New α- and β-cyclodextrin derivatives with cinchona alkaloids used in asymmetric organocatalytic reactions

Article abstract of DOI:10.3762/bjoc.15.80

The preparation of new organocatalysts for asymmetric syntheses has become a key stage of enantioselective catalysis. In particular, the development of new cyclodextrin (CD)-based organocatalysts allowed to perform enantioselective reactions in water and

Full text of DOI:10.3762/bjoc.15.80

New α- and β-cyclodextrin derivatives with cinchona alkaloids
used in asymmetric organocatalytic reactions
Iveta Chena Tichá1, Simona Hybelbauerová2 and Jindřich Jindřich*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 830–839.
1Department of Organic Chemistry, Faculty of Science, Charles
University, Hlavova 8, 128 43, Prague 2, Czech Republic and
2Department of Teaching and Didactics of Chemistry, Faculty of
Science, Charles University, Hlavova 8, 128 43, Prague 2, Czech
Republic
doi:10.3762/bjoc.15.80
Received: 06 January 2019
Accepted: 12 March 2019
Published: 01 April 2019
Email:
Associate Editor: M. Rueping
Jindřich Jindřich* - jindrich@natur.cuni.cz
© 2019 Tichá et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
asymmetric allylic amination; cinchona alkaloids; CuAAC click
reaction; cyclodextrin; organocatalysts
Abstract
The preparation of new organocatalysts for asymmetric syntheses has become a key stage of enantioselective catalysis. In particu-
lar, the development of new cyclodextrin (CD)-based organocatalysts allowed to perform enantioselective reactions in water and to
recycle catalysts. However, only a limited number of organocatalytic moieties and functional groups have been attached to CD scaf-
folds so far. Cinchona alkaloids are commonly used to catalyze a wide range of enantioselective reactions. Thus, in this study, we
report the preparation of new α- and β-CD derivatives monosubstituted with cinchona alkaloids (cinchonine, cinchonidine, quinine
and quinidine) on the primary rim through a CuAAC click reaction. Subsequently, permethylated analogs of these cinchona alka-
loid–CD derivatives also were synthesized and the catalytic activity of all derivatives was evaluated in several enantioselective
reactions, specifically in the asymmetric allylic amination (AAA), which showed a promising enantiomeric excess of up to 75% ee.
Furthermore, a new disubstituted α-CD catalyst was prepared as a pure AD regioisomer and also tested in the AAA. Our results in-
dicate that (i) the cinchona alkaloid moiety can be successfully attached to CD scaffolds through a CuAAC reaction, (ii) the per-
methylated cinchona alkaloid–CD catalysts showed better results than the non-methylated CDs analogues in the AAA reaction,
(iii) promising enantiomeric excesses are achieved, and (iv) the disubstituted CD derivatives performed similarly to monosubsti-
tuted CDs. Therefore, these new CD derivatives with cinchona alkaloids effectively catalyze asymmetric allylic aminations and
have the potential to be successfully applied in other enantioselective reactions.
Introduction
Cyclodextrins (CDs) [1], cyclic oligosaccharides consisting of form supramolecular inclusion complexes [2]. CD derivatives
α-D-glucopyranoside units, and their derivatives are widely have been increasingly applied in catalysis and biomimetic
used in many industrial and research areas for their ability to reactions [3,4] thanks to host–guest interactions and to the non-
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Beilstein J. Org. Chem. 2019, 15, 830–839.
toxic, chiral skeleton of CDs. More specifically, CDs applied in used per-6-amino-β-CD as the promoter (not in a catalytic
reactions involving metal catalysis [5], organocatalysis [6] and amount) of a Henry reaction and obtained the product with
artificial enzymes [7] have been recently studied, thus high- 99% ee. Subsequently, Doyagüez et al. [17] attached L-proline
lighting their high potential as effective catalysts.
