenium (MTO), in
combination with UHP as the stoichiometric oxidant,
in the epoxidation of glycals, in view of the usefulness
of 1,2-anhydrosugars and their uneasy preparation,
requiring oxidants not immediately available. In this
Communication we report the domino epoxidation-
nucleophilic ring opening of glycals catalyzed by MTO.
Keywords: glycosyl phosphates; glycosyl donors; methyltrioxorhe-
nium; ionic liquids; catalysis; oxidation.
* Corresponding author. Tel.: +39-055-4573505; fax: +39-055-
4573531; e-mail: andrea.goti@unifi.it
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01386-8

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G. Soldaini et al. / Tetrahedron Letters 44 (2003) 5589–5592
Glycosyl phosphates, recently prepared from 1,2-anhy-
drosugars and HOP(O)(OR)2,15 are powerful, albeit
scarcely employed, glycosyl donors. They react with
hindered glycosyl acceptors and furnish disaccharides in
high yield, comparing favorably with other types of
glycosylating agents.16 Thus, the MTO-catalyzed epoxi-
dation-nucleophilic ring opening was studied on tri-O-
benzylglucal (3b) as model substrate by introduction of
dibutylphosphate (DBP) in the reaction mixture (Table
1). With 3 equiv. of DBP, a 1:1 mixture of glycosyl
phosphate 6 and 1,2-diol 7 was formed (entry 2);
increase of the amount of DBP to 5 equiv., in order to
suppress formation of 7, however, resulted in lower
conversions of glycal (entry 3), showing a detrimental
effect of phosphate on the epoxidation rate. Switch to a
room temperature ionic liquid17 as solvent allowed to
limit this effect, while increasing the selectivity towards
formation of 6 (entry 4).18 With [BMIM]BF4 as solvent
the glycosyl phosphate 6 was always the major product,
and the reaction reached complete conversions by using
4 mol% of MTO and 5 equiv. of DBP at rt. The 6:7
ratio could be raised up to 4:1 drying the ionic liquid
before use. These parameters were chosen as optimal
reaction conditions (Table 1, entry 9). With 2 mol% of
MTO, as well as at a temperature of 0°C, the reaction
was slower, and use of minor (3 equiv.) or major (10
equiv.) amounts of DBP resulted in decreased 6:7 ratios
(Table 1, entries 4, 12, 5 and 7). Apparently, the dibutyl
glycosyl phosphate 6 undergoes slow hydrolysis under
the reaction conditions, as showed by the lower ratio
obtained when the reaction is stopped after 22 h (Table
1, entry 13 vs. 9).
Scheme 1. Reagents and conditions: (i) MTO (2 mol%), UHP
(3 equiv.), MeOH, rt, 20 h for 3, 15 h for 4; (ii) Ac2O, py, rt,
15 h, a: 92%, b: 87%.
Reaction of tri-O-acetylglucal (3a) and tri-O-benzylglu-
cal (3b) with MTO (2 mol%) and UHP (3 equiv.) in
MeOH as solvent gave, with complete conversion of the
starting glycals, a b/a mixture of methyl glycosides 4
and 5 (Scheme 1), deriving from methanolysis of the
intermediate epoxides, not isolable under the reaction
conditions. The diastereoselectivity of the epoxidation
1
was determined by H NMR analysis after acetylation
of the crude product mixtures. As expected, with the
bulkier benzyl groups a higher level of diastereoselectiv-
ity in favor of the a-epoxidation (anti to the OR group
at C-3), with preferred formation of glucose derivative
4, was observed.
All efforts to isolate the epoxides performing the oxida-
tion reaction in non-nucleophilic solvents failed.
Indeed, in CH2Cl2 or CH3CN no appreciable conver-
sion of the starting material occurred, while in acetone
the 1,2-unprotected sugar 7 (as a mixture of 4 isomers)
deriving from hydrolysis of the intermediate epoxides
,
was formed in 72% yield (Table 1, entry 1). Use of 3 A
molecular sieves in the reaction mixture was not
efficient in avoiding hydrolysis, ascribed to the forma-
tion of water in the reduction of UHP.
The optimal reaction conditions (Table 1, entry 9), were
then applied for the domino catalytic oxidation to
Table 1. Domino catalytic oxidation of tri-O-benzylglucal (3b) with MTO and UHP-nucleophilic ring opening with
dibutylphosphate a
Entry
Solvent
MTO (mol%)
DBP (equiv.)
