Chiral recognition of carboxylates by a static library of thiourea receptors with amino acid arms

Article abstract of DOI:10.1021/acs.joc.5b00403

Chiral recognition is based on a large network of very subtle interactions whose outcome is difficult to predict. A combinatorial approach is therefore the most suitable to search for the most efficient receptor and obtain a structure-enantioselectivity correlation. We synthesized a set of 12 receptors constructed with 1,9-diaminoantracene and α-amino acid esters, linked via thiourea groups. The association constants and enantioselectivities for the complexes with mandelate and N-acetylphenylalanine were determined by competitive NMR titrations. Association constants quite regularly depend on the substituents in the receptor structure, but the distribution of enantioselectivities across the library could not easily be rationalized.

Full text of DOI:10.1021/acs.joc.5b00403

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Chiral Recognition of Carboxylates by a Static Library of Thiourea
Receptors with Amino Acid Arms
Filip Ulatowski and Janusz Jurczak*
Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw 01-224, Poland
S
* Supporting Information
ABSTRACT: Chiral recognition is based on a large network of very subtle interactions whose outcome is difficult to predict. A
combinatorial approach is therefore the most suitable to search for the most efficient receptor and obtain a structure−
enantioselectivity correlation. We synthesized a set of 12 receptors constructed with 1,9-diaminoantracene and α-amino acid
esters, linked via thiourea groups. The association constants and enantioselectivities for the complexes with mandelate and N-
acetylphenylalanine were determined by competitive NMR titrations. Association constants quite regularly depend on the
substituents in the receptor structure, but the distribution of enantioselectivities across the library could not easily be rationalized.
1. INTRODUCTION
2. RESULTS AND DISCUSSION
Chiral recognition is a phenomenon that relies on very subtle
effects. The selectivities that have so far been obtained for
artificial receptors, especially in the chiral recognition of
carboxylates, are usually not very impressive, although many
attempts have been made in the last 20 years.1−40 At the same
time, however, nature indicates that obtaining perfect
enantioselectivity with high affinities is not impossible, not
ruled out by some fundamental laws. Let the selectivity for
(S)-naproxene in the human body be a representative example
of such systems.41
One of the major problems in the development of receptors
for chiral recognition is our inability to predict their
enantioselectivity efficiency before their synthesis and tedious
experiments are performed. It is the exception rather than the
rule that the observed selectivity can easily be explained by a
simple stereochemical model with just the total number of
attractive and repulsive interactions rationalizing the chiral
recognition.42,43 It seems that it is the entropic rather than the
enthalpic factor that controls the selectivity.9 The entropy of
binding is, however, extremely difficult to predict, especially
when two compared complexes are in a diastereoisomeric
relationship. This indicates that chiral recognition requires a
large scope combinatorial approach. The usefulness of such an
approach has already been shown in the field of chiral
recognition of cations.44
In this paper, we present our new45 and more successful
library of chiral anion receptors, which is, to the best of our
knowledge, the most extensive ever investigated. Bisthioureidic
receptors of type 1 are formally composed of 1,10-
diaminoanthracene and two amino acid esters. The
diaminoantharcene platform has already proved to be readily
obtainable and its thiourea derivatives effectively bind
carboxylates in polar solvents.22 The application of amino
acids has many advantages; e.g., they are readily available in
enantiopure form with high diversity in their side chains and
the possibility of modifying the C-terminus with various
amines or alcohols. The N-terminus of the amino acid is used
in the formation of thiourea moiety. We decided to employ
the following amino acids: alanine (the smallest group), valine
(bulky side chain), phenylalanine (aromatic group), and
tryptophane (additional hydrogen bond donor). The C-
termini of the chiral amino acids were modified into ester
groups with methyl (small), isopropyl (bulky), n-butyl (long
chain), and benzyl (aromatic) alcohols.
The synthesis of chiral receptors is outlined in Scheme 1
(path A). Bisisothiocyanate 4 was synthesized in three steps
from dinitroantroquinone (2) following the literature.46
Received: February 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b00403
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Scheme 1. Synthesis of Receptors 1 by Routes A and B
a
Reagents and conditions: (a) Na2S, iPrOH, reflux, 12 h; (b) NaBH4, NaOH, iPrOH, reflux, 12 h; (c) thiophosgene, DCM/NaHCO3(aq), rt, 30
min; (d) R2OH, EDCI, DMAP, DCM, rt, 12 h; (e) 4 M HCl in dioxane, rt, 30 min; (f) DIPEA, DCM, 1 h; (g) 3, DCM, rt, 2 h.
Compound 4 was purified by crystallization and then reacted
with an appropriate amino acid ester (7) to yield the
receptors 1. An alternative synthesis path was also tested
(Scheme 1, path B); this employed the formation of
isothiocyanates (8) derived from the amino acid ester and
their reaction with diamine 3. The second approach generally
resulted in a better yield; however, it is less convenient in
terms of library synthesis and increases the exposure to toxic
thiophosgene.
method. Enantioselectivities (α = KS/KR or KL/KD) were then
calculated for each receptor−anion pair (Tables 1 and 2).
The receptors were evaluated for their enantioselectivities
toward two model chiral anions: (R/S)-mandelate (Man) and
N-acetyl-D/L-phenylalanine (AcPhe) used as tetrabutylammo-
nium (TBA) salts. In the first step, the stoichiometry of the
complexes was determined by analysis of direct 1H NMR
titrations and classical Job plots in MeCN-d3. For the
receptors containing alanine, valine, and phenylalanine (1a−
l), the classical Job plot indicates a simple 1:1 stoichiometry,
which is consistent with the titration curves (Figure 1a) and
stochastic distribution of residuals. However, a closer look at
the titration course of the tryptophane-based receptor 1m
indicates a more complex behavior (Figure 1b). The indole
NH signal does not reach a plateau after 1 equiv of guest but
continues to move downfield; similarly, the proton at position
9 in the anthracene moiety (green curve) switches its
direction of movement after exceeding 1 equiv of anion.
