Synthesis and pKa determination of new enantiopure dimethyl-substituted acridino-crown ethers containing a carboxyl group: Useful candidates for enantiomeric recognition studies

Article abstract of DOI:10.1002/chir.22721

New enantiopure dimethyl-substituted acridino-18-crown-6 and acridino-21-crown-7 ethers containing a carboxyl group at position 9 of the acridine ring [(S,S)-8, (S,S)-9, (R,R)-10] were synthesized. The pK_a values of the new crown ethers [(S,S)-8, (S,S)-9, (R,R)-10] and of an earlier reported macrocycle [(R,R)-2] were determined by UV-pH titrations. Crown ether (S,S)-8 was attached to silica gel by covalent bonds and the enantiomeric separation ability of the newly prepared chiral stationary phase [(S,S)-CSP-12] was studied by high-performance liquid chromatography (HPLC). Homochiral preference was observed and the best separation was achieved for the enantiomers of 1-NEA. Ligands (S,S)-9 and (R,R)-10 are precursors of enantioselective sensor and selector molecules for the enantiomers of protonated primary amines, amino acids, and their derivatives.

Full text of DOI:10.1002/chir.22721

Received: 9 January 2017
DOI: 10.1002/chir.22721
Revised: 19 May 2017
Accepted: 22 May 2017
R E G U L A R A R T I C L E
Synthesis and pK determination of new enantiopure dimethyl‐
a
substituted acridino‐crown ethers containing a carboxyl group:
Useful candidates for enantiomeric recognition studies
1
1,2
1
1,2
2
Tamás Németh | Gergő Dargó | József Levente Petró | Zsófia Petrik | Sándor Lévai |
3
3
1
2
1
Balázs Krámos | Zoltán Béni | József Nagy | György Tibor Balogh | Péter Huszthy
|
1
Tünde Tóth
1
Department of Organic Chemistry and
Abstract
Technology, Budapest University of
Technology and Economics, Budapest,
Hungary
New enantiopure dimethyl‐substituted acridino‐18‐crown‐6 and acridino‐21‐crown‐
7
ethers containing a carboxyl group at position 9 of the acridine ring [(S,S)‐8, (S,S)‐
2
Compound Profiling Laboratory, Chemical
9
, (R,R)‐10] were synthesized. The pK values of the new crown ethers [(S,S)‐8,
a
Works of Gedeon Richter Plc, Budapest,
Hungary
(
S,S)‐9, (R,R)‐10] and of an earlier reported macrocycle [(R,R)‐2] were determined
3
by UV‐pH titrations. Crown ether (S,S)‐8 was attached to silica gel by covalent bonds
and the enantiomeric separation ability of the newly prepared chiral stationary phase
Spectroscopic Research, Chemical Works
of Gedeon Richter Plc, Budapest, Hungary
[(S,S)‐CSP‐12] was studied by high‐performance liquid chromatography (HPLC).
Correspondence
Tünde Tóth, Department of Organic
Chemistry and Technology, Budapest
University of Technology and Economics H‐
Homochiral preference was observed and the best separation was achieved for the
enantiomers of 1‐NEA. Ligands (S,S)‐9 and (R,R)‐10 are precursors of
enantioselective sensor and selector molecules for the enantiomers of protonated
primary amines, amino acids, and their derivatives.
1
521 Budapest, PO Box 91, Hungary.
Email: ttoth@mail.bme.hu
Funding information
New National Excellence Program of the
Ministry of Human Capacities, Grant/Award
Number: ÚNKP‐16‐3‐III.; New Széchenyi
Development Plan, Grant/Award Number:
TÁMOP‐4.2.1/B‐09/1/KMR‐2010‐0002;
National Research, Development and Inno-
vation Office, NKFIH, Grant/Award Num-
ber: NKFIH/OTKA K112289
KEYWORDS
acridino‐crown ethers, chiral stationary phase, enantiomeric recognition, HPLC, pK determination,
a
zwitterionic form
1
| INTRODUCTION
determination of the enantiomeric composition of these
organic compounds is of great importance, especially in the
Molecular recognition is a generally occurring vital phenom-
enon in nature. Enantiomeric recognition, which can be
regarded as a special case of molecular recognition, involves
the discrimination between the enantiomers of a chiral guest
molecule by a chiral host molecule. There are many examples
of its action, such as the metabolism of single enantiomeric
forms of amino acids and sugars, enzyme‐substrate interac-
tions, immunological responses, and effects of drugs. Differ-
ent enantiomers of various amines and amino acids may
possess different biological activities; therefore, the
pharmaceutical, pesticide, food, and cosmetic industries.
Since the seminal work of Cram and coworkers, a large
1
number of different chiral crown ethers have been synthetized
and studied for their enantiomeric recognition ability toward
the enantiomers of protonated chiral primary amines, amino
2-14
acids, and their derivates.
One of the main factors that determines the enantiomeric
recognition ability of these crown ethers, the π–π interaction,
can be enhanced by incorporating a heterocyclic unit contain-
ing a more extended aromatic system into the macroring,
Chirality. 2017;1–14.
wileyonlinelibrary.com/journal/chir
© 2017 Wiley Periodicals, Inc.
1

2
NÉMETH ET AL.
1
5-23
such as an acridine unit.
The tricyclic ring system also
and its pK values have been determined. Crown ether (S,S)‐8
a
makes the crown ether framework more rigid, which may fur-
ther improve selectivity. Selected enantiopure acridino‐18‐
crown‐6 ethers [(R,R)‐1–(R,R)‐3] have been attached by
covalent bonds to silica gel and these chiral stationary phases
has been attached by covalent bonds to silica support by the
22
modification of an earlier‐described procedure. The enan-
tiomeric separation ability of the newly prepared chiral sta-
tionary phase [(S,S)‐CSP‐12] has been studied by high‐
performance liquid chromatography (HPLC) towards the
enantiomers of protonated primary aralkylamines [1‐(1‐
naphthyl)ethylamine hydrogen perchlorate (1‐NEA), 1‐(2‐
naphthyl)ethylamine (2‐NEA), 1‐phenylethylamine (PEA),
1‐(4‐bromophenyl)ethylamine (Br‐PEA), and 1‐(4‐nitrophe-
(CSPs) [(R,R)‐CSP‐4–(R,R)‐CSP‐6, see Figure 1] have been
used for chromatographic enantioseparation of racemic pro-
1
7,22,23
tonated primary amines and their derivates.
The chiral
recognition ability of crown ethers can be modified by chang-
ing the position of the chiral center and also by expanding the
crown ether macroring.
nyl)ethylamine hydrogen chloride (NO ‐PEA)] and α‐amino
2
A glucose‐based acridino‐21‐crown‐7 ether was able to
differentiate between the enantiomers of 1‐phenylethylamine
acid derivatives [PGME hydrogen chloride salt and
Kynurenine] (Figure 2). These analytes were selected as the
subjects of study in our experiments, as they are typical model
compounds in enantiomeric recognition studies or possess
biological significance. Using (S,S)‐CSP‐12, almost baseline
enantioseparation of 1‐NEA enantiomers was achieved.
(PEA), 1‐(1‐naphthyl)ethylamine (1‐NEA), phenylglycine
6
methyl ester (PGME), and phenylalanine methyl ester
24
(
PAME). In our research group we have also demonstrated
the enantiomeric recognition ability of the dimethyl‐
substituted sensor (S,S)‐7 (Figure 1) toward the enantiomers
19
of PGME. These test compounds are biologically relevant;
2
2
| MATERIALS AND METHODS
.1 | Chemicals and solvents
for example, the derivatives of 1‐NEA possess local anes-
2
5
thetic and antiarrhythmic properties and phenylglycine can
2
6
enhance the absorption of l‐Dopa. Also, through the
kynurenine pathway, an essential amino acid, L‐tryptophan,
is metabolized. Therefore, the development of CSPs for the
separation of these compounds is of great significance. In
continuation of our studies in this area of research, our atten-
tion turned to the preparation of new enantiopure dimethyl‐
substituted acridino‐18‐crown‐6 and acridino‐21‐crown‐7
ether type macrocycles containing a carboxyl group at posi-
tion 9 of the acridine ring [(S,S)‐8, (S,S)‐9, (R,R)‐10, see
Figure 1]. These macrocycles can be transformed into such
derivatives, which are able to function as effective sensor
Reagents were purchased from Sigma‐Aldrich (St. Louis,
MO) unless otherwise noted. Silica gel 60 F254 (Merck,
Darmstadt, Germany) plates were used for thin‐layer chro-
matography (TLC). Silica gel 60 (70–230 mesh, Merck)
was used for column chromatography. Ratios of solvents
for the eluents are given in volumes (mL/mL). Solvents
were dried and purified according to well‐established
27
methods. Evaporation of the solvents was carried out
under reduced pressure.
and selector molecules. The pK values of the newly synthe-
a
2
.2 | Apparatus and chromatography
sized crown ethers and of a recently published analogous
compound [(R,R)‐2] have been measured by UV‐pH titra-
tions. Significant differences between the predicted and the
Melting points were taken on a Boetius micro‐melting point
apparatus and were uncorrected. Infrared spectra were
recorded on a Bruker (Billerica, MA) Alpha‐T FT‐IR
spectrometer. Optical rotations were taken on a Perkin‐Elmer
(Boston, MA) 241 polarimeter that was calibrated by
measured pK values have been observed, thus clarifying this
a
phenomenon further; an analogous dimethoxy‐substituted
parent compound (11, see Figure 1) has also been synthesized
FIGURE 1 Enantiopure acridino‐18‐
crown‐6 and acridino‐21‐crown‐7 ethers and
a 9‐acridinecarboxylic acid analog

