Electronically varied quinazolinaps for asymmetric catalysis

Article abstract of DOI:10.1039/b810936b

The synthesis and resolution of electronically varied axially chiral Quinazolinaps is reported. These ligands bear different aryl groups on the donor phosphorus atom and were synthesised as part of our investigations into electronic effects within this ligand class. A diastereomerically pure palladacycle of one ligand was characterised by X-ray crystallography. The application of these Quinazolinaps to the rhodium-catalysed hydroboration of vinylarenes resulted in enantioselectivities of up to 92%. Their application to the palladium-catalysed allylic alkylation of 1,3-diphenylprop-2-enyl acetate resulted in conversions of up to 99% and enantioselectivities of up to 94%. The Royal Society of Chemistry 2008.

Full text of DOI:10.1039/b810936b

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Electronically varied quinazolinaps for asymmetric catalysis†
Aoife C. Maxwell,a Celine Franc,a Laurent Pouchain,b Helge Mu¨ller-Bunza and Patrick J. Guiry*a
Received 27th June 2008, Accepted 15th July 2008
First published as an Advance Article on the web 19th August 2008
DOI: 10.1039/b810936b
The synthesis and resolution of electronically varied axially chiral Quinazolinaps is reported. These
ligands bear different aryl groups on the donor phosphorus atom and were synthesised as part of our
investigations into electronic effects within this ligand class. A diastereomerically pure palladacycle of
one ligand was characterised by X-ray crystallography. The application of these Quinazolinaps to the
rhodium-catalysed hydroboration of vinylarenes resulted in enantioselectivities of up to 92%. Their
application to the palladium-catalysed allylic alkylation of 1,3-diphenylprop-2-enyl acetate resulted in
conversions of up to 99% and enantioselectivities of up to 94%.
insights into electronic effects in our Quinazolinap series, we
Introduction
have commenced a study on electronic variations at the donor
phosphorus atom, ligands 3a–b, by including electron-donating
and electron-withdrawing groups on the diarylphosphine unit.
2-iPr-Quinazolinap 2e was chosen as the parent ligand as it has
consistently given the best results of the Quinazolinap family in
the asymmetric transformations studied.9 Herein we now wish
to report the synthesis and resolution of ligands 3a–b and their
application in the rhodium-catalysed hydroboration of vinylarenes
and palladium-catalysed allylic alkylation.
Much of the success in enantioselective homogeneous catalysis
is dependent upon the application of specifically designed chiral
ligands to important synthetic transformations. The develop-
ment of atropisomeric diphosphines such as Binap has found
widespread applicability in asymmetric hydrogenation, olefin
isomerization, allylic alkylation, the Heck reaction and enan-
tioselective hydroboration.1–5 Subsequently, the development of
axially chiral heterobidentate systems has become an active area of
research, with the phosphinamine ligand class receiving the most
interest due to the combination of steric and electronic effects
exerted on substrates at the coordination sphere of the transition
metal to which they are bound.6,7 Following on from work by
Brown et al.,8 who developed the first successful axially chiral
phosphinamine Quinap 1, we have designed a series of axially
chiral phosphinamines termed Quinazolinaps. Previously, we have
reported the synthesis and resolution of a steric series of these
ligands 2a–f, which have been applied to the rhodium-catalysed
asymmetric hydroboration of vinylarenes where they induced
excellent conversions, regioselectivities and enantioselectivities up
to 99.5%.9 We have also synthesised Quinazolinaps 2g–h, as an
investigation into the effect of having a hemilabile donor nitrogen
atom on the 2-aryl substituent and applied them to the palladium-
catalysed allylic alkylation of 1,3-diphenylpropenyl acetate with
excellent conversions and enantioselectivities up to 81%.10
Results and discussion
Synthesis and resolution
The majority of reports of ligand modification have followed
from systematic variation of the spatial demands of the catalyst.
However, research on substituent-controlled electronic tuning
of chiral ligands has demonstrated that catalyst activity and
selectivity can often be improved.11 In order to gain further
Racemic Quinazolinaps 3a–b were synthesised using a synthetic
route originally developed for the preparation of an electronic
series of Quinap ligands.12 This involved the coupling of 1-(2-
isopropyl-quinazolin-4-yl)-2-naphthyl(trifluoromethyl)sulfonate
4, a late stage intermediate in the preparation of ligand 2e9e
with the diarylphosphine oxides 5a–b (Scheme 1) in moderate
to good yields (53–76%).13–15 This was followed by reduction of
the coupled phosphine oxide 6a–b in 48–70% yields to afford the
desired ligands 3a–b.