These observations indicate the subsequent formation of an
HG2 complex in the case of the tryptophan-containing host.
This complex behavior is known to make the determination
of association constants less reliable, and competitive methods
cannot be applied. Thus, this receptor was excluded from
further examination.
Ka values exhibited dependence on the R1 and R2 groups. A
comparison of various R1 moieties was performed with scaled
K′ = K/(K (R1 = Me)) (for constant R2 and a given anion);
the values are presented in Figure 2a and compared with
Taft’s steric parameters.51,52 The highest Ka’s were observed
for the valine based receptors (1e−h) with K′ = 2.33−2.91,
although they possess the bulkiest i-Pr substituent (ES=
−0.47). The phenylalanine-based receptors (1i−l) exhibit
affinities ca. half as high (K′ = 0.50−0.76, ES = −0.38) as
those in the alanine series (1a−d, ES = 0 by definition). This
trend indicates that the bulky substituents may not only block
the entrance to the binding pocket between the thiourea
groups but also, in certain cases, help to preorganize the
receptor to a conformation suitable for carboxylate binding. In
the case of R1 = i-Pr, the preorganization effect predominates,
while benzyl groups mainly limit the availability of the binding
pocket. A similar substituent effect analysis was performed for
R2 groups (K″ = K/(K (R2 = Me)), Figure 2b), and we found
this influence substantially weaker. On average, the Ka changes
in the following order: i-Pr < n-Bu < Bn ≈ Me. Apart from
benzyl, the remaining three groups qualitatively follow the
Taft steric parameters as depicted in the graph. The presence
of a benzyl group in the ester moiety increases the binding
affinities most probably by receptor preorganization. The
aforementioned observations are consistent with our recent
results for receptors of similar structure.45
The association constants of the complexes with the model
anions were determined in MeCN-d3 by competitive NMR
titration2,45,47−50 using an achiral receptor 9 as an internal
reference45 (Figure 1c). This titration is insensitive to
concentration errors and is a far more accurate and precise
B
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Figure 1. (a) NMR titration of 1i indicating 1:1 stoichiometry, (b) NMR titration of 1m with (S)-Man indicating the formation of an HG2
complex, (c) an example of competitive titration of 1e and 9 with (S)-Man, the equivalents of guests calculated against the sum of the two hosts.
All measurements in MeCN-d3, 303 K, anions used as TBA salts.
C
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a
Table 1. Association Constants (M−1) and Enantioselectivities (α) of Receptors 1 with Man
receptor
R1
Ka
α
R2
S
R
KR/KS
1a
1b
1c
1d
1e
1f
Me
Me
Me
Me
i-Pr
i-Pr
i-Pr
i-Pr
Bn
Me
i-Pr
n-Bu
Bn
1.36 × 104 7.0 (%)
1.00 × 104 2.9 (%)
1.15 × 104 2.4 (%)
1.20 × 104 4.0 (%)
3.21 × 104 4.2 (%)
2.07 × 104 4.5 (%)
2.68 × 104 8.3 (%)
3.16 × 104 3.6 (%)
6.64 × 103 5.5 (%)
5.90 × 103 3.8 (%)
6.06 × 103 3.4 (%)
7.36 × 103 6.0 (%)
1.44 × 104 3.5 (%)
1.13 × 104 3.3 (%)
1.26 × 104 1.3 (%)
1.34 × 104 3.5 (%)
3.82 × 104 1.7 (%)
2.43 × 104 1.1 (%)
3.10 × 104 7.7 (%)
3.66 × 104 1.4 (%)
8.11 × 103 5.9 (%)
6.32 × 103 5.4 (%)
6.32 × 103 5.4 (%)
8.35 × 103 4.5 (%)
1.06 7.8 (%)
1.12 4.4 (%)
1.09 2.7 (%)
1.12 5.3 (%)
1.19 4.5 (%)
1.18 4.7 (%)
1.16 11 (%)
1.16 3.9 (%)
1.22 8.1 (%)
1.08 6.6 (%)
1.04 6.4 (%)
1.14 7.5 (%)
Me
i-Pr
n-Bu
Bn
1g
1h
1i
Me
i-Pr
n-Bu
Bn
1i
Bn
1k
1l
Bn
Bn
a
Competitive NMR titration in MeCN-d3, 303 K.
a
Table 2. Association Constants (M−1) and Enantioselectivities (α) of Receptors 1 with AcPhe
receptor
R1
Ka
α
R2
D
L
KL/KD
1a
1b
1c
1d
1e
1f
Me
Me
Me
Me
i-Pr
i-Pr
i-Pr
i-Pr
Bn
Me
i-Pr
n-Bu
Bn
1.48 × 105 1.9 (%)
1.14 × 105 1.7 (%)
1.37 × 105 2.8 (%)
1.42 × 105 3.2 (%)
4.02 × 105 3.8 (%)
2.90 × 105 4.2 (%)
3.78 × 105 2.2 (%)
4.13 × 105 2.8 (%)
8.36 × 104 1.8 (%)
6.88 × 104 4.0 (%)
7.61 × 104 1.7 (%)
1.08 × 105 5.5 (%)
1.58 × 105 2.8 (%)
1.22 × 105 2.0 (%)
1.47 × 105 1.6 (%)
1.48 × 105 3.7 (%)
3.90 × 105 6.3 (%)
2.91 × 105 3.2 (%)
3.45 × 105 4.9 (%)
4.15 × 105 2.8 (%)
8.45 × 104 4.2 (%)
7.04 × 104 1.5 (%)
7.91 × 104 3.5 (%)
1.11 × 105 4.00 (%)
1.06 3.4 (%)
1.07 2.6 (%)
1.08 3.2 (%)
1.04 4.9 (%)
0.97 7.4 (%)
1.00 5.3 (%)
0.91 5.4 (%)
1.01 4.0 (%)
1.01 4.6 (%)
1.02 4.3 (%)
1.04 3.9 (%)
1.02 6.8 (%)
Me
i-Pr
n-Bu
Bn
1g
1h
1i
Me
i-Pr
n-Bu
Bn
1i
Bn
1k
1l
Bn
Bn
a
Competitive NMR titration in MeCN-d3, 303 K.
