Carbohydrate functionalization using cationic iron carbonyl complexes

Article abstract of DOI:10.1016/j.carres.2008.04.020

Cationic iron carbonyl cyclohexadiene complexes were employed in the derivatization of the 3-OH position of unprotected and protected methyl β-d-galactopyranosides using two different approaches, giving access to galactopyranosides with an aromatic or cyc

Full text of DOI:10.1016/j.carres.2008.04.020

Available online at www.sciencedirect.com
Carbohydrate Research 343 (2008) 1808–1813
Note
Carbohydrate functionalization using cationic iron
carbonyl complexes
a
a
a
b
´
Anders Bergh, Henrik Graden, Nu´ria Parera Pera, Thomas Olsson,
Ulf J. Nilssonc,* and Nina Kanna,*
aOrganic Chemistry, Department of Chemical and Biological Engineering, Chalmers University of Technology,
SE-41296 Go¨teborg, Sweden
bAstraZeneca R&D Mo¨lndal, SE-43183 Mo¨lndal, Sweden
cOrganic Chemistry, Lund University, PO Box 124, SE-22100 Lund, Sweden
Received 13 February 2008; received in revised form 9 April 2008; accepted 11 April 2008
Available online 22 April 2008
Abstract—Cationic iron carbonyl cyclohexadiene complexes were employed in the derivatization of the 3-OH position of unpro-
tected and protected methyl b-D-galactopyranosides using two different approaches, giving access to galactopyranosides with an
aromatic or cyclohexadienoic functionality in this position.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Iron carbonyl complex; Galactose; Cyclohexadienyl cation; Galectin inhibitor; Carbohydrate
Cationic iron carbonyl complexes of both cyclic and
acyclic dienes are highly reactive towards many different
types of nucleophiles, providing a means for the deriva-
tization of such compounds.1,2 Amongst the precursor
dienes, the cyclohexadiene structure has been the most
studied and was the first cationic complex of this type
prepared by Fischer in 1960.3 Complexation of the diene
is generally effected by heating with Fe(CO)5 or
Fe2(CO)9, and subsequent treatment with a strong acid
such as triphenylmethyl tetrafluoroborate then generates
the stabilized cation.1 The scope of nucleophiles that re-
act with this type of cation is wide, and includes alco-
hols,4 amines,5 phosphines and phosphites,6 hydride,5
and activated carbon nucleophiles such as silyl enol
ethers,1 enamines7 and electron rich aromatics,8 thus
providing methodology for both carbon–carbon and
carbon–heteroatom formation. The reaction proceeds
under mild conditions, and is generally highly regiose-
lective, the selectivity determined by the initial substitu-
tion pattern on the cyclohexadiene structure.9,10
As part of a study aimed at preparing potential galec-
tin inhibitors, we wished to investigate if cationic iron
carbonyl dienyl complexes could be applied in the deriv-
atization of carbohydrate structures,11 galactose deriva-
tives, in particular. Galectins are a family of proteins
that share a similar carbohydrate recognition domain
(CRD).12 They can have both intra- and extracellular
activities, and a majority of their functions are associ-
ated with carbohydrate–protein interactions. Galectin-
1, for example, possesses immunomodulatory effects13,14
and displays increased expression in cancer cells com-
pared to normal cells and has thus been the focus of
much cancer research in the last years.15 Moreover,
studies on Galectin-3 had demonstrated its expression
in cancer16 and inflammation processes.17–19 Ample
information is available concerning structures of galec-
tins in complexes with lactose or LacNAc and all show
extended binding pockets close to the 3-hydroxy group
of the galactose residue.20–25 That has allowed the study
and design of new potential galectin inhibitors and
it is known that replacing the 3-hydroxyl group from
*
Corresponding authors. Tel.: +46 31 7723070; fax: +46 31 7723657
(N.K.); e-mail addresses: ulf.nilsson@organic.lu.se; kann@chalmers.
se
0008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.04.020

A. Bergh et al. / Carbohydrate Research 343 (2008) 1808–1813
1809
D-galactose with different functionalities enhances bind-
ing and improves affinity to the galectin compared to
lactose or LacNAc.26–30
formed from this reaction then allowed the isolation of
pure 8, in a 12% yield calculated over three steps from
the cationic complex 6. Although this particular product
could also be formed via a Suzuki reaction on a haloge-
nated aromatic substrate, our method has the advantage
that no functional group such as a halogen is necessary
on the cyclohexadiene moiety, and that the application
of cationic iron methodology allows the introduction
of a variety of nucleophiles, both carbon and hetero-
atom, onto the scaffold, that is, the method is not limited
to the formation of biarylic structures. By introducing
the nucleophile at a late stage rather than tethering
pre-prepared aromatic esters to a carbohydrate scaffold,
the methodology allows for facile diversification of the
scaffold and preparation of a variety of target com-
pounds in a library format.
