Asymmetric Diels–Alder Reaction of α-Substituted and β,β-Disubstituted α,β-Enals via Diarylprolinol Silyl Ether for the Construction of All-Carbon Quaternary Stereocenters

Article abstract of DOI:10.1002/chem.201602345

The asymmetric Diels–Alder reaction of α-substituted acrolein proceeds in the presence of the trifluoroacetic acid salt of trifluoromethyl-substituted diarylprolinol silyl ether to afford the exo-isomer with both excellent diastereoselectivity and high en

Full text of DOI:10.1002/chem.201602345

DOI: 10.1002/chem.201602345
Full Paper
&
Chiral Synthesis
Asymmetric Diels–Alder Reaction of a-Substituted and b,b-
Disubstituted a,b-Enals via Diarylprolinol Silyl Ether for the
Construction of All-Carbon Quaternary Stereocenters
Yujiro Hayashi,*[a, b] Bojan P. Bondzic,[b] Tatsuya Yamazaki,[b] Yogesh Gupta,[a]
Shin Ogasawara,[a] Tohru Taniguchi,[c] and Kenji Monde[c]
Abstract: The asymmetric Diels–Alder reaction of a-substi-
tuted acrolein proceeds in the presence of the trifluoroacetic
acid salt of trifluoromethyl-substituted diarylprolinol silyl
ether to afford the exo-isomer with both excellent diastereo-
selectivity and high enantioselectivity. In the Diels–Alder re-
good exo-selectivity and excellent enantioselectivity was ob-
tained when the perchloric acid salt of the bulky triisopropyl
silyl ether of trifluoromethyl substituted diarylprolinol was
employed as an organocatalyst in the presence of water. In
both cases, all-carbon quaternary stereocenters are con-
structed enantioselectively.
action of
a b,b-disubstituted a,b-unsaturated aldehyde,
were developed for the asymmetric Diels–Alder reaction.[7]
Some of the catalysts can be effective with a-substituted acro-
lein derivatives such as a-acyloxyacrolein or a-(N,N-diacylami-
no)acrolein, as reported by Ishihara,[8] and with acrolein bear-
ing an a-alkyl substituent, as reported by Maruoka.[9] In spite
of these successful results, methacrolein, which possesses
a small methyl a-substituent, is a difficult substrate with which
to achieve high levels of enantioselectivity through the use of
an organocatalyst.
Introduction
The Diels–Alder reaction is one of the most synthetically useful
cycloaddition reactions in organic synthesis. The reaction
allows regio- and stereo-defined cyclohexene derivatives to be
prepared, which are important building blocks in the synthesis
of natural products and biologically interesting compounds.[1]
For the asymmetric catalytic Diels–Alder reaction, chiral Lewis
acids have been widely employed as the catalyst.[2]
However, the construction of all-carbon quaternary stereo-
centers is a significant current topic in synthetic organic
chemistry.[3] The asymmetric Diels–Alder reaction of a-alkyl
substituted acrolein is a useful method for the construction of
such moieties; thus, chiral Lewis[4] and Brønsted acids[5] pro-
mote this type of Diels–Alder reaction to generate quaternary
stereocenters with excellent enantioselectivity.
Our group[10a] and Jørgensen’s group[10b] have independently
developed diarylprolinol silyl ether as an effective organocata-
lyst. We reported that trifluoromethyl-substituted diarylprolinol
silyl ether with a combination of acid catalyzes the exo-selec-
tive Diels–Alder reaction with excellent enantioselectivity.[11] We
also reported the diarylprolinol silyl ether-mediated asymmet-
ric Diels–Alder reaction in the presence of water.[12]
In 2000, MacMillan reported the organocatalyst-mediated
asymmetric Diels–Alder reaction of a b-mono-substituted a,b-
unsaturated aldehyde that proceeded via an iminium ion inter-
mediate.[6] After this seminal paper, several organocatalysts
For the reaction of a-substituted acrolein, it is generally be-
lieved that secondary amine catalysts are not effective because
of steric repulsion.[13] However, we reported the asymmetric
epoxidation of a-substituted acrolein by using diphenylprolinol
silyl ether for the construction of tetrasubstituted tertiary cen-
ters.[14] We also developed nitrocyclopropanation of a-substi-
tuted acrolein catalyzed by the same catalyst for the construc-
tion of all-carbon quaternary stereogenic centers.[15] These re-
sults prompted us to investigate the asymmetric Diels–Alder
reaction of a-substituted acrolein with our catalyst. We further
investigated the Diels–Alder reaction of b,b-disubstituted acro-
lein. Herein, we describe the construction of quaternary stereo-
centers by using such reactions.
