Enantiomeric recognition of carboxylic anions by a library of neutral receptors derived from α-amino acids and o-phenylenediamine

Article abstract of DOI:10.1016/j.tetasy.2014.06.004

A library of eight neutral anion receptors consisting of α-amino acid esters attached to o-phenylenediamine by urea groups was synthesized and analysed in terms of capacity for chiral recognition of carboxylates. The NMR titrations revealed that the assoc

Full text of DOI:10.1016/j.tetasy.2014.06.004

Tetrahedron: Asymmetry 25 (2014) 962–968
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Tetrahedron: Asymmetry
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Enantiomeric recognition of carboxylic anions by a library of neutral
receptors derived from a-amino acids and o-phenylenediamine
⇑
Filip Ulatowski, Janusz Jurczak
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 March 2014
Accepted 6 June 2014
A library of eight neutral anion receptors consisting of
a-amino acid esters attached to o-phenylenedi-
amine by urea groups was synthesized and analysed in terms of capacity for chiral recognition of carbox-
ylates. The NMR titrations revealed that the association constants of complexes consisting of a chiral
guest and a chiral host are two orders of magnitude lower than those of achiral partners. Diverse substit-
uents in the receptor structure modify both the affinities and enantioselectivities.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
group, which are potent hydrogen bond donors that are very useful
in the anion binding process.3–10
Carboxylic acids are one of the most common and relevant types
of organic molecules found in living organisms. The great majority
of them are chiral, that is, the lactic, mandelic, tartaric, gluconic and
In view of the above considerations we decided to synthesize and
evaluate a family of C2 symmetrical receptors where the amino acid
moieties are bonded to the core unit by urea groups. Herein we
report work using the simple and readily available o-phenylenedi-
amine as the model core unit11 (1, Fig. 1). Two urea groups in close
proximity should allow high anion affinity while the amino acid side
chains constitute the chiral environment for the guest. The amino
acids, valine (R1 = iPr) and phenylalanine (R1 = Bn), were used, as
representatives of aliphatic and aromatic side chains, respectively.
For the modification of the C-terminus (R2), we used methyl, isopro-
pyl, n-butyl, and benzyl alcohols representing the small, bulky, long
chain, and aromatic groups, respectively. As model anions we
decided to use mandelate (Man) and N-acetylphenylalanine (AcPhe)
anions, both as tetrabutylammonium (TBA) salts.
above all
such as non-steroidal anti-inflammatory drugs (NSAI) (e.g.,
naproxen, ibuprofen, ketoprofen and baclofen), -DOPA, many anti-
a-amino acids. They are also frequently found in drugs,
L
biotics (penicillin), etc. In most cases, each enantiomer of an acid
possesses different biological activity.1 It should be noted that car-
boxylic acids exist in their dissociated form at physiological pH.
Therefore the supramolecular chemistry of acids resembling bio-
logical interactions should in fact be the chemistry of carboxylate
anions. It is mainly the biological relevance of chiral carboxylates
that makes their chiral recognition of prime importance.
Very little is known about the process of chiral recognition.
Some models, for instance the three-point-binding model,2 give
us a general idea of the phenomenon but do not support any
details on preferable receptor structures. Therefore, the most valu-
able method for examining chiral recognition remains evaluating a
library of receptors with systematically varying structures. Analy-
sis of such a library in terms of structure versus binding abilities
may provide guidelines ref designing novel receptors.
O
O
R1
NH
HN
R1
NH
HN
R2OOC
COOR2
Natural amino acids are very useful building blocks in the syn-
thesis of such libraries. They are a readily available source of chiral-
ity, with side chains that vary in size, polarity and hydrogen bond
acceptor/donor abilities. Moreover, both their C- and N-termini
may be easily modified with a large range of moieties. Their amino
group may, for example, be incorporated into an amide or urea
1
Figure 1. General structure of urea type receptors.
2. Results and discussion
The synthesis of the receptors 1a–h is outlined in Scheme 1.
Commercially available hydrochlorides of methyl esters of amino
acids 2a and 2e were reacted with triphosgene and the resulting
⇑
Corresponding author. Tel.: +48 223432330; fax: +48 226326681.
E-mail address: janusz.jurczak@icho.edu.pl (J. Jurczak).
http://dx.doi.org/10.1016/j.tetasy.2014.06.004
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