Two different strategies were envisioned for the deriv-
atization of the carbohydrate scaffold. The galactoside
could be attached to the cationic iron carbonyl cyclo-
hexadienyl scaffold in the form of an ester (Scheme 1,
sequence A), allowing the use of different carbon or
heteroatom nucleophiles in the reaction with the cation,
giving access to a wide variety of derivatives. Alterna-
tively, the protected galactoside could be used directly
as the nucleophile in the reaction with the cationic salt
of the iron carbonyl cyclohexadienyl complex (sequence
B). In theory, both approaches could give access either
to cyclohexadiene derivatives as the final products, or
the corresponding aromatic compounds if an oxidation
reaction was applied as the final step.
An alternative method to prepare methyl b-D-galacto-
pyranosides derivatized at the C3-position could be to
employ the carbohydrate as the nucleophile in a direct
reaction with a cationic iron carbonyl dienyl complex
(Scheme 1, sequence B). We thus studied the reaction
of acetyl protected galactoside 9 (Scheme 3) in a reaction
with the known cationic complex 10.31 The reaction pro-
duced a mixture of regioisomers of 11a, indicating that
the migration of acetyl groups had taken place under
the reaction conditions, exposing alternative positions
on the carbohydrate moiety to reaction with the cationic
complex. A number of other bases (collidine, (i-Pr)2NEt,
2,3-di-t-butylpyridine, Cs2CO3) and solvent systems
(toluene, acetonitrile, DMF) were tested but with the
same disappointing results. We then switched to the
benzyl protected galactoside 2 (used in sequence A)
instead, to avoid the problem of migrating protecting
groups. No reaction occurred in this case, however.
Most likely, the benzyl protected carbohydrate is too
sterically hindered to function in a direct reaction with
the cationic complex.
To test the concept of sequence A, benzyl-protected
methyl b-D-galactopyranoside (2, Scheme 2) was con-
verted to the corresponding cyclohexadienyl carboxylic
ester 4 via reaction with acid chloride 3, prepared in situ
from carboxylic acid 1. Subsequent complexation with
diiron nonacarbonyl afforded 5, which was then con-
verted to the cationic salt 6 upon treatment with trip-
henylcarbenium hexafluorophosphate. Electron rich
aromatics can function as nucleophiles in the reaction
with cationic iron carbonyl dienyl, and trimethoxyben-
zene was selected for the test sequence, allowing the for-
mation of a carbon–carbon bond under mild conditions.
Thus, compound 6 was reacted with trimethoxyben-
zene in the presence of a polymer-supported base
(PS-DIEA) in dichloromethane at room temperature.
To remove the iron carbonyl still tethered to the product
diene, the crude product was then treated with a mild
oxidant, trimethylamine N-oxide (TMANO). Although
we had anticipated being able to isolate diene 7 at this
1
stage, H NMR analysis of the crude product revealed
that a mixture of 7 and the corresponding aromatic
product 8 had been formed. We thus subjected this mix-
ture to oxidation with DDQ to convert all material to
the aromatized product. Purification of the material
A solution to the problems caused by the protecting
groups could be to employ the unprotected methyl
galactopyranoside 12 (Scheme 4), and activate the C3-
position via formation of the corresponding stannylene
Scheme 1. Retrosynthetic strategies for the preparation of cyclohexadiene galactoside derivatives.

1810
A. Bergh et al. / Carbohydrate Research 343 (2008) 1808–1813
Scheme 2. Reaction of an aromatic nucleophile with a cationic iron carbonyl-complexed galactoside ester (sequence A).
Scheme 3. Direct reaction of protected galactoside 9 or 2 with cationic complex 10 (sequence B).