NÉMETH ET AL.
3
Detector L‐2450, a LaChrom L‐2310 pump, an L‐2200
autosampler, and an L‐2300 column oven, using a Reprosil
Chiral MIA HPLC column. Isocratic elution was applied with
a solvent system of 1:9 mixture of isopropanol / CH CN +
3
0
.1% trifluoroacetic acid. Enantiomeric purity (enantiomeric
excess, ee >99%) was confirmed for all studied compounds
macrocycles (R,R)‐32, (R,R)‐20, (R,R)‐16 and (R,R)‐10].
[
The chromatograms of the appropriate crown ethers are
presented in the Supporting Information.
FIGURE 2 Structures of the aralkylamines and α‐amino acid esters
used in the enantiomeric separation studies
2.4 | Quantum mechanical pK calculations
a
Quantum mechanical pKa calculations were carried out
within the Schrödinger program suite using Jaguar v.
2
8,29
measuring the optical rotations of both enantiomers of
menthol. Nuclear magnetic resonance (NMR) spectra were
recorded on a Bruker 300 Avance spectrometer (at 300
9.1.
The applied protocol involves five main steps. 1) A
30
conformational search using Macromodel (MM force field:
OPLS3, GB/SA continuum solvent model, solvent: water) to
determine the lowest energy conformers of the protonated
and deprotonated states; 2) gas‐phase geometry optimization
of the lowest energy conformers for both states at the Density
Functional Theory (DFT) level using B3LYP/6 31G* func-
1
13
MHz for H and at 75.5 MHz for
C spectra).
HPLC‐DAD‐MS/MS (diode array detection, tandem mass
spectroscopy) experiments were performed on an Agilent
(Palo Alto, CA) 1200 HPLC system (G1379B degasser,
31,32
G1312B binary gradient pump, G1367C autosampler,
G1316B column thermostat and G1315C diode array
detector) coupled with an Agilent 6410 triple quadrupole
mass spectrometer equipped with an electrospray ionization
tional and basis sets
; 3) gas‐phase single point energy
calculation at the B3LYP/(aug) cc pVTZ level where
augmented basis sets are applied for protonation and depro-
tonation centers; 4) solvatation energy calculation of the
protonated and deprotonated states using implicit solvent
(ESI) ion source (Agilent Technologies, Waldbronn,
33,34
Germany). Masshunter B.03.01 software was used for data
acquisition and qualitative analyses. Elemental analyses were
performed on a Vario EL III instrument (Elementanalyze) in
the Microanalytical Laboratory of the Department of Organic
Chemistry, Institute for Chemistry, L. Eötvös University,
Budapest, Hungary. The packing of the HPLC column was
performed in Bio‐Sol‐Dex Ltd. (Budapest, Hungary).
Adsorbent (S,S)‐CSP‐12 was packed into a 150×4 mm stain-
less steel empty HPLC column using the slurry packing
method. The packing was performed by using a Haskel‐pump
at 500 bar. Chromatography was performed on a Hitachi
model (Poisson Boltzmann model,
water); 5) raw pKa
calculation and empirical correction. The two apparent pKa
values were estimated from the calculated four equilibrium
constants (K , K , K , K in Figure 3) using the relationship
A
B
C
D
3
5
described in the literature.
2
.5 | Spectrophotometric pK determination
in aqueous medium
a
The UV‐pH titrations were performed using the D‐PAS
technique attached to a Sirius‐T3 Instrument (Sirius Analyti-
cal, Forest Row, UK).
36,37
(Tokyo, Japan) HPLC system, involving an L‐2450UV‐
The pK values were calculated by
a
detector, an L‐2130 pump, an L‐2200 autosampler, and an
L‐2300 column oven. Isocratic elution was applied with
Sirius‐T3Refine software (Sirius Analytical). Spectropho-
tometry can be applied for a pK measurement provided that
a
solvent system of 1:4 mixture of CH CN / 25 mmol/L or
the compound has a chromophore in proximity to the ioniza-
tion center, and the absorbance changes sufficiently as a func-
tion of pH. All measurements were performed in solutions of
3
40 mmol/L ammonium acetate.
2
.3 | Determination of enantiomeric purity
Macrocyclization reaction of chiral pentaethylene glycol
ditosylate (S,S)‐29 and formamide 26 is an S 2 type reaction
N
that involves the total inversion of the configuration. In order
to prove this mechanism, the enantiomeric purity of the
crown ethers derived from ditosylate (S,S)‐29 [macrocycles
(
R,R)‐32, (R,R)‐20, (R,R)‐16 and (R,R)‐10] was studied by
HPLC. Chromatography was performed on a VWR Hitachi
FIGURE 3 Equilibrium constants and equations used during the QM
Elite (Tokyo, Japan) HPLC system, involving a Diode Array
a
pK calculations