Figure 2. (a, b) Correlation between anion affinities and R1 (a) or R2 groups (b). Left vertical axis (K′ or K″) is on a logarithmic scale; right
vertical axis corresponds to ES.
Enantioselectivities for the two model anions are presented
in Tables 1 and 2 and Figure 3. All of the receptors studied
exhibit consistent preference for the (R)-Man, while the
selectivities of the AcPhe enantiomers have a more complex
distribution−alanine and phenylalanine receptors (1a−d,i−k)
bind L-AcPhe more strongly, while valine-based receptors (1e
and 1g) possess a reverse selectivity. Several receptors
(1b,c,g) were found to be quite successful in chiral
recognition of both guests. The distributions of selectivities
may seem stochastic for the two model anions, but a graphical
analysis of the selectivity vs R1 and R2 substituents presented
in Figure 2e,f facilitates the observation of some trends. For a
mandelate guest, R1 = i-Pr (Val) results in the best chiral
recognition properties (all |log(α)| > 0.6), and R2 = Me gives
the best results for R1 = i-Pr or Bn. In the case of the AcPhe
anion, the receptors incorporating alanine (R1 = Me) are
D
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Figure 3. (a, b) Distributions of enantioselectivities (log(α)) of receptors 1 with Man and AcPhe, respectively. (c, d) Graphical analysis of
influence of R1, R2 on enantioselectivities (|log(α)|) with Man and AcPhe anions, respectively.
slightly more effective, and R2 = n-Bu is preferable across the
series. Each guest exhibits a different preference for receptor
structure. The highest observed selectivities are KR/KS = 1.22
for 1e with Man and KD/KL = 1.10 for 1g with AcPhe. Both
results did not appear at the intersection of the most
promising R1 and R2 groups but emerged for receptors with
different substituents. These observations indicate that some
global analyses can be performed; however, the highest
enantioselectivities are the consequences of a unique,
nonadditive match between the substituents.
for BocAla and BocVal, respectively (Table 3). We have
further confirmed these results by UV−vis titration. However,
Table 3. Enantioselectivities of Receptor 10 Determined by
Various Methods
The level of enantioselectivity in our receptors seems quite
low, especially when compared to the results reported by Kim
et al.22 In the cited paper, the authors describe receptor 10,
decorated with glucose derivatives, which is based on the
same 1,8-diaminoanthracene platform as our hosts of type 1.
Receptor 10 was tested with a set of Boc- or DNB-protected
α-amino acid anions by fluorometic titration. The reported
enantioselectivities reach values up to 10. Concerned about
the dissonance between the results by Kim et al. and ours, we
decided, in the first step, to check receptor 10 in chiral
recognition of our model carboxylates. The enantioselectivities
determined by NMR competitive titrations are 1.02 and 1.06
for Man and AcPhe, respectively, which are comparable with
the results for our receptors 1a−l. Significantly higher
enantioselectivities reported by Kim et al. for Boc- and
DNB-amino acids suggested that both Man and AcPhe may
be particularly difficult guests in obtaining high chiral
recognition. We therefore decided to confirm some of the
enantioselectivities reported by Kim et al. by our competitive
titration method. According to our results, the selected α
values are far lower: 1.3 instead of 5.5 and 1.2 insted of 4.3
enantioselectivity α = KD/KL
fluorometric titration by
NMR competitive
titration
UV−vis
guest
Man
Kim et al.
titration
1.02
1.06
1.31
1.22
1.18
AcPhe
Boc-Ala
Boc-Val
Boc-Phe
5.5
4.3
1.2
1.40
1.02
when we performed titration under fluorometric control, as in
the cited paper, we found that fitting the data is quite difficult
due to complex mechanism of fluorescence quenching (see
the Supporting Information for details). In this case Benesi−
Hildebrand linearization53 cannot be applied, which is the
E
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General Procedure for Boc Deprotection. Boc-amino ester 6
(3 mmol) was dissolved in 4 M HCl in dioxane (15 mL) and stirred
for 2 h at rt. The mixture was concentrated on a rotary evaporator to
yield a white solid. The reaction proceeds quantitatively, and the
product−amino acid ester hydrochloride is pure enough for the next
step.
General Procedure for the Synthesis of Receptors 1, Path
A. Amino acid ester hydrochloride 7 (3 mmol) was dissolved in
DCM and DIPEA (0.85 mL, 5 mmol), 1,8-diisothiocyanoantracene 4
(292 mg, 1 mmol) was added, and the reaction was carried out for 2
h at rt. The mixture was then directly subjected to chromatography,
and the receptors were eluted with 2−4% acetone in DCM. The
product was further purified by dissolving in minimum amount of
DCM and titruated with hexane. The yellow (or beige) precipitate
was filtered off and dried in vacuo.
main reason for the false results obtained by Kim et al. In
view of these facts, all values of association constants and
enantioselectivities reported in that paper are doubtful.
This finding indicates that obtaining a high level of
enantiodiscrimination in the supramolecular chemistry of
carboxylates is not very common, and some results that act
as the gold standard are actually experimental artifacts. It is
worth mentioning here that from the point of view of modern
chiral stationary phases in HPLC or GC the selectivity at a
level of 1.1 is not only sufficient but even optimal.43 Most of
the receptors 1a−l exhibit enantioselectivity of the model
carboxylates close to this optimal level.
3. CONCLUSIONS
General Procedure for the Synthesis of Receptors 1, Path
B. This procedure involves very toxic thiophosgene, and the reaction
should be carried with caution under a well-ventilated hood. Amino
acid ester hydrochloride 7 (3 mmol) was dissolved in DCM (30
mL), and a satd solution of NaHCO3 (30 mL) was added to the
flask. Thiophosgene (6 mmol) was added into the DCM phase, and
the mixture was stirred intensively for 30 min at room temperature.