to β-CD via different linkers (including a triazole linker) and
used the resulting organocatalysts in an aldol reaction in water,
CDs represent an ideal skeleton with a cavity-containing struc- albeit with a lower enantiomeric excess (54% ee). Conversely,
ture for catalysts. Moreover, using native or modified CDs, Shen et al. [18] performed an aldol reaction in a buffer using L-
organic reactions can be performed under green conditions and D-proline-derived CDs connected through a pyrrolidine
[8-10]. In addition, CDs improve the rate and modulate the skeleton as catalysts and observed 94% ee. More recently,
regioselectivity and enantioselectivity of reactions [11]. For ex- Liu et al. [19] reported the excellent enantioselectivity of
ample, metal-based CD catalytic systems and CD derivatives 99% ee in an aldol reaction catalyzed by β-CD with L-proline
for organocatalysis have already shown promising results in the attached through a urea moiety. Therefore, mainly proline-
studies by Hapiot and Monflier [12], Armspach [13] and others derived CDs have been previously tested as organocatalysts and
[14,15].
mainly in aldol-type reactions.
The chemical modification of native CD skeletons with new The limited number of functional groups attached to CD com-
functional groups enhances the application of CDs and provides prising mainly L-proline restricts the potential of asymmetric
access to new organic chemistry transformations and catalytic organocatalytic reactions using CD derivatives. However, a
systems. Among the approaches used for chemical derivatiza- wide range of catalytic groups, especially cinchona alkaloids
tion of CD skeletons, monosubstitution on the primary rim of (Figure 2), have been used in organocatalysis with excellent
CD (Figure 1) is a well-explored strategy [2] which can be used results. These naturally occurring compounds and their deriva-
to prepare various types of CD derivatives.
tives are commonly applied in various enantioselective reac-
tions (mainly because of the nucleophilic center on the chiral
Several examples of modified-CD derivatives with a catalytic quinuclidine skeleton) [20]. More importantly, they are a privi-
nucleophilic center have been reported in the area of organocat- leged class of chiral catalysts, which are well known for their
alytic asymmetric reactions [11]. Initially, Kanagaraj et al. [16] use in Michael additions [21], Morita–Baylis–Hillman reac-
Figure 1: Schematic cone-shaped (a) and structure representations (b) of α-CD (six glucopyranoside units) and β-CD (seven glucopyranoside units).
Figure 2: Common cinchona alkaloids (cinchonine, cinchonidine, quinine, quinidine).
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Beilstein J. Org. Chem. 2019, 15, 830–839.
tions [22], and aldol reactions [23], among others [24]. Hence, Our study shows that the CuAAC reaction is a good and
combining cinchona alkaloids with CDs has the potential to high-yielding method for the functionalization of the CD
widen the applications of CD derivatives in asymmetric skeleton when attaching sterically demanding cinchona groups.
organocatalysis.
Additionally, some of these new CD derivatives showed
promising results of up to 75% ee in the AAA reactions of
The combination of cinchona alkaloids with CDs was first re- Morita–Baylis–Hillman (MBH) carbamates and significant
ported by Liu et al. [25] who prepared inclusion complexes of differences depending on the attached cinchona alkaloid
cinchona alkaloids and organoselenium-bridged bis-β-CDs. (cinchonine, cinchonidine, quinine, quinidine) as well as on the
Subsequently, the same research group [26] investigated the size of the cavity, i.e., β-CD or α-CD derivatives). Thus, this
performance of inclusion complexes of native and permethyl- study showed that cinchona-substituted CD catalysts are active
ated β-CDs and cinchona alkaloids as pH-responsive binding in organocatalytic reactions.
systems. Nevertheless, to the best of our knowledge, CD deriva-
Results and Discussion
tives with covalently bonded cinchona alkaloids have never
Synthesis of monosubstituted non-methyl-
ated CD derivatives
Initially, the method for attaching cinchona alkaloids to non-
methylated CDs was developed. For our purposes of using the
derivatives as catalysts for enantioselective reactions, we
focused on α- and β-CD skeletons.
been prepared and tested in asymmetric organocatalysis. Thus,
in this study, we investigated methods for attaching cinchona
alkaloids to CD skeletons, and we assessed the enantiomeric
excess of the resulting CD derivatives as organocatalysts in
asymmetric reactions, specifically in the asymmetric allylic
amination (AAA).
