Carbonyl umpolung reactivity of enals: NHC-catalyzed synthesis of aldol products via epoxide ring opening

Article abstract of DOI:10.1055/s-0029-1218563

A novel one-pot N-heterocyclic carbene catalyzed synthesis of aldol products and their application to a facile and highly cis-selective synthesis of tetrahydropyran-4-ones is reported. The protocol involves carbonyl umpolung reactivity of enals in which the carbonyl carbon attacks nucleophilically on electrophilic terminal epoxides, regioselectively, to afford aldol adducts in good to excellent yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218563

240
LETTER
Carbonyl Umpolung Reactivity of Enals: NHC-Catalyzed Synthesis of Aldol
Products via Epoxide Ring Opening
C
arbonyl Umpo
a
lung
R
eact
l
ivityof EnalsDhar S. Yadav,*a Santosh Singh,a Vijai K. Raia,b
a
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
Fax +91(532)2460533; E-mail: ldsyadav@hotmail.com
b
School of Chemistry, College of Science, Shri Mata Vaishno Devi University, Katra, Jammu 182 320, India
Received 28 October 2009
lished as early as 1979 few examples of the Michael addi-
tion of enals as acyl anions.6 Since then, there has been no
report on NHC-catalyzed umpolung reactivity of enals
rendering them acyl anion equivalents (d1 nucleophiles)
Abstract: A novel one-pot N-heterocyclic carbene catalyzed syn-
thesis of aldol products and their application to a facile and highly
cis-selective synthesis of tetrahydropyran-4-ones is reported. The
protocol involves carbonyl umpolung reactivity of enals in which
the carbonyl carbon attacks nucleophilically on electrophilic termi- although it would be of considerable synthetic utility.
nal epoxides, regioselectively, to afford aldol adducts in good to ex-
In view of filling this remarkable gap in the literature and
cellent yields.
in continuation of our ongoing efforts to develop synthet-
Key words: N-heterocyclic carbenes, umpolung, epoxides, aldols,
ically useful processes,7 we report herein a NHC-cata-
enals, tetrahydropyran-4-ones
lyzed efficient synthesis of aldol products b¢-hydroxy-
a,b-unsaturated ketones 4 via carbonyl umpolung reaction
of enals 1 with terminal epoxides 2 (Scheme 1).
Over the last decade, there has been a continuously grow-
ing number of successful and novel applications of N-het-
Interestingly, ketones of the type 4 are present in diverse
natural products8 and have recently been found to be high-
erocyclic carbenes (NHC) as organocatalysts and reagents
ly potent against cancer with the anticipation that these
compounds will be active against both the sensitive and
resistant solid tumors.8d From the chemical viewpoint, the
synthesized aldol products 4 contain a minimum of three
chemospecific functional groups, that is, hydroxyl, a,b-
unsaturated carbonyl (Michael acceptor), and active
methylene groups, thereby providing handles for further
manipulation in a multitude of synthetic organic transfor-
mations. Literature records only few reports on the syn-
thesis of such unusual aldol-type products8b,e,f,9 consisting
of both an a,b-unsaturated ketone and a b-hydroxy ke-
tone, although they appear as an attractive scaffold for ex-
ploiting chemical diversity and generating a druglike
library to screen for lead candidates. Thus, our novel, sim-
ple, and step-economic approach would offer an efficient
for an expanding set of reactions.1 This is not only because
of the great versatility of these organocatalytic transfor-
mations,1 but also because of the possibilities that arise
from the NHC characteristic that causes inversion of the
classical reactivity, that is, umpolung.2
Following the seminal work of the groups of Bode3 and
Glorius,4 NHC-catalyzed umpolung reactivity of a,b-un-
saturated aldehydes (enals) via Breslow or homoenolate
intermediate has been well documented.3–5 In all these
reactions the addition of an appropriate NHC to an enal
renders it a d3 nucleophile. In the context of investigations
towards the extension of the scope of their NHC-catalyzed
Michael-type addition of the acyl anions to electron-poor
olefins (Stetter reaction), Stetter and co-workers pub-
O
O
OH
O
O
3
BF3⋅OEt2
Ar1
Ar2
Ar2
+
Ar1
H
DBU
Ar1
O
Ar2
5
1
2
4
Ph
Ph
Mes
Cl–
Ph
N+
N+
S
N
N
N
Cl–
N
Ph
N+
Ph
Cl–
I–
N+
N+
N
–
ClO4
Mes
3d
Ph
3a
3b
3c
3e
Mes = 2,4,6-trimethylphenyl
Scheme 1 Synthesis of aldol products 4 and their cyclization to tetrahydropyran-4-ones 5
SYNLETT 2010, No. 2, pp 0240–0246
x
x.
x
x.