4
NÉMETH ET AL.
0.15 M KCl under nitrogen atmosphere, from pH 2 to pH 12
3‐(triethoxysilyl)propylamine (1 equiv) and CH Cl (5 ml)
2
2
at t = 25.0 ± 0.5°C. Sample concentrations of 20–40 μM
were used for UV‐pH titration. The absorbance values in
the spectral region of 250–450 nm were used in the analysis;
were added to it, and the mixture was stirred for 10 min.
The precipitate was filtered and washed with CH Cl (2 × 8
2
2
mL). The filtrate and washings were combined, dried over
specific experimental conditions for the pK determination
MgSO and evaporated. The crude product [(S,S)‐13] was
a
4
can be found in the Supporting Information.
used for the preparation of (S,S)‐CSP‐12 without purification.
A mixture of crude product (S,S)‐13 (130 mg) and HPLC‐
quality spherical silica gel (Superspher Si 60, Cat. No.
2
.6 | Spectrophotometric pK determination
a
1
19609, Merck; mean particle size: 4 μm, 1.50 g) in toluene
in cosolvent (MeOH) –water mixtures
(30 mL) was heated with mechanical stirring under Ar at
reflux temperature for 24 h. After cooling the mixture to rt
the modified silica gel [(S,S)‐CSP‐12] was collected by filtra-
tion, washed successively with a 1:1 EtOH/toluene mixture
The cosolvent dissociation constants (p K values) of the
s
a
compounds were determined in various MeOH–water
mixtures between 40 and 72 w/w%. The same titration
protocol was performed as above. Each sample was
measured at least at three different MeOH–water ratios and
the average values are reported; specific experimental condi-
tions for the pKa determination can be found in the
Supporting Information.
(
3 × 15 mL), EtOH (15 mL), a 1:1 MeOH/CH Cl mixture
2 2
(
2 × 15 mL), CH Cl (3 × 15 mL), and dried at 80°C for
2 2
1
6 h. A sample of blank silica gel was dried in the same
way and it gave a combustion analysis of C, 0.27; H, 1.30;
N, 0.00. The combustion analysis of (S,S)‐CSP‐12 gave C,
3
.90; H, 1.93; N, 0.32. This result shows that each gram of
S,S)‐CSP‐12 contained 0.112 mmol (by C%) and 0.114
mmol (by N%) of chiral crown ether.
(
2
.7 | Potentiometric determination of partition
coefficients
Typically, 0.5–2.5 ml of 0.5–10 mM solutions of (S,S)‐8 were
2
.8.2 | General procedure for the synthesis of
carboxylic acids (S,S)‐8, (S,S)‐9, (R,R)‐10 and 11
see Scheme 2)
titrated under the same conditions as in pK determinations
a
but in the presence of various amounts of the partitioning
solvent, water‐saturated n‐octanol. The phase ratio applied
varied from 0.5 ml water – 0.5 ml n‐octanol to 1.0 ml water
(
Isatin derivative (S,S)‐14 (216 mg, 0.49 mmol) or (S,S)‐15
110 mg, 0.23 mmol) or (R,R)‐16 (52 mg, 0.108 mmol) or
7 (600 mg, 2.11 mmol) was heated in 2% aqueous
(
1
–
2.0 ml n‐octanol. From the n‐octanol‐containing titrations
the p K (the apparent ionization constant in the presence of
o
a
tetramethylammonium hydroxide (33 mL for (S,S)‐14, 16
ml for (S,S)‐15, 8 ml for (R,R)‐16, 80 ml for 17) for 4 h.
The reaction mixture was cooled to rt, the pH was adjusted
to 7 by 10% aqueous hydrochloric acid, and the aqueous
solution was extracted with CH Cl (4 × 35 mL for (S,S)‐8,
n‐octanol) and then logP values were estimated and refined
by a weighted nonlinear least‐squares procedure, where the
aqueous pK values (taken from aqueous titrations) were used
a
as unrefined contributions. Nine titrations at different phase
volume ratios were performed, and the respective average
logP values were calculated. The ion‐pair partitioning of
charged species was characterized, also from the titrations
of different phase ratios. The relevant relationships between
logP, pK , and p K , for mono‐ and multiprotic substances,
2
2
4
× 20 mL for (S,S)‐9, 4 × 15 mL for (R,R)‐10, 4 × 100
mL for 11). The combined organic phase was dried over
MgSO , filtered, and the solvent was evaporated. The crude
4
product was purified by PLC on silica gel using MeOH‐
CH Cl 1:6 mixture as eluent for (S,S)‐8 or MeOH‐CH Cl
a
o a
2
2
2
2
including cases of ion‐pair formation, have been described
38
1:10 mixture as eluent for (S,S)‐9 and (R,R)‐10 or MeOH‐
CH Cl 1:2 mixture as eluent for 11.
in detail earlier.
2
2
2
2
.8 | Synthesis of new compounds
(7S,15S)‐7,15‐Dimethyl‐6,7,9,10,12,13,15,16‐octahydro‐1,21‐
1,4,7,10,13,16
methanodibenzo[n,q]
3‐carboxylic acid [(S,S)‐8]
Yield: 42 mg (20%), yellow crystals; R = 0.28 (MeOH‐
pentaoxazacyclooctadecine‐
.8.1 | Procedure for the preparation of (S,S)‐
2
CSP‐12 (see Scheme 1)
f
25
Crown ether (S,S)‐8 (85 mg, 0.19 mmol), SOCl (5 mL) and a
CH Cl2 1:6); mp 236–238°C (decomposition); [α]D
=
2
2
catalytic amount of dimethylformamide (DMF) were
refluxed under Ar for 2 h. The solution was cooled to room
temperature (rt), the volatile compounds were evaporated,
toluene was added (2 × 20 mL), then evaporated from the
mixture. The crude product (100 mg) was dissolved in
+30.7 (c = 0.42 in MeOH); IR (KBr) νmax 3441 (br), 2981,
2923, 2879, 1603, 1570, 1472, 1425, 1385, 1327, 1276,
‐
1
1
1198, 1157, 1127, 1085, 1020, 967, 752 cm ; H‐NMR
(300 MHz, MeOH‐d ) δ 1.41 (d, J = 5.7 Hz, 6H, CH ),
4
3
3.58–3.83 (m, 8H, OCH ), 4.18–4.46 (m, 6H, OCH ), 7.09
2
2
CH Cl2 (10 mL) under Ar at rt and a solution of
(d, J = 7.5 Hz, 2H, Ar‐H), 7.40 (t, J = 8.1 Hz, 2H, Ar‐H),
2