Phases were separated, the aqueous phase was extracted with DCM,
and combined organic phases were dried over sodium sulfate. The
drying agent was filtered off, and the solution was concentrated on a
rotary evaporator (equipped with water jet pump to neutralize the
thiophosgene vapors in water). The obtained isocyanate was
dissolved in DCM, and amine 3 (1 mmol) was added. The reaction
was carried out at rt for 1 h, and the product was purified as in path
A. Figure 4 shows the numbering scheme of protons in 1.
The library of thiourea receptors 1 was easily synthesized in a
convergent mode. A tryptophan-based receptor, equipped
with an additional hydrogen bond donor, binds carboxylates
with a complex HG + HG2 stoichiometry, while other
receptors form 1:1 complexes exclusively. The amino acid side
chains (R1) strongly influence binding affinities either by
receptor preorganization or by hindering the thiourea groups.
This library exhibits modest enantioselectivity values which
depend on both R1 and R2 groups. Although some regularity
in the structure−enantioselectivity relationship was found, the
influences of the substituents were determined not to be
simply additive. The enantioselectivity values are in the range
of 1.0−1.22, which is quite consistent with results obtained in
our group for similar receptors.36 We also proved that the
very high enantioselectivities obtained by Kim et al. for
receptor 10 are artifacts resulting from misuse of the Benesi−
Hildebrand approximation, and the real selectivity values are
close to those obtained by us.
4. EXPERIMENTAL SECTION
Dichloromethane used in the syntheses was distilled over CaH2. The
reactions were carried under Ar. Preparative chromatography was
performed with silica gel (silicagel 60, 230−400 mesh); typically, a
40-fold mass excess of gel was used. Abbreviations of the signal
multiplicity in the signal listing: s, singlet; d, doublet; t, triplet; q,
quartet; quint, quintet; sext, sextet; sept, septet; m, complex
multiplet; bs, broad signal. HRMS measurements were performed
with ESI ionization and TOF analyzer. Optical rotations (O.R.) were
measured in 10 cm cuvettes, and [α]2D0 values are given in deg cm3
dm−1 g−1.
Figure 4. Numbering scheme of protons in receptors 1.
1a. Yellow powder. Yield: 174 mg (35%). Mp: 164−165
°C.1HNMR (MHz, DMSO-d6) δ: 9.90 (s, 2 H, Ha); 8.67 (1 H, s,
J = 5.1 Hz, H10); 8.66 (s, 1 H); 8.10 (2 H, d, J = 7.3 Hz, H2); 8.02
(2 H, d, J = 8.4 Hz, H4); 7.60 (2 H, d, J = 7.0 Hz, Hb); 7.58−7.51
(m, 2 H, H3); 5.03 (2 H, p, J = 7.3 Hz, Hα); 3.67 (s, 6 H, R2); 1.39
(6 H, d, J = 7.3 Hz, R1). 13CNMR (MHz, DMSO-d6) δ: 182.0;
173.0; 134.8; 132.0; 127.8; 127.0; 126.4; 125.4; 123.8; 116.6; 52.6;
51.9; 17.4. HRMS: calcd for C24H26NO4S2 + H 499.1454, found
499.1447. Anal. Calcd for C24H26N4O4S2: C, 57.81; H, 5.26; N,
11.24, S, 12.86. Found: C, 57.91; H, 5.25; N, 11.13; S, 12.76. O.R.:
[α]2D0 = −110.24 (c = 0.37, DCM).
1b. Beige powder. Yield: 122 mg (22%). Mp: 204−206 °C.
1HNMR (500 MHz, DMSO-d6) δ: 9.92 (s, 2 H, Ha); 8.68 (s, 2 H,
H10 + H9); 8.02 (4 H, m, H2 + H4); 7.62 (2 H, d, J = 7.1 HzHb);
7.59−7.50 (m, 2 HH3); 5.48−4.65 (m, 4 H, Hα + R2); 1.37 (6 H, d,
J = 7.2 Hz, R2); 1.23 (6 H, d, J = 6.4 Hz, R2); 1.21 (6 H, d, J = 6.4
Hz, R1). 13CNMR (126 MHz, DMSO-d6) δ: 182.0; 172.0; 134.8;
132.0; 127.8; 127.0; 126.3; 125.4; 123.7; 116.6; 68.1; 52.8; 21.5;
21.4; 17.5. HRMS: calcd for C28H34N4O4S2 + H 499.1454, 555.2095,
found 555.2100. Anal. Calcd for C28H34N4O4S2: C, 60.62; H, 6.18;
N, 10.10; S, 11.56. Found: C, 60.44; H, 6.21; N, 10.02; S, 11.47.
O.R.: [α]2D0 = −106 (c = 0.503, DCM).
Methyl ester hydrochlorides 7a,e,i,m are commercially available.
Synthesis of other esters was performed as described previously.45
1
Boc-L-AlaOiPr, 6b. Colorless oil. Yield: 3.23 g (70%). HNMR
(400 MHz, DMSO-d6) δ: 7.22 (1 H, d, J = 7.2 Hz); 4.87 (1 H, sept,
J = 6.3 Hz); 3.90 (1 H, p, J = 7.3 Hz); 1.37 (s, 9 H); 1.24−1.12 (m,
9 H). 13CNMR (100 MHz, DMSO-d6) δ: 172.6; 155.3; 78.0; 67.6;
49.2; 28.2; 21.6; 21.5; 16.7. HRMS: calcd for C11H21NO4 + Na
254.13628, found 254.1368. O.R.: [α2D0] = −31.0 (c = 1, MeOH).