F. Ulatowski, J. Jurczak / Tetrahedron: Asymmetry 25 (2014) 962–968
963
R1
R1
O
O
triphosgene
NH3+Cl-
NCO
OR2
OR2
1 = iPr, R2 = Me
2e R1 = Bn, R2 = Me
2i
3a
R
1 = iPr, R2 = Me
2a
R
3e R1 = Bn, R2 = Me
1 = H, R2 = Et
3i
R
1 = H, R2 = Et
R
R1
R1
R1
R2OH, EDCl
1) HCl
O
O
NCO
NHBoc
O
NHBoc
2) phosgene
OR2
OH
4a
OR2
R
1 = iPr
4b R1 = Bn
5b
3b
R
1 = iPr, R2 = iPr
R
1 = iPr, R2 = iPr
5c R1 = iPr, R2 = nBu
3c R1 = iPr, R2 = nBu
Val
Val
5d
3d
R
R
1 = iPr, R2 = Bn
1 = iPr, R2 = Bn
5f R1 = Bn, R2 = iPr
3f R1 = Bn, R2 = iPr
5g
3g
R
R
1 = Bn, R2 = nBu
1 = Bn, R2 = nBu
Phe
Phe
5h R1 = Bn, R2 = Bn
3h R1 = Bn, R2 = Bn
O
O
NH2
NH2
R1
NH
HN
R1
3a-i
+
NH
HN
R2OOC
COOR2
6
1a
R
1 = iPr, R2 = Me
1b R1 = iPr, R2 = iPr
Val
1c
R
1 = iPr, R2 = nBu
1d R1 = iPr, R2 = Bn
1e
R
1 = Bn, R2 = Me
1f R1 = Bn, R2 = iPr
Phe
Gly
1g
R
1 = Bn, R2 = nBu
1h R1 = Bn, R2 = Bn
1i R1 = H, R2 = Et
Scheme 1. Synthesis of receptors 1a–i.
isocyanates 3a and 3e were distilled under reduced pressure before
reaction with o-phenylenediamine, to yield receptors 1a and 1e.
Two Boc protected amino acids 4a and 4e were esterified with
isopropyl, n-butyl and benzyl alcohols in the presence of 1-ethyl-
3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI)
and 4-(dimethylamino)pyridine (DMAP) to afford products 5b–d,
5f–h in good yields.12 The amino group was then deprotected
and transformed into an isocyanate with phosgene;13 the two-step
sequence proceeded quantitatively and isocyanates 3b–d, 3f–h
were used without further purification. The isocyanates were
reacted with o-phenylenediamine (oDAB) to produce the respec-
tive receptors in moderate yields. The final products were purified
by flash chromatography and crystallized. Additionally, two
In our preliminary studies we decided to compare the binding
affinities of the chiral receptors with an achiral receptor equipped
with phenyl groups in the side arms, which are typical for studies
in the field of achiral anions. One of the chiral receptors 1a, achiral
1i, and the model achiral receptor 7 were titrated with benzoate
(BzO), (S)-mandelate, and N-acetyl-L-phenylalanine as tetrabutyl-
ammonium salts in DMSO-d6 + 0.5% H2Oà (Table 1). For all recep-
tors, the association constants of the complexes increase in the
following order: Man, AcPhe, and BzO, which reflects the electron
densities in the carboxylate group and is consistent with other
reports.14,15 Similarly, for all guests employed, amino acid based
receptors 1a, 1e exhibit lower affinities. This indicates that aliphatic
side chains result in a reduction of anion affinities due to changes in
electron density in the urea groups.16,17 When changing from achiral
benzoate to chiral Man and AcPhe anions the association constants
for complexes with all receptors decreased but the complexes with
chiral receptor 1a are mostly affected. This effect must be attributed
to the steric effects; both the host and guest in the Man-1a or AcPhe-
1a pairs are quite bulky and exhibit repulsive interactions between
their side-chains. Overall, the association constant of the complex
of chiral receptor 1a with the mandelate, the model chiral guest is
nearly two orders of magnitude lower than the Ka of the achiral
receptor achiral with the model chiral benzoate. These titrations
show that examination of chiral recognition requires that the most
effective receptor architectures developed so far should be
employed, otherwise no binding may occur in competitive solvents.
Due to the low association constant for the (S)-Man 1a complex
in DMSO (Ka = 29 Mꢀ1) we decided to use a less competitive sol-
vent, acetonitrile, which is another standard solvent in the field
receptors
starting from
Boc- -phenylalanine, respectively. The racemic mixtures, obtained
D
-1e and
D-1f were synthesized by following two paths
D
-phenylalanine methyl ester hydrochloride and
D
by mixing the pairs of enantiomeric receptors, were successfully
resolved using chiral HPLC and the enantiomeric purities of the
representative receptors 1e and 1f were determined to be >99%
ee. An alternative synthetic pathway, that would be more useful
in the synthesis of multiple analogues was tested. Ester 1a was
hydrolysed to a corresponding diacid, which we attempted to
transform into another ester; however, the standard reaction of
EDCI and the appropriate alcohol failed.
An achiral model compound was synthesized according to the
literature.11
O
O
NH
HN
NH
HN
à
0.5% water content is used for standardisation of measurements in hygroscopic
7
DMSO.