NÉMETH ET AL.
5
1
3
+
7
.69 (d, J = 8.5 Hz, 2H, Ar‐H); C‐NMR (75.5 MHz,
(Ar‐C), 185.23 (Ar‐COOH); MS: 284.1 (M+H) ; Anal Calcd
MeOH‐d ) δ 14.47 (CH ), 64.18, 69.49, 70.24, 72.02
for C H NO : C 67.84, H 4.63, N 4.94. Found: C 67.58, H
4.95, N 5.03.
4
3
16 13
4
(
OCH, OCH ), 107.94, 118.96, 122.34, 125.41, 140.02,
2
1
+
47.93, 152.60 (Ar‐C), 173.04 (Ar‐COOH); MS: 442.1 (M
H) ; Anal Calcd for C H NO : C 65.29, H 6.16, N
24 27 7
+
2
.8.3 | General procedure for the synthesis of
3
.17. Found: C 65.45, H 6.19, N 3.20.
isatins (S,S)‐14, (S,S)‐15, (R,R)‐16 and 17 (see
Scheme 3)
(7S,18S)‐7,18‐Dimethyl‐6,7,9,10,12,13,15,16,18,19‐
1
,4,7,10,13,16,19
decahydro‐1,24‐methanodibenzo [q,t]
zacycloheneicosin‐26‐carboxylic acid [(S,S)‐9]
Yield: 45 mg (41%) yellow crystals; R = 0.7 (MeOH‐
CH Cl2 1:4); mp 200–203°C (from MeOH); [α]D
+
hexaoxa‐
To a solution of crown ether (S,S)‐18 (1.6 g, 4.14 mmol) or
(S,S)‐19 (1.55 g, 3.59 mmol) or (R,R)‐20 (1.89 g, 4.38 mmol)
39
or 2,2'‐dimethoxydiphenylamine 21 (1 g, 4.36 mmol) in
toluene (80 mL) was added oxalyl chloride (600 μL, 7 mmol)
dropwise under Ar at rt. The reaction mixture was stirred at
70°C for 3 h. After cooling the reaction mixture to rt the
solvent was removed to give acyl chloride (S,S)‐22 or (S,S)‐
23 or (R,R)‐24 or 25. Crude acyl chloride was dissolved in
bromobenzene (70 mL), and iodine (100 mg) was added to
the latter solution. The reaction mixture was stirred at reflux
temperature for 16 h (in the cases of (S,S)‐14, (S,S)‐15, (R,R)‐
16) or for 20 h (in the case of 17), then the solvent was
removed under reduced pressure (1 mmHg). The crude
product was purified by column chromatography on silica
gel using EtOAc‐toluene 1:1 mixture as an eluent to give
isatin (S,S)‐14 or (S,S)‐15 or (R,R)‐16 or 17.
f
25
=
2
30.1 (c = 1.07 in MeOH); IR (KBr) νmax 3425 (br), 2980,
919, 2877, 1620, 1601, 1570, 1472, 1424, 1388, 1326,
275, 1197, 1156, 1083, 966, 755 cm ; H‐NMR (300
2
1
‐
1
1
MHz, MeOH‐d ) δ 1.40 (d, J = 4.5 Hz, 6H, CH ), 3.40–
4
3
3.74 (m, 10H, OCH ), 3.77–3.88 (m, 2H, OCH ), 4.31–
2
2
4.46 (m, 6H, OCH ), 7.15 (br s, 2H, Ar‐H), 7.42 (t, J = 6.3
2
1
3
Hz, 2H, Ar‐H), 7.74 (d, J = 8.3 Hz, 2H, Ar‐H); C‐NMR
(75.5 MHz, MeOH‐d ) δ 16.33 (CH ), 66.75, 70.61, 71.18,
4
3
72.15, 74.15 (OCH, OCH ), 110.08, 120.50, 123.81,
2
127.03, 141.46, 149.48, 154.21 (Ar‐C), 174.42 (Ar‐COOH);
+
MS: 486.2 (M+H) ; Anal Calcd for C H NO : C 64.32, H
2
6
31
8
6.44, N 2.88. Found: C 64.51, H 6.61, N 2.92.
(
6R,19R)‐6,19‐Dimethyl‐6,7,9,10,12,13,15,16,18,19‐
(7S,15S)‐7,15‐Dimethyl‐6,7,9,10,12,13,15,16‐octahydro‐22H‐
1,4,7,10,13,16,19
1,4,7,10,13,16
decahydro‐1,24‐methanodibenzo [q,t]
cycloheneicosin‐26‐carboxylic acid [(R,R)‐10]
Yield: 30 mg (58%) yellow crystals; R = 0.71 (MeOH‐
hexaoxaza‐
1,22‐ethanodibenzo [n,q]
23,24‐dion [(S,S)‐14]
pentaoxazacyclooctadecine‐
Yield: 216 mg (12%), red crystals; R = 0.45 (EtOAc‐toluene
f
f
2
5
25
CH Cl 1:4); mp 255°C (decomposition); [α]
= –21.03
1:1), mp 165–170°C (from EtOAc); [α]D = –44.5 (c = 0.12
2
2
D
(
2
1
c = 1.07 in MeOH); IR (KBr) νmax 3441 (br), 2973, 2919,
in MeOH); IR (KBr) νmax 3078, 3054, 3029, 2966, 2931,
2910, 2876, 2821, 1745, 1732, 1614, 1598, 1506, 1498,
1446, 1368, 1311, 1287, 1246, 1109, 1102, 1021, 1003,
873, 1617, 1603, 1567, 1471, 1423, 1386, 1323, 1275,
‐
1
1
196, 1153, 1083, 958, 753, 463 cm ; H‐NMR (300
‐
1
1
MHz, MeOH‐d ) δ 1.56 (d, J = 6.1 Hz, 6H, CH ), 3.65–
3
942, 832, 778, 757, 726, 694, 626 cm ; H‐NMR (300
MHz, CDCl ) δ 0.82 (d, J = 6.2 Hz, 3H, CH ), 1.07 (d, J
4
3
.80 (m, 10H, OCH ), 3.82–3.85 (m, 2H, OCH ), 3.87–
2
2
3
3
3
.96 (m, 2H, OCH ), 4.05–4.17 (m, 2H, OCH ), 4.96–5.07
= 6.2 Hz, 3H, CH ), 3.12–3.24 (m, 1H, OCH ), 3.31–3.75
2
2
3
2
(
=
m, 2H, OCH ), 7.18 (d, J = 7.4 Hz, 2H, Ar‐H), 7.45 (t, J
8.1 Hz, 2H, Ar‐H), 7.79 (d, J = 8.6 Hz, 2H, Ar‐H); C‐
(m, 10H, OCH ), 3.78–3.95 (m, 2H, OCH ), 4.20–4.29 (m,
2
2
2
13
1H, OCH ), 6,97–7.23 (m, 4H, Ar‐H), 7.26–7.42 (m, 3H,
2
3
1
NMR (75.5 MHz, MeOH‐d ) δ 16.02 (CH ), 70.81, 71.16,
Ar‐H); C‐NMR (75.5 MHz, CDCl ) δ 17.20, 17.81
4
3
3
7
1.82, 74.02, 74.83 (OCH, OCH ), 111.92, 120.88, 124.12,
(CH ), 69.24, 69.58, 71.81, 71.84, 73.56, 73.60, 74.69,
2
3
1
26.88, 142.25, 149.97, 152.95 (Ar‐C), 174.53 (Ar‐COOH);
74.81 (OCH, OCH ), 113.26, 117.58, 118.94, 120.50,
2
+
MS: 486.2 (M+H) ; Anal Calcd for C H NO : C 64.32, H
6
123.93, 124.31, 125.04, 129.03, 129.86, 140.46, 145.77,
2
6
31
8
+
.44, N 2.88. Found: C 64.54, H 6.67, N 2.94.
155.07 (Ar‐C), 158.37, 183.44 (C=O); MS: 442.2 (M+H) ;
Anal Calcd for C H NO : C 65.29, H 6.16, N 3.17. Found:
24
27
7
4
,5‐Dimethoxyacridine‐9‐carboxylic acid (11)
C 65.47, H 6.31, N 3.29.
Yield: 125 mg (21%) pale yellow crystals; R = 0.79 (MeOH‐
f
CH Cl 1:1); mp >350°C; IR (KBr) ν
3425 (br), 3068,
(7S,18S)‐7,18‐Dimethyl‐6,7,9,10,12,13,15,16,18,19‐
decahydro‐25H‐1,25‐ethanodibenzo[q,t]
2
2
max
1
,4,7,10,13,16,19
3002, 2970, 2940, 2839, 1627, 1595, 1499, 1462, 1390,
1
326, 1271, 1210, 1159, 1086, 1019, 980, 744, 608, 513
hexaoxazacycloheneicosin‐26,27‐dion [(S,S)‐15]
‐
1
1
cm ; H‐NMR (300 MHz, D O) δ 4.04 (s, 6H, OCH ),
Yield: 240 mg (14%), red oil; R = 0.46 (EtOAc‐toluene 1:1);
2
3
f
25
7.17 (t, J = 4.3 Hz, 2H, Ar‐H), 7.53 (d, J = 4.3 Hz, 4H,
[α]D = –83.1 (c = 0.91 in CHCl ); IR (neat) ν
3058,
3
max
13
Ar‐H); C‐NMR (75.5 MHz, D O) δ 55.73 (OCH ),
3033, 3005, 2967, 2928, 2870, 1782, 1734, 1685, 1610,
2
3
107.75, 117.47, 121.98, 127.14, 129.48, 140.12, 154.24,
1600, 1498, 1446, 1363, 1280, 1267, 1241, 1109, 1027,