2
0
1
0
Advanced online publication: 11.12.2009
DOI: 10.1055/s-0029-1218563; Art ID: G35909ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Carbonyl Umpolung Reactivity of Enals
241
alternative method for the synthesis of such fine chemi- Next, in order to investigate the substrate scope and gen-
cals.
eral validity of the reaction, a variety of a,b-unsaturated
aldehydes 1 and epoxides 2 were used employing the
present optimized reaction conditions, and the yields were
found to be good to excellent (Table 2), the highest yield
of 4 being 95% (Table 2, 4o). Relatively, lower yields
were obtained in the case of aldols bearing 4-
MeOC6H4CHOH moiety due to their dehydration
(Table 2, 4g–l). In other cases there was no appreciable
dehydration. This is in conformity with the earlier obser-
vation during the synthesis of such aldols from allenic al-
cohols and aldehydes.8e
For a model experiment, we investigated the optimization
of reaction conditions in regard with NHC catalyst and
solvent both. Herein, cinnamaldehyde (1a) and epoxide
2a were chosen as substrates for the synthesis of represen-
tative ketone 4a, and the reaction was performed at room
temperature (Table 1). Different types of NHC precursors
3a–e were tested and 3a was found to be the most effec-
tive precatalyst for the preparation of 4a under the present
reaction conditions (Table 1, entries 4–8). The optimum
loading for the precatalyst 3a was found to be 30 mol%
along with 30 mol% of DBU. When the amount of the pre- The formation of aldols 4 may be tentatively rationalized
catalyst was decreased from 30 mol% to 25 mol% relative by initial addition of NHC 10 to a,b-unsaturated aldehyde
to substrate 1a, the yield of the ketone 4a reduced 1 followed by proton shift in 1 to generate conjugated acyl
(Table 1, entry 9), but the use of 35 mol% of 3a did not af- anion equivalent 7 (Scheme 2). In previous reports, the
fect the yield (Table 1, entries 4 and 10). The reaction did equilibrium was shifted mostly towards homoenolate 7¢
not occur without using the precatalyst 3 (Table 1, entry employing an appropriate, highly hindered catalyst.3,4,10
11). It was also noted that a higher reaction temperature, On the basis of the previous reports3,4,10 and the work of
for example, in a refluxing solvent instead of room tem- Stetter and co-workers on enals 1, we reasoned that an ap-
perature did not increase the yield.
propriately substituted NHC could shepherd the umpol-
ung reactivity of enals to the carbonyl group presumably
by sterically blocking the b-position. To our delight, the
NHC 3a mediated reaction of enals 1 with epoxides 2 pro-
ceeded well via acyl anion to afford aldols 4 in good to ex-
cellent yields (Table 2).11
Table 1 Optimization of Reaction Conditions for the Formation of
Representative Compound 4aa
O
O
OH
O
3 (30 mol%)
+
H
Ph
Ph
DBU (30 mol%)
solvent, r.t., 15 h
Ph
Ph
Furthermore, the preparation of a probe for demonstrating
the utility of the prepared aldol products 4 in the synthesis
of tetrahydropyran-4-ones 5 is also reported herein. The
tetrahydropyran-4-one ring is ubiquitous in natural prod-
uct arena and is the key structural element in various
medicinal compounds.12 Due to prevalence of tetrahydro-
pyran-4-ones, several methods including Prins cycliza-
tions,13 hetero-Diels–Alder reactions,14 and intra-
molecular nucleophilic reactions15 have been developed
for their construction. Here, we report a straightforward,
convenient, and one-pot process for the synthesis of tet-
rahydropyran-4-ones 5 in excellent yields (87–90%) via
oxy-Michael intramolecular reaction of 4 (Table 3).16 The
compounds 5 were identified by their spectral analysis
and also by comparing with the data reported in the liter-
ature.14c,15g
1a
2a
4a
Entry
Precatalyst (mol%) Solvent
Yield (%)b
1
2
3a (30)
3a (30)
3a (30)
3a (30)
3b (30)
3c (30)
3d (30)
3e (30)
3a (25)
3a (35)
–
THF
51
28
64
89
53
35
0
CH2Cl2
THF–H2Oc
3
4
THF–t-BuOHc
THF–t-BuOH
THF–t-BuOH
THF–t-BuOH
THF–t-BuOH
THF–t-BuOH
THF–t-BuOH
THF–t-BuOH
5
6
7
8
13
81
89
0
9
Several Lewis acid catalysts such as CeCl3·7H2O,
BF3·OEt2, FeCl3, AlCl3, and Ce2(SO4)3 were tested, and
the best result was obtained with BF3·OEt2. We also ex-
amined the effect of solvents on the formation of 5 and
found that amongst THF, CH2Cl2, MeOH, and 1,4-diox-
ane, CH2Cl2 was the best solvent in terms of yield and
diastereoselectivity.
