A molecular receptor selective for zwitterionic alanine

Article abstract of DOI:10.1039/c6ob02237e

A molecular receptor has been synthesized joining an aza-crown ether with a chiral chromane which mimics the oxyanion hole of the enzymes. With this receptor an apolar host-guest complex with zwitterionic alanine has been achieved through the formation of up to seven H-bonds. This complex allows the extraction of aqueous alanine to a chloroform phase, while other natural amino acids are poorly extracted or are not extracted at all. Due to the chiral nature of the receptor, enantioselective extraction from the aqueous alanine solution to a chloroform phase takes place. X-Ray analysis combined with anisotropic effects, NOE and CD studies revealed the absolute configuration of both strong and weak complexes. Modelling studies also support the proposed structures. The presence of an oxyanion-hole motif in this structure was corroborated by X-ray diffraction studies.

Full text of DOI:10.1039/c6ob02237e

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Chem., 2016, DOI: 10.1039/C6OB02237E.
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A molecular receptor selective for zwitterionic alanine
Omayra H. Rubio,a Rachid Taouil,a Francisco M. Muñiz,b Laura M. Monleón,a Luis Simón Rubio,c
Francisca Sanzd and Joaquín R. Morána
Received 00th January 20xx,
Accepted 00th January 20xx
A molecular receptor has been synthesized joining an aza-crown ether with a chiral chromane which mimics the oxyanion
hole of the enzymes. With this receptor an apolar host-guest complex with zwitterionic alanine has been achieved through
the formation of up to seven H-bonds. This complex allows the extraction of aqueous alanine to a chloroform phase, while
other natural amino acids are poorly extracted or are not extracted at all. Due to the chiral nature of the receptor,
enantioselective extraction from the aqueous alanine solution to a chlorform phase takes place. X-Ray analysis combined
with anisotropic effects, NOE and CD studies revealed the absolute configuration of both strong and weak complexes.
Modelling studies also support the proposed structures. The presence of an oxyanion-hole motif in this structure was
corroborated by X-ray diffraction studies.
DOI: 10.1039/x0xx00000x
www.rsc.org/
recognition requires establishment of at least three non-
equivalent interactions between the two molecules involved.
In the case of zwitterionic amino acids, the carboxylate group
Introduction
Amino acids are scientifically and technically important
compounds. Despite being small molecules, they are essential
in nature as building blocks of biological molecules and as a
source for chirality and molecular recognition.1 They are also
attractive guests,2 since they are able to experience many H-
bonds due to the large functional group density they exhibit.
Natural amino acids in its zwitterionic state are highly polar
compounds. Hydrogen-bonds formation strongly stabilizes the
charges in the amino acid groups, yielding good water
solubility. On the contrary, they show a low solubility in
organic solvents, which lack H-bond donor abilities. Therefore,
the association of amino acids in a low polarity organic solvent
provides the first binding site.7 The recognition of the
ammonium function provides the second anchoring point to
the receptor. Crown ethers have been extensively used for
their ability to bind ammonium cations and many synthetic
receptors capable of associating amino acids in organic apolar
solvents incorporate such ethers combined with H-bond
donors.8,9 The third point may come from a steric interaction
due to the amino acid side chain.8a,8b,8m
In this paper,
a chromane fragment including different
substituents capable of forming H-bonds (figure 1) is linked
with an aza-18-crown-6 ether to provide a molecular receptor
is
a
challenging issue. Accordingly, most of the
1, which forms an oxyanion hole for the association of
enantioselective receptors for amino acids found in the
literature associate amino acid derivatives and not the natural
zwitterionic amino acid. Nevertheless, the literature shows
many ingenious receptors for amino acids in natural products
supramolecular chemistry3 and in water-soluble receptors.4
Our group has also been successful in the preparation of
several receptors for both zwitterionic amino acids and their
derivatives.5
zwitterionic amino acids and a small cavity suitable to be filled
with the methyl group of an alanine side chain.
Despite being a non-essential amino acid, alanine is of great
importance in the diet, since it can regulate the amount of
glucose10 in the blood.11 L-alanine supplements are used in
cases of hypoglycaemia to prevent the organism from suffering
low blood sugar or insuline shocksand. Alanine supplements in
the diet may also improve health.12
The three-point interaction model6 implies that chiral
a.Organic Chemistry Department, University of Salamanca, Plaza de los Caídos 1-5,
37008 Salamanca, Spain.
Results and discussion
b.Department of Organic Chemistry, Faculty of Chemical Sciences, University of
Concepción, Edmundo Larenas 129, PO Box 160-C, Concepción, Chile.
c. Engineering Chemistry Department, University of Salamanca, Plaza de los Caídos
1-5, 37008 Salamanca, Spain.
The structure of receptor
1 is shown in figure 1. Modelling
studies13 suggest the formation of four H-bonds with the
amino acid carboxylate group, while three more H-bonds
stabilize the ammonium group inside the aza-crown ether
cavity.
d.X-Ray Diffraction Service, University of Salamanca, Plaza de los Caídos 1-5; 37008
Salamanca, Spain.
