The influence of microwave irradiation on stereospecific Mo(VI)-catalyzed transformation of deoxysugars

Article abstract of DOI:10.1016/j.tetasy.2009.05.010

The stereospecific mutual isomerization of 5-, 6-, and 7-deoxysugars in a microwave field with Mo(VI) as a catalyst is reported. The reaction cycle allows the use of catalytic amounts of molybdate ions to form highly reactive catalytically active dimolybd

Full text of DOI:10.1016/j.tetasy.2009.05.010

Tetrahedron: Asymmetry 20 (2009) 1239–1242
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The influence of microwave irradiation on stereospecific Mo(VI)-catalyzed
transformation of deoxysugars
*
Zuzana Hricovíniová
Institute of Chemistry, Slovak Academy of Sciences, SK-845 38 Bratislava, Slovakia
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereospecific mutual isomerization of 5-, 6-, and 7-deoxysugars in a microwave field with Mo(VI) as
a catalyst is reported. The reaction cycle allows the use of catalytic amounts of molybdate ions to form
highly reactive catalytically active dimolybdate complexes that create conditions for stereospecific intra-
molecular rearrangement. The microwave-enhanced Mo(VI)-catalyzed transformation of deoxyaldoses
occurred with full stereospecificity resulting in the formation of the corresponding epi-deoxyaldoses in
very good yields. The microwave field has a substantial effect on the transformation studied.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 11 March 2009
Accepted 11 May 2009
Available online 8 June 2009
Dedicated to the memory of
Professor V. Bílik (1929–1994)
1. Introduction
rather difficult. However, sufficient amounts of these compounds
could be useful for the study of their biosynthetic pathways and
Naturally occurring deoxysugars are essential biological mole-
cules that play a number of roles in many physiologically signifi-
cant processes such as cell signaling, immuno-stimulation, target
recognition of microorganisms and antibiotics. They occur fre-
quently as components of glycoproteins, glycolipids, and polysac-
charides and have received an increased interest as they were
shown to be substantial cell wall components of several human
novel interventions in antibacterial chemotherapy.
The synthesis of rare carbohydrates with biological activity,
which are applicable mainly in medicinal chemistry, is an attrac-
tive problem. Carbohydrate chemistry is currently dealing with
the development of efficient methods for the conversion of carbo-
hydrates into more valuable, enantiomerically pure products. Tran-
sition metal-catalyzed reactions belong to the powerful tools of
contemporary organic synthesis.10 The interaction of carbohy-
drates with metal ions has been extensively studied for a long
time.11 The formation of molybdate complexes with saccharides
and unusual epimerization of aldoses have been studied in de-
tail.12–14 Such reactions allow a considerable increase in molecular
complexity in a single step and usually proceed with excellent ste-
reoselectivity. Furthermore, the use of microwave radiation in or-
ganic synthesis has become more common and is very useful as
an alternative heat source in chemistry. It is increasingly being
studied due to its better yields, cleaner products, reduction of reac-
tion time and side reactions.15–17
Recently, we have developed the stereochemical transformation
of reducing saccharides in a microwave field by using molybdate
ions as a catalyst. This approach appears to be an ideal reaction
for the isomerization of a carbohydrate carbon skeleton with high
stereospecificity. The procedure led to efficient preparation of
aldoses,18 2-C-(hydroxymethyl)-aldoses, ketoses,19 and (1?6)-
linked disaccharides.20 As a part of our research program aimed
at the study of saccharide–molybdate complexes, Mo(VI)-cata-
lyzed rearrangement of reducing sugars and the development of
facile and straightforward synthetic routes to various sugar deriv-
atives, we herein report the preparation of several 5-, 6-, and
7-deoxyaldoses by direct skeletal isomerization in microwave
field.
pathogens.1 6-Deoxy-
L-hexoses, as constituents of the surface
polysaccharide structures of gram-positive and gram-negative hu-
man pathogenic bacteria are involved in host–pathogen interac-
tions, and
molecules results in a significant decrease in bacterial virulence.
-Fucose (6-deoxy- -galactose) has been investigated as a potential
agent to prevent tumor cell growth2 and as an anti-inflammatory
drug to alleviate rheumatoid arthritis.3
-Fucose, -rhamnose
(6-deoxy- -mannose), and -pneumose (6-deoxy- -talose), are,
a deficiency in the production of these surface
L
L
L
D
D
L
L
respectively, components of the cell surface lipopolysaccharides
of Helicobacter pylori, Pseudomonas aeruginosa, and Actinobacillus
actinomycetemcomitans serotype a.4,5
L-Rhamnose and
L
-qiunovose
are also found as constituents of extracellular, gram-negative bac-
terial polysaccharides, such as the Salmonella and Escherichia coli
O-antigen.
L-Qiunovose (6-deoxy-L-glucose) is the part of disaccha-
ride in digitalin which is a powerful cardiac stimulant.6,7 6-Deoxy-
heptoses
6-deoxy-
(6-deoxy-
L
-galacto-heptose,
6-deoxy-
L-talo-heptose,
D
-altro-heptose, and 6-deoxy-D-manno-heptose) are rare
components of bacterial lipopolysaccharides.8,9 Deoxysugars occur
in very small amounts and their isolation from natural sources is
* Tel.: +4212 5941 0282; fax: +4212 5941 0222.
E-mail address: chemhric@savba.sk
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.05.010