10
11
a For the experimental procedure, see ref. 11.
b Yield of isolated and purified product.
c THF–H2O (10:01) and THF–t-BuOH (10:01) were used.
The reaction was performed at 0 °C. The formation of tet-
rahydropyran-2-ones 5 was entirely diastereoselective in
favor of the cis-isomer. The relative stereochemistry of 5
was established by NOE experiments (Figure 1). Strong
NOE (6.1–6.8%) was observed between 2-H and 6-H of
products 5, which conclusively demonstrates their cis ste-
reochemistry and it was further confirmed by comparison
with the literature reports.15c,g
Optimization of solvents for the synthesis of 4a employ-
ing the precatalyst 3a was also undertaken and it was
found that amongst THF, CH2Cl2, THF–H2O, and THF–
t-BuOH (Table 1, entries 1–4), the best solvent system in
terms of yield was THF–t-BuOH (Table 1, entry 4), and
we used this solvent system throughout the present study.
Synlett 2010, No. 2, 240–246 © Thieme Stuttgart · New York

242
L. D. S. Yadav et al.
LETTER
Ph
N+
Ph
O
O–
OH
Ar1
H
N+
–
1
Ar1
Ar1
H
N
N
6
Ph
7'
Ph
Ph
N+
N
Ph
OH
N
N
10
Ph
Ar1
Ph
N+
O–
Ar2
7
4
OH
Ph
N+
Ph
Ar2
2
Ar2
O
1,5-H
shift
Ar1
Ar1
OH
O–
N
N
Ph
8
Ph
9
Scheme 2 A plausible mechanism for the formation of 4
Table 2 Reaction of E-Enals 1 with Epoxides 2 Yielding Aldol Products 4
Entry
Enal 1
Epoxide 2
Product 4
Time (h)a Yield (%)b,c
O
O
OH
O
H
1
15
15
89
86
4a
O
O
OH
O
O
O
O
H
2
3
4
5
MeO
4b
MeO
O2N
Cl
O
O
OH
H
17
15
15
90
88
87
O2N
4c
O
O
OH
H
Cl
4d
O
O
OH
H
Me
4e
Me
O
O
OH
O
H
6
17
85
OMe
4f
OMe
Synlett 2010, No. 2, 240–246 © Thieme Stuttgart · New York

LETTER
Carbonyl Umpolung Reactivity of Enals
243
Table 2 Reaction of E-Enals 1 with Epoxides 2 Yielding Aldol Products 4 (continued)
Entry
7
Enal 1
Epoxide 2
Product 4
Time (h)a Yield (%)b,c
O
O
OH
O
O
H
16
16
67
65
OMe
MeO
4g
O
O
OH
H
8
9
OMe
MeO
MeO
MeO
MeO
MeO
4h
MeO
O
O
OH
O
O
O
H
18
15
15
68
66
67
OMe
O2N
4i
O2N
O
O
OH
H
10
11
OMe
Cl
4j
Cl
O
O
OH
H
OMe
Me
4k
Me
O
O
OH
O
H
12
16
64
OMe
MeO
OMe
4l
OMe
O
O
OH
O
O
H
13
14
15
18
92
90
NO2
O2N
4m
O
O
OH
H
NO2
MeO
O2N
4n
MeO
O
O
OH
O
H
15
17
95
NO2
O2N
O2N
4o
O2N
Synlett 2010, No. 2, 240–246 © Thieme Stuttgart · New York