† Electronic Supplementary Information (ESI) available: [NMR, IR and HMR spectra
, X-ray diffraction data and modelling studies are included. CCDC 1502523-
1502525]. See DOI: 10.1039/x0xx00000x
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scheme 1. The phenoxymalonate
3
obtained from the reaction
of these two compounds was then alkylated with
chloroisobutene. The olefin, compound , cyclizes with Eaton’s
reagent14 to provide the chromane skeleton
4
5.
Nitration, reduction and treatment of the resulting amine with
chlorophenyl isocyanate yield the crucial H-bond donors of the
urea moiety. Monohydrolysis of the malonate in compound
7
followed by coupling of the acid with 3-aminobenzyl alcohol
using the anhydride method yield a benzyl alcohol (compound
9
), which undergoes aminolysis with methylamine.
Figure 1. Structure of the associate of receptor 1 with zwitterionic alanine.
The preparation of receptor
1 was carried out from p-
chlorophenol and dimethyl chloromalonate as shown in
Scheme 1. Preparation of receptor 1 [a) Na/MeOH, 3-chloro-2-methyl-1-propene; b) MeSO3H, P2O5; c) HNO3, CH2Cl2; d) 1) Zn, AcOH, 2) p-chlorophenyl isocyanate, CH2Cl2; e) LiOH,
MeOH; f) DCC, (3-aminophenyl)methanol, CHCl3; g) MeNH2, MeOH; h) SOCl2; i) 1-aza-18-crown-6, CHCl3].
The resulting methylamide 10 experiences a significant change crystalize the free receptor 1. However, the purification of this
in the urea conformation, which can be detected in its 1H NMR compound can be easily achieved once dissolved in methanol
spectrum due to the strong shielding of the H-7 proton, which after the addition of L-alanine.
1
The H NMR spectrum of this mixture in deuterated methanol
moves from 7.51 ppm in the ester
9
to only 6.49 ppm in the
methylamide 10 (figure 2).
showed initially the splitting of the receptor
1 signals, due to
the formation of two diastereomeric complexes. After a few
minutes, the signals of both compounds disappeared due to its
precipitation and only the impurities could be detected. After
filtering, the crystals show a sharp melting point at 220°C.
OH
OH
Cl
Cl
NH
HN
N
N
H
H
O
H
NH
HN
O
O
1
HNMe
HNMe
Nevertheless, the H NMR spectrum in deuterated chloroform
O
H
O
O
7
O
7
O
reveals the presence of the two diastereomeric complexes in a
1/1 ratio. In the spectrum of this mixture, all eight NHs show
up as different signals, which we were able to assign with COSY
and ROESY spectra (see ESI).
Cl
Cl
Figure 2. Conformational equilibrium in the methylamide 10.
Crystallization from chloroform/methanol mixtures provided
crystals suitable for X-ray analysis (figure 3).
The benzyl alcohol, once transformed in the chloride with
thionyl chloride, can be linked with the aza-crown ether to
yield the expected receptor
1. It has not been possible to
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proposed structures, since this methyl group lies in the
shielding cone of the aminomethylphenyl fragment in the “l”
complex and is therefore shielded at 1.02 ppm, compared to
the weak absorption of this methyl group in the “u” complex at
1.27 ppm. The ROESY spectrum of the strong complex shows a
correlation of the alanine methyl group with one of the
aromatic protons of the aminomethylphenyl fragment,
showing the proximity of these groups in the associate.
Meanwhile, in the weak complex a similar correlation is
obtained between the alanine methyl group and the
methylamide.
(S) receptor 1–L-ala
(R) receptor 1–L-ala
Crystallization of the racemic receptor
1 with glycine provides
Figure 3. X ray structure of the quasi-racemate formed between racemic receptor 1 and
L-alanine.
again crystals with a very similar melting point (221°C). The
structure obtained by an X-ray analysis of these crystals is
shown in figure 5, is very similar to the “l” strong complex with
alanine. The H-bonds distances of 3.00 Å and 2.89 Å with the
NHs of the urea moiety, 3.20 Å with the NH of the benzylamide
and 2.80 Å with the NH of the methylamide are also similar in
the alanine strong complex.
The structure obtained in the X-ray study showed the presence
of both diastereomeric complexes in the crystal in a 1/1 ratio
forming a quasi-racemate in which both enantiomers of the
receptor
1 alternate. The (S) receptor 1 presents the L-alanine
methyl group in a cavity formed by the crown ether and the
aminophenylmethanol; on the other side, the (R) receptor
places the L-alanine methyl group close to the receptor
1
1
methylamine in an apparent exo position. A similar experiment
carried out with D,L-alanine yielded crystals with a similar
melting point (218°C), but in this case, the X-ray analysis
(figure 4) shows the presence of two enantiomeric complexes,
in which the (S) receptor
1 combines with L-alanine; while the
(R) receptor 1 combines with D-alanine forming “l” complexes.