6
NÉMETH ET AL.
‐
1 1
7
6
3
3
(
3
51, 694 cm ; H‐NMR (300 MHz, CDCl ) δ 0.75 (d, J =
3.81 g, 7.20 mmol] or pentaethylene glycol ditosylate [(S,
S)‐28, 4.14 g, 7.20 mmol or (S,S)‐29, 4.14 g, 7.20 mmol]
3
40
.2 Hz, 3H, CH ), 1.13 (d, J = 6.3 Hz, 3H, CH ), 3.12–
.19 (m, 1H, OCH ), 3.27–3.68 (m, 14H, OCH ), 3.71–
.76 (m, 1H, OCH ), 3.85–4.02 (m, 1H, OCH ), 4.04–4.19
3
3
and K CO (7.62 g, 55 mmol) in acetonitrile (150 mL) was
2
2
2
3
vigorously stirred under Ar at 50°C for 7 days. The reaction
mixture was cooled to rt and the solvent was removed. The
residue was taken up in water (400 mL) and CH Cl (300
2
2
m, 1H, OCH ), 6.95–7.18 (m, 4H, Ar‐H), 7.24–7.38 (m,
2
1
3
H, Ar‐H); C‐NMR (75.5 MHz, CDCl ) δ 17.46, 17.72
3
2
2
(
CH ), 69.18, 69.27, 70.62, 70.98, 71.05, 71.07, 71.11,
mL). The phases were shaken well and separated. The aque-
ous phase was extracted with CH Cl (4 × 150 mL). The
combined organic phase was washed with saturated brine
3
7
1
1
(
2
3.33, 74.23, 74.65 (OCH, OCH ), 112.42, 117.49, 118.83,
2
2
2
20.54, 123.80, 124.36, 124.81, 129.06, 129.89, 140.51,
45.69, 154.70 (Ar‐C), 158.39, 183.32 (C=O); MS: 486.2
(150 mL), dried over MgSO , filtered, and the solvent was
4
+
M+H) ; Anal Calcd for C H NO : C 64.32, H 6.44, N
evaporated. The crude product was purified by column chro-
matography on silica gel using EtOAc‐toluene 1:2 mixture as
an eluent to give (S,S)‐30 or (S,S)‐31 or (R,R)‐32.
2
6
31
8
.88. Found: C 64.58, H 6.61, N 3.01.
(
2
6R,19R)‐6,19‐Dimethyl‐6,7,9,10,12,13,15,16,18,19‐decahydro‐
5H‐1,25‐ethanodibenzo[q,t]
1
,4,7,10,13,16,19
(7S,15S)‐7,15‐Dimethyl‐6,7,9,10,12,13,15,16‐octahydro‐22H‐
1,4,7,10,13,16
hexaoxazacycloheneicosin‐26,27‐dion [(R,R)‐16]
dibenzo[n,q]
carbaldehyde [(S,S)‐30]
Yield: 1.95 g (72%), gray oil; R = 0.3 (EtOAc‐toluene 1:1);
pentaoxazacyclooctadecine‐22‐
Yield: 320 mg (15%), red oil; R = 0.18 (EtOAc‐toluene 1:1);
f
2
5
[
α]D = +10.05 (c = 1.10 in MeOH); IR (KBr) νmax 3073,
f
25
3
1
6
031, 2970, 2930, 2871, 1735, 1613, 1601, 1504, 1448,
[α]D = –186.1 (c = 0.69 in CHCl ); IR (neat) ν
3067,
3
max
367, 1309, 1282, 1243, 1195, 1113, 1046, 1005, 756, 695,
3030, 3016, 2972, 2947, 2921, 2887, 2866, 1686, 1596,
‐
1 1
26, 438 cm ; H‐NMR (300 MHz, MeOH‐d ) δ 0.86 (d, J
1501, 1454, 1331, 1272, 1248, 1103, 1028, 958, 815, 749,
4
‐
1 1
=
6.2 Hz, 3H, CH ), 1.21 (d, J = 6.2 Hz, 3H, CH ), 3.04–
671, 607 cm ; H‐NMR (300 MHz, CDCl ) δ 1.00 (d, J =
3
3
3
3
.16 (m, 2H, OCH ), 3.37–3.61 (m, 12H, OCH ), 3.63–
5.9 Hz, 3H, CH ), 1.12 (d, J = 5.5 Hz, 3H, CH ), 3.52–
2
2
3
3
3
.76 (m, 2H, OCH ), 4.37–4.50 (m, 1H, OCH ), 4.52–4.65
3.79 (m, 10H, OCH ), 3.90–4.13 (m, 4H, OCH ), 6.88–
2
2
2
2
(
m, 1H, OCH ), 6,95‐7.21 (m, 4H, Ar‐H), 7,23‐7.52 (m,
7.02 (m, 4H, Ar‐H), 7.03–7.12 (m, 1H, Ar‐H), 7.13–7.33
(m, 3H, Ar‐H), 8.54 (s, 1H, CHO); C‐NMR (75.5 MHz,
2
3
1
13
3
1
7
1
1
4
6
H, Ar‐H); C‐NMR (75.5 MHz, MeOH‐d ) δ 16.94,
4
7.07 (CH ), 71.60, 71.64, 71.76, 71.88, 71.93, 71.98,
CDCl ) δ 18.10, 18.14 (CH ), 68.10, 68.17, 72.26, 72.58,
3
3
3
5.36, 75.60, 75.90, 75.94 (OCH, OCH ), 115.24, 118.17,
72.64, 72.74, 73.89, 74.12 (OCH, OCH ), 113.47, 113.76,
2
2
20.80, 121.47, 125.79, 126.86, 127.59, 131.11, 131.22,
120.78, 120.98, 126.95, 127.92, 128.64, 128.65, 128.98,
42.46, 146.38, 155.71 (Ar‐C), 160.55, 184.74 (C=O); MS:
130.93, 153.44, 154.08 (Ar‐C), 163.22 (CHO); MS: 416.2
+
+
86.2 (M+H) ; Anal Calcd for C H NO : C 64.32, H
(M+H) ; Anal Calcd for C H NO : C 66.49, H 7.04, N
2
6
31
8
23 29
6
.44, N 2.88. Found: C 64.56, H 6.63, N 2.99.
3.37. Found: C 66.62, H 7.15, N 3.42.
7
‐Methoxy‐1‐(2‐methoxyphenyl)indoline‐2,3‐dione (17)
(7S,18S)‐7,18‐Dimethyl‐6,7,9,10,12,13,15,16,18,19‐decahydro‐
1,4,7,10,13,16,19
Yield: 185 mg (15%), red crystals; R = 0.8 (EtOAc‐toluene
25H‐dibenzo[q,t]
carbaldehyde [(S,S)‐31]
hexaoxazacycloheneicosin‐25‐
f
1
2
1
:1); mp 177–180°C; IR (KBr) νmax 3068, 3011, 2953,
915, 2849, 1730, 1677, 1597, 1498, 1458, 1365, 1264,
Yield: 1.98 g (66%), pale brown crystals; R = 0.2 (EtOAc‐
f
25
‐1
1
239, 1022, 877, 754, 721, 692, 617, 597, 436 cm ; H‐
toluene 1:1), mp 76°C (from EtOAc); [α]D = –40.2 (c =
NMR (300 MHz, CDCl ) δ 3.51 (s, 3H, OCH ), 3.58 (s,
0.84 in MeOH); IR (KBr) νmax 3065, 3035, 3009, 2971,
3
3
3
H, OCH ), 6,91‐7.15 (m, 4H, Ar‐H), 7,27‐7.43 (m, 3H,
2929, 2871, 1685, 1595, 1501, 1453, 1372, 1274, 1236,
3
3
1
‐1
1
Ar‐H); C‐NMR (75.5 MHz, CDCl ) δ 55.73, 56.55
1124, 1103, 1031, 764, 754, 669 cm ; H‐NMR (300
MHz, CDCl ) δ 1.05 (s, 3H, CH ), 1.16 (s, 3H, CH ),
3
(OCH ), 111.29, 117.63, 119.04, 120.34, 122.90, 124.36,
3
3
3
3
1
1
24.54, 129.09, 129.94, 140.62, 146.51, 155.42 (Ar‐C),
58.36, 183.44 (C=O); MS: 284.1 (M+H) ; Anal Calcd for
3.52–3.64 (m, 12H, OCH ), 3.65–3.79 (m, 2H, OCH ),
2
2
+
3.81–3.92 (m, 2H, OCH ), 3.95–4.14 (m, 2H, OCH ),
2
2
C H NO : C 67.84, H 4.63, N 4.94. Found: C 68.01, H
6.85–7.02 (m, 4H, Ar‐H), 7.05–7.13 (m, 1H, Ar‐H), 7.15–
13
1
6
13
4
4.88, N 4.85.
7.36 (m, 3H, Ar‐H), 8.63 (s, 1H, CHO); C‐NMR (75.5
MHz, CDCl ) δ 17.51, 17.67 (CH ), 69.03, 69.12, 70.93,
3
3
7
1.02, 71.06, 71.19, 72.75, 72.91, 74.31, 74.44 (OCH,
2
.8.4 | General procedure for the synthesis of
carbaldehydes (S,S)‐30, (S,S)‐31 and (R,R)‐32
see Scheme 4)
OCH ), 113.39, 113.43, 120.98, 121.08, 126.97, 127.68,
2
1
1
28.75, 128.89, 129.39, 131.13, 153.26, 154.17 (Ar‐C),
(
+
63.79 (CHO); MS: 460.2 (M+H) ; Anal Calcd for
17
A mixture of N,N‐bis(2‐hydroxyphenyl)‐formamide (26,
.5 g, 6.5 mmol), tetraethylene glycol ditosylate [(S,S)‐27,
C H NO : C 65.34, H 7.24, N 3.05. Found: C 65.45, H
25 33 7
7.50, N, 3.18.
19
1