964
F. Ulatowski, J. Jurczak / Tetrahedron: Asymmetry 25 (2014) 962–968
Table 1
Comparison of the binding affinities of achiral and chiral receptors towards achiral and chiral anionsa
Receptor
O
O
O
O
O
O
Anion
NH HN
NH HN
NH HN
NH
HN
NH
HN
NH
HN
EtOOC
COOEt
MeOOC
COOMe
7
1i
1a
O
1300b
O-
325
21
605
29
OH
O-
152
890
O
O
O-
145
198
NHAc
b Ref. 11.
a
Association constants (Mꢀ1) determined by 1H NMR titrations in DMSO-d6 + 0.5% H2O (298K, errors estimated to be 10%, anions used as TBA salts).
Table 2
of anion binding. The association constant was found to be
Association constants and selectivities of receptors 1a–h with mandelates
ꢁ7000 Mꢀ1. In both solvents the stoichiometry of the complexes
with all carboxylates was 1:1, as indicated by the Job plots and sto-
chastic distribution of residuals.
Regardless of the level of the association constants, they must
be determined with the highest possible precision since the ratio
of (R)- and (S)-guest association constants (KR/KS) rarely exceeds
2.18 We decided to employ the competitive titration method,19
which is insensitive to the errors in concentrations and gives more
accurate results. We tried to determine the enantioselectivity
(a = KS/KR) in a single experiment by titration of a racemic mixture
of anionic guest with a homochiral receptor.20–23 The addition of a
receptor resulted in a shift of signals of the anions, but the splitting
of the signals of the enantiomers was too small for all of the recep-
tors tested. We therefore determined the relative association con-
stants using an achiral receptor 1i. Mixtures of the given chiral
receptor and the achiral reference were titrated with a homochiral
TBA salt. The ratio of the two relative association constants gave
the enantioselectivity a:
KS
KrSel
¼
¼
ð1Þ
ð2Þ
Table 3
Kref
Association constants and selectivities of receptors with N-acetylphenylalanine
anions
KR
Kref
KrRel
KrSel
KrRel
¼
a
ð3Þ
We determined the Kref for 1f with Man and AcPhe by UV–Vis
titration, and used these values to recalculate the relative associa-
tion constants of chiral receptors into absolute ones (Tables 2 and
3). The Ka values for 1a–h with Man are in the range of
0.76–1.1 ꢂ 104 Mꢀ1, while with the AcPhe anion the values are
on average eight times higher: 6.2–9.1 ꢂ 104 Mꢀ1. The distribution
of association constants among the family of receptors 1, presented
in Figure 2, indicate the moderate influence of the R1 and R2 groups
on the anion binding affinity. The valine based receptors a–d

F. Ulatowski, J. Jurczak / Tetrahedron: Asymmetry 25 (2014) 962–968
965
0.05
a
(S) - Man
(R)- Man
0.2
10000
8000
6000
4000
2000
0
K’
S (Taft)
0.00
E
0.0
- 0.2
- 0.4
- 0.6
- 0.05
- 0.10
- 0.15
M e
iPr
nBu
Bn
a
b
c
d
e
f
g
h
R1
Receptor
Figure 3. Distribution of reduced association constants (K0, left axis) and their
comparison with Taft steric parameters (ES, right axis).
D-AcPhe
L- AcPhe
b
80000
60000
40000
20000
0
0.02
a
Man
0.00
a
b
c
d
e
f
g
h
-0.02
-0.04
a
b
c
d
e
f
g
h
Receptor
b
AcPhe
Figure 2. Graphical comparison of association constants of receptors 1 with (a)
mandelate, and (b) N-acetylphenylalanine enantiomers.
0.04
0.02
exhibit slightly higher binding affinities for both anions tested
compared to the phenylalanine based receptors e–h with the same
R2 moiety. The isopropyl group is more bulky then the benzyl one
according to the Taft steric parameters24,25 ES (ꢀ0.47 and ꢀ0.38,
respectively); therefore an opposite observation was expected.
The dependence of the association constant on the R2 moiety is
also visible and is consistent for both R1 groups and both anions;
the Ka values increase in the following order: iPr < nBu < Bn < Me.
The reduced association constants (K0 ¼ K=KR2¼Me) are in a qualita-
tive correlation with Taft steric parameters (ES) (Fig. 3), except for
the benzyl moieties, which seem to increase the affinity towards
the model anions by either by preorganisation of receptor struc-
0.00
a
b
c
d
e
f
g
h
-0.02
-0.04
Figure 4. Plots of enantioselectivities of receptors 1a–h with (a) mandelate, and (b)
N-acetylphenylalanine.
ture (entropy) or by additional
(enthalpy).
p–p attractive interactions
responsible for the observed selectivity. Only a proper combination
of the two groups may result in the desired properties.
The enantioselectivities of the receptor family towards both
anions tested were low. The highest observed value was 1.09 for
1d with the AcPhe anion; the most successful receptor for mandel-
ate was 1e. The distribution of selectivities among the receptors is
stochastic (Fig. 4); it is therefore impossible to perform a struc-
ture–enantioselectivity correlation. A preference for the (R)-man-
delate can be observed among the library, however the
magnitude of the selectivity cannot be rationalised. In the case of
AcPhe guests, the selectivity distribution is more complicated;
3. Conclusion
Herein we have proven that supramolecular complexes with chi-
ral components are less stable compared to achiral receptors and
typical achiral guests, which makes the investigation of chiral recog-
nition even more demanding. We have synthesised a series of eight
receptors 1, which proved successful in the chiral recognition of two
model carboxylates. This small combinatorial study indicates that
there are no preferable substituents, whose application will result
in high selectivity. Preparing an efficient receptor requires a
fine tuning of its side arms, including both amino acid and its
receptors 1a–c exhibit a preference for
L-AcPhe, while receptors
1d–g bind -AcPhe anion more strongly (1h showed no selectivity).
D
Hosts 1e,f were successful in the chiral recognition of both model
anions. In neither case was the presence of a specific R1 or R2 group