We successfully prepared a series of monosubstituted α- and Our successful approach consisted of attaching these molecules
β-CDs derivatives with the cinchona alkaloids cinchonine, through copper-catalyzed alkyne–azide cycloaddition
cinchonidine, quinine, and quinidine with up to 95% isolated (CuAAC). First, the required starting materials 6I-azido-6I-
yield through CuAAC click reactions. By this simple, high- deoxy-α-CD (1) [27] and 6I-azido-6I-deoxy-β-CD (2) [27] and
yielding and quick method we synthesized eight new CD deriv- 9-O-propargylated cinchona alkaloid derivatives 3a–d [28]
atives, four based on the α-CD and four based on β-CD were synthesized followed by optimization of the conditions for
skeleton. In addition, to widen the usability and to improve the the CuAAC click reaction (Scheme 1).
solubility of the prepared CD derivatives, the corresponding
eight permethylated analogs were also synthesized. Further- The CuAAC click reaction conditions were initially optimized
more, to test more advanced types of catalysts, a disubstituted using α-CD (Table 1). Initially, the reaction was performed in a
α-CD derivative as a pure AD regioisomer with two identical THF/H2O mixture with 1.5 equiv of 9-O-propargylated cincho-
cinchona alkaloid residues was prepared and tested in the AAA nine (3a) and 50 mol % CuI affording the product in 78% yield
reaction.
(Table 1, entry 1). Reducing both the amount of propargylated
Scheme 1: CuAAC click reaction of propargylated cinchona alkaloids 3a–d with 6I-azido-6I-deoxy-α-CD (1) and 6I-azido-6I-deoxy-β-CD (2).
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Beilstein J. Org. Chem. 2019, 15, 830–839.
Table 1: Optimized conditions of the CuAAC click reactions of non-methylated azido-CDs with propargylated cinchona alkaloids depicted in
Scheme 1.
Entry
CD
Alkaloid
R1
x (equiv)
y (mol %)
Solvent
Yielda in % (product)
1
1
1
1
1
1
1
2
2
2
2
2
1
3a (8R,9S)
3a (8R,9S)
3a (8R,9S)
3b (8S,9R)
3c (8S,9R)
3d (8R,9S)
3a (8R,9S)
3a (8R,9S)
3b (8S,9R)
3c (8S,9R)
3d (8R,9S)
3a (8R,9S)
H
1.5
1.3
1.05
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
50
20
20
20
20
20
20
20
20
20
20
20
THF/H2O 1:1
THF/H2O 1:1
THF/H2O 1:1
THF/H2O 1:1
THF/H2O 1:1
THF/H2O 1:1
THF/H2O
DMF
78 (4a)
77 (4a)
56 (4a)
86 (4b)
72 (4c)
74 (4d)
20 (5a)
89 (5a)
70 (5b)
80 (5c)
95 (5d)
38 (4a)
2
H
3
H
4
H
5
OCH3
OCH3
H
6
7b
8
H
9
H
DMF
10
11
12b
OCH3
OCH3
H
DMF
DMF
DMF
aIsolated yield. bAfter 48 hours.
cinchona alkaloid 3a to 1.3 equiv and the amount of the Cu salt methylated CD derivatives 8a–d, 9a–d were isolated in high
to 20 mol % resulted in virtually the same yield of the product yields of up to 69% (Scheme 2).
(Table 1, entry 2). Conversely, the further decreasing the
amount of propargylated cinchonine (3a) to 1.05 equiv led to a As outlined in Table 2, the conditions assessed using the non-
significantly lower conversion to the product (56%, Table 1, methylated CDs were applied to prepare per-Me-α-CD (6)
entry 3). Thus, based on the optimal conditions identified for analogs. Thus, reaction 6 with 1.3 molar equivalents of the
the α-CD skeleton (Table 1, entry 2), the subsequent syntheses propargylated cinchona alkaloid 3a in the presence of 20 mol %
were performed using 1.3 equiv of cinchona alkaloids 3b–d in a CuI in DMF afforded product 8a in 59% yield (Table 2, entry
mixture of THF/H2O with 20 mol % CuI. The corresponding 1). Subsequently, we prepared the other permethylated
α-CD products (4a–d, 5a–d) were isolated in high yields of up cinchona–α-CD derivatives 8b–d with moderate yields
to 86% yield (Table 1, entries 2 and 4–6).