1
Boc-L-AlaOnBu, 6c. Colorless oil. Yield: 4.02 g (82%). HNMR
(400 MHz, DMSO-d6) δ: 7.25 (1 H, d, J = 7.3 Hz); 4.12−3.92 (m, 3
H); 1.59−1.48 (m, 2 H); 1.44−1.28 (m, 11 H); 1.22 (3 H, d, J = 7.3
Hz); 0.87 (3 H, t, J = 7.4 Hz). 13CNMR (100 MHz, DMSO-d6) δ:
173.2; 155.3; 78.1; 63.9; 49.1; 30.2; 28.2; 18.6; 16.8; 13.5. HRMS:
C12H23NO4 + Na 268.15193, found 268.1503. O.R.: [α]2D0 = −35.7 (c
= 1.09, MeOH) (lit.:54 [α]D20 = −41).
1
Boc-L-AlaOBn, 6d. Colorless oil. Yield: 2.95 g (53%). HNMR
(400 MHz, DMSO-d6) δ: 7.40−7.30 (m, 1 H); 5.15 (1 H, d, J =
12.7 Hz); 5.08 (1 H, d, J = 12.7 Hz); 4.07 (1 H, quint, J = 7.3 Hz);
1.37 (s, 2 H); 1.26 (1 H, d, J = 7.5 Hz). 13CNMR (100 MHz,
DMSO-d6) δ: 173.0; 155.3; 136.1; 128.4; 128.0; 127.7; 78.2; 65.8;
49.2; 28.2; 16.8. HRMS: calcd for C15H21NO4 + Na 302.13628,
found 302.1381. O.R.: [α]2D0 = 33.6 (c = 1.26, MeOH).
1c. Beige powder. Yield: 163 mg (28%). Mp: 165−168 °C.
1HNMR (500 MHz, DMSO-d6) δ: 9.95 (s, 2 H, Ha), 8.68 (s, 1 H,
H10); 8.67 (s, 1 H, H9); 8.06 (2 H, d, J = 7.3 Hz, H2); 8.02 (2 H, d,
J = 8.5 Hz, H4); 7.60 (2 H, d, J = 7.0 Hz, Hb); 7.58−7.50 (m, 2 H,
F
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H3); 5.00 (2 H, p, J = 7.2 Hz, Hα); 4.19−4.05 (m, 4 H, R2); 1.67−
1.50 (m, 4 H, R2); 1.45−1.24 (m, 10 H, R2); 0.89 (6 H, t, J = 7.4
Hz, R1). 13CNMR (126 MHz, DMSO-d6) δ: 182.0; 172.6; 134.8;
132.1; 127.8; 127.1; 126.4; 125.4; 123.8; 116.7; 64.2; 52.8; 30.1;
18.6; 17.5; 13.5. HRMS: calcd for C30H38N4O4S2 + H 583.2413,
found 583.2406. Anal. Calcd for C30H38N4O4S2: C, 61.83; H, 6.57;
N, 9.61; S, 11.00. Found: C, 61.97; H, 6.51; N, 9.48; S, 10.91. O.R.:
[α]2D0 = −83.3 (c = 0.475, DCM).
C40H42N4O4S2: C, 67.96; H, 5.99; N, 7.93; S, 9.07. Found: C, 67.90;
H, 6.07; N, 7.92; S, 9.05. O.R.: [α]2D0 = −141 (c = 0.5; DCM).
1i. Yellow powder. Yield: 292 mg (45%). Mp: 107−110 °C.
1HNMR (500 MHz, DMSO-d6) δ: 10.05 (s, 2 H, Ha); 8.71 (s, 1 H,
H10); 8.70 (s, 1 H, H9); 8.02 (2 H, d, J = 8.5 Hz, H2); 7.89 (2 H, d,
J = 7.7 Hz, Hb); 7.57−7.45 (m, 2 H, R1); 7.41 (2 H, d, J = 7.0 Hz,
H4); 7.37−7.08 (m, 10 H, H3 + R1); 5.60−4.90 (m, 2 H, Hα);
3.69(s, 6 H, R2); 3.17−3.08 (m, 4 H, R1). 13CNMR (126 MHz,
DMSO-d6) δ: 182.1; 171.7; 136.5; 134.6; 132.1; 129.2; 128.3; 127.8;
127.2; 126.6; 126.5; 125.4; 123.8; 116.5; 58.3; 51.9; 37.1. HRMS:
calcd for C36H34N4O4S2 + H 651.2100, found 651.2087. Anal. Calcd
for C36H34N4O4S2: C, 66.44; H, 5.27; N, 8.61; S, 9.85. Found: C,
66.49; H, 5.54; N, 8.35; S, 9.75. O.R.: [α2D0] = −168.3 (c = 0.485;
DCM).
1j. Yellow powder. Yield: 177 mg (25%). Mp: 101−103 °C.
1HNMR (500 MHz, DMSO-d6) δ: 10.07 (s, 2 H, Ha); 8.73 (s, 1 H,
H10); 8.70 (s, 1 H, H9); 8.03 (2 H, d, J = 7.6 Hz H2); 7.80 (2 H, d,
J = 7.9 Hz, H4); 7.55−7.47 (m, 4 H, H4 + R1); 7.40−7.09 (m, 10 H,
H3 + R1); 5.25−5.17 (m, 2 H, R2); 4.96−4.75 (m, 2 H, Hα); 3.17 (2
H, dd, J = 13.5; 5.9 Hz, R1); 3.09 (2 H, dd, J = 13.5; 7.1 Hz, R1);
1.13 (6 H, d, J = 6.2 Hz, R2); 1.05 (6 H, d, J = 6.2 Hz, R2).
13CNMR (126 MHz, DMSO-d6) δ: 181.9; 170.6; 136.5; 134.6;
132.1; 129.2; 128.3; 127.8; 127.2; 126.6; 126.5; 125.4; 123.8; 116.5;
68.3; 58.2; 37.2; 21.4; 21.3. HRMS: calcd for C40H42N4O4S2 + H
707.2726, found 707.2726. Anal. Calcd for C40H42N4O4S2: C, 67.96;
H, 5.99; N, 7.93; S, 9.07. Found: C, 67.74; C, 6.17; N, 7.83; S, 9.16.