The formation of diastereomeric complexes with enantiopure
palladium amine complexes, followed by fractional crystallisa-
tion, is an important strategy in the resolution of phosphorus-
containing ligands. In particular, the ortho-palladated derivatives
of (R)-dimethyl(1-(1-naphthyl)ethyl)amine 7 have received signif-
icant attention;16,17 it has been used as the resolving agent for the
aCentre for Synthesis and Chemical Biology, School of Chemistry and
Chemical Biology, UCD Conway Institute, University College Dublin,
Belfield, Dublin 4, Ireland
bInstitut de Chimie, Universite´ de RENNES 1, Campus de Beaulieu, 35042,
Rennes Cedex, France. E-mail: p.guiry@ucd.ie; Fax: +(353)-1-716-2501
† Electronic supplementary information (ESI) available: Characterisation
data for compounds 3a–b, 6a–b, 8–9, 11a–b, 6a–b, details of the resolution
of 3a–b, and general procedures employed for asymmetric hydrobora-
tion and allylic alkylation. CCDC reference number 664580. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b810936b
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diethyl ether. The crystal structure obtained indicated that the iso-
lated complex was (S,R)-di(3,5-xylyl)(1-(2-isopropyl-quinazolin-
4-yl)(2-naphthyl)phosphine diastereomer (S,R)-9 (Fig. 1).
Scheme 1 Reagents and conditions: (i) Pd(OAc)2, dppb, DIPEA, DMSO,
110 ◦C, 24 h; (ii) HSiCl3, Et3N, toluene, 100 ◦C, 24 h.
resolution of Quinap, Phenap and previously synthesised members
of the Quinazolinap ligand class.8–10,18
A mixture of monodentate palladacycles (R,R)-8a and (S,R)-8a
were obtained by stirring ligand 3a overnight in methanol with
resolving agent 7 but all attempts at separation by fractional crys-
tallisation were unsuccessful at this stage (Scheme 2). The mixture
was redissolved in methanol, and after the addition of potassium
hexafluorophosphate in water and stirring overnight, a creamy
precipitate was obtained. This precipitate was a mixture of biden-
tate palladacycles (R,R)-9 and (S,R)-9. Fractional crystallisation
of this mixture, using hot chloroform and diethyl ether, yielded a
precipitate that was determined by 1H and 31P NMR spectroscopy
to be diastereomerically pure. Crystals suitable for X-ray crystal-
lographic analysis were grown from deuterated chloroform and
Fig. 1 ORTEP representation of (S,R)-9 (hydrogen atoms and counter
ion omitted for clarity).
Using a similar approach, a mixture of monodentate pallada-
cycles (R,R)-8b and (S,R)-8b were obtained by stirring ligand
3b overnight in dichloromethane with resolving agent 7 (Scheme
2). After stirring overnight, a creamy yellow-coloured precipitate
had formed. The precipitate and filtrate were combined and
recrystallised from hot chloroform and ether. A long crys-
tallisation period of three weeks eventually resulted in yellow
1
crystals which, by H and 31P NMR spectroscopy, were found
to be diastereomerically pure. To date no X-ray crystallographic
analysis of this complex has been obtained; however, the isolated
diastereomeric complex has been assigned the configuration (S,R)-
8b based on comparing the optical rotation of the free ligand to
previously investigated members of the Quinazolinap ligand class
and the sense of induction obtained in asymmetric catalysis (vide
infra).
Enantiomerically pure (S)-di(3,5-xylyl)(1-(2-isopropyl-quina-
zolin-4-yl)(2-naphthyl)phosphine 3a and (S)-di(3,5-difluorop-
thenyl)(1-(2-isopropyl-quinazolin-4-yl)(2-naphthyl)phosphine 3b
were readily obtained by decomplexation of the resolved
diastereomers (S,R)-9 and (S,R)-8b, respectively, with 1,2-
bis(diphenylphosphino)ethane in dichloromethane (Scheme 3).