244
L. D. S. Yadav et al.
LETTER
Table 2 Reaction of E-Enals 1 with Epoxides 2 Yielding Aldol Products 4 (continued)
Entry
16
Enal 1
Epoxide 2
Product 4
Time (h)a Yield (%)b,c
O
O
OH
O
O
H
15
15
93
91
NO2
Cl
O2N
4p
Cl
O
O
OH
H
17
18
NO2
Me
O2N
4q
Me
O
O
OH
O
H
15
92
NO2
O2N
OMe
4r
OMe
a Stirring time at r.t.
b Yield of isolated and purified product.
c All compounds gave C, H, and N analyses 0.36% and satisfactory spectral (IR, 1H NMR, 13C NMR and EIMS) data.
Table 3 Oxy-Michael Intramolecular Reaction of 4 Leading to 5a
In summary, our work fills a remarkable gap in the litera-
ture on the NHC-catalyzed carbonyl umpolung reactivity
of enals. It offers a general and elegant method for the
preparation of synthetically and pharmaceutically impor-
tant aldol products via regioselective ring opening of
epoxides with enals. We have also successfully demon-
strated the utility of these aldols in a facile and highly cis-
selective synthesis of biologically potent tetrahydropyran-
4-ones. The present atom-economic reactions would be a
practical alternative to the existing procedures for the syn-
thesis of such kind of fine chemicals.
F
B
F
F
O
OH
O
O
O
BF3
– BF3
Ar1
Ar1 HO
Ar2
Ar1
Ar2
Ar1
O
Ar2
••
HO
Ar2
4
5
Compound Ar1
Ar2
Time
Yield
(%)c
(min)b
5a
5b
5c
5d
5e
5f
Ph
Ph
Ph
40
90
87
89
90
88
89
Acknowledgment
4-O2NC6H4
4-O2NC6H4
Ph
40
We sincerely thank SAIF, Punjab University, Chandigrah, for pro-
viding microanalyses and spectra. One of us (S.S.) is grateful to the
CSIR, New Delhi, for the award of a junior Research Fellowship
(JRF).
4-ClC6H4
35
3-O2NC6H4
4-MeOC6H4
4-O2NC6H4
30
4-O2NC6H4
4-O2NC6H4
40
40
References and Notes
a For experimental procedure, see ref. 16.
b Stirring time at 0 °C.
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c Yield of isolated and purified product.
6.1–6.8%
NOE
O
H
H
Ar2
(3) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc.
2004, 126, 14370.
(4) Burstein, C.; Glorius, F. Angew. Chem. Int. Ed. 2004, 43,
O
Ar1
5
6205.
Figure 1
Synlett 2010, No. 2, 240–246 © Thieme Stuttgart · New York

LETTER
Carbonyl Umpolung Reactivity of Enals
245
(5) (a) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905. (b) He,
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6.76 (d, 1 H, J = 16.1 Hz, a-H), 7.31-7.01 (m, 4 Harom, 3-
MeOC6H4), 7.51–7.39 (m, 5 Harom, Ph), 7.59 (d, 1 H, J = 16.1
Hz, b-H). 13C NMR (100 MHz, CDCl3–TMS): d = 49.5,
56.3, 70.3, 111.9, 114.7, 119.5, 126.7, 127.5, 128.1, 129.4,
130.3, 136.9, 141.5, 144.3, 161.3, 200.4. MS (EI): m/z = 282
[M+]. Anal. Calcd for C18H18O3: C, 76.57; H, 6.43. Found: C,
76.92; H, 6.33.