O.R.: [α]2D0 = −129.3 (c = 0.55; DCM).
1k. Yellow powder. Yield: 257 mg (35%). Mp: 71−75 °C.
1HNMR (500 MHz, DMSO-d6) δ: 10.07 (s, 2 H, Ha); 8.72 (s, 1 H,
H10); 8.70 (s, 1 H, H9); 8.03 (2 H, d, J = 8.5 Hz, H2); 7.82 (2 H, d,
J = 7.6 Hz, H4); 7.56−7.48 (m, 2 H, R1); 7.45 (2 H, d, J = 7.0 Hz,
Hb); 7.30−7.17 (m, 6 H, R1); 7.13 (4 H, m, H3 + R1); 5.30−5.23
(m, 2 H, Hα); 4.04−3.92 (m, 4 H, R2); 3.16 (2 H, dd, J = 13.8; 6.2
Hz, R1); 3.09 (2 H, dd, J = 13.6; 6.9 Hz, R1); 1.49−1.40 (m, 4 H,
R2); 1.25−1.16 (m, 4 H, R2); 0.82 (6 H, t, J = 7.4 Hz, R2). 13CNMR
(126 MHz, DMSO-d6) δ: 182.4; 171.7; 136.9; 135.1; 132.5; 129.6;
128.7; 128.2; 127.7; 127.1; 127.0; 125.8; 124.3; 117.0; 64.8; 58.8;
37.7; 30.4; 18.9; 14.0. HRMS: calcd for C42H46N4O4S2 + H
735.3039, found: 735.3034. Anal. Calcd for C42H46N4O4S2: C, 68.64;
H, 6.31; N, 7.62; S, 8.73. Found: C, 68.45; H, 6.50; N, 7.54; S, 8.80.
O.R.: [α]2D0 = 136.9 (c = 0.55; DCM).
1d. Yellow powder. Yield: 240 mg (37%). Mp: 99−101 °C.
1HNMR (500 MHz, DMSO-d6) δ: 9.93 (s, 2 H, Ha); 8.68 (s, 1 H,
H10); 8.67 (s, 1 H, H9); 8.15 (2 H, d, J = 7.3 Hz, H2); 8.01 (2 H, d,
J = 8.4 Hz, H4); 7.56 (2 H, d, J = 6.9 Hz, Hb); 7.53−7.46 (m, 2 H,
H3); 7.45−7.28 (m, 10 H, R2); 5.17 (4 H, s, R2); 5.14−4.95 (m, 2
H, Hα); 1.40 (6 H, d, J = 7.2 Hz, R1). 13CNMR (126 MHz, DMSO-
d6) δ: 182.5; 172.9; 136.4; 135.3; 132.5; 128.9; 128.5; 128.3; 128.3;
127.5; 126.9; 125.9; 124.2; 117.1; 66.5; 53.4; 17.8. HRMS: calcd for
C36H34N4O4S2 + H 651.2100, found 651.2100. Anal. Calcd for
C36H34N4O4S2: C, 66.44; H, 5.27; N, 8.61; S, 9.85. Found: C, 66.45;
H, 5.36; N, 8.34; S, 9.70. O.R.: [α]2D0 = −89.45 (c = 0.45; DCM).
1e. Yellow powder. Yield: 250 mg (45%). Mp: 177−179 °C.
1HNMR (500 MHz, DMSO-d6) δ: 10.05 (s, 2 H, Ha); 8.73 (s, 1 H,
H10); 8.68 (s, 1 H, H9); 8.08 (2 H, d, J = 7.6 Hz, H4); 7.99 (2 H, d,
J = 8.5 Hz, H2); 7.80 (2 H, d, J = 7.0 Hz, Hb); 7.54 (2 H, t, J = 7.8
Hz, H3); 4.95 (2 H, dd, J = 7.6; 5.3 Hz, Hα); 3.70 (s, 6 H); 2.26−
2.15 (m, 2 H); 0.98 (12 H, s, J = 6.7 Hz). 13CNMR (126 MHz,
DMSO-d6) δ: 182.7; 171.9; 134.9; 131.9; 127.5; 127.3; 125.9; 125.2;
123.4; 115.4; 62.0; 51.7; 30.6; 18.7; 18.5. HRMS: calcd for
C28H34N4O4S2 555.2100, found 555.2096. Anal. Calcd for
C28H34N4O4S2: C, 60.62; H, 6.18; N, 10.10; S, 11.56. Found: C,
60.55; H, 6.09; N, 9.95; S, 11.62. O.R.: [α]2D0 = −220 (c = 0.55;
DCM).
1f. Yellow powder. Yield: 183 mg (30%). Mp: 200−204 °C.
1HNMR (500 MHz, DMSO-d6) δ: 10.08 (s, 2 H, Ha); 8.74 (s, 1 H,
H10); 8.68 (s, 1 H, H9); 8.06−7.86 (m, 4 H, H2 + H4); 7.81 (2 H, d,
J = 7.1 Hz, Hb); 7.54 (2 H, t, J = 7.8 Hz), H3; 5.07−4.92 (m, 2 H,
R2); 4.88 (2 H, dd, J = 7.7; 5.0 Hz, Hα); 2.31−2.15 (m, 2 H, R1);
1.24 (6 H, d, J = 6.6 Hz, R2); 1.23 (6 H, d, J = 6.8 Hz, R2); 1.00−
0.93 (12 H, m, J = 6.7 Hz, R1). 13CNMR (126 MHz, DMSO-d6) δ:
182.5; 170.7; 134.9; 131.9; 127.5; 127.3; 125.8; 125.2; 123.3; 115.4;
68.1; 61.9; 30.6; 21.6; 21.5; 18.58; 18.58. HRMS: calcd for
C32H42N4O4S2 + H 611.2726, found 611.2733. Anal. Calcd for
C32H42N4O4S2: C, 62.92; H, 6.93; N, 9.17; S, 10.50. Found: C,
63.08; H, 7.00; N, 9.16; S, 10.56. O.R.: [α]2D0 = −159.5 (c = 0.485;
DCM).