Scheme 4. Alternative strategy to sequence B, employing galactoside 12 activated as the corresponding stannylene acetal.
acetal, rather than protecting the other hydroxyl posi-
tions. Compound 12 was treated with di-n-butyltin in
benzene, and the intermediate stannylene acetal was
then exposed to cation 10 in the presence of triethyl-
amine. Once the initial reaction was complete, the free
hydroxyl groups were then acetylated to facilitate
work-up. Decomplexation with TMANO in this case
afforded diene 13, without concomitant aromatization
as in the earlier case, in a 30% yield calculated over four
steps. To see if the aromatic compound 14 could also be
produced using the same route, 13 was subjected to
DDQ in order to oxidize the diene. These reaction con-
ditions were found to be too harsh, causing elimination
of the pendant galactoside, producing benzoic acid

A. Bergh et al. / Carbohydrate Research 343 (2008) 1808–1813
1811
methyl ester instead. Despite various attempts using
other oxidative conditions, the aromatized product 14
could not be formed. However, the described method
nevertheless provides a viable method for accessing the
cyclohexadiene derivative 13.
Methyl 2,4,6-tri-O-benzyl-galactopyranoside (2)33 and
methyl 2,4,6-tri-O-acetyl-galactopyranoside (9)34,35 were
prepared according to published procedures. Tri-
carbonyl(1-carbomethoxycyclohexa-1,3-dienyl)iron hexa-
fluorophosphate (10)36 was prepared using a method
reported for the corresponding ethyl ester.37
In summary, we have reported two different routes to
methyl b-D-galactopyranosides derivatized in the C3-
position. Preparation of a cyclohexadienoic acid ester
of the galactoside and subsequent conversion to a
cationic iron carbonyl complex enabled reaction with
an aromatic nucleophile, affording, after oxidation, a
galactoside derivatized with a substituted benzoic ester
in the C3-position. Although we have only reported
the proof of concept in this report, we envisage that this
methodology can be expanded to other nucleophiles
(carbon and heteroatom), allowing the formation of a
wide variety of related derivatives with a meta-substi-
tuted aromatic ester in the C3-position. Alternatively,
the galactoside can instead be activated as the corre-
sponding stannylene acetal and used directly as the
nucleophile in the reaction of a pre-prepared iron cation
complex of a cyclohexadienoic ester. This method
instead afforded carbohydrate with a substituted cyclo-
hexadiene attached directly to the galactoside. To our
knowledge, this is the first report of the use of cationic
iron mediated reactions in the derivatization of galact-
osides in the C3-position, and we envision that this
method can find use in the preparation of new carbo-
hydrate derivatives of biological interest.
1.3. Methyl 2,4,6-tri-O-benzyl-3-O-(cyclohexa-1,3-diene-
carbonyl) b-D-galactopyranoside (4)
1.3.1. Cyclohexa-1,3-dienecarboxylic acid chloride
(3). 1-Chloro-N,N,2-trimethylpropenylamine (Ghosez’
reagent) (134 mg, 4.83 mmol) was added to a solution of
1,3-cyclohexadienoic acid32 (200 mg, 1.61 mmol) in dry
CH2Cl2 (5 mL) and stirred under an atmosphere of
nitrogen for 5 h. The reaction mixture was then concen-
trated in vacuo and the compound was used directly in
the next reaction without further purification or iso-
1
lation due to its instability. Crude product: H NMR
(400 MHz, CDCl3):
d
7.34 (d, J = 5.6 Hz, 1H,
CH@CC(O)Cl), 6.37–6.32 (m, 1H) and 6.18–6.11 (m,
1H, CH@CH), 2.53–2.45 (m, 2H, CH2) and 2.36–2.26
(m, 2H,CH2).