NÉMETH ET AL.
7
(
2
6R,19R)‐6,19‐Dimethyl‐6,7,9,10,12,13,15,16,18,19‐decahydro‐
(7S,15S)‐7,15‐Dimethyl‐6,7,9,10,12,13,15,16‐octahydro‐22H‐
1,4,7,10,13,16
1
,4,7,10,13,16,19
5H‐dibenzo[q,t]
hexaoxazacycloheneicosin‐25‐
dibenzo [n,q]
pentaoxazacyclooctadecine [(S,S)‐18]
carbaldehyde [(R,R)‐32]
Yield: 2.03 g (67%), pale brown crystals; R = 0.2 (EtOAc‐
Yield: 1,63 g (82%), pale brown oil; R = 0.61 (EtOAc‐tolu-
ene 1:1); [α]D = +29.9 (c = 0.76 in MeOH); IR (neat) νmax
f
25
f
2
5
toluene 1:1), mp 72°C (from EtOAc); [α]D = –159.29 (c
0.99 in MeOH); IR (KBr) νmax 3078, 3054, 3029, 2966,
3395, 3080, 3042, 3015, 2969, 2917, 2867, 1600, 1586,
‐
1
=
1522, 1496, 1454, 1373, 1334, 1241, 1115, 831, 736 cm ;
1
2
1
1
931, 2910, 2876, 2821, 1745, 1732, 1614, 1598, 1506,
498, 1446, 1368, 1311, 1287, 1246, 1109, 1102, 1021,
003, 942, 832, 778, 757, 726, 694, 626 cm ; H‐NMR
H‐NMR (300 MHz, CDCl ) δ 1.27 (d, J = 5.1 Hz, 6H,
3
CH ), 3.63–3.87 (m, 8H, OCH ), 3.93–4.12 (m, 6H,
3
2
‐
1 1
OCH ), 6.79–6.95 (m, 6H, Ar‐H), 7.38 (d, J = 6.7 Hz, 2H,
2
13
(
300 MHz, MeOH‐d ) δ 1.29 (d, J = 6.2 Hz, 3H, CH ),
Ar‐H); C‐NMR (75.5 MHz, CDCl ) δ 16.70 (CH ),
4
3
3
3
1
3
3
4
7
.35 (d, J = 6.3 Hz, 3H, CH ), 3.32–3.41 (m, 1H, OCH ),
69.24, 71.06, 72.82, 74.33 (OCH, OCH ), 111.92, 116.12,
120.16, 120.86, 132.97, 148.65 (Ar‐C); MS: 388.2 (M+H) ;
3
2
2
+
.43–3.45 (m, 1H, OCH ), 3.47–3.63 (m, 12H, OCH ),
2
2
.65–3.72 (m, 2H, OCH ), 4.62–4.72 (m, 1H, OCH ),
Anal Calcd for C H NO : C 68.20, H 7.54, N 3.61. Found:
2
2
22 29
5
.77–4.84 (m, 1H, OCH ), 6.90–7.05 (m, 2H, Ar‐H), 7.13–
C 68.35, H 7.66, N 3.75.
2
.24 (m, 2H, Ar‐H), 7.25–7.40 (m, 4H, Ar‐H), 8.62 (s, 1H,
13
CHO); C‐NMR (MeOH‐d , 75.5 MHz) δ 16.66, 17.40
(7S,18S)‐7,18‐Dimethyl‐6,7,9,10,12,13,15,16,18,19‐decahydro‐
1,4,7,10,13,16,19
4
(CH ), 71.42, 71.56, 71.74, 71.77, 71.87, 72.35, 75.09,
25H‐dibenzo[q,t]
19]
hexaoxazacycloheneicosin [(S,S)‐
3
7
1
1
5.16, 75.31, 75.38 (OCH, OCH ), 115.93, 116.18, 121.85,
22.00, 129.55, 129.67, 130.16, 131.30, 131.33, 132.78,
54.90, 154.97 (Ar‐C), 167.11 (CHO); MS: 460.2 (M+H) ;
2
Yield: 1,65 g (89%), pale brown oil; R = 0.48 (EtOAc‐tolu-
f
+
25
ene 1:1); [α]D = –3.5 (c = 0.57 in MeOH); IR (neat) νmax
Anal Calcd for C H NO : C 65.34, H 7.24, N 3.05. Found:
3418, 3057, 3031, 3004, 2971, 2929, 2868, 1601, 1588,
25
33
7
C 65.39, H 7.38, N 3.12.
1513, 1496, 1460, 1435, 1349, 1242, 1115, 1032, 833, 737
‐
1 1
cm ; H‐NMR (300 MHz, MeOH‐d ) δ 1.25 (d, J = 3.8
4
Hz, 6H, CH ), 3.50–3.76 (m, 12H, OCH ), 4.48 (broad s,
3
2
6
H, OCH ), 6.75–6.98 (m, 6H, Ar‐H), 7.27 (dd, J = 6.8
2
o
2
.8.5 | General procedure for the synthesis of
13
Hz, Jm = 2.3 Hz, 2H, Ar‐H); C‐NMR (75.5 MHz,
MeOH‐d ) δ 17.97 (CH ), 70.03, 71.84, 72.43, 73.56,
7
134.24, 149.83 (Ar‐C); MS: 432.3 (M+H) ; Anal Calcd for
C H NO : C 66.80, H 7.71, N 3.25. Found: C 66.98, H
amines (S,S)‐18, (S,S)‐19 and (R,R)‐20 (see
4
3
Scheme 4)
5.72 (OCH, OCH ), 113.40, 117.01, 121.59, 122.17,
2
+
To a solution of N‐formyl‐crown ether (S,S)‐30 (2.14 g, 5.18
mmol) or (S,S)‐31 (1.98 g, 4.31 mmol) or (R,R)‐32 (2.0 g,
24
33
6
4.36 mmol) in MeOH (60 mL) was added 30% aqueous
7.87, N 3.30.
hydrochloric acid (3.5 mL, 32.67 mmol) and the resulting
reaction mixture was stirred at 50°C for 24 h. The reaction
mixture was cooled to rt and water (50 mL) was added. The
pH was adjusted to 7 by aqueous KOH solution (10%). The
aqueous solution was extracted with EtOAc (1 × 200 mL,
then 3 × 100 mL). The combined organic phase was shaken
(6R,19R)‐6,19‐Dimethyl‐6,7,9,10,12,13,15,16,18,19‐decahydro‐
1
,4,7,10,13,16,19
25H‐dibenzo[q,t]
[(R,R)‐20]
hexaoxazacycloheneicosin
Yield: 1,67 g (89%), pale brown oil; R = 0.43 (EtOAc‐tol-
f
25
uene 1:1); [α]D = –18.56 (c = 1.11 in MeOH); IR (KBr)
νmax 3078, 3054, 3029, 2966, 2931, 2910, 2876, 2821,
1745, 1732, 1614, 1598, 1506, 1498, 1446, 1368, 1311,
1287, 1246, 1109, 1102, 1021, 1003, 942, 832, 778, 757,
with water (100 mL), dried over MgSO , filtered, and the
4
solvent was removed. The crude product was purified by
column chromatography on silica gel using EtOAc‐toluene
‐
1
1
1:1 mixture as an eluent to give amine (S,S)‐18 or (S,S)‐19
726, 694, 626 cm ; H‐NMR (300 MHz, MeOH‐d ) δ
4
or (R,R)‐20.
1.25 (d, J = 6.1 Hz, 6H, CH ), 3.49–3.62 (m, 8H,
3
SCHEME 1 Preparation of the new chiral stationary phase

8
NÉMETH ET AL.
OCH ), 3.65–3.77 (m, 8H, OCH2), 4.43–4,58 (m, 2H,
0°C then extracted with ether (1 × 400, 3 × 200 mL).
The combined organic phase was shaken with 3% aqueous
HCl (1 × 150 mL), distilled water (1 × 500 mL), and sat-
2
OCH ), 6.72–6.90 (m, 4H, Ar‐H), 6.96 (d, J = 7.3 Hz,
2
1
3
2
H, Ar‐H), 7.23 (d, J = 7.5 Hz, 2H, Ar‐H); C‐NMR
(
75.5 MHz, MeOH‐d ) δ 17.10 (CH ), 71.85, 72.04,
urated brine (2 × 300 mL), then dried over MgSO and fil-
4
3
4
7
1
2.19, 75.57, 76.10 (OCH, OCH ), 116.54, 117.56,
21.52,122.71,135.70,148.58(Ar‐C);MS:432.2(M+H) ;Anal
tered, and the solvent evaporated. The crude product was
purified by column chromatography on silica gel using
EtOAc‐hexane 2:3 as an eluent to give (S,S)‐29 (9.9 g, 70%)
as a colorless oil.
2
+
Calcd for C H NO : C 66.80, H 7.71, N 3.25. Found: C
6
24
33
6
6.95, H 7.88, N 3.31.
25
R = 0.76 (EtOAc); [α]D = –4.3 (c = 0.7; CHCl ); IR
f
3
(
1
6
neat) νmax 2999, 2944, 2872, 1597, 1491, 1448, 1357,
2.8.6 | [(2S,15S)‐4,7,10,13‐tetraoxahexadeca‐
2,15‐diyl]‐ditosylate (S,S)‐29 (see Scheme 5)
302, 1291, 1187, 1170, 1149, 1092, 1015, 983, 811, 795,
‐
1 1
64, 572, 548, 447 cm ; H‐NMR (300 MHz, CDCl ) δ
3
To
a
stirred
solution
of
(2S,15S)‐4,7,10,13‐
1.27 (d, J = 6.4 Hz, 6H, CH ), 2.44 (s, 6H, CH ), 3.41–
3
3
4
1
tetraoxahexadecane‐2,15‐diol [(S,S)‐33,
mmol] in pyridine (80 mL) at 0°C and under Ar was added
tosyl chloride (10.87 g, 57 mmol) dissolved in pyridine
6.6 g, 24.78
3.68 (m, 16H, OCH ), 4.63–4.77 (m, 2H, OCH ), 7.33 (d, J
2
2
13
= 7.9 Hz, 4H, Ar‐H), 7.80 (d, J = 8.1 Hz, 4H, Ar‐H); C‐
NMR (75.5 MHz, CDCl ) δ 17.64 (CH ), 21.65 (Ar‐CH ),
3
3
3
(
160 mL). The reaction mixture was stirred at 0°C for 10
70.47, 70.64, 70.84, 73.43, 78.13 (OCH, OCH ), 127.86,
129.72, 134.34, 144.52 (Ar‐C); MS: 575.2 (M+H) ; Anal
2
+
min, and at room temperature for 3 days, then it was
poured into ice‐water (500 mL). This stirred mixture was
made weakly acidic (pH=3) with 37% aqueous HCl at
Calcd for C H O S : C 54.34, H 6.67, S 11.16. Found:
26 38 10 2
C 54.65, H 6.93, S 11.27.
SCHEME 2 Synthesis of acridino‐carboxylic acids (S,S)‐8, (S,S)‐9,
(R,R)‐10 and 11
SCHEME 4 Macrocyclization and deformylation reactions
SCHEME 3 Synthesis of isatin
derivatives (S,S)‐14, (S,S)‐15, (R,R)‐16 and
1
7