1240
Z. Hricovíniová / Tetrahedron: Asymmetry 20 (2009) 1239–1242
and new C-1–C-3 bond are formed stereospecifically. Effective ste-
2. Results and discussion
reospecific transformation occurs in the case of deoxyaldoses with
C-2–C-3 bond cleavage and transposition. Dissociation of the com-
plex produces the epimeric deoxyaldose as shown in Scheme 1C.
The thermodynamic equilibrium favours the saccharide with a
lower value of conformational instability. The ratio of deoxyaldose
and epi-deoxyaldose in an equilibrium reaction mixture was com-
parable regardless of the starting sugar. These results matched well
with our previous observations18 and are also in agreement with
NMR experiments analyzing the mechanism of this transformation
with 13C-enriched saccharides.13,14,26,27 It was determined that this
transformation could be sped up by applying microwave irradia-
tion. The reaction time decreased from hours to minutes and is
60 to 120-fold shorter than in the case of conventional oil-bath
heating, in addition to obtaining the better yields and cleaner
products.
Thermal effects result from dipolar polarization as a conse-
quence of dipole–dipole interactions between polar molecules
and the electromagnetic field. They originate from the dissipation
of energy into heat as a result of intermolecular friction when
the dipoles change their mutual orientation at each alternation of
the electric field at a high frequency. As carbohydrates have per-
manent dipole moments they are suitable chemical substances
for microwave irradiation. Accordingly, controlled microwave irra-
diation can be used to transfer significant amounts of energy into
the reaction and satisfy the high energy demands required for
the monomolecular C–C bond rearrangement. Thus, the rearrange-
ment process can be completed in a very short time. Selective
absorption of microwave energy is able to shift the reaction equi-
librium and product distribution is affected by the structure of li-
gand. The best yields were obtained with the microwave
irradiation power of 600 W. Table 1 shows the results of Mo(VI)-
catalyzed isomerization of the selected deoxyaldoses in both cases.
The isomerization reaction progressed smoothly in microwave
field and reached thermodynamic equilibrium within 3–5 min
compared to the 3–10 h required for conventional conditions.
The results suggest that the ability of molybdate ions to form cat-
alytically active complexes with deoxyaldoses and to promote the
isomerization process during microwave irradiation is improved.
The rate enhancement may be attributed to the absorption of more
energy by the polar media, which generates sufficient heat energy
to promote the demanding isomerization reaction.
The knowledge of the structure of saccharide–Mo(VI) com-
plexes21–24 and mechanism of the highly stereospecific isomeriza-
tion reaction14 lead us to the idea that microwave irradiation
might have a considerable effect also on the isomerization of deox-
ysugars. The influence of a microwave irradiation on the stereose-
lective transformation of eight representative deoxysugars was
studied. It was observed that the isomerizations of selected deox-
yaldoses in the presence of molybdate ions in microwave field
were more effective than those using conventional heating.25
Aqueous solutions of sugars containing molybdate ions generated
in microwave field gave thermodynamically equilibrated mixtures
of epimeric deoxyaldoses in a few minutes. The transformation is
proposed to involve the formation of a dimolybdate species of
the corresponding saccharides. The reaction cycle allows the use
of a catalytic amount of molybdate ions to form highly reactive cat-
alytically active Mo(VI) complexes that create conditions for ste-
reospecific intramolecular rearrangement producing desired
epimeric deoxyaldose. All the deoxyaldoses examined reacted sim-
ilarly, producing equilibrium mixtures of two C-2 epimers. It was
determined that the microwave irradiation had a substantial effect
on the yield of the corresponding epi-deoxyaldoses. Scheme 1
shows the one-pot synthetic preparation of various deoxyaldoses.
The transformation proceeds via an acyclic dimolybdate–saccha-
ride complexes. The formation of the dimolybdate complex with
the carbonyl-oxygen atom C-1 and the adjacent three hydroxylic
oxygen atoms at C-2, C-3, and C-4 of the deoxyaldose in acyclic-hy-
drated form (Scheme 1A), leads to the transition state (Scheme 1B)
in which the rearrangement occurs. The saccharide functions as a
bidentate ligand bound to the metal center. The critical C-2–C-3
O
O
O
O
Mo
O
Mo
O
O
OH
O
O
H
H
H
C
C
C
C
C
R
H
H
H
A
Different final concentrations of 2-epimers were obtained under
different reaction conditions (Table 1). This is in agreement with
epimerizations of aldoses where final product concentrations also
vary.18 Examination of the data suggested that final concentrations
depended upon the stereochemistry of starting compounds,
namely cis- or trans-configurations at C-3 and C-4 carbons. If deox-
yaldoses have cis configuration of hydroxyl groups at C-3 and C-4,
=
O
O
O
O
O
Mo
Mo
OH
O
O
O
O
H
H
H
C
C
OH
C
C
C
R
for example, 6-deoxy-
tion does not proceed to true equilibrium. In the case of the
trans-configuration, for example, 6-deoxy- -mannose/6-deoxy-
L-galactose and 6-deoxy-L-talose, the reac-
H
H
H
L
L-
B
glucose interconversion, the true equilibrium was reached. It thus
appears, that the configuration at C-3 and C-4 carbons is an impor-
tant factor that influences the final equilibria of the products ob-
tained under microwave conditions. The reason for this behavior
is not fully understood at present, but might originate in a lower
stability of the cis-configured aldoses due to steric effects.
The primary reaction produces the 2-epimers. However, in case
of longer conventional heating, secondary products are also formed
in addition to the 2-epimers.25,27 Such a secondary reaction pro-
duces a certain amount of 3-epimer of the starting deoxyaldose,
which immediately equilibrates with its 2-epimer. The presence
of 3-epimers complicates product separation. This problem can
simply be solved by a microwave approach since the energy absorp-
tion is different from the conventional mode of heating. NMR anal-
O
O
O
O
(1) R = H
O
Mo
Mo
C
O
(2) R = CH3
O
O
(3) R = CH2-CH3
O
H
H
C
C
OH
C
C
R
H
H
H
H
C
Scheme 1.