(42–49% yield, Table 2, entries 2–4). In the case of per-Me-β-
CD 7, following the same procedure, the products 9a–d were
In the reactions with β-CD (2, Table 1, entries 7–11), no full also isolated with good to high yields (up to 69% yield, Table 2,
conversion into the product could be achieved in the solvent entries 6–9). Concomitantly, the reaction was investigated in the
mixture THF/H2O even after 48 hours of reaction (Table 1,
entry 7). However, when changing the solvent to DMF a full
Table 2: Yields for optimized conditions of CuAAC click reaction of
conversion into the product was observed within 2 hours of
reaction affording the products with high to excellent yields
(95%, 5a–d, Table 1, entries 8–11). Conversely, the product
yield was low when using DMF for a CuAAC reaction with
α-CD resulting in only 38% of product 4a after 48 hours
(Table 1, entry 12).
permethylated azido-CDs with propargylated cinchona alkaloids from
Scheme 2.
Entry
CD
Alkaloid
R1
Yielda in %
(product)
1
2
3
4
5b
6
7
8
9
6
6
6
6
6
7
7
7
7
3a (8R,9S)
3b (8S,9R)
3c (8S,9R)
3d (8R,9S)
3c (8S,9R)
3a (8R,9S)
3b (8S,9R)
3c (8S,9R)
3d (8R,9S)
H
59 (8a)
48 (8b)
49 (8c)
42 (8d)
34 (8c)
64 (9a)
69 (9b)
48 (9c)
63 (9d)
H
Synthesis of monosubstituted methylated CD
derivatives
OCH3
OCH3
OCH3
H
After developing the approach for attaching of cinchona alka-
loids to non-methylated CD skeletons, we next focused on the
functionalization of permethylated CD derivatives. First, we
prepared the starting CD compounds, per-Me-N3-α-CD (6) [29]
and per-Me-N3-β-CD (7) [30], and subjected them to the previ-
ously optimized conditions of the CuAAC click reaction with
propargylated cinchona alkaloids (3a–d). The resulting per-
H
OCH3
OCH3
aIsolated yield. bTHF/H2O solvent mixture.
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Beilstein J. Org. Chem. 2019, 15, 830–839.
Scheme 2: CuAAC click reaction of per-Me-N3-α-CD (6) or per-Me-N3-β-CD (7) and propargylated cinchona alkaloids 3a–d.
THF/H2O solvent mixture (Table 2, entry 5), however, the reac- at position 6 on the primary rim (Figure 3). Generally, we ob-
tion in DMF afforded a higher isolated yield (Table 2, entry 3).
served four different regions with the typical signals: the first,
well-resolved aromatic region belongs to the quinoline part of
the cinchona alkaloid (9.00–7.55 ppm) and to the hydrogen
Synthesis of disubstituted CD derivatives
To open the way for the preparation of more versatile types of signal of the triazole (8.21 ppm), thus confirming the success-
enantioselective organocatalysts containing a CD skeleton and ful attachment of the cinchona alkaloid to the CD skeleton
cinchona alkaloids, a method for the synthesis of a disubsti- through the CuAAC click reaction. The second part of the
tuted derivative of cinchona alkaloid–non-methylated CD was 1H NMR spectrum comprises the resolved signal for the double
developed. The prepared derivative was subsequently tested in bond on the quinuclidine skeleton of the cinchona alkaloid
an AAA reaction. In contrast to the monosubstituted deriva- (5.93 ppm). The third part of the spectrum consists of the CD
tives, disubstituted CDs should be considered as possible mix- region (5.50–3.20 ppm) with H-1 atoms of unsubstituted
tures of regioisomers and pseudoenantiomers [31,32]. Because glucose units (4.80 ppm) and H-1I (5.03 ppm) for the substi-
of the results published by our group previously [33], we chose tuted glucose. The signals of the H-2, H-3, H-4 and H-6 atoms
an AD regioisomer (as a pure regioisomer) on an α-CD skeleton of unsubstituted units are observed at around 4.00–3.00 ppm; on
for the preparation of the catalyst.
the other hand, the signal for H-6I is separately visible around
4.75 ppm (especially in the HSQC and 1H,1H COSY spectra).