Scheme 3 Reagents and conditions: (i) DPPE, CH2Cl2, RT, 3 h.
Rhodium-catalysed hydroboration
The rhodium-catalysed enantioselective hydroboration of olefins
is a valuable synthetic transformation, typically employing a chiral
Scheme 2 Reagents and conditions: (i) CH2Cl2–MeOH, RT, 18 h; (ii)
MeOH, KPF6, H2O, RT, 18 h.
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catalyst and an achiral borane source. The ease of transformation
of the organoboranes produced into various functional groups
has made hydroboration a valuable synthetic technique in or-
ganic chemistry.19 The steric series of Quinazolinaps 2a–f have
been successfully applied to the asymmetric rhodium-catalysed
hydroboration9e and we now wish to report the application of the
novel Quinazolinaps 3a–b to this transformation.
Styrene and two vinylarene derivatives 12–14 were tested
as hydroboration substrates using in situ-prepared rhodium-
Quinazolinap complexes (S)-11a–b as the active catalysts
(Scheme 4).9e Reactions were carried out both at room temperature
and at 0 ◦C and it was found that reactions at the higher
temperature always gave superior results so it is these results that
are reported (Table 1).
of the results obtained with rhodium complexes of ligands 3a and
3b shows that substitution at the m-positions with fluorine rather
than methyl groups, results in better regio- and enantioselectivities,
although the conversions tend to be somewhat lower.
Palladium-catalysed allylic alkylation
Allylic alkylation is an important reaction for forming different
types of carbon–carbon and carbon–heteroatom bonds.20,21 The
reaction involves the nucleophilic displacement of an allylic leaving
group and is catalysed by a variety of transition-metal catalysts,
although palladium remains the most widely used. Quinazolinaps
(S)-3a–b were applied to the palladium-catalysed asymmetric
allylic alkylation involving the addition of the dimethyl malonate
anion to 1,3-diphenylprop-2-enyl acetate 17. As the active pal-
ladium(0) species for allylic alkylation are not isolable, an air-
stable form of the ligand complexes was prepared. The reaction of
(S)-3a–b, with di-m-chloro-bis(p-allyl)dipalladium 15 and sodium
3
tetrafluoroborate in dichloromethane gave the h -palladium-allyl
complexes (S)-16a–b in high yields of 83–90% (Scheme 5).
Scheme 4 Formation of rhodium-Quinazolinap catalysts.
The application of catalyst complexes (S)-11a–b to the hy-
droboration of substrates 12–14 gave both significantly decreased
enantioselectivities and conversions compared to those observed
with the catalyst derived from parent 2-isopropyl-Quinazolinap
2e.9e However, the regioselectivities obtained with (S)-11a–b were
generally high, in particular complex (S)-11b, containing the 3,5-
difluorophenylphosphine moiety, gave consistently higher regios-
electivities than 2-isopropyl-Quinazolinap (typically in the range
77 : 23 to 81 : 19). The best result with these substrates (entry 4–
76% conversion, 92% ee and 86 : 14 regioselectivity) was obtained
using catalyst (S)-11b in the hydroboration of p-methoxystyrene
(entry 4). By comparison, the application of the catalyst based
on 2-iPr-Quinazolinap ligand 2e under the same conditions also
resulted in 92% ee combined with 76 : 24 regioselectivity. There was
a marked reduction in enantioselectivities when changing from an
electron-releasing to an electron-withdrawing substituent in the
substrate vinylarenes (compare entries 5,6 with 1–4). An analysis
Scheme 5 Reagents and conditions: (i) NaBF4, CH2Cl2, RT, 18 h.
The two standard methods employed for the reaction between
dimethyl malonate and 1,3-diphenylprop-2-enyl acetate are the
bis-trimethylsilylacetamide (BSA) procedure, in which the nu-
cleophile is generated in situ upon addition of a base; and the
malonate procedure, in which the nucleophile is pre-formed as
its sodium salt. Both methods were applied in the current study.
Although dimethylformamide, tetrahydrofuran and acetonitrile
were also screened as solvents, dichloromethane gave superior
results in all cases. When using the malonate method, a selection
of bases (KOAc, NaOAc, LiOAc and CsCO3) was also screened.
Reactions were carried out at room temperature, 40 ◦C and 0 ◦C
and the results for each method is presented (Tables 2 and 3).