Z. Hricovíniová / Tetrahedron: Asymmetry 20 (2009) 1239–1242
1241
Table 1
Mo(VI)-catalyzed isomerizations of deoxyaldoses under conventional heating and microwave irradiation.
Deoxyaldose
epi-Deoxyaldose
Conventional heating
Deoxyaldose /Epi-deoxyaldose
3:1a
Microwave field
Deoxyaldose /epi-deoxyaldose (%)
2.2:1
Time (min)
240
Time (min)
3
Yieldc
66/30
5-Deoxy-
L
-arabinose28
5-Deoxy-L
-ribose28
O
O
OH
OH
HO
OH
CH3
OH
CH3
OH
5-Deoxy-
6-Deoxy-
L
-ribose
5-Deoxy-
6-Deoxy-
L
-arabinose
240
180
1:3a
3
3
1:2
2.3:1
30/60
64/29
L
-glucose29
L
-mannose29
1.5:1b
HO
HO
O
O
OH
OH
CH3
OH
CH3
OH
OH
HO
6-Deoxy-
6-Deoxy-
L
-mannose
6-Deoxy-
6-Deoxy-
L
-glucose
-talose29
180
480
1:1.5b
4:1a
3
5
1:2.3
3.1:1
30/62
70/20
L
-galactose29
L
O
O
OH
OH
CH3
CH3
OH
HO
HO
HO
HO
OH
a
6-Deoxy-
7-Deoxy-
L
-talose
6-Deoxy-
7-Deoxy-
L
-galactose
480
600
1:4
5
5
1:2.1
6.5:1
26/61
81/10
L
-galactoheptose30
L
-taloheptose30
9:1a
O
OH
O
OH
OH
CH3
OH
OH
CH3
HO
HO
HO
HO
OH
-galactoheptose
7-Deoxy-
L-taloheptose
7-Deoxy-
L
600
1:9a
5
1:4.5
10/77
a
Ref. 25.
Ref. 13.
Semi-preparative scale.
b
c
ysis clearly showed that only insignificant amounts of 3-epimers
(up to 3%) are present in equilibrated reaction mixtures obtained
under microwave conditions. The differences in the composition
of the reaction mixtures can be rationalized by these effects and
the tendency of microwave irradiations to prevent secondary reac-
tions. The relative energies that are necessary for the creation of
dominant and secondary products are different and a selective
absorption of microwave energy in a system increases the propor-
tion of primary product and decreases the proportion of secondary
product compared to a conventional approach.
fructose unit of
D-palatinose was isomerized to 2-C-(hydroxy-
methyl)-
D
-ribose.20 Dissociation of the complex produces the start-
ing deoxyketose and the isomeric product generated by the
stereospecific rearrangement. Examination of the NMR spectra
showed that the conversion reached its equilibrium in 5 min. The
mechanism of the rearrangement is in accordance with our previ-
ous observations32 but the reaction equilibrium is strongly shifted
to the starting compound (10:1).
In terms of application, microwave radiation enables rapid syn-
thetic transformations and offers significant improvements with
regard to yield, reaction time, and simplicity of the operation.
The method is suitable for preparative purposes, as the epimers
can be effectively obtained by chromatography. Identical experi-
ments were conducted according to the literature.25 Isomeric prod-
ucts were also obtained by this conventional way, but the yields
were markedly lower. Comparison of these results clearly shows
that microwave irradiation considerably accelerated the isomeri-
zation process and that the fast and homogeneous transfer of en-
ergy can minimize the side reactions. Microwave chemistry thus
opens up new possibilities for effective preparation of various
carbohydrates.
The transformation was also studied with one deoxyketose, 6-
deoxy-
reaction mixture obtained from the treatment of 6-deoxy-
L
-fructose. The preliminary 1H NMR investigation of the
L
-fruc-
tose31 with Mo(VI) in a microwave field revealed the presence of
two singlets 5.22 and 5.12 ppm, in the anomeric reagion of the
spectra with a prevalence for the b-furanose form. A comparison
of the signals with the published data32 suggests that they corre-
spond to two tautomeric forms of 2-C-(hydroxymethyl)-5-deoxy-
L
-ribose. The new compound is of high purity due to its significant
retention on a strongly acidic cation-exchange resin in the Ba2+
form. In this case formation of the dimolybdate complex with the
carbonyl-oxygen atom C-2 and the adjacent three hydroxyl groups
at C-3, C-4 and C-5 of 6-deoxy-L-fructose leads to the transition
3. Conclusion
state in which the critical C-3–C-4 and new C-2–C-4 bond is
formed stereospecifically. Similar evidence was seen during the
interconversion of (1?6)-linked disaccharides, where the terminal
In conclusion, we have demonstrated an easy approach toward
the stereoselective mutual transformation of terminal deoxysugars