Figure 5. X-ray structure of the complex between racemic receptor 1 and glycine.
Since the structure of the weak “u” complex is different, with
H-bonds distances of 2.87 Å and 2.96 Å with the NHs of the
urea moiety, 2.94 Å with the NH of the phenylamide and 3.02
Å with the NH of the methylamide, there are probably steric
interactions which reduce the stability of the “u” complex, due
to collision between the alanine methyl group and the
Figure 4. a) X-ray structure of the complex between racemic receptor 1 and racemic
alanine (only the complex between the (S) receptor 1 and L-ala is shown for simplicity);
b) space filling representation of receptor 1 showing the cavity generated for the
association of alanine.
methylamide. Therefore, the cavity of receptor
1 seems to be
ideally suited to host the alanine methyl group in the “l”
geometry.
The crystallization of these two enantiomeric “l” complexes
points to a certain degree of chiral discrimination, being the “l”
complex more stable than the “u” complex. Indeed, dissolution
of the previous crystals in deuterochloroform reveals the
presence of two different sets of signals in the 1H NMR
Amino acids with larger side chains are expected to undergo
steric hindrance in their complexes and therefore, they should
show a reduced stability. Attempts to crystallize receptor
1
with phenylalanine, leucine, valine and cysteine yielded only
oily compounds.
spectrum for both receptor
1 and alanine, due to a slow
breaking and forming complexes in the 1H NMR time scale.
These two sets of signals can be assigned to the two
diastereomeric “l” and “u” complexes, being the intensity of
the more stable “l” complex three times larger than that of the
corresponding “u” type (see ESI). The different absorptions of
the alanine methyl groups are in good agreement with the
Since it was not possible to crystallize a single enantiomer of
receptor
1
using amino acids as guests, we tried to resolve the
with preparative TLC using
racemic mixture of receptor
1
chromatographic plates impregnated with L-alanine. This
procedure has yielded good results for previous hosts.15 Even if
the surfaces of the “l” and “u” complexes of the racemic
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receptor
1 with L-alanine are very similar and, therefore, Washing again the chloroform solution with water five times
identical Rfs are expected, the fact that one complex is three allows the isolation of the oily free receptor
times more stable than the other should help the separation.
1 enantiomers.
The CD spectra of these compounds confirm both the
presence of two different enantiomers and their absolute
Indeed, the presence of the alanine in the TLC plates strongly
increases the Rf of receptor , when eluted with methylene
1
configuration. Figure
6
shows the good agreement
chloride/isopronanol mixtures, yielding finally two different
spots for the two diastereomeric complexes.
experimental CD spectra and the corresponding modeling
studies (see details in ESI section).
Scratching the silica of both spots and eluting it with a mixture
of CH2Cl2/isopropanol yielded in both cases the complexes of
receptor
1
with L-alanine.
(-)-R-receptor 1
(+)-S-receptor 1
Figure 6. Experimental CD spectra of receptor 1 enantiomers (above; solvent: CH2Cl2; concentration: 0.1 mg/mL) and the corresponding calculated spectra (bellow).
The fit of the alanine methyl group within the cavity of the “l” Polar amino acids like serine, aspartic acid, glutamic acid and
associate suggested a good selectivity for this amino acid. A tryptophan are not even extracted with receptor
1.
study was undertaken with aqueous saturated solutions of Nevertheless, more lipophilic amino acids like leucine (entry 1),
racemic alanine and other amino acids. Extraction with a 10-2M cysteine (entry 4), phenylalanine (entry 2) and valine (entry 3)
chloroform solution of racemic receptor
1
allowed a direct are also extracted to the chloroform solution in the presence
, although in all cases, there is a clear preference
assessment of the selectivity of the extraction, since the four of receptor
1
possible complexes can be detected in the solutions and for alanine despite the fact that this amino acid is less
proton integration of the 1H NMR spectra yielded the lipophilic than the previous ones.
corresponding concentrations (table 1).
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Table 1. Chiral recognition of receptor
1 (CDCl3, 20°C) and several amino acids
modelling studies, showing steric hindrance as the main source
for the receptor selectivity.
(Krel) and selectivity in the extraction of amino acids (CDCl3 / H2O, 20°C) compared to
alanine with receptor 1 (R1-Ksel) and with receptor 2 (R2-Ksel). The last column shows
the increased preference for the alanine complexation in the absence of the
1
lipophilicity of the amino acid
.
Experimental
Entry
Amino acid
Leucine
Krel
5.0
1.7
1.3
0.6
R1-Ksel
2.0
R2-Ksel
0.10
0.19
0.56
0.08
R1-Ksel/R2-Ksel
General experimental procedures
1
2
3
4
20
16
20
25
Solvents were purified by standard procedures and distilled
before use. Reagents and starting materials obtained from
commercial suppliers were used without further purification.