Initially, we synthesized the starting material, 6A,6D-diazido- This part of the spectrum also includes the primary rim OH
6A,6D-dideoxy-α-CD (10) [34-36] and reacted it with propargy- groups (4.49–4.34 ppm) and secondary rim OH groups
lated cinchona alkaloid 3c. The disubstituted product 11 with a (5.91–5.53 ppm). Finally, the quinuclidine skeleton part of
quinine moiety (3c) at position 1,4 on the primary rim of the the cinchona alkaloid is identified in the region around
α-CD skeleton was isolated in 76% yield (Scheme 3).
2.00–1.20 ppm.
NMR elucidation of the prepared
cinchona–CD derivatives
Subsequently, 13C NMR, DEPT-edited HSQC and HMBC
spectra also confirmed the substitution on the primary rim of the
The structures of mono- (4a–d, 5a–d) and disubstituted (11) CD skeleton (Figure 4). The C-6 atom of the substituted glucose
non-methylated CDs and permethylated (8a–d, 9a–d) CD deriv- unit is correlated with the hydrogen signal of the triazole ring
atives were unambiguously confirmed by NMR measurements. (50.41 ppm of C-6I to 8.16 ppm of H-14' of triazole) and
As representative example of the prepared CD derivatives, we 126.13 ppm of C-14' triazole is correlated to the signal at 4.57
chose the α-CD derivative substituted with quinidine 4d. The ppm of the quinidine part. Additional 2D NMR spectra (COSY,
1H NMR spectra of the non-methylated CD derivatives in HSQC, HMBC, ROESY) are included in Supporting Informa-
DMSO-d6 are in accordance with monosubstituted derivatives tion File S2 and Supporting Information File S3.
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Beilstein J. Org. Chem. 2019, 15, 830–839.
Scheme 3: Synthesis of difunctionalized α-CD 11 with quinine moieties.
Figure 3: Representative 1H NMR spectrum of the non-methylated quinidine–α-CD derivative 4d.
Moreover, we also investigated a possible inclusion of the cross-peaks between the substituent (hydrogen atoms of the
cinchona alkaloid substituent in the CD cavity in the case of double bond of the quinuclidine skeleton) and the inner H-3
cinchonine–β-CD 5a in D2O. The 2D ROESY spectrum showed atoms of the β-CD cavity. However, the low solubility of non-
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Beilstein J. Org. Chem. 2019, 15, 830–839.
Figure 4: Representative 13C NMR spectrum and parts of the HMBC spectrum of the non-methylated quinidine–α-CD derivative 4d.
methylated β-CDs in H2O (1 mg/1 mL) did not allow us to Catalytic activity of cinchona–CD derivatives
further investigate the nature of the inclusion, e.g., by concen- Lastly, the activity of all prepared CD derivatives was tested in
tration dependency measurements. Thus, the observed cross- asymmetric organocatalytic reactions. After unsuccessful appli-
peaks could be caused by intermolecular interactions (inclusion cation in Morita–Baylis–Hillman and aldol-type reactions, we
of the part of the cinchonine moiety into the second CD cavity) focused on their application in the decarboxylative asymmetric
or by intramolecular interactions. Nevertheless, the rotation of allylic amination (AAA) [38] of MBH carbamate 12 affording
the substituted glucopyranoside unit as discussed by Hapiot and the product 13 with enantiomeric excesses of up to 75%
Monflier [37], leading to the formation of the in isomer, is not (Scheme 4).
very probable in our case, due to the large steric demand of the
cinchona substituent. Moreover, the CD inner hydrogens However, compared with the published procedure [38] (up to
showed no cross-peaks with the triazole ring hydrogen as well 97% ee, aromatic solvent, 40 °C, and 168 hours), the solvent of
as with no cinchona hydrogens which are close to the triazole. the reaction had to be changed in the case of non-methylated
The results of these NMR measurements in D2O are collected in CDs due to their lower solubility in organic solvents. The reac-
Supporting Information File 2.
tion conditions and results are summed up in Table 3.