1.3.2. Methyl 2,4,6-tri-O-benzyl-3-O-(cyclohexa-1,3-
dienecarbonyl) b-D-galactopyranoside (4). Cyclohexa-
1,3-dienecarboxylic acid chloride (3) (458 mg, 3.23
mmol)
and
4-dimethylaminopyridine
(145 mg,
1.18 mmol) was added to a solution of 2 (500 mg,
1.07 mmol) in dry CH2Cl2 (5 mL) and stirred under an
atmosphere of nitrogen. Trimethylamine (300 lL,
2.15 mmol) was added dropwise and the reaction mix-
ture was stirred for 6 h. Thereafter, the reaction mixture
was concentrated in vacuo and EtOAc (5 mL) was
added. The organic phase was washed with brine
(3 Â 5 mL) and water (3 Â 5 mL), the organic layer
dried over magnesium sulfate and filtered. The filtrate
was concentrated in vacuo and the residue purified by
flash chromatography (petroleum ether–EtOAc 5:1) to
give 4 as a yellow oil (422 mg, 68%): IR (neat) m 2928,
1. Experimental
1.1. General methods
All solvents and reagents were obtained commercially
and used as received. Methyl galactopyranoside (12)
and 1-chloro-N,N,2-trimethylpropenylamine were pur-
chased from SigmaAldrich. Reactions were performed
under a nitrogen or argon atmosphere using oven-dried
glass equipment. Infra-red spectra were obtained using a
Perkin–Elmer 1600 FTIR. NMR spectra were recorded
on a Varian 400 MHz UNITY-VXR 5000. Chemical
shifts are reported using deuterated chloroform as refer-
ence. Column chromatography was carried out using
1
2864, 1701, 1463 cmÀ1; H NMR (400 MHz, CDCl3):
d 7.36–7.18 (m, 15H, Ph), 6.87 (d, J = 5.3 Hz, 1H,
CH@CC(O)), 6.13 (m, 1H) and 6.03–5.99 (m, 1H,
CH@CH), 5.03 (dd, J = 7.2, 3.9 Hz, 1H), 4.83 (d,
J = 11.6 Hz, 1H), 4.63 (dd, J = 4.8, 11.6 Hz, 2H),
4.51–4.36 (m, 4H, 2Bn CH2), 3.99 (d, J = 2.8 Hz, 1H),
3.81 (dd, J = 7.7, 2.5 Hz, 1H), 3.73 (dd, J = 4.3,
6.8 Hz, 1H), 3.61–3.58 (m, 2H, Bn CH2), 3.56 (s, 3H,
OMe), 2.39 (m, 2H, CH2), 2.25 (m, 2H, CH2); 13C
NMR (100 MHz, CDCl3): d 166.5, 138.4, 138.3, 138.1,
137.8, 134.1, 133.9, 129.8, 128.4, 128.1, 127.9, 127.9,
127.7, 127.7, 127.7, 127.5, 127.4, 123.9, 104.8, 76.8,
74.9, 74.8, 74.5, 74.4, 73.4, 73.1, 68.4, 57.1, 22.8, 20.6
(one carbon overlaps with the signal from CHCl3).
FABMS m/z calcd for C35H38O7Na [M+Na]+:
593.2516. Found: 593.2519.
˚
Matrix Si 60 A 35–70 lm. Thin layer chromatography
(TLC) was performed using precoated alumina-backed
plates (Merck 25 DC Alufolien Kieselgel 60 F254). Visu-
alization was effected either by UV fluorescence
(m = 254 nm) or by heating the plates after treatment
with 10% H2SO4.