IR spectra were recorded as neat film or in nujol and
frequencies are given in cm−1. Melting points are given in °C.
NMR spectra were recorded on 200 MHz and 400 MHz
spectrometers. 1H NMR chemical shifts are reported in ppm
with tetramethylsilane (TMS) as an internal standard. Data for
1H are reported as follows: chemical shift (in ppm), number of
hydrogen atoms, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, quint = quintet, m = multiplet, br s = broad
singlet) and coupling constant (in Hz). Splitting patterns that
could not be clearly distinguished are designated as multiplets
(m). Data for 13C NMR are reported in ppm and hydrogen
multiplicity is included. High-resolution mass spectral analyses
(HRMS) were performed using ESI ionization and a quadrupole
TOF mass analyzer. Column chromatographies were
performed on 0.060-0.200 mm, 60 A silica gel.
Phenylalanine
Valine
3.0
11.0
2.0
Cysteine
To illustrate the large preference that the cavity of receptor
shows for alanine, an additional study was carried out with a
combination of 18-crown-6 ether and receptor (figure 7),
prepared from compound by treatment with methylamine. A
similar experiment as the previously described for receptor
1
2
7
1
under the same concentrations showed large preferences for
the extraction of the most apolar amino acid (table 1). No
chiral discriminations were detected with receptor
extraction of amino acids.
2 in the
Dimethyl 2-(4-chlorophenoxy)malonate (3). Commercial p-
clorofenol (200 g, 1.56 mol) was treated with a KOH solution
(103 g, 1.56 mol) in methanol (300 mL) and once it was all
solved, methanol was eliminated under reduced pressure. The
crude potassium salt thus obtained was solved in a mixture of
bis(2-methoxyethyl) ether (500 mL) and toluene (200 mL) and
the resulting mixture was distilled to remove water from the
medium. Then, dimethyl chloromalonate (260 g, 1.56 mol) was
added drop-wise from an addition funnel over the mixture
obtained after the distillation described. Once the addition
was completed, the reaction was worked up. Water and
hexane were added to the mixture, the phases were separated
and the organic one was steam distilled. The distillate was
then cooled in an ice bath and filtered to recover the
Figure 7. Structure of receptor 2 and the ternary complex formed with 18-crown- ether
and alanine.
precipitate formed, corresponding to compound
3 (300 g, 75%
yield), which can be purified by recrystallization with a
MeOH/CH2Cl2 mixture. Mp 75–80 °C; 1H NMR (200 MHz, CDCl3)
Conclusions
The racemic receptor
1 can be readily prepared from
δ
(ppm) 3.65 (6H, s), 5.19 (1H, s), 6.89 (2H, d, J = 9.0 Hz), 7.26
(2H, d, J = 9.0 Hz); 13C NMR (50 MHz, CDCl3)
commercially available starting materials, linking a chromane,
which acts as a multiple H-bond donor, with an aza-crown
ether, that provides a suitable cavity for an ammonium group.
This receptor shows an oxyanion hole observed in its X-ray
structure and the presence of a complementary surface with
alanine allowed the formation of an apolar host-guest complex
by H-bond interactions. Due to this preference for alanine, this
amino acid can be extracted exclusively from an aqueous
solution in the presence of polar natural amino acids and
selectively in the presence of lipophilic amino acids. Alanine
also provides an easy way to resolve the racemic receptor
mixture, making use of preparative TLCs impregnated in the
amino acid. The structure of both diastereomeric complexes
has been analysed by 1H NMR, circular dichroism and
δ
(ppm) 53.6
(2CH3), 77.0 (CH), 117.0 (2CH), 128.1 (C), 129.9 (2CH), 155.5
(C), 165.9 (2C); IR (film) 750, 826, 1005, 1113, 1215, 1445,
1486, 1584, 1768, 1742, 2949 cm-1; HRMS (ESI) Calcd for
C11H11O5NaCl 281.0187, found 281.0193 (M + Na)+.
Dimethyl 2-(4-chlorophenoxy)-2-(2-methylallyl)malonate (4).