[a] Prof. Dr. Y. Hayashi, Y. Gupta, S. Ogasawara
Department of Chemistry, Graduate School of Science
Tohoku University, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: yhayashi@m.tohoku.ac.jp
Homepage: http://www.ykbsc.chem.tohoku.ac.jp
[b] Prof. Dr. Y. Hayashi, Dr. B. P. Bondzic, T. Yamazaki
Before July, 2012: Department of Industrial Chemistry
Faculty of Engineering, Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
[c] Prof. Dr. T. Taniguchi, Prof. Dr. K. Monde
Faculty of Advanced Life Science
Frontier Research Center for Advanced Material and Life Science
Hokkaido University, Kita 21 Nishi 11, Sapporo 001-0021 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201602345.
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presence of 20 mol% salt 2, the reaction proceeded slowly and
the product was obtained in 29% yield with excellent exo-se-
lectivity, but the enantioselectivity was moderate (68%ee,
entry 1). A range of solvents was then screened with salt 2 as
a catalyst. Among the organic solvents examined, including
MeCN, MeNO2, CH2Cl2, and THF (entries 2–5), MeCN was found
to afford a good result in terms of enantioselectivity (89%ee,
entry 2), and was identified as the best solvent in this reaction.
The effect of the counterion of the catalyst was then investi-
gated. When PhCO2H, p-TSA, or MeSO3H were used as an addi-
tive, the enantioselectivity was unsatisfactory (entries 7–9). The
desired product was not obtained in the presence of a strong
acid such as TfOH and the catalyst 3 did not promote the reac-
tion, either. This is because of polymerization of the cyclopen-
tadiene (entries 10, 11). Thus, trifluoroacetic acid was identified
as the most suitable acid. When trifluoroacetic acid salt 2 was
used in 20 mol%, a reasonable yield (67%) with excellent dia-
stereoselectivity (exo/endo, 99:1) and enantioselectivity
(89%ee) was realized (entry 13). Notably, the reaction also pro-
ceeded efficiently using water as a solvent (entry 6).
Results and Discussion
Diels–Alder reaction of a-substituted a,b-unsaturated alde-
hyde
We selected methacrolein as a model of a-substituted acrolein
and examined the Diels–Alder reaction with cyclopentadiene
(Eq. (1), Table 1). We have previously reported the asymmetric
Table 1. Effect of solvent and acid in the Diels–Alder reaction of metha-
crolein and cyclolopentadiene catalyzed by diarylprolinol silyl ether.[a]
Entry Catalyst
(X mol%)
Solvent Time
[h]
Yield[b][%] exo/
endo[c]
ee[d]
[%]
1
2
3
4
5
6
7
8
9
2 (10)
2 (10)
2 (10)
2 (10)
2 (10)
2 (10)
toluene
MeCN
MeNO2
CH2Cl2
THF
72
72
72
72
96
72
72
72
72
n.d.
n.d.
72
96
72
29
35
39
33
43
37
30
87
90
99:1
68
89
50
48
46
87
86
5
98:2
97:3
99:1
88:12
97:3
99:1
90:10
92:8
n.d.
Having established the optimum reaction conditions, the
generality of the reaction was then investigated (Table 2). The
exo-isomer was obtained with excellent diastereoselectivity in
all reactions using cyclopentadiene as the diene component
(entries 1–6). Not only methacrolein but also a-substituted
acrolein derivatives such as 2-methylenebutanal and 4-phenyl-
2-methylenebutanal gave Diels–Alder products with both ex-
cellent exo-selectivity and enantioselectivity (entries 2 and 3).