1g. Yellow powder. Yield: 185 mg (29%). Mp: 173−175 °C.
1HNMR (500 MHz, DMSO-d6) δ: 10.07 (s, 2 H, Ha); 8.73 (s, 1 H,
H10); 8.68 (s, 1 H, H9); 8.07−7.92 (m, 4 H, H2 + H4); 7.80 (2 H, d,
J = 7.1 Hz, Hb); 7.54 (2 H, t, J = 7.8 Hz, H3); 4.93 (2 H, dd, J =
7.8; 5.2 Hz, Hα); 4.29−3.90 (m, 4 H, R2); 2.27−2.14 (m, 2 H, R1);
1.74−1.52 (m, 4 H, R2); 1.41−1.32 (m, 4 H, R2); 0.97 (12 H, d, J =
6.9 Hz, R1); 0.90 (6 H, t, J = 7.4 Hz, R2). 13CNMR (126 MHz,
DMSO-d6) δ: 182.6; 171.3; 134.8; 131.9; 127.5; 127.3; 125.8; 125.2;
123.3; 115.4; 64.1; 62.0; 30.6; 30.1; 18.7; 18.6; 18.4; 13.4. HRMS:
calcd for C34H46N4O4S2 + H 639.3027, found 639.3050. Anal. Calcd
for C34H46N4O4S2: C, 63.92; H, 7.26; N, 8.77; S, 10.04. Found: C,
63.65; H, 7.06; N, 8.68; S, 10.15. O.R.: [α]2D0 = −172.0 (c = 0.62;
DCM).
1h. Yellow powder. Yield: 148 mg (21%). Mp: 153−156 °C.
1HNMR (500 MHz, DMSO-d6) δ: 10.08 (s, 2 H, Ha); 8.73 (s, 1 H,
H10); 8.68 (s, 1 H, H9); 8.08 (2 H, d, J = 7.7 Hz, H2); 7.99 (2 H, d,
J = 8.5 Hz, H4); 7.79 (2 H, d, J = 7.0 Hz, Hb); 7.63−7.48 (m, 2 H,
H3); 7.48−7.30 (m, 10 H, R2); 5.22 (2 H, d, J = 12.4 Hz, R2); 5.17
(2 H, d, J = 12.4 Hz, R2); 4.98 (2 H, dd, J = 7.7; 5.2 Hz, Hα); 2.27−
2.15 (m, 2 H, R1); 0.96 (6 H, d, J = 7.1 Hz, R1); 0.94 (6 H, d, J =
7.1 Hz, R1). 13CNMR (126 MHz, DMSO-d6) δ: 182.7; 171.2; 135.8;
134.8; 131.9; 128.4; 128.09; 128.05; 127.5; 127.3; 127.1; 125.8;
125.2; 123.3; 115.5; 66.0; 62.1; 30.6; 18.7; 18.4. HRMS: calcd for
C40H42N4O4S2 + H 707.2726, found 707.2706. Anal. Calcd for
1l. Yellow powder. Yield: 297 mg (37%). Mp: 99−101 °C.
1HNMR (500 MHz, DMSO-d6) δ: 10.05 (s, 2 H, Ha); 8.71 (s, 1 H,
H10); 8.70 (s, 1 H, H9); 8.02 (2 H, d, J = 8.5 Hz, H2); 7.89 (2 H, d,
J = 7.7 Hz, Hb); 7.57−7.45 (m, 2 H, R1); 7.41 (2 H, d, J = 7.0 Hz,
H4); 7.37−7.08 (m, 10 H, H3 + R1); 5.22 (2 H, d, J = 12.4 Hz, R2);
5.17 (2 H, d, J = 12.4 Hz, R2); 5.10−4.90 (m, 2 H, Hα); 3.69(s, 6 H,
R2); 3.17−3.08 (m, 4 H, R1). 13CNMR (100 MHz, DMSO-d6) δ:
181.8; 171.6; 137.7; 137.1; 135.6; 135.4; 129.4; 129.1; 128.3; 128.2;
127.2; 124.6; 123.4; 120.4; 119.7; 116.2; 66.7; 55.8; 37.6. HRMS:
calcd for C48H42n4O4S2 + H 803.2726, found 803.2715. O.R.: [α]D20
−149.8 (c = 0.46; DCM).
=
1m. Yellow powder. Yield: 240 mg (37%). Mp: 154−157 °C.
1HNMR (500 MHz, DMSO-d6) δ: 10.87 (s, 2 H, Ha); 10.07 (s, 2 H,
R1); 8.74 (s, 1 H, H10); 8.68 (s, 1 H, H9); 8.00 (2 H, d, J = 7.7 Hz,
Hb); 7.84 (2 H, d, J = 6.5 Hz, H4); 7.53−7.40 (m, 6 H, R1 + H3);
7.34 (2 H, d, J = 8.0 Hz); 7.12−6.98 (m, 4 H, R1); 6.93 (2 H, t, J =
7.3 Hz, R1); 5.37−5.28 (m, 2 Hα); 3.31 (s, 4 H, R1). 13CNMR (126
MHz, DMSO-d6) δ: 181.9; 172.1; 136.0; 134.7; 132.0; 127.7; 127.2;
127.1; 126.3; 125.3; 123.9; 123.6; 121.0; 118.4; 118.1; 116.4; 111.4;
108.6; 57.8; 51.9; 27.2. HRMS: calcd for C40H36N4O4S2 + H
729.2318, found 729.2315. Anal. Calcd for C40H36N6O4S2: C, 65.91;
H, 4.98; N, 11.53; S, 8.80. Found: C, 65.00; H, 5.15; N, 11.14; S,
8.63.