Compound 4i: IR (KBr): nmax = 3441, 3027, 2920, 1679,
1618, 1606, 1584, 1458, 1349 cm–1. 1H NMR (400 MHz,
CDCl3): d = 3.09 (dd, 1 H, J = 17.5, 8.5 Hz, a¢-Ha), 3.19 (dd,
1 H, J = 17.5, 3.8 Hz, a¢-Hb), 3.49 (d, 1 H, J = 2.9 Hz, OH),
3.83 (s, 3 H, OMe), 5.21 (ddd, 1 H, J = 8.5, 3.8, 2.9 Hz, b¢-
H), 6.69 (d, 1 H, J = 16.5 Hz, a-H), 6.93 (d, 2 Harom, J = 8.7
Hz, 4-MeOC6H4), 7.23 (d, 2 Harom, J = 8.7 Hz, 4-MeOC6H4),
7.62 (d, 2 Harom, J = 8.9 Hz, 4-O2NC6H4), 7.71 (d, 1 H,
J = 16.5 Hz, b-H), 8.21 (d, 2 Harom, J = 8.9 Hz, 4-O2NC6H4).
13C NMR (100 MHz, CDCl3–TMS): d = 49.3, 60.1, 69.7,
115.2, 122.3, 126.9, 128.1, 129.3, 133.9, 142.3, 144.1,
148.4,159.8, 200.1. MS (EI): m/z = 327 [M+]. Anal. Calcd
for C18H17NO5: C, 66.05; H, 5.23; N, 4.28. Found: C, 65.69;
H, 5.34; N, 4.51.
Compound 4o: IR (KBr): nmax = 3431, 3028, 2930, 1681,
1623, 1608, 1585, 1456, 1351 cm–1. 1H NMR (400 MHz,
CDCl3): d = 3.11 (dd, 1 H, J = 17.3, 9.2 Hz, a¢-Ha), 3.17 (dd,
1 H, J = 17.3, 3.1 Hz, a¢-Hb), 3.74 (d, 1 H, J = 3.0 Hz, OH),
5.43 (ddd, 1 H, J = 9.2, 3.1, 3.0 Hz, b¢-H), 6.78 (d, 1 H,
J = 16.5 Hz, a-H), 7.63 (d, 1 H, J = 16.5 Hz, b-H), 8.29–7.71
(m, 8 Harom, 2 ´ 4-O2NC6H4). 13C NMR (100 MHz, CDCl3–
TMS): d = 49.3, 69.5, 121.5, 122.3, 125.9, 127.9, 128.7,
142.4, 144.5, 146.2, 147.1, 147.9, 200.1. MS (EI): m/z = 342
[M+]. Anal. Calcd for C17H14N2O6: C, 59.65; H, 4.12; N,
8.18. Found: C, 59.90; H, 4.24; N, 7.91.
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37, 2691. (b) Sohn, S. S.; Bode, J. W. Org. Lett. 2005, 7,
3873.
(11) General Procedure for the Synthesis of Aldol Products 4
A flame-dried round-bottom flask was charged with
benzimidazolium salt 3a (0.3 mmol). a,b-unsaturated
aldehyde 1 (1.0 mmol), epoxide 2 (1.5 mmol), and THF–
t-BuOH (10:1, 5 mL) under positive pressure of nitrogen
followed by addition of DBU (0.3 mmol) with a syringe. The
resulting yellow-orange solution was stirred for 15–18 h at
r.t. (Table 2). After completion of the reaction (monitored by
TLC), the reaction mixture was concentrated under reduced
pressure. The residue was purified by flash column chroma-
tography on silica gel using hexane–EtOAc (10:1) as eluent
to afford analytically pure 4.
Characterization Data of Representative Compounds 4
Compound 4c: IR (KBr): nmax = 3439, 3021, 2929, 1676,
1627, 1608, 1585, 1453, 1347 cm–1. 1H NMR (400 MHz,
CDCl3): d = 3.09 (dd, 1 H, J = 17.3, 9.1 Hz, a¢-Ha), 3.17 (dd,
1 H, J = 17.3, 3.5 Hz, a¢-Hb), 3.69 (d, 1 H J = 2.9 Hz, OH),
5.20 (ddd, 1 H, J = 9.1, 3.5, 2.9 Hz, b¢-H), 6.73 (d, 1 H,
J = 16.5 Hz, a-H), 7.53–7.41 (m, 5 Harom, Ph), 7.59 (d, 2
H
arom, J = 8.7 Hz, 4-O2NC6H4), 7.65 (d, 1 H, J = 16.5 Hz, b-
H), 8.27 (d, 2 Harom, J = 8.7 Hz, 4-O2NC6H4). 13C NMR (100
MHz, CDCl3–TMS): d = 48.6, 69.5, 122.3, 126.5, 127.8,
128.5, 129.1, 129.9, 134.2, 141.3, 144.1, 147.9, 199.7. MS
(EI): m/z = 297 [M+]. Anal. Calcd for C17H15NO4: C, 68.68;
H, 5.09; N, 4.71. Found: 68.96; H, 4.82; N, 4.50.