Sodium methoxide was prepared first solving the sodium (6.7
g, 0.29 mol) in absolute methanol (150 mL). Then, compound
3
(75 g, 0.29 mol) and 3-chloro-2-methyl-1-propene (31.6 mL,
0.29 mol) were consecutively added to the reaction mixture
while it was heated in an oil bath at 80-90 °C. The resulting
mixture was heated under vigorous stirring for an hour and
then, it was cooled to room temperature, poured onto a 2M
aqueous solution of HCl and extracted with hexane. The
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organic phase was dried over anhydrous Na2SO4, filtered and remove the solid mass of Zn and the filtrate was poured onto
the solvent was eliminated under reduced pressure. iced water and filtered again to recover the white solid which
Compound
yellow oil. 1H NMR (200 MHz, CDCl3)
(2H, s), 3.75 (6H, s), 4.80 (1H, s), 4.90 (1H, s), 6.65 (2H, d, J = and treated with p-chlorophenyl isocyanate (3.4 g, 22.4 mmol)
9.0 Hz), 7.20 (2H, d, J = 9.0 Hz); 13C NMR (50 MHz, CDCl3)
and when all the solid was dissolved, the solvent was
(ppm) 23.8 (CH3), 41.8 (CH2), 53.3 (2CH3), 86.1 (C), 116.1 (CH2), eliminated under reduced pressure to isolate compound (8.1
119.5 (2CH), 127.9 (C), 129.5 (2CH), 139.5 (C), 153.9 (C), 168.2 g, 75% yield) as a white solid. Mp 190–195 °C; H NMR (200
(2C); IR (film) 827, 911, 1073, 1225, 1441, 1495, 1594, 1751, MHz, CDCl3) (ppm) 1.21 (6H, s), 2.44 (2H, s), 3.78 (6H, s), 6.78
2949 cm-1; HRMS (ESI) Calcd for C15H18O5Cl 313.0837, found (1H, d, J = 2.3 Hz), 7.20 (2H, d, J = 8.8 Hz), 7.38 (2H, d, J = 8.8
313.0846 (M + H)+, 335.0657 (M + Na)+.
Hz), 8.07 (1H, br s, NH), 8.16 (1H, d, J = 2.3 Hz), 8.47 (1H, br s,
NH); 13C NMR (50 MHz, CDCl3)
(ppm) 30.8 (2CH3), 31.0 (C),
4
(93 g, 100% yield) was isolated as a viscous light precipitates, that corresponds to the desired intermediate
δ
(ppm) 1.76 (3H, s), 3.00 amine (7.3 g). This amine was then solved in CH2Cl2 (20 mL)
δ
7
1
δ
δ
Dimethyl
6-chloro-4,4-dimethylchroman-2,2-dicarboxylate
41.8 (CH2), 54.1 (2CH3), 81.0 (C), 117.5 (CH), 118.5 (CH), 120.2
(2CH), 122.2 (C), 124.0 (C), 127.7 (C), 129.1 (2CH), 130.1 (C),
131.9 (C), 138.1 (C), 167.5 (C), 168.8 (2C); IR (film) 671, 812,
1056, 1208, 1441, 1538, 1652, 1755, 3320 cm-1; HRMS (ESI)
Calcd for C22H23N2O6Cl2 481.0928, found 481.0927 (M + H)+,
503.0752 (M + Na)+.
(5). Methanesulfonic acid (428 mL, 6.59 mol) was dried with
P2O5 (130 g, 0.92 mol) and heating in an oil bath at 150 °C until
all the P2O5 was dissolved. Then, the mixture was cooled to
60 °C and compound
4 (93 g, 0.29 mol) was added drop-wise
from an addition funnel, keeping the temperature of the
reaction mixture below 60 °C. Once the addition was
completed, the mixture was slowly poured onto iced water 6-Chloro-8-(3-(4-chlorophenyl)ureido)-2-(methoxycarbonyl)-
and extracted with ethyl acetate. The organic phase was 4,4-dimethylchroman-2-carboxylic acid (8). Compound (8.1
7
consecutively washed with an NH3 aqueous solution until basic g, 16.8 mmol) was suspended in methanol (64 mL), treated
pH and with water. Then it was dried over anhydrous Na2SO4 with LiOH∙H2O (0.7 g, 16.8 mmol) and heated in an oil bath at
and filtered and the solvent was eliminated under reduced 80 °C under argon atmosphere until all the solid was dissolved.
pressure. Compound 5 (56 g, 62% yield) was isolated as a Then the solvent was eliminated under reduced pressure and
1
white solid. Mp 85–90 °C; H NMR (200 MHz, CDCl3)
δ
(ppm) the crude product obtained was solved in ethyl acetate and
1.26 (6H, s), 2.46 (2H, s), 3.81 (6H, s), 6.96 (1H, d, J = 8.7 Hz), washed with a 2M aqueous solution of HCl. The resulting
7.10 (1H, dd, J = 2.5, 8.7 Hz), 7.18 (1H, d, J = 2.5 Hz); 13C NMR organic phase was dried over anhydrous Na2SO4 and filtered
(50 MHz, CDCl3)
δ
(ppm) 30.6 (C), 30.9 (2CH3), 40.6 (CH2), 53.6 and the solvent was eliminated under reduced pressure. 6.2 g
were isolated as a white solid. Mp
(ppm) 1.19 (3H, s),
(2CH3), 80.5 (C), 119.1 (CH), 126.1 (CH), 127.0 (C), 127.9 (CH), (79% yield) of compound
8
132.2 (C), 150.0 (C), 168.6 (2C); IR (film) 825, 1060, 1222, 1278, 170–178 °C; 1H NMR (200 MHz, CDCl3)
δ
1431, 1487, 1762, 2959 cm-1; HRMS (ESI) Calcd for 1.25 (3H, s), 2.40 (1H, d, J = 13.0 Hz), 2.50 (1H, d, J = 13.0 Hz),
C15H17O5NaCl 335.0657, found 335.0660 (M + Na)+, 313.0863 3.77 (3H, s), 6.78 (1H, d, J = 2.5 Hz), 7.19 (2H, d, J = 8.8 Hz),
(M + H)+.