1.2. Preparation of precursors 1, 2, 9 and 10
Cyclohexa-1,3-diene carboxylic acid was prepared
according to a procedure described by us earlier.32

1812
A. Bergh et al. / Carbohydrate Research 343 (2008) 1808–1813
1.4. Tricarbonyl[methyl 2,4,6-tri-O-benzyl-3-O-(cyclo-
hexa-1,3-dienecarbonyl) b-D-galactopyranoside]iron
complex (5, two diasteromers)
was then filtrated through a plug of silica and concen-
trated in vacuo. Thereafter, the residue was dissolved
in dry CH2Cl2 (10 mL) and TMANO (92 mg, 1.2 mmol)
was added. The reaction mixture was then stirred under
an atmosphere of nitrogen for further 6 h. Thereafter,
the solution was filtered through a plug of silica gel
and concentrated in vacuo. The residue was dissolved
in dry toluene (5 mL) and DDQ (150 mg, 0.66 mmol)
was added. The solution was stirred under an atmo-
sphere of nitrogen for 5 h, and then filtered through a
plug of alumina, and concentrated in vacuo to give 8
as a colourless oil (20 mg, 12% over three steps): IR
(neat) 3002, 2943, 2292, 2252, 1635, 1442, 1375,
A solution of 4 (518 mg, 0.91 mmol) in degassed toluene
(10 mL) was added to a slurry of diiron nonacarbonyl
(5.00 g, 13.8 mmol) in degassed toluene (20 mL). The
mixture was stirred at 55 °C under an atmosphere of
argon for 18 h. After cooling to room temperature, the
mixture was then concentrated in vacuo and the residue
purified by flash chromatography (petroleum ether–
EtOAc, 8:2), to give 5 as a yellow oil (430 mg, 64%):
IR (neat) 2862, 2052, 1983, 1702, 1496, 1453 cmÀ1; H
1
NMR (400 MHz, CDCl3, two diastereomers):à d 7.43–
7.19 (m, 15H, Ph), 6.03 (m, 1H), 5.90 (m, 1H), 5.41–
5.31 (m, 2H), 5.1–3.3 (m, 12H), 3.06 (s, 3H), 2.2–2.0
(m, 2H) and 1.9–1.8 (m, 2H, CH2); 13C NMR
(100 MHz, CDCl3, two diastereomers): d 172.2, 172.0,
138.6, 138.6, 138.2, 138.1, 137.9, 137.8, 133.1, 129.8,
128.4, 128.2, 128.1, 128.0, 128.0, 127.9, 127.8, 127.7,
127.7, 127.7, 127.6, 127.5, 127.4, 127.4, 104.9, 104.9,
89.4, 89.3, 85.3, 85.0, 77.2, 76.9, 75.9, 75.6, 75.5, 75.0,
74.9, 74.9, 74.8, 74.6, 74.6, 74.5, 74.4, 74.3, 73.5, 73.4,
73.4, 73.2, 73.1, 73.0, 68.6, 68.4, 68.4, 64.3, 64.3, 63.3,
62.9, 57.1, 57.1, 25.1, 24.9, 22.9, 22.8. FABMS m/z calcd
for C38H38FeNaO10 [M+Na]+: 733.1712. Found:
733.1716.
1038 cmÀ1 1H NMR (400 MHz, CDCl3): d 8.02 (s,
;
1H, Ar), 7.90 (d, J = 7.2 Hz, 1H, Ar), 7.55 (d, J =
7.6 Hz, 1H, Ar), 7.43 (t, J = 7.2 Hz, 1H, Ar), 7.32–
7.11 (m, 15H, Ph), 6.21 (s, 2H, anisyl Ar), 5.22 (dd,
J = 10.4, 3.2 Hz, 1H), 4.80 (d, J = 11.2 Hz, 1H), 4.69
(t, J = 11.2 Hz, 2H), 4.50–4.39 (m, 4H, 2CH2), 4.04 (d,
J = 2.8 Hz, 1H), 3.91–3.87 (m, 4H, anisyl OMe and
1H), 3.75 (t, J = 6.4 Hz, 1H), 3.62–3.60 (m, 7H, 2 anisyl
OMe and 1H), 3.57 (s, 3H, OMe), 3.58–3.55 (m, 1H);
13C NMR (100 MHz, CDCl3): d 166.0, 160.8, 158.2,
138.1, 137.8, 136.3, 134.5, 132.9, 129.1, 128.5, 128.4,
128.4, 128.2, 128.2, 128.1, 128.0, 128.0, 127.8, 127.7,
127.7, 127.7, 127.5, 127.4, 111.2, 104.9, 100.4, 90.7,
77.5, 77.2, 77.1, 76.5, 75.4, 74.8, 74.5, 74.2, 73.4, 73.2,
68.5, 57.1, 55.8, 55.7, 55.4, 29.7, 29.7. FABMS m/z calcd
for C44H46NaO10 [M+Na]+: 757.2989. Found:
757.2997.
1.5. Tricarbonyl[methyl 2,4,6-tri-O-benzyl-3-O-(cyclo-
hexa-1,3-dienecarbonyl) b-D-galactopyranoside]iron
hexafluorophosphate (6)
1.7. Methyl-3-(5-cyclohexa-1,3-dienoic acid methyl
ester)2,4,6-tri-O-acetyl-b-D-galactopyranoside (13)
Ph3CPF6 (347 mg, 0.89 mmol) was added in two por-
tions to a solution of complex 5 (540 mg, 0.74 mmol)
in the minimum amount possible of dry CH2Cl2 and
stirred under an atmosphere of argon for 3 h. Thereaf-
ter, diethyl ether was added to induce crystallization
and the residue was filtered to give 6 as a red solid
(490 mg, 75%). Anal. Calcd for C38H37F6FeO10P: C,
53.41; H, 4.36. Found C, 53.48; H, 4.33.