NÉMETH ET AL.
9
1
7
3
3
| RESULTS AND DISCUSSION
.1 | Synthesis
Macrocyclization of formamide 26 and ditosylate (S,S)‐
19 40
2
7, (S,S)‐28 and (S,S)‐29 was performed in the presence
of potassium carbonate in acetonitrile. Removal of the formyl
protecting group from the resulting carbaldehydes (S,S)‐30,
The new chiral stationary phase [(S,S)‐CSP‐12] was prepared
from carboxylic acid (S,S)‐8. The latter carboxylic acid was
first reacted with thionyl chloride and a catalytic amount of
dimethylformamide. The resulting acid chloride, due to its
unstable nature, was then reacted with 3‐(triethoxysilyl)
propylamine. Crown ether (S,S)‐13 was heated without
purification with spherical HPLC‐quality silica gel in toluene
to obtain (S,S)‐CSP‐12 (Scheme 1). This method was faster
and it gave better yield then the procedure reported by us
previously for the preparation of dimethyl‐substituted
(
S,S)‐31 and (R,R)‐32 gave macrocycles (S,S)‐18, (S,S)‐19
and (R,R)‐20 (Scheme 4). Tetraethylene glycol ditosylate
S,S)‐27 and pentaethylene glycol ditosylate (S,S)‐28 were
(
19,40
obtained as described in the literature.
Chiral pentaethylene glycol ditosylate (S,S)‐29 was
41
prepared from diol (S,S)‐33 using tosyl chloride (TsCl) in
pyridine as a base and a solvent (see Scheme 5).
3
.2 | UV‐pH titration experiments
2
2,23
acridino‐18‐crown‐6 ether‐based CSPs.
The new acridino‐18‐crown‐6 and acridino‐21‐crown‐7
ether carboxylic acids [(S,S)‐8, (S,S)‐9, (R,R)‐10] were pre-
pared from chiral isatins (S,S)‐14, (S,S)‐15 and (R,R)‐16
using aqueous tetramethylammonium hydroxide applying
similar conditions as reported for the preparation of analo-
The basic nitrogen atom of the acridine subunit has an impor-
tant role in the formation of the tripod‐like hydrogen bond
with organic ammonium salts, and thus in the enantiomeric
recognition. In this regard the determination of the pK values
a
of these compounds can help to better understand the
1
7,22
gous acridino‐18‐crown‐6 ethers.
The dimethoxy‐
complexation process. The pK values of the newly synthe-
a
substituted acridino‐carboxylic acid 11 has also been
prepared in a similar way (Scheme 2).
sized acridino‐crown ethers [(S,S)‐8, (S,S)‐9, (R,R)‐10] and
22
of a recently reported analogous compound [(R,R)‐2] have
been determined by the UV‐pH titration method (Table 1).
The new isatin derivatives (S,S)‐14, (S,S)‐15, (R,R)‐16
and 17 were synthesized as shown in Schemes 3 and 4. Acyl-
ation of the secondary amino group of (S,S)‐18, (S,S)‐19,
42
In addition, the formerly reported pK values of 9‐acridine
a
carboxylic acid (34) (Figure 4) and the pK values of 11 and
a
39
(
R,R)‐20 and 21 with oxalyl chloride in toluene, followed
34 measured by our methods were also used as reference
points. The pH‐dependent absorbance spectra of the appropri-
ate compounds and the distribution of molecular species as a
function of pH can be found in the Supporting Information.
First, UV‐pH titrations in aqueous media were performed,
by a Friedel‐Crafts type reaction in the presence of a catalytic
amount of iodine in bromobenzene, gave the appropriate
isatin derivatives (S,S)‐14, (S,S)‐15, (R,R)‐16 and 17, respec-
tively (Scheme 3). The low yields can be attributed to sterical
hindrance.
where only a single pK between 4.5 and 5.5 could be
a
FIGURE 4 Structure and formerly reported experimental pK
values of 9‐acridinecarboxylic acid (34)
a
SCHEME 5 Preparation of chiral pentaethylene glycol ditosylate (S,
S)‐27
4
2
TABLE 1 Experimental pK values of acridino‐carboxylic acid derivatives
a
Aqueous pK
a
values
s a
p K values in 65± 5 w/w% MeOH
Compounds
pKa,1
n.m.
n.m.
n.m.
n.m.
n.m.
n.m.
SD
—
—
—
—
—
—
pKa,2
4.82
4.67
4.53
4.98
4.58
5.42
SD
p
s
K
a,1
SD
n
3
5
3
3
3
6
p
s
K
a,2
SD
n
3
3
3
3
3
3
(R,R)‐2
(S,S)‐8
(S,S)‐9
(R,R)‐10
0.02
0.02
0.02
0.02
0.01
0.00
1.40
1.29
1.22
1.40
1.20
0.83
0.03
0.02
0.05
0.04
0.03
0.06
3.66
3.50
3.31
3.76
4.36
4.92
0.02
0.01
0.02
0.01
0.01
0.01
1
3
1
4
n.m.: not measurable; n: number of experiments.

1
0
NÉMETH ET AL.
obtained in all cases (Table 1). Although chemical intuition
suggested that these values corresponded to the basic centers
of the acridine subunits, in order to verify this suggestion,
~65 w/w% of MeOH was used as a cosolvent, two pKa values
could be detected (Table 1). The appearance of the second
proton‐dissociation step, from which the p K
values
a,1
s
prediction of the acidic and basic pKa values (cpK values,
between 0.8 and 1.4 could be calculated, indicates that the
a
Table 2) were accomplished using different software pack-
cosolvent increased the apparent pK values into the measur-
a
43
ages and prediction algorithms (Chemaxon/MarvinSketch,
able pH range of the pH‐metric method, suggesting that these
values are related to an acidic proton‐dissociation step. In the
case of the pKa,2 values, the decreasing p K values as a
4
4
28
ACDLabs/Percepta,
Schrödinger/Jaguar ). Surprisingly,
the pK values estimated for the crown ether compounds were
a
s a,2
confusing. While two predictors (Chemaxon/MarvinSketch
and ACDLabs/ACD Classic algorithm) suggested that all of
the investigated crown ethers were ordinary ampholytes
function of increasing MeOH ratio (Figure 5).clearly indicate
a basic proton‐dissociation step. Furthermore, the basic
character of this ionization process was also confirmed by
lipophilicity determination (recording the logD‐pH function)
in the case of the crown‐ether (S,S)‐8 by a pH‐metric method
independent of the psKa measurements. The shift towards
lower pHs in the Bjerrum plot (Figure 5) in the case of this
measurement indicates that the given dissociation step corre-
sponds to the basic center of the acridine subunit.
Taking all these pieces of information into account, we
can say that all the investigated compounds listed in
Table 2 have zwitterionic characters. Comparing the pKa
values of 34 to 11, the introduction of the two methoxy
groups to the acridine ring decreased both the acidic and
basic character of the molecule. As compared to 11, the four
(
pKa,1 > pK ), the other two predictors (ACDLabs/ACD
a,2
GALAS algorithm and Schrödinger/Jaguar) suggested that
they have zwitterionic characters (pKa,1 < pKa,2).
Even if the cpKa,2 values derived from the ACD GALAS
algorithm and from the empirically corrected quantum
mechanical (QM) calculations (Schrödinger/Jaguar) were
the closest to the experimentally determined aqueous pKa
values, it was still ambiguous to assign them to the basic
center; thus, we suggest that the investigated compounds
have a zwitterionic character.
In order to clarify this question, the UV‐pH titrations
were repeated in the presence of MeOH as cosolvent. When
TABLE 2 Calculated pK
a
values of acridino‐carboxylic acids
ACD Classic
MarvinSketch
ACD GALAS
Jaguar
Compounds
cpKa (COOH)
cpKa (N(Ar))
1.15
cpKa (COOH)
cpKa (N(Ar))
‐0.26
cpKa (COOH)
cpKa (N(Ar))
3.56
cpKa (COOH)
cpKa (N(Ar))
7.47
(R,R)‐2
(S,S)‐8
(S,S)‐9
(R,R)‐10
3.58
3.58
3.58
3.58
2.60
2.60
2.60
2.60
1.62
1.62
1.62
1.62
2.25
2.13
4.23
1.80
1.16
‐0.27
‐0.27
‐0.27
3.56
7.32
1.10
3.56
6.97
1.15
3.56
7.56
ordinary ampholytes
ordinary ampholytes
zwitterionic
zwitterionic
1
1
4
3.58
0.75
1.17
6.81
2.68
0.72
0.40
5.36
1.66
3.63
5.01
2.27
2.11
5.47
5.40
3
1.99
4
3
44
a
cpK values were calculated by MarvinSketch 15.1.19.0 (ChemAxon Ltd.), ACD/Percepta 14.0.0 (Build 2726), and within the Schrödinger program suite using Jaguar
v. 9.1 (see the details in the Materials and Methods section).
2
8
FIGURE 5
s
p Ka,2 shift of (S,S)‐8 in the presence of MeOH (left) and Bjerrum plot of lipophilicity measurement (right)