An ethoxycarbonylmethyl substituent at the a-position of acro-
lein does not interfere with the reaction, which provides the
product with excellent enantioselectivity (entry 4). In addition
to a-alkyl substituted acrolein, a-acyloxy substituted acrolein
derivatives were also suitable dienophiles, providing the prod-
uct in good yield and with excellent stereoselectivity (entries
5–10). With respect to the diene component, besides cyclopen-
tadiene, isoprene and 2,3-dimethylbutadiene could also be em-
ployed in the Diels–Alder reaction of a-acyloxyacrolein to pro-
vide products in good yield and with excellent enantioselectiv-
ity (entries 7–10).
H2O
1+PhCO2H (10) MeCN
1+p-TSA (10) MeCN
1+MeSO3H (10) MeCN
2
10[e] 1+TfOH (10)
MeCN
MeCN
MeCN
MeCN
neat
<10
<10
45
n.d.
n.d.
90
89
67
11
12
13
14
3 (10)
2 (15)
2 (20)
2 (20)
n.d.
99:1
99:1
96:4
67
74
[a] Unless otherwise indicated, all the reactions were carried out with
methacrolein (0.5 mmol), cyclopentadiene (2.0 mmol) and catalyst in sol-
vent (0.25 mL) at À208C. Cyclopentadiene was freshly distilled just before
use. [b] Yield of the isolated product after column chromatography.
[c] exo/endo ratio was determined by 1H NMR of crude reaction mixture.
[d] ee=Enantiomeric excess. Enantioselectivity was determined by HPLC
analyses on chiral phase, see the Supporting Information for details.
[e] Reaction mixture polymerized upon addition of TfOH.
Diels–Alder reaction of b-mono-substituted a,b-unsaturated al-
dehyde catalyzed by trifluoromethyl substituted diarylprolinol
silyl ether 1 (Figure 1) with a combination of trifluoroacetic
acid (TFA) in toluene;[11] herein, we examined the reaction with
the trifluoroacetic acid salt of diarylprolinol silyl ether 1. In the
We conducted the reaction of methacrolein and cyclopenta-
diene on a gram scale (Eq. (3)). It was found that the reaction
proceeds efficiently to provide the product in 69% yield with
excellent exo-selectivity (exo/endo=98:2) and similar enantio-
selectivity (88%ee) as the small scale reaction within the exper-
imental error.
Figure 1. Organocatalysts examined in this study.
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Table 2. Generality of asymmetric Diels–Alder reaction of a-substituted acroleins.[a]
Entry
1
Dienophile[b]
Diene
CP
Product
Time [h]
96
Yield [%][c]
67
exo/endo[d]
ee [%][e]
89 (2R)
5
99:1
2[f]
6
7
CP
CP
96
96
50
53
96:4
96:4
88
83
3[f]
4
5
6
8
9
CP
CP
CP
96
72
80
51
95
90
94:6
95:5
95:5
87
91
10
88 (2S)
7[g]
9
9
IP
72
72
72
72
78
60
75
75
88
8[h]
DB
IP
92 (S)
87 (S)
82 (S)
9[g]
10
10
10[g]
DB
[a] Unless otherwise indicated, all the reactions were carried out with dienophile (0.5 mmol), diene (2.0 mmol), catalyst 2 (0.1 mmol) in MeCN (0.25 mL) at
À208C. Cyclopentadiene was freshly distilled just before use. [b] CP=cylopentadiene, IP=isoprene, DB=2,3-dimethylbutadiene. [c] Yield of the isolated
product after column chromatography. [d] exo/endo ratio was determined by 1H NMR of the crude reaction mixture. [e] ee=Enantiomeric excess. Enantio-
meric excess of exo-isomer was determined by HPLC analyses on chiral phase. [f] Reaction run with 30 mol% catalyst. [g] The reaction was performed at
room temperature. [h] The reaction was performed at 08C.