7.37 (2H, d, J = 8.8 Hz), 8.13 (1H, d, J = 2.5 Hz); 13C NMR (50
MHz, CDCl3) (ppm) 30.6 (C), 31.0 (2CH3), 41.0 (CH2), 53.6
δ
Dimethyl
6-chloro-4,4-dimethyl-8-nitrochroman-2,2-
(CH3), 80.9 (C), 117.2 (CH), 118.6 (CH), 120.2 (2CH), 127.2 (C),
127.6 (C), 128.9 (2CH), 129.5 (C), 131.8 (C), 137.8 (C), 138.3 (C),
169.2 (2C), 169.7 (C); IR (film) 827, 1076, 1162, 1232, 1442,
1572, 1723, 1777, 2968 cm-1; HRMS (ESI) Calcd for
C21H20N2O6NaCl2 489.0591, found 489.0586 (M + Na)+.
dicarboxylate (6). Fuming HNO3 (1.526 g/mL) (5.3 mL, 128
mmol) was added onto a solution of compound (10 g, 32
5
mmol) in CH2Cl2 (20 mL). Once the addition was completed,
the reaction mixture was poured onto iced water and the
phases were separated. The organic phase was then washed
with water, dried over anhydrous Na2SO4 and filtered and the Methyl
solvent was eliminated under reduced pressure, which led to 8 (hydroxymethyl)phenyl)carbamoyl)-4,4-dimethylchroman-2-
g (70% yield) of compound , as a deep yellow solid. Mp 108– carboxylate (9). N,N’-dicyclohexylcarbodiimide (1.7 g, 8.2
112 °C; 1H NMR (200 MHz, CDCl3)
(ppm) 1.30 (6H, s), 2.52 mmol) was added to a solution of compound (4.0 g, 8.6
(2H, s), 3.82 (6H, s), 7.41 (1H, d, J = 2.6 Hz), 7.68 (1H, d, J = 2.6 mmol) in chloroform (100 mL). After 2 minutes of continuous
Hz); 13C NMR (50 MHz, CDCl3)
(ppm) 30.7 (2CH3), 31.3 (C), stirring at room temperature, 3-aminobenzyl alcohol (1.0 g, 8.1
6-chloro-8-(3-(4-chlorophenyl)ureido)-2-((3-
6
δ
8
δ
40.3 (CH2), 53.9 (2CH3), 81.1 (C), 123.7 (CH), 126.5 (C), 130.5 mmol) was added, following the progress of the reaction by
1
(CH), 136.0 (C), 144.0 (C), 152.5 (C), 167.5 (2C); IR (film) 841, registering H NMR spectra of aliquots directly taken from the
1061, 1144, 1217, 1242, 1427, 1457, 1550, 1750, 2952, 3084 reaction medium. When the reaction was over, the crude
cm-1; HRMS (ESI) Calcd for C15H16NO7NaCl 380.0507, found product was dissolved in CH2Cl2 and purified by column
380.0508 (M + Na)+, 358.0690 (M + H)+.
chromatography (CH2Cl2/EtOAc 6:4 mixture as the eluent),
isolating 3.9 g (79% yield) of compound as a vitreous solid.
(ppm) 1.24 (3H, s), 1.30 (3H, s),
9
Dimethyl
6-chloro-8-(3-(4-chlorophenyl)ureido)-4,4-
1
RMN H (200 MHz, CDCl3)
δ
dimethylchroman-2,2-dicarboxylate (7). Compound
6 (8 g,
2.53 (2H, dd, J = 14.3 Hz), 3.76 (3H, s), 4.61 (2H, s), 6.96 (1H, d,
J = 2.4 Hz), 7.03 (1H, d, J = 7.5 Hz), 7.11 (2H, d, J = 8.8 Hz), 7.19
(1H, t, J = 8.0 Hz), 7.23 (2H, d, J = 9.6 Hz), 7.48 (1H, d, J = 8.2
Hz), 7.56 (1H, s), 7.62 (1H, d, J = 2.4 Hz), 8.06 (1H, s), 8.11 (1H,
22.4 mmol) was slowly added, in portions, onto a suspension
of Zn (10.9 g, 166.8 mmol) in acetic acid (36.5 mL), as the
reaction occurs violently and is strongly exotermic. After the
addition was completed, the reaction mixture was filtered to
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s), 9.51 (1H, s); 13C NMR (50 MHz, CDCl3)
δ (ppm) 30.2 (C), 31.3 water. The phases were separated and the organic one was
(2CH3), 40.5 (CH2), 64.5 (CH2), 82.4 (C), 120.6 (2CH), 123.9 dried over anhydrous Na2SO4 and filtered and the solvent was
(2CH), 126.1 (CH), 127.9 (C), 128.3 (C), 128.8 (C), 129.1 (3CH), eliminated under reduced pressure. 1.9 g of receptor (64%
129.3 (2CH), 133.3 (C), 137.5 (C), 137.7 (C), 137.9 (C), 142.1 (C), yield) were isolated, as a vitreous solid. RMN 1H (200 MHz,
151.9 (C), 166.1 (C), 169.8 (C); IR (film) 1123, 1541, 1606, 1670, CDCl3) (ppm) 1.33 (3H, s), 1.35 (3H, s), 2.51 (2H, s), 2.74 (4H,
1
δ
1730, 3299 cm-1; HRMS (ESI) Calcd for C28H27N3O6NaCl2 t, J = 5.6 Hz), 2.87 (3H, d, J = 4.6 Hz), 3.57-3.64 (20H, m), 3.65
594.1169, found 594.1167 (M + Na)+.