(16) General Procedure for the Diastereoselective Synthsis of
Tetrahydropyran-4-ones 5
Compound 4f: IR (KBr): nmax = 3421, 3011, 2921, 1665,
1626, 1603, 1587, 1451 cm–1. 1H NMR (400 MHz, CDCl3):
d = d 3.01 (dd, 1 H, J = 17.1, 8.5 Hz, a¢-Ha), 3.09 (dd, 1 H,
J = 17.1, 3.7 Hz, a¢-Hb), 3.78 (s, 3 H, OMe), 3.49 (d, 1 H,
J = 2.8 Hz, OH), 5.19 (ddd, 1 H, J = 8.5, 3.7, 2.8 Hz, b¢-H),
A mixture of aldol adduct 4 (0.2 mmol) and BF3·OEt2 (0.2
mmol) in CH2Cl2 (5 mL) was stirred at 0 °C for 30–40 min
(Table 3). After completion of the reaction (monitored by
TLC), the mixture was diluted with EtOAc (30 mL), washed
Synlett 2010, No. 2, 240–246 © Thieme Stuttgart · New York

246
L. D. S. Yadav et al.
LETTER
2 Harom, J = 8.8 Hz, 4-O2NC6H4). 13C NMR (100 MHz,
CDCl3–TMS): d = 49.3, 50.1, 78.1, 79.3, 122.9, 128.1,
129.5, 130.2, 134.7, 136.4, 145.9, 148.2, 205.2. MS (EI):
m/z = 331, 333 [M+, M+ + 2]. Anal. Calcd for C17H14ClNO4:
C, 61.55.; H, 4.25; N, 4.22. Found: C, 61.19; H, 4.51; N,
4.01.
with sat. aq NaHSO3 solution (2 × 30 mL) and then with
brine (1 × 30 mL). The organic phase was separated and
dried over anhyd MgSO4. The solvent was removed under
reduced pressure to give the crude product 5, which was
purified by flash column chromatography on silica gel using
hexane–EtOAc (20:1) as eluent to afford an analytically pure
sample of 5.
Compound 5f: IR (KBr): nmax = 3055, 2957, 1725, 1605,
1587, 1449, 1352 cm–1. 1H NMR (400 MHz, CDCl3):
d = 2.88–2.73 (m, 4 H, CH2), 5.03 (dd, 2 H, J = 12.1, 3.3 Hz,
Characterization Data of the Representative
Compounds 5
Compound 5c: IR (KBr): nmax = 3051, 2950, 1718, 1605,
1585, 1456, 1346 cm–1. 1H NMR (400 MHz, CDCl3):
d = 2.93–2.51 (m, 4 H, 2 × CH2), 4.93 (dd, 1 H, J = 11.0, 4.1
Hz, H-2), 5.01 (dd, 1 H, J = 12.3, 2.6 Hz, H-6), 7.61 (d, 2
Harom, J = 8.8 Hz, 4-O2NC6H4), 7.67 (d, 2 Harom, J = 8.7 Hz,
4-ClC6H4), 7.88 (d, 2 Harom, J = 8.7 Hz, 4-ClC6H4), 8.29 (d,
H-2, H-6), 8.31–7.51 (m, 8 Harom, 2 × 4-O2NC6H4). 13
C
NMR (100 MHz, CDCl3–TMS): d = 49.8, 50.3, 78.1, 79.5,
122.2, 123.8, 128.5, 129.2, 142.8, 143.9, 147.6, 148.5,
205.2. MS (EI): m/z = 342 [M+]. Anal. Calcd for
C17H14N2O6: C, 59.65; H, 4.12; N, 8.18. Found: C, 59.92; H,
3.89; N, 7.91.
Synlett 2010, No. 2, 240–246 © Thieme Stuttgart · New York

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