The Diels–Alder reaction of b,b-disubstituted a,b-unsaturat-
ed aldehyde
pentadiene was investigated (Table 3). When the reaction was
performed in the presence of catalyst 1 and TFA in MeCN,
The Diels–Alder reaction of b,b-disubstituted a,b-unsaturated
aldehyde was examined. Ethyl 2-methyl-4-oxobutenoate was
selected as a model dienophile and the reaction with cyclo-
which was a suitable solvent for the reaction with a-substitut-
ed acrolein as a dienophile, poor diastereo- and enantio-selec-
tivities were obtained (entry 1). Other solvents, such as THF
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yl, tert-butoxycarbonyl, and acetyl groups could all be success-
fully employed to afford the Diels–Alder adduct with excellent
enantioselectivity (entries 1–3). Alkyl substituents such as dime-
thoxymethyl and benzoyloxymethyl could also be used as
a suitable substituent, affording the Diels–Alder product with
excellent enantioselectivity (entries 4 and 5). Low to moderate
levels of diastereoselectivity were generally observed for for-
mation of the exo and endo isomers. Even though the E/Z ratio
of the starting dienophile was low in the reaction of dime-
thoxymethyl substituent, excellent enantioselectivity was ob-
tained, which indicates that facile isomerization of the dieno-
phile occurred (entry 4).[17] In contrast to these successful re-
sults, almost no reaction took place with dienophiles possess-
ing an aromatic and aliphatic groups at the b-position, such as
3-phenyl-2-butenal, 3-(p-bromophenyl)-2-butenal, and 3-
methyl-5-phenylpent-2-enal. This would be because LUMO of
these dienophiles is not low enough to react with diene. In-
stead of cyclopentadiene, we employed 2,3-dimethyl-1,3-buta-
diene as a diene, and the reaction with ethyl 2-methyl-4-oxo-
butenoate was investigated, but the reaction did not proceed.
Next, a,b-disubstituted a,b-unsaturated aldehyde was exam-
ined as a dienoplile. But it was found that no reaction proceed-
ed in the case of 2-methylbut-2-enal and cyclopentadiene in
the presence of 4 using water as a reaction medium.
Table 3. The effect of catalyst and solvent in the Diels–Alder reaction of
ethyl 2-methyl-4-oxobutenoate and cyclopentadiene.[a]
Entry
Catalyst
Solvent
Time
[h]
Yield
[%][b]
exo/endo[c]
ee [%][d]
exo, endo
1
2
3
4
1+TFA
1+TFA
1+TFA
1+TFA
3
3
3
4
MeCN
THF
CH2Cl2
toluene
H2O
H2O
H2O
H2O
34
48
10
7.5
1.5
2.5
12
6
55
21
59
40
73
78
75
92
48:52
25:75
65:35
56:44
62:38
63:37
65:35
74:26
48, 52
<5, <5
58, 72
70, 86
98, 88
97, 91
98, 90
98, 95
5
6[e]
7[e,f]
8[e]
[a] Unless shown otherwise, the reaction was performed by employing alde-
hyde (0.7 mmol), cyclopentadiene (2.1 mmol), and catalyst (0.07 mmol) with
or without TFA (0.14 mmol) in the indicated solvent (organic solvent:
1.4 mL, H2O: 0.35 mL) at room temperature for the indicated time. Cyclo-
pentadiene was freshly distilled just before use. [b] Isolated yield. [c] Deter-
mined by 1H NMR of crude materials. [d] ee=Enantiomeric excess. Deter-
mined by HPLC analysis on chiral phase. [e] The catalyst (5 mol%) was em-
ployed. [f] The reaction was performed at 08C.
and CH2Cl2 were also not suitable (entries 2 and 3). A better
enantioselectivity was obtained when the reaction was con-
ducted in toluene, but the yield was not satisfactory (entry 4).
Water was then used as solvent. Given that we previously re-
ported that the perchloric salt of diarylprolinol silyl ether 1 in
the presence of water[16] was effective in the reaction of the b-
mono-substituted a,b-unsaturated aldehyde,[12] we applied this
catalytic system for the reaction with the b,b-disubstituted a,b-
unsaturated aldehyde. The reaction proceeded faster com-
pared with the reaction in organic solvent, and provided the
Diels–Alder adduct in good yield with excellent enantioselec-
tivity but with low diastereoselectivity (entry 5). The use of
5 mol% catalyst was sufficient to promote the reaction within
2.5 h, which proceeded with good enantioselectivity (entry 6).
Lowering the temperature from room temperature to 08C did
not increase the selectivity (entry 7). When a mixture of E- and
Z-isomers of ethyl 2-methyl-4-oxobutenoate (E/Z=95:5) was
employed in organic solvent, the Diels–Alder adduct derived
from the minor Z-isomer was generated in a small amount (ca.