Time (h)
Temperature
6:7 Ratiob
Conversion (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
acetone
acetone
acetone
2
2
2
2
4
4
4
4
4
4
4
4
4
–
3
5
5
3
5
10
–
5
5
1.5
3
3
3.5
5
3
rt
0:100
1:1
–
3:1
2:1
3:1
2:1
1:1
4:1
100
100
30
0°C
0°C
rt
rt
rt
rt
rt
rt
rt
c
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
DBP
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
80
100
100
100
100
100
100
100
70
5
4.5
3.5
3.5
2.5
6
c
c,d
c
4:1
0:100
3:1
-
5
5
rt
0°C
rt
c
c
22
1.7:1
100
a Reagents and conditions: (i) MTO, UHP (3 equiv.), HOP(O)(OBu)2(DBP), solvent, nitrogen atmosphere.
b Calculated by integration of the 1H NMR spectra of the crude mixtures.
c Dried by heating at 80°C for 1 h under reduced pressure.
d
,
In the presence of 3 A molecular sieves.

G. Soldaini et al. / Tetrahedron Letters 44 (2003) 5589–5592
5591
Table 2. Catalytic oxidation of glycals to glycosyl phosphates in [BMIM]BF4 with MTO and UHP a
Entry
Substrate
Reaction time
(h)
Conversion (%) b 9:10:11 ratio b Yield (%) c
a/b Epoxidation selectivity b
1
2
3
4
3a: R=Ac, R%=H,
R%%=OAc
3b: R=Bn, R%=H,
R%%=OBn
8a: R=Ac, R%=OAc,
R%%=H
8b: R=Bn, R%=OBn,
R%%=H
16
100
100
100
100
1.1:1:1.2
8.3:1:1.7
12.3:5.3:1
10:1:0
66
58
62
41
1.8:1
5.5:1
3.5
17.5
4
17.6:1
>50:1
a Reagents and conditions: (i) MTO (4% mol), UHP (3 equiv.), DBP (5 equiv.), dry [BMIM]BF4, nitrogen atmosphere, rt; (ii) py, Ac2O, rt, 15 h.
b Calculated by integration of the 1H NMR spectra of the crude mixtures.
c Isolated by flash column chromatography.
glycosyl phosphates of tri-O-acetylglucal (3a) and tri-
O-acetyl and tri-O-benzylgalactals (8a and 8b, respec-
tively) (Table 2). Direct acetylation of the crude
mixtures allowed determination of the diastereoselectiv-
2. Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int.
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1
ity of the epoxidation by H NMR analysis. Satisfac-
tory isolated yields (41–66%) were obtained in all
cases.19 Products 9 and 10, that derive from the a
epoxide, were always the major diastereomers, but the
diastereoselectivity of the epoxidation is notably higher
for galactals with respect to glucals (Table 2, entries 3,4
vs. 1,2) and with benzyl protecting groups with respect
to acetyl protecting groups (Table 2, entries 2 vs. 1 and
4 vs. 3).
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porphyrin catalyst has been reported: Liu, C.-J.; Yu,
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7364–7369.
In conclusion, the first catalytic methodology to con-
vert glycals into glycosyl phosphates employing safe,
commercially available and inexpensive reagents and a
‘green solvent’ such as [BMIM]BF4 is presented. Fur-
ther work is in progress in our laboratories to widen the
scope and application of this methodology.
9. Di Bussolo, V.; Kim, Y.-J.; Gin, D. Y. J. Am. Chem. Soc.
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Tetrahedron Lett. 1999, 40, 1989–1992; (e) Cicchi, S.;
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Acknowledgements
We thank the National Research Council (CNR, Pro-
getto Giovani-Agenzia 2000), Italy and the Ministry of
Instruction, University and Research (MIUR, Cofin
2002), Italy for financial support.
11. (a) Beattie, R.; Jones, P. J. Inorg. Chem. 1979, 18, 2318–
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12. Goti, A.; Cardona, F.; Soldaini, G. Org. Synth., in press.
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19. Typical procedure: MTO (2.5 mg, 0.01 mmol), UHP (71
mg, 0.75 mmol), dibutyl phosphate (263 mg, 1.25 mmol)
and the glycal (0.25 mmol) were added sequentially,
under N2, to dry [BMIM]BF4 (0.5 mL). The resulting
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Na2SO4. The solvent was removed under vacuum. The
crude oil was dissolved in pyridine (1 mL) and acetic
anhydride (0.5 mL) was added dropwise. After stirring at
rt for 15 h the mixture was concentrated and the dibutyl
glycosyl phosphates were collected by chromatography
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18. MTO has been used in ionic liquids for the epoxidation