1242
Z. Hricovíniová / Tetrahedron: Asymmetry 20 (2009) 1239–1242
by using Mo(VI) as a catalyst in a microwave field. The transforma-
tion studied involves reactive, catalytically active dimolybdate
complexes as intermediates, which enable the stereospecific rear-
rangement in the catalytic cycle. The present reaction may provide
insight into the development of other stereoselective transforma-
tions in carbohydrate synthesis.
Ba2+ form with water as eluent. In the case of 5-deoxy-
deoxy-
-Rib the Dowex 50W X8 in Ca2+ form and aqueous
0.001 M TEA as eluent was used. The yields of products are listed
L-Ara/5-
L
in Table 1. Branched deoxyaldose, 2-C-(hydroxymethyl)-5-deoxy-
L
-ribose, was separated on Dowex 50W X8 in Ba2+ form with water
as the eluent. dC (D2O, 600 MHz): 101.90 (C-1), 78.45 (C-2), 78.17
(C-5), 75.70 (C-4), 70.85 (C-3), 64.05 (CH2(C-2)). HRMS m/z calcd
for C6H12O5 164.1565; found 187.1543 [M+Na]+.
4. Experimental
4.1. General and experimental methods
Acknowledgments
Saccharides 5-deoxy-
glycero- -galacto-heptose, 7-deoxy-
prepared according to the literature.25 6-Deoxy-
rhamnose) was purchased from Fluka, 6-deoxy- -galactose (
L
-arabinose, 5-deoxy-
-glycero- -talo-heptose were
-mannose (
-fu-
L-ribose, 7-deoxy-L-
This research was supported by VEGA Grant 2/0108/08 and SP
Grant 2003SP200280203.
L
L
L
L
L-
L
L
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4.2. Representative procedure
The deoxyaldose (200 mg, 0.6 mmol) in 0.5% molybdic acid
(10 mg, 0.0617 mmol) in D2O (2 ml) was exposed to microwave
irradiation using a microwave oven operated at 600 W for an
appropriate time. The composition of the reaction mixture was
determined by 1H NMR spectroscopy to determine the ratio of
the epimers present in the thermodynamic equilibrium mixture
(Table 1). The ion-exchange resin Amberlite IRA-400 in the
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