5%). However, this diastereomer was not detected at all in the
reaction conducted in water as the solvent. This result would
indicate that the isomerization of E- and Z-isomers of the dien-
ophile is fast in the presence of water, because of the Michael
and retro-Michael reactions of nucleophilic water and a,b-un-
saturated aldehydes activated by the organocatalyst.[17] Fur-
thermore, when the bulky triisopropylsilyl ether of diphenyl-
prolinol 4 was employed, the diastereoselectivity of the reac-
tion improved (entry 8).
Relative and absolute configuration
For a-substituted acrolein, the Diels–Alder adducts of entries
1,[18] 6,[8a] 8,[8a] 9,[8a] and 10[8a] in Table 2 were known. Thus, the
relative and absolute configurations of these Diels–Alder prod-
ucts were determined by comparison with the reported data.
A transition-state model is indicated in Figure 2A, in which
Figure 2. The approach of cyclopentadiene toward iminium ion of a-substi-
tuted acrolein (A) and b,b-disubstituted a,b-unsaturated aldehyde (B).
the reaction proceeds via an s-trans iminium ion intermedi-
ate,[15] and cyclopentadiene reacts from the opposite side of
the bulky diphenylsiloxymethyl substituent through the exo
mode.[19]
In the case of b,b-disubstituted a,b-unsaturated aldehyde,
we determined the relative and absolute configurations as fol-
lows (Scheme 1): Diels–Alder products 11-exo and 11-endo of
3-ethoxycarbonyl-2-butenal and cyclopentadiene (Table 4,
entry 1) were reduced with NaBH4 to afford a mixture of alco-
hols 12-exo and 12-endo, which was treated with I2. From the
exo-isomer, iodo-lactonization proceeded to provide iodo lac-
tone 13 in 60% yield, whereas iodo-etherification proceeded
from the endo-isomer to afford iodo ether 14 in 20% yield. Io-
Having determined the optimum reaction conditions, the
generality of the reaction with respect to b,b-disubstituted
a,b-unsaturated aldehyde as a dienophile was investigated
(Table 4). One of the b-substituents was fixed as a methyl
group and the second b-substituent was varied. Ethoxycarbon-
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Table 4. The Diels–Alder reaction of b,b-disubstituted a,b-unsaturated aldehyde and cyclopentadiene catalyzed by 4.[a]
Entry
1
R
Amount of catalyst [%]
Product
Time [h]
Yield [%][b]
exo/endo[c]
ee [%][d] exo, endo
CO2Et
(E/Z=95:5)
5
6
92
74:26
71:29
73:27
88:12
88:12
98, 95
CO2tBu
(E/Z=90:10)
2
5
5
6
7
quant.
99, 98
97, 89
97, 51
95, 94
Ac
3
89
(E/Z=90:10)
CH(OMe)2
(E/Z=78:22)
4[e]
10
12
60
CH2OBz
(E/Z=99:1)
5
5
6
55
[a] Unless shown otherwise, the reaction was performed by employing aldehdye (0.7 mmol), cyclopentadiene (2.1 mmol), and organocatalyst
4
(0.035 mmol) in H2O (0.35 mL) at 08C for the indicated time. Cyclopentadiene was distilled cracked just before use. [b] Isolated yield. [c] Determined by
1H NMR of crude materials. [d] Determined by HPLC analysis on chiral phase. [e] ee=Enantiomeric excess. Dimethyl acetal was hydrolyzed in the reaction
and bis-aldehyde was isolated, see the Supporting Information for details.
The absolute configuration of iodolactone 13 was elucidated
by vibrational circular dichroism (VCD).[20] Calculations of IR
and VCD spectra of arbitrarily chosen (1R,2R,3R,6S,7R,9S)-7-hy-
droxymethyl-2-iodo-6-methyl-4-oxotricyclo[2.2.1.23.6]non-5-one
(13) started with a preliminary MMFF conformational search
using SPARTAN’10 software.[21] The resultant six geometries
within 12 kcalmolÀ1 from the most stable were optimized by
the DFT/B3LYP/DGDZVP level of theory using Gaussian 09.[22]
The IR and VCD spectra of the obtained five conformers within
1.6 kcalmolÀ1 from the most stable conformer were calculated
at the same level of theory, and the final spectra were simulat-
Scheme 1. Conversion of the Diels–Alder adduct 11-exo to iodo lactone 13.