The application of catalysts (S)-16a–b in the palladium-
catalysed allylic alkylation of 1,3-diphenylprop-2-enyl acetate 17
using the BSA method resulted in good to excellent enantiomeric
excesses of 80–94% (Table 2). In particular, catalyst (S)-16a gave
consistently high enantioselectivities; the highest obtained was
94% after 120 h at 0 ◦C when using NaOAc as the base (entry 6).
By comparison, the application of the catalyst derived from 2-iPr-
Quinazolinap ligand 2e resulted in a maximum enantioselectivity
Table 1 Rhodium-catalysed hydroboration of substituted styrenes
a
Entry
Catalyst
Substrate
Conversion (%)a
a : b
Ee (%)b
◦
of 91% at 0 C when using KOAc as the base.22 The maximum
enantioselectivity achieved with catalyst (S)-16b was 84% (entry 8).
The use of the malonate method, in which the nucleophile is
used as its sodium salt, resulted in a lowering of conversion in all
cases. It resulted in increased enantioselectivity, however, in the
case of catalyst (S)-16a. Under all conditions, enantioselectivities
of over 90% were obtained using this catalyst system (Table 2,
entries 1–4). This catalyst gave the highest ee (94%) obtained to
date within the Quinazolinap series. Enantioselectivities obtained
1
2
3
4
5
6
(S)-11a
(S)-11b
(S)-11a
(S)-11b
(S)-11a
(S)-11b
12
12
13
13
14
14
89
55
93
76
69
56
81 : 19
85 : 15
68 : 32
86 : 14
81 : 19
85 : 15
68 (S)
72 (S)
80 (S)
92 (S)
44 (S)
58 (S)
a Conversions and regioselectivities determined by 1H NMR spectroscopy.
b Enantiomeric excesses determined by chiral GC.
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Table 2 Palladium-catalysed allylic alkylation, BSA procedure
Entry
Catalyst
Base
Temperature
Time
Conversion (%)a
Ee (%)b
1
2
3
4
5
6
7
8
9
(S)-16a
(S)-16a
(S)-16a
(S)-16a
(S)-16a
(S)-16a
(S)-16b
(S)-16b
(S)-16b
KOAc
NaOAc
KOAc
NaOAc
KOAc
NaOAc
KOAc
LiOAc
KOAc
RT
RT
24 h
24 h
16 h
16 h
5 d
83
94
100
61
94
76
100
96
35
86 (R)
88 (R)
92 (R)
90 (R)
92 (R)
94 (R)
84 (R)
84 (R)
80 (R)
40 ◦
40 ◦
C
C
0 ◦
0 ◦
C
C
5 d
RT
RT
40 ◦
48 h
48 h
16 h
C
a Conversions determined by 1H NMR spectroscopy. b Enantiomeric excesses determined by chiral HPLC.
Table 3 Palladium-catalysed allylic alkylation, malonate procedure
superior results. Indeed, the use of (S)-3b has led to the highest ee
observed in this reaction to date using the Quinazolinap series.
The difference in activity observed in the two catalytic appli-
cations demonstrates the practicality of optimising ligands for
specific reactions. Work continues on the expansion of the range
of electronically-varied Quinazolinaps and the results will be
reported in due course from these laboratories.
Entry Catalyst Temperature Time
Conversion (%)a Ee (%)b
1
(S)-16a
(S)-16a
(S)-16a
(S)-16a
(S)-16b
(S)-16b
(S)-16b
RT
RT
40 ◦
120 h 57%
92 (R)
94 (R)
90 (R)
92 (R)
70 (R)
70 (R)
56 (R)
Experimental details
2c
3
120 h 33%
16 h 47%
5 d 50%
48 h 10%
24 h 27%
24 h 22%
C
General experimental
4
6
0 ◦
C
RT
40 ◦
40 ◦
Melting points were determined using a Gallenkamp melting point
apparatus and are uncorrected. Infrared spectra were recorded on
a Perkin-Elmer Paragon 1000 infrared FT spectrometer. The Mi-
croanalytical Laboratory, University College Dublin, performed
elemental analyses. Electrospray mass spectra were recorded on a
Micromass Quattro with electrospray probe. Exact mass ESI mass
spectra (HRMS) were measured on a micromass LCT orthogonal
time of flight mass spectrometer with leucine enkephalin (Tyr-
7
C
C
8c
a Conversions determined by 1H NMR. b Enantiomeric excesses deter-
mined by chiral HPLC. c 15-crown-5 added.
with catalyst (S)-16b using this method reached a maximum of
70% (entries 6 and 7) although with poor conversions.