Competitive titrations47 were conducted in MeCN-d3 (0.05%
H2O, Eurisotop, packed in vial with septum) on a mixture of chiral
host (∼0.01 M) and achiral reference 9 (∼0.005 M); the differences
in concentrations enabled unambiguous assignment of signals. To
this mixture were added aliquots of solution of homochiral guest in
G
DOI: 10.1021/acs.joc.5b00403
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
several steps until [G]0 ≈ [H] + [Href]. Changes in chemical shifts of
inner urea protons were followed. Ratios of association constants
were calculated according to the equation
max
(11) Qin, H.; He, Y.; Qing, G.; Hu, C.; Yang, X. Tetrahedron:
Asymmetry 2006, 17, 2143−2148.
(12) Xu, K.; He, Y.; Qing, G.; Qin, H.; Liu, S.; Meng, L. Chin. J.
Chem. 2007, 25, 390−394.
Δδ
ref
− 1
(13) Xu, K.-x.; Qing, G.-y.; He, Y.-b.; Qin, H.-j.; Hu, L. Supramol.
Chem. 2007, 19, 403−409.
(14) Yakovenko, A. V.; Boyko, V. I.; Kalchenko, V. I.; Baldini, L.;
Casnati, A.; Sansone, F.; Ungaro, R. J. Org. Chem. 2007, 72, 3223−
31.
KH
Kref
Δδref
ΔδHmax
ΔδH
Krel
=
=
− 1
(1)
where Δδmax correspond to chemical shift of the pure supermolecule
max
ref
(host fully saturated with guest). Δδ values for the complexes of
(15) Qing, G.-y.; He, Y.-b.; Wang, F.; Qin, H.-j.; Hu, C.-g.; Yang, X.
the achiral receptor with both anions were determined in separate
experiments, by classical NMR titration. Two parameters: ΔδmHax and
Krel were fitted to obtain the best match between calculated and
experimental values by Origin software (OriginPro 8, OriginLab
Corp., Northampton, MA) curve-fitting algorithm:
Eur. J. Org. Chem. 2007, 2007, 1768−1778.
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Asymmetry 2007, 18, 1769−1774.
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Hong, J.; Ham, S.; Sessler, J. L.; Lee, C.-H. Angew. Chem., Int. Ed.
2007, 46, 2508−11.
KrelΔδHmax
ΔδH
=
max
ref
(18) Jadhav, V. D.; Schmidtchen, F. P. J. Org. Chem. 2008, 73,
1077−87.
Δδ
Krel
+
− 1
Δδref
(2)
(19) Willener, Y.; Joly, K. M.; Moody, C. J.; Tucker, J. H. R. J. Org.
Chem. 2008, 73, 1225−33.
The latter equation does not include any variable referring to the
concentrations of the reagents; therefore, mixtures of any (even
unknown) compositions may be used. This eliminates the common
errors arising from errors in concentrations. In addition, lower purity
of hosts and guest does not affect the results (only if the impurities
do not significantly change the chemical shifts). Lowest error is
obtained for data points with 0.1 < Δδ/Δδmax < 0.9. Uncertainty of
the single competitive titration was calculated by an Origin fitting
algorithm (asymptotic error). The uncertainty of enantioselectivity
was calculated according to the following formula: Δα/α = ((ΔKrSel/
(20) Wang, H.; Chan, W.-h.; Lee, A. W. M. Org. Biomol. Chem.
2008, 6, 929−34.
(21) Choi, M. K.; Kim, H. N.; Choi, H. J.; Yoon, J.; Hyun, M. H.
Tetrahedron Lett. 2008, 49, 4522−4525.
(22) Kim, Y. K.; Lee, H. N.; Singh, N. J.; Choi, H. J.; Xue, J. Y.;
Kim, K. S.; Yoon, J.; Hyun, M. H. J. Org. Chem. 2008, 73, 301−4.
(23) Bartoli, S.; Mahmood, T.; Malik, A.; Dixon, S.; Kilburn, J. D.
Org. Biomol. Chem. 2008, 6, 2340−5.
KrSel)2 + (ΔKRrel/KRrel)2)1/2
.
(24) Su, X.; Luo, K.; Xiang, Q.; Lan, J.; Xie, R. Chirality 2009, 21,
539−46.
(25) Huang, X.-h.; He, Y.-b.; Hu, C.-g.; Chen, Z.-h. J. Fluoresc.
2009, 19, 97−104.
ASSOCIATED CONTENT
* Supporting Information
Titration plots and NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
(26) Qing, G.-y.; Sun, T.-l.; Wang, F.; He, Y.-b.; Yang, X. Eur. J.
Org. Chem. 2009, 2009, 841−849.
(27) Qing, G.; Sun, T.; Chen, Z.; Yang, X.; Wu, X.; He, Y. Chirality
2009, 21, 363−73.
AUTHOR INFORMATION
Corresponding Author
*E-mail: janusz.jurczak@icho.edu.pl
(28) Bois, J.; Bonnamour, I.; Duchamp, C.; Parrot-Lopez, H.;
Darbost, U.; Felix, C. New J. Chem. 2009, 33, 2128.
(29) Lu, Q.-s.; Dong, L.; Zhang, J.; Li, J.; Jiang, L.; Huang, Y.; Qin,
S.; Hu, C.-w.; Yu, X.-q. Org. Lett. 2009, 11, 669−72.
(30) Swamy, K. M. K.; Jiten Singh, N.; Yoo, J.; Kwon, S. K.;
Chung, S.-Y.; Lee, C.-H.; Yoon, J. J. Inclusion Phenom. Macrocycl.
Chem. 2009, 66, 107−111.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financed by a Polish National Science Centre
grant (Maestro UMO-2011/02/A/ST5/00439).
(31) Yang, L.; Qin, S.; Su, X.; Yang, F.; You, J.; Hu, C.; Xie, R.;
Lan, J. Org. Biomol. Chem. 2010, 8, 339−48.
(32) Xu, K.-x.; Yang, L.-r.; Wang, Y.-X.; Zhao, J.; Wang.-j, C.
Supramol. Chem. 2010, 22, 563−570.
■
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