ed based on the Boltzmann population average of each con-
former. Figure 3 shows the experimental and theoretical spec-
dolactone 13 and iodoether 14 were easily separated by silica-
gel chromatography. Given that iodolactone 13 and iodoether
14 should be generated from exo- and endo-isomers, respec-
tively, exo and endo relative stereochemistries of the Diels–
Alder product 11 were determined.
tra of 13. Most of the peaks seen in the observed VCD showed
a one-to-one correspondence with those in the calculated
spectra, including their sign. The overall agreement in these
spectra unambiguously confirmed the absolute configuration
of 13 as 1R,2R,3R,6S,7R,9S. Thus, the absolute configuration of
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Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas “Advanced Molecular Transforma-
tions by Organocatalysts” from The Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan.
Keywords: all-carbon quaternary stereocenter · asymmetric
reaction · chirality · Diels–Alder reaction · organocatalysis
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Figure 3. Comparison of the observed and calculated VCD (top) and IR
(bottom) spectra of 13. Each number indicates the corresponding peaks be-
tween the experimental and theoretical VCD. Meanwhile, asterisks indicate
disagreed signals, though these are minor. Measurement condition: CDCl3,
c=0.4m, l=50 mm, 16 scans for IR, 3000 scans for VCD; measured on JAS-
CO FVS-6000 spectrometer; corrected by solvent spectra recorded under
identical conditions; not corrected by the %ee of the sample. Calculation
condition: DFT/B3LYP/DGDZVP.
the parent compound 11-exo was concluded to be that shown
in Scheme 1.
This result led us to propose that the reaction of b,b-disub-
stituted a,b-unsaturated aldehyde proceeds via a similar transi-
tion state of b-mono-substituted a,b-unsaturated aldehyde,
shown in Figure 2B, in which the reaction proceeds via an s-
trans iminium ion intermediate,[15] and cyclopentadiene reacts
from the opposite side of the bulky diphenylsiloxymethyl sub-
stituent through the exo mode.[4k,7e,g,23]
Conclusions
We have accomplished two asymmetric Diels–Alder reactions
using diarylprolinol silyl ether as an organocatalyst. There are
several noteworthy features in these reactions: The exo-Diels–
Alder product was obtained with excellent diastereoselectivity
and high enantioselectivity via the s-trans iminium ion as an in-
termediate, when a-substituted acrolein was treated with the
trifluoroacetic acid salt of trifluoromethyl substituted diarylpro-
linol silyl ether in CH3CN. In the Diels–Alder reaction of b,b-di-
substituted a,b-unsaturated aldehyde, moderate exo-selectivity
and excellent enantioselectivity was obtained, when the
perchloric acid salt of the bulky triisopropyl silyl ether of tri-
fluoromethyl substituted diarylprolinol was employed as a cata-
lyst in the presence of water. In both cases, all-carbon quater-
nary stereocenters were constructed enantioselectively. Given
that the reaction is easily performed without complete removal
of oxygen and water, and that the reaction conditions are
mild, the present Diels–Alder reaction would be a suitable
method for the large-scale preparation of chiral all-carbon qua-
ternary stereocenters.
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Published online on && &&, 0000
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FULL PAPER
All-carbon quaternary stereocenters
were constructed by asymmetric Diels–
Alder reaction of a-substituted and b,b-
disubstituted a,b-enals in a highly enan-
tioselective manner. Diarylprolinol silyl
ether acts as an effective organocatalyst
with a combination of an acid, and the
reaction proceeds at 08C or room tem-
perature in CH3CN, or by using water as
a green solvent. This is a practical enan-
tioselective method for the synthesis of
all-carbon quaternary stereocenters.
&
Chiral Synthesis
Y. Hayashi,* B. P. Bondzic, T. Yamazaki,
Y. Gupta, S. Ogasawara, T. Taniguchi,
K. Monde
&& – &&
Asymmetric Diels–Alder Reaction of a-
Substituted and b,b-Disubstituted a,b-
Enals via Diarylprolinol Silyl Ether for
the Construction of All-Carbon
Quaternary Stereocenters
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Chem. Eur. J. 2016, 22, 1 – 8
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8
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!