In conclusion, we unambiguously confirmed the cinchona alka- First, the racemic version of this reaction with DABCO gave
loid attachment to the CD skeleton through the triazole by 89% yield of the product (Table 3, entry 1). Pure permethylated
2D NMR measurements. This thorough investigation revealed α- and β-CDs without cinchona alkaloid modification were also
no triple bond and a new triazole hydrogen signal while corre- tested (Table 3, entries 2 and 3) as blank catalysts but complete-
lating carbon C6 of the substituted glucose unit with the tri- ly failed. Promising results were achieved with permethylated
azole. Therefore, the prepared CD derivatives are substituted on CD–cinchonidine derivatives 8b and 9b affording the product in
the primary side. Further characterization data are included in 74 and 69% ee, respectively (Table 3, entries 5 and 9). Other
Supporting Information Files 1–3.
permethylated CD derivatives 8a, 8c, 8d, 9a, 9c, 9d resulted in
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Beilstein J. Org. Chem. 2019, 15, 830–839.
Scheme 4: AAA reaction of MBH carbamate 12 catalyzed by the prepared CD derivatives 4a–d, 5a–d, 8a–d, 9a–d, 11.
Table 3: Catalytic activity of the CD derivatives in the AAA reaction of MBH carbamate 12.a
Entry
Catalyst
Solvent
Yieldb (%)
ee (%)
1
DABCO
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CHCl3
89
n.d.
n.d.
62
42
76
47
37
55
12
44
63
63
73
15
n.d.
n.d.
10
n.d.
5
–
2c
per-Me-α-CD
–
3c
per-Me-β-CD
–
4
8a
13
74
25
27
15
69
15
25
69
69
33
75
–
5
8b
8c
6
7
8d
9a
8
9
9b
9c
10
11
12
13
14
15d
16c
17c
18
19c
20
21
22
23
24
25
26
27
28
29c
30c,e
9d
9b
9b
9b
9b
α-CD
β-CD
4a
MTBE
MeOH
toluene
ACN/H2O
ACN/H2O
ACN/H2O
DMF
–
3
4b
4b
4c
–
ACN/H2O
ACN/H2O
ACN/H2O
ACN/H2O
DMF
0
12
18
26
9
0
4d
5a
21
5
5b
5b
5b
5c
25
23
19
0
DMSO
19
19
5
ACN/H2O
ACN/H2O
ACN/H2O
ACN/H2O
ACN/H2O
5d
11
21
n.d.
n.d.
13
–
11
–
aStandard conditions: 10 mol % catalyst, 0.4 M solution, solvent, 40 °C, 168 hours. bIsolated yield. cn.d. = not detected, – = not measured.
dTemperature 25 °C. eWith 5 mol % (1S)-CSA.
low ee (Table 3, entries 4, 6–8, 10 and 11). Based on these cule without any modification has no influence on the reaction
results, the promising catalyst 9b was selected and investigated (Table 3, entries 16 and 17). Furthermore, the non-methylated
under different conditions (solvents and temperature, Table 3, monosubstituted CD derivatives 4a–d, 5a–d afforded on one
entries 12–15) with similar results. Lastly, native α- and β-CDs side lower enantiomer excesses (Table 3, entries 18–28), on the
were also tested as blank catalysts to confirm that the CD mole- other hand, they showed some catalytic activity in the solvent
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Beilstein J. Org. Chem. 2019, 15, 830–839.
ORCID® iDs
mixture acetonitrile/H2O, which could be promising for future
applications of these catalysts in water. The disubstituted CD
derivative 11 was not active in this enantioselective reaction
(Table 3, entry 29) and this derivative was also tested in the
AAA reaction with (1S)-10-camphorsulfonic acid (CSA) ac-
cording to the original procedure [38], in which the cocatalyst
(1S)-CSA enhanced the efficiency of dimeric cinchona alka-
loids (Table 3, entry 30). However, there was no difference
observable under these conditions.
Iveta Chena Tichá - https://orcid.org/0000-0002-7628-0665
Jindřich Jindřich - https://orcid.org/0000-0003-3770-0214
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