(2H, s), 6.66 (1H, s), 7.02 (1H, d, J = 2.3 Hz), 7.13 (2H, d, J = 8.7
Hz), 7.14 (1H, d, J =8.0 Hz), 7.23 (1H, t, J = 7.7 Hz), 7.36 (2H, d, J
= 8.7 Hz), 7.50 (1H, s), 7.62 (1H, d, J = 7.9 Hz), 8.37 (1H, s), 8.60
6-Chloro-8-(3-(4-chlorophenyl)ureido)-N-(3-
(hydroxymethyl)phenyl)-N,4,4-trimethylchroman-2,2-
(1H, s), 8.76 (1H, s), 10.32 (1H, s); RMN 13C (50 MHz, CDCl3)
δ
dicarboxamide (10). Compound
9 (3.9 g, 6.8 mmol) was added
(ppm) 26.8 (CH3), 30.3 (CH3), 30.4 (CH3), 31.1 (C), 42.7 (CH2),
53.9 (2CH2), 59.8 (CH2), 70.3 (10CH2), 81.3 (C), 119.6 (CH),
120.0 (2CH), 121.2 (CH), 123.1 (CH), 124.0 (CH), 125.9 (CH),
126.1 (C), 126.8 (C), 127.2 (C), 128.6 (2CH), 128.8 (CH), 132.1
(C), 136.9 (C), 138.0 (C), 143.4 (C), 154.4 (2C), 167.8 (C), 169.9
(C); IR (film) 1125, 1236, 1313, 1495, 1541, 1599, 1697, 3306
cm-1; HRMS (ESI) Calcd for C40H52N5O9Cl2 816.3137, found
816.3167 (M + H)+.
onto a mixture of methylamine (2.0 mL, 40% aqueous solution)
and methanol (5.0 mL). When the reaction was over (1H NMR),
the solvent was eliminated under reduced pressure, isolating
1
3.6 g (93% yield) of compound 10, as a vitreous solid. RMN H
(200 MHz, CDCl3) δ (ppm) 1.30 (3H, s), 1.34 (3H, s), 2.41 (1H, d,
J = 13.9 Hz), 2.60 (1H, d, J = 13.9 Hz), 2.89 (3H, d, J = 4.7 Hz),
4.62 (2H, s), 6.49 (1H, d, J = 2.2 Hz), 7.03 (1H, d, J = 2.5 Hz),
7.03 (1H, d, J =7.5 Hz), 7.11 (2H, d, J = 8.8 Hz), 7.29 (1H, t, J =
7.4 Hz), 7.34 (2H, d, J = 8.9 Hz), 7.60 (1H, d, J = 12.4 Hz), 7.71 Methyl 6-chloro-8-(3-(4-chlorophenyl)ureido)-4,4-dimethyl-2-
(1H, s), 8.30 (1H, s), 8.57 (1H, s), 10.7 (1H, s); 13C NMR (50 (methylcarbamoyl)chroman-2-carboxylate (receptor 2).
MHz, CDCl3) (ppm) 27.2 (CH3), 30.5 (2CH3), 31.3 (C), 41.6 solution of compound (400 mg, 0.83 mmol) in CH2Cl2 (1 mL)
(CH2), 65.0 (CH2), 81.1 (C), 119.6 (CH), 120.4 (CH), 120.2 (2CH), was treated with an excess of methylamine (290 L, 3.32
A
δ
7
ꢀ
123.6 (CH), 124.1 (CH), 124.5 (CH), 126.4 (C), 126.8 (C), 127.6 mmol, 40% aqueous solution) and the resulting mixture was
(C), 129.0 (2CH), 129.3 (CH), 131.9 (C), 137.4 (C), 138.1 (C), stirred at room temperature for 10 minutes. Then the solvent
142.2 (C), 144.7 (C), 154.7 (C), 168.6 (C), 170.3 (C); IR (film): was eliminated under reduced pressure and the crude product
1223, 1541, 1606, 1684, 3312 cm-1; HRMS (ESI) Calcd for thus obtained was purified by column chromatography (9:1
C28H28N4O5NaCl2 593.1329, found 593.1325 (M
571.1500 (M + H)+.