NÉMETH ET AL.
11
crown ethers show that both the size of the macroring and
the position of chiral centers slightly affect the basicity of
the acridine nitrogen. The position of the chiral centers has
an apparent effect: (R,R)‐2 and (R,R)‐10 have higher exper-
conformational flexibility of the crown ethers and to the
difficulty of appropriately assessing solvation energies in
the case of these molecules.
29
imental pK values than (S,S)‐8 and (S,S)‐9. Regarding the
a
3.3 | HPLC
structures, the higher pK values are most probably due to
a
a lower distance of the electron‐donating methyl groups to
the ionization center in (R,R)‐2 and (R,R)‐10. In contrast,
Optimal analysis times and effective resolutions were
achieved with the earlier‐mentioned eluents (see Apparatus
and Chromatography, above) and applying a flow rate of
1.0 mL/min at 25°C. For the determination of the elution
order of the enantiomers we used a mixture of the (R)‐
and (S)‐enantiomers at a ratio of 2:1. Our previous observa-
the effect of the size of the macroring on the pK values is
a
not this straightforward. While in the case of (R,R)‐2 and
(
R,R)‐10 crown ether pairs the increasing macroring size
increases the pK , in the case of (S,S)‐8 and (S,S)‐9 pair
a
14
the opposite is observed. With the assigned pK values at
tions, using CSPs containing pyridino‐ or acridino‐crown
17,22,23
a
hand it can be concluded that the ACD Classic algorithm
and the MarvinSketch plugin fail in the prediction of the
molecular character, while those taking more structural
parameters (to a different extent) into account (ACD
GALAS algorithm and Jaguar) at least predict these crown
ethers and acridine‐carboxylic acid derivatives to have
zwitterionic characters. In addition, the experimentally
ethers
as chiral selectors attached to a silica gel,
suggest that generally the heterochiral complexes [(S,S)‐
crown ether‐(R)‐ammonium salt or (R,R)‐crown ether‐(S)‐
ammonium salt] have higher stabilities than the homochiral
ones [(S,S)‐crown ether‐(S)‐ammonium salt or (R,R)‐crown
ether‐(R)‐ammonium salt]. This behavior was also supported
45,46
by XRD measurements.
Additionally, upon studying the
determined trends in pK values upon changing the position
of the chiral centers or the size of the macroring is correctly
reproduced by the empirically corrected QM‐based calcula-
enantiomeric recognition ability of the dimethyl‐substituted
sensor molecule (S,S)‐7 (Figure 1) an analog compound of
(S,S)‐CSP‐12, by the fluorescence spectroscopic method
we observed heterochiral preference toward the enantiomers
a
tions (Jaguar). The estimated pK values derived from this
a
19
method are still largely overestimated compared to the
experimental values. This is most probably due to the high
of PGME.
However, it was found for the studied compounds that the
(
R)‐enantiomer eluted with a shorter retention time than that
TABLE 3 Chromatographic data for the separation of the mixtures of
enantiomers of protonated primary aralkylamines on (S,S)‐CSP‐12
of its antipode, meaning a higher stability of homochiral
complexes compared to that of heterochiral complexes. This
unusual behavior may be explained by the position of the
chiral centers, by changing the position of the chiral center,
steric repulsion, one of the main factors which influences
the enantiomeric recognition processes, between the host
and guest molecules becomes less significant. Other second-
ary interactions such as H‐bonding and π–π interaction play
the key roles during the enantiomeric separation process. In
order to gain a deeper insight into the effect of secondary
Analytes
t (R) [min]
11.02
t (S) [min]
13.51
α
R
S
1
‐NEA
‐NEA
1.23
1.02
1.06
2.05
1.20
<0.2
0.34
<0.2
2
15.96
16.35
Br‐PEA
NO ‐PEA
9.47
10.05
2
7.62
7.84
Isocratic condition: 1:4 mixture of CH
case of 1‐NEA, 1:4 mixture of CH CN / 40 mmol/L ammonium acetate in the
cases of 2‐NEA, Br‐PEA and NO ‐PEA.
3
CN / 25 mmol/L ammonium acetate in the
3
2
FIGURE 6 Chromatograms of separations of mixtures of 1‐NEA enantiomers using (S,S)‐CSP‐12. Isocratic condition: 1:4 mixture of CH
3
CN / 25
mmol/L ammonium acetate (A), 1:4 mixture of CH CN / 40 mmol/L ammonium acetate (B) (flow rate: 1.0 mL/min)
3

1
2
NÉMETH ET AL.
interactions on enantiomeric recognition, our further aim is
the preparation and study by XRD measurements of the crys-
tal structure of the diastereomeric complexes formed by
enantiopure dimethyl‐substituted acridino‐18‐crown‐6 ether
sensor and selector molecules for protonated chiral primary
amines, amino acids, and their derivatives. These crown ether
derivatives can easily be attached to silica gel with covalent
bonds to produce new CSPs.
(
S,S)‐7 (Figure 1) (the parent compound of (S,S)‐CSP‐12)
and the enantiomers of 1‐(1‐naphthyl)ethylammonium per-
chlorate. The novel chiral stationary phase separated the
enantiomers of 1‐NEA with enantioseparation factor Rs
ACKNOWLEDGMENTS
Financial support from the National Research, Development
and Innovation Office, NKFIH (earlier OTKA) (NKFIH/
OTKA K112289), of the New Széchenyi Development Plan
(TÁMOP‐4.2.1/B‐09/1/KMR‐2010‐0002) are gratefully
acknowledged. The research was also supported by the
ÚNKP‐16‐3‐III. New National Excellence Program of the
Ministry of Human Capacities. The authors thank Róbert
Iványi (PhD) (www.cd‐screen.com) for technical assistance
in packing of the chiral HPLC column. The authors thank
Dr. Eszter Riethmüller for measuring and evaluating the
MS spectra.
1.20. A small degree of selectivity was observed toward the
enantiomers of 2‐NEA, Br‐PEA, and NO ‐PEA. (Table 3 and
2
Figure 6). In the cases of PEA, PGME, and kynurenine,
enantiomeric discrimination was not observed. The
enantioseparation factors of the new chiral stationary phase
(
S,S)‐CSP‐12 compared to the enantioseparation factors of
the reported acridino‐crown ether–based CSPs [(R,R)‐CSP‐
1
7,22,23
4, (R,R)‐CSP‐5, [(R,R)‐CSP‐6]
indicate worse separa-
tion and resolution factors for all of the studied analytes.
These observations also suggest that the position of the chiral
center is crucial for the degree of enantiomeric recognition.
Placing the methyl groups (Figure 1) further away from the
acridine moiety decreases the degree of selectivity. By
increasing the quantity of ammonium acetate in the eluent
system from 25 mmol/L to 40 mmol/L retention times also
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Additional Supporting Information may be found online in
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