1
Gly-Phe-Leu) as an internal lock mass. H NMR spectra and
1H-1H COSY spectra were recorded on a 300 MHz Varian-
Unity spectrometer, a 400 MHz Varian-Unity spectrometer or a
500 MHz Varian-Unity spectrometer. Chemical shifts are quoted
in ppm relative to tetramethylsilane and coupling constants (J) are
quoted in Hz and are uncorrected. CDCl3 was used as the solvent
for all NMR spectra unless otherwise stated. 75.4 MHz 13C spectra
were recorded on a 300 MHz Varian-Unity spectrometer and
100 MHz 13C spectra on a 400 MHz Varian-Unity spectrometer.
Tetramethylsilane was used as the internal standard in all 13C
spectra recorded. 121.4 MHz 31P spectra were recorded on a
300 MHz Varian-Unity spectrometer and 162 MHz 31P spectra
on a 400 MHz Varian-Unity spectrometer. 31P Chemical shifts are
reported relative to 85% aqueous phosphoric acid (0.0 ppm). Flash
chromatography was performed using Merck Kieselgel 60 (Art.
9385). Merck precoated Kieselgel 60F254 was used for thin layer
chromatography. GC and HPLC analysis was carried out using a
Conclusions
Two new axially chiral Quinazolinaps have been synthesised,
resolved and applied in rhodium-catalysed hydroboration and
palladium-catalysed allylic alkylation with ees of up to 92% and
94%, respectively. As well as expanding the range of Quina-
zolinaps available for asymmetric catalysis, these ligands were
synthesised in order to study potential electronic effects within
the series. When they were applied in the hydroboration of
substituted styrenes, it was Quinazolinap (S)-3b, containing a
3,5-difluorophenylphosphine moiety that performed the better of
the two ligands. Comparison of the results obtained with ligands
(S)-3a–b to those obtained using 2-isopropyl-Quinazolinap 2e
show that both electronically modified Quinazolinaps seemed to
demonstrate a decrease in activity and selectivity which may be
attributed to the steric effect of the substitution on the aryl rings.
In the screening of Quinazolinaps (S)-3a–b in palladium-catalysed
allylic alkylation, it was (S)-3a, rather than (S)-3b, which gave
R
Supelco 2-4304 beta-Dexꢀ 120 (30 ¥ 0.25 mm, 0.25 mm film) and a
Chiralcel OD column (0.46 cm I.D. ¥ 25 cm) respectively. Optical
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rotation values were measured on a Perkin-Elmer 241 polarimeter.
[a]D values are given in 10-1 deg cm2 g-1. All commercially available
solvents were purified and dried before use. Tetrahydrofuran was
distilled from sodium–benzophenone and dichloromethane was
distilled from calcium hydride. Where necessary, other solvents
and reagents used were purified according to the procedures in
‘Purification of Laboratory Chemicals’.23 Pd salts were obtained
on loan from Johnson Matthey. Solvents were degassed using three
freeze–thaw cycles. Oxygen-free nitrogen was obtained from BOC
gases.
Procedures for the preparation of 6a–b, 3a–b, 11a–b, 16a–b,
the resolution of 3a–b, details of the X-ray analysis of (S)-9 are
described and physical data for 6a–b, 3a–b, (S)-9, 11a–b, 16a–b,
are available in the ESI.† The general procedures employed for
the asymmetric hydroboration and allylic alkylation are described
below.
6.34 (1H, dd, J = 15.8, 8.4, H2), 4.27 (1H, dd, J = 10.8, 8.5
Hz, H1), 3.95 (1H, d, J = 10.8 Hz, CH(CO2Me)2), 3.70 (3H, s,
OMe) and 3.52 (3H, s, OMe). The % conversion could also be
determined by filtering the quenched reaction mixture over silica
to remove catalyst. The % conversion and enantiomeric excess were
then determined by chiral HPLC [Daicel (Chiracel OD) column,
0.46 cm I.D. ¥ 25 cm], hexane–isopropanol 99 : 1, 0.3 mL min-1,
Rt = starting material 26 min and 30 min, (R)-product—34 min,
(S)-product—37 min.