+
Na)+, CH2Cl2/EtAcO mixture as eluent), isolating 210 mg (53 % yield)
of the desired compound, receptor , as a vitreous solid. RMN
1H (400 MHz, CDCl3)
(ppm) 1.22 (3H, s), 1.27 (3H, s), 2.28 (1H,
2
δ
6-Chloro-N-(3-(chloromethyl)phenyl)-8-(3-(4-
d, J = 14.3 Hz), 2.65 (1H, d, J = 14.3 Hz), 2.85 (3H, d, J = 4.7 Hz),
3.80 (3H, s), 6.88 (1H, d, J = 2.5 Hz), 7.02 (1H, br s), 7.24 (2H, d,
J = 9.0 Hz), 7.38 (2H, d, J = 9.0 Hz), 7.93 (1H, br s), 8.05 (1H, d, J
chlorophenyl)ureido)-N,4,4-trimethylchroman-2,2-
dicarboxamide (11). Compound 10 (3.6 g, 6.3 mmol) was
dissolved in thionyl chloride (3.0 mL) and this latest compound
was then eliminated under reduced pressure. The crude
product thus obtained was purified by crystallization in CH2Cl2
and 2.8 g (75% yield) of compound 11 were isolated. Mp 184-
= 2.5 Hz), 8.07 (1H, br s); RMN 13C (100 MHz, CDCl3)
δ (ppm)
26.8 (CH3), 30.0 (CH3), 30.2 (CH3), 31.1 (C), 40.8 (CH2), 53.9
(CH3), 81.8 (C), 118.3 (CH), 119.2 (CH), 120.5 (2CH), 127.5 (2C),
128.0 (C), 128.9 (2CH), 132.4 (C), 137.3 (C), 138.3 (C), 152.8 (C),
167.4 (C), 170.5 (C); IR (film) 670, 868, 1050, 1157, 1226, 1542,
1665, 1750, 3311 cm-1; HRMS (ESI) Calcd for C22H23N3O5Cl2
480.3, found 480.1056 (M + H)+, 502.0907 (M + Na)+.
185°C; RMN 1H (200 MHz, CDCl3)
δ (ppm) 1.34 (3H, s), 1.40
(3H, s), 2.38 (1H, d, J = 13.0 Hz), 2.67 (1H, d, J = 13.0 Hz), 2.92
(3H, d, J = 4.6 Hz), 4.50 (2H, s), 6.35 (1H, d, J = 2.1 Hz), 7.04
(1H, d, J = 2.4 Hz), 7.16 (2H, d, J = 8.7 Hz), 7.24 (1H, d, J =9.1
Hz), 7.32 (1H, t, J = 8.0 Hz), 7.36 (2H, d, J = 8.8 Hz), 7.74 (1H, d,
J = 12.9 Hz), 7.78 (1H, s), 8.32 (1H, s), 8.55 (1H, s), 11.95 (1H,
Acknowledgements
s); 13C NMR (50 MHz, CDCl3)
δ (ppm) 26.8 (CH3), 30.4 (C), 31.4
The authors would like to thank the University of Salamanca
(project 184113) and Government of Chile (FONDECYT N°
1151440) for financial support. O. H. R. wishes to thank the
University of Salamanca for a predoctoral fellowship. The
authors also thank Cesar Raposo from the mass spectrometry
service and Anna Lithgow from the NMR service of the
NUCLEUS Platform of the University of Salamanca. We
acknowledge the employment of University of Salamanca
server housing service. We thank A. López García and J. A.
González Ramos for IT support.
(2CH3), 43.0 (CH2), 46.0 (CH2), 81.4 (C), 120.2 (2CH), 120.7 (CH),
120.9 (CH), 122.3 (CH), 122.7 (CH), 125.5 (C), 126.7 (CH), 127.4
(C), 127.7 (C), 129.0 (2CH), 129.5 (CH), 132.4 (C), 137.5 (C),
137.8 (C), 138.6 (C), 142.3 (C), 154.3 (C), 168.0 (C), 170.1 (C); IR
(film) 1236, 1554, 1586, 1670, 3182, 3331 cm-1; HRMS (ESI)
Calcd for C28H27N4O4NaCl3 611.0990, found 611.0996 (M +
Na)+.
N-(3-((1,4,7,10,13-Pentaoxa-16-azacyclooctadecan-16-
yl)methyl)phenyl)-6-chloro-8-(3-(4-chlorophenyl)ureido)-
N,4,4-trimethylchroman-2,2-dicarboxamide (receptor 1). 1-
Aza-18-crown-6 (1.2 g, 4.6 mmol) was added onto a solution of
compound 11 (2.1 g, 3.6 mmol) in chloroform (20 mL). The
resulting reaction mixture was heated for 3 h at 60 °C in an oil
bath under continuous stirring and then it was washed with
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