To a round-bottom flask, equipped with a Dean–Stark
trap, di-n-butyltin oxide (165 mg, 0.66 mmol) was added
to a solution of methyl b-D-galactopyranoside (117 mg,
0.60 mmol) in benzene (25 mL) and the reaction mixture
was heated at reflux overnight. Thereafter, the clear
solution was cooled to room temperature and 10
(275 mg, 0.65 mmol) was added. The reaction mixture
was stirred at room temperature for 2 h whereupon tri-
ethylamine (50 lL, 0.36 mmol) was added. The mixture
was stirred for further 2 h and then concentrated in va-
cuo. The crude residue was dissolved in a solution of
pyridine and acetic anhydride (1:3, 25 mL) and stirred
for 1 h. The crude product was co-evaporated with tol-
uene, re-dissolved in CH2Cl2 whereupon TMANO
(74 mg, 2.7 mmol) was added. The reaction mixture
was stirred at room temperature for 5 h. The residue
was purified by flash chromatography (petroleum
ether–EtOAc, 5:1) affording 13 as a yellow syrup
(86 mg, 30%, over four steps). 1H NMR (400 MHz,
CDCl3): d 7.03 (d, J = 6.1 Hz, 1H, CH@CCO2Me),
6.26–6.22 (m, 1H) and 6.15–6.08 (m, 1H, CH@CH),
5.41 (br app d, J = 3.4 Hz, 1H, H-4), 5.17 (app t,
1.6. Methyl 2,4,6-tri-O-benzyl-3-[O-(trimethoxyphenyl)-
benzoic acid] b-D-galactopyranosyl ester (8)
1,3,5-Trimethoxybenzene (43 mg, 0.25 mmol) was added
to a solution of the cationic complex 6 (200 mg,
0.23 mmol) and PS-DIEA (25 mg, 0.25 mmol) in dry
CH2Cl2 (15 mL) and the reaction mixture was stirred
under an atmosphere of nitrogen for 8 h. The polymer
was removed by filtration and the reaction mixture
The diiron nonacarbonyl was treated with 1 M HCl to remove any
traces of pyrophoric free metallic iron and subsequently washed
several times with ethanol and toluene before use.
à Severe line broadening due to the presence of paramagnetic Fe-
species. Chemical shifts are approximate.

A. Bergh et al. / Carbohydrate Research 343 (2008) 1808–1813
1813
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J = 9.1 Hz, 1H, CH@CH–CHO), 4.99 (dd, J = 9.2,
3.2 Hz, 1H, H-2), 4.36 (d, J = 7.8 Hz, 1H, H-1), 4.18–
4.01 (m, 1H, H-6), 3.78 (m, 4H, CO2Me and H-6),
3.65–3.62 (m, 1H, H-5), 3.51 (s, 3H, OMe), 3.41 (app
t, J = 9.1 Hz, 1H, H-3), 2.89–2.79 (m, 1H) and 2.60–
2.50 (m, 1H, C@CCH2), 2.15 (s, 3H, Ac), 2.05 (s, 3H,
Ac), 1.97 (s, 3H, Ac); 13C NMR (100 MHz, CDCl3): d
170.2, 69.6, 167.3, 130.5, 130.5, 130.4, 127.4, 127.3,
126.0, 102.2, 72.3, 71.2, 69.2, 67.6, 65.3, 57.1, 51.9,
27.9, 20.9, 20.8, 20.7; IR (neat) 2957, 2924, 2852, 1750,
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1724, 1222, 1073 cmÀ1
. FABMS m/z calcd for
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C21H28NaO11 [M+Na]+: 479.1529. Found: 479.1537.
Acknowledgements
Financial support from the Swedish Foundation for
Strategic Research and AstraZeneca R&D Mo¨lndal is
gratefully acknowledged.
´
´
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Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.carres.
2008.04.020.
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