BSA procedure. Base (0.05 mmol) and the corresponding
catalyst (0.005 mmol, 2 mol%) were added to a Schlenk tube under
an atmosphere of nitrogen. Dry degassed solvent (0.2 mL) was
added, followed by (E)-1,3-diphenylprop-2-enyl-acetate (0.063 g,
0.25 mmol) in dry degassed solvent (0.3 mL). Dimethyl mal-
onate (31.5 mL, 0.275 mmol) and N,O-bis(trimethylsilyl)acetamide
(BSA) (68 mL, 0.275 mmol) were then added via syringe. The
reaction was stirred under nitrogen at the required temperature
and the reaction progress was monitored by TLC (pentane–diethyl
ether, 2 : 1). The work-up was the same as described above for the
malonate procedure.
Asymmetric hydroboration general procedure. The required
Quinazolinap-rhodium(1,5-cyclooctadiene)trifluoromethanesulf-
onate catalyst (5 mmol) in THF (2 mL) was placed under nitrogen
in a Schlenk tube. Freshly distilled catecholborane (53 mL,
0.5 mmol) was added via microlitre syringe and the light brown
solution was allowed to stir for five minutes at the required
temperature. The substrate olefin (0.5 mmol) was injected and the
reaction mixture was stirred for either two hours or twenty-four
hours at room temperature or at 0 ◦C. The reaction was then
cooled to 0 ◦C; ethanol (1 mL) was added; followed by 1 M
NaOH (3 mL) and H2O2 (3 mL). The ice bath was removed
and the solution was stirred for one hour at room temperature.
The reaction mixture was transferred to a separatory funnel and
diethyl ether (10 mL) was added. The organic layer was washed
with 1 M NaOH (10 mL), brine (10 mL) and dried with MgSO4.
The solution was filtered and the solvent was removed in vacuo
to give the hydroborated product as an oil. Conversion and
Acknowledgements
We wish to thank the Irish Research Council for Science, Engi-
neering and Technology (IRCSET) for a Research Scholarship
(RS/2002/64-1) awarded to ACM and Enterprise Ireland for a
Basic Research Award to support CF (SC/2002/349). We also
acknowledge the facilities provided by the Centre for Synthesis
and Chemical Biology (CSCB), funded by the Higher Education
Authority’s Programme for Research in Third-Level Institutions
(PRTLI). We are grateful to Dr Jimmy Muldoon and Dr Dilip Rai
of the CSCB for NMR and mass spectra, respectively.
1
regioselectivity were determined by H NMR spectroscopy. The
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Allylic alkylation procedures
Malonate ion procedure. Sodium dimethyl malonate (0.042 g,
0.275 mmol) and the required catalyst (0.005 mmol, 2 mol%) were
placed in a Schlenk tube under an atmosphere of nitrogen. Dry
degassed solvent (0.2 mL) and 15-crown-5 (if required) (55 mL,
0.275 mmol) were added, followed by (E)-1,3-diphenylprop-2-
enyl-acetate (0.063 g, 0.25 mmol) in dry degassed solvent (0.3 mL).
The suspension was stirred for the required time under an
atmosphere of nitrogen and the progress was monitored by TLC
(pentane–diethyl ether, 2 : 1). The reaction was quenched by the
addition of acetic acid (0.1 mL). The solvent was removed in
vacuo and water (25 mL) was added to the reaction mixture before
transfer to a separatory funnel. The suspension was then extracted
with diethyl ether (25 mL); the organic layer was washed with water
(25 mL), brine (25 mL) and dried over anhydrous MgSO4. The
solution was filtered and reduced in vacuo to leave a clear yellow
1
oil. H NMR of the crude product gave the % conversion. The
product was purified using preparative silica plates (2 : 1 pentane–
diethyl ether) to afford (R) or (S)-methyl-2-carbomethoxy-3,5-
diphenylpent-4-enoate as a clear oil. 1H NMR (300 MHz, CDCl3)
d = 7.34–7.20 (10H, m, Ar-H), 6.47 (1H, d, J = 15.8 Hz, H3),
3852 | Org. Biomol. Chem., 2008, 6, 3848–3853
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