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F. Ulatowski, J. Jurczak / Tetrahedron: Asymmetry 25 (2014) 962–968
C-terminus. So far no generalisation on the structure—chiral recog-
nition correlation can be made. It is very likely that only a large-scale
combinatorial approach will result in efficient receptors and guide-
lines on their preferable structures. This work demonstrates that a
variety of esters of amino acids can be easily synthesized and trans-
formed into urea type receptors via the corresponding isocyanates.
Many core units known to bind anions efficiently are also bisam-
ines.16,26–28 We plan to employ them with amino acid side chains
in the future investigations of the chiral recognition of carboxylates.
4.08–3.93 (2H, m), 2.97 (1H, dd, J = 13.7, 5.6 Hz), 2.87 (1H, dd,
J = 13.7, 9.5 Hz), 1.54–1.39 (2H, m), 1.32 (9H, s), 1.31–1.17 (2H,
m), 0.85 (3H, t, J = 7.4 Hz); dC (126 MHz, DMSO) 172.1, 155.3,
137.6, 129.0, 128.1, 126.4, 78.2, 64.0, 55.3, 36.5, 30.1, 28.1, 18.5,
13.5; HRMS (ESI, [M+Na]+): calcd for (C18H27NO4+Na+)
344.18323, found: 344.18309, [
a
]
D
20 = ꢀ7.55 (c 1.46, MeOH).
Boc-Phe-OBn 5h: white crystals (1.98 g, 56%), mp 64–65 °C
(Lit.30 62–63 °C), dH (600 MHz, DMSO) 7.54–7.01 (11H, m), 5.10
(2H, s), 4.22 (1H, ddd, J = 9.8, 8.1, 5.5 Hz), 3.01 (1H, dd, J = 13.7,
5.4 Hz), 2.90 (1H, dd, J = 13.7, 9.9 Hz), 1.32 (9H, s). dC (151 MHz,
DMSO) 172.0, 155.4, 137.5, 135.8, 129.1, 128.3, 128.2, 128.0,
127.7, 126.4, 78.3, 65.9, 55.4, 36.3, 28.1. HRMS (ESI, [M+Na]+):
calcd for (C21H25NO4+Na+) 378.16758, found: 378.16725,
4. Experimental
4.1. Syntheses: General remarks
[a]
20 = ꢀ11.6 (c 1.06, MeOH) (Lit.29 ꢀ10).
D
All reagents and solvents were of purest p.a. quality. Dichloro-
methane for reactions with EDCI or isocyanates was distilled over
CaH2. Column chromatography was performed with silica gel 60
(60–230 mesh).
4.1.2. Synthesis of receptors 1a,e
Caution: All operations with triphosgene should be carried in a
well ventilated hood, and the rotary evaporator should be
equipped with a water jet pump to adsorb the gaseous phosgene.
Amino acid methyl ester hydrochloride (20 mmol) was sus-
pended in toluene (50 mL), after which triphosgene (1.32 g,
13.3 mmol) was added and the well stirred mixture was heated
at reflux. HCl evolving through the top of the condenser was
trapped in water. After 3 h of reflux, the solution was evaporated
on a rotary evaporator and the crude isocyanate was purified by
distillation under reduced pressure (89 °C/4 torr for Val and
115 °C/4 torr for Phe). Yield 80% (Val), 84% (Phe). The pure isocya-
nate (15 mmol) was dissolved in dichloromethane (20 mL) and o-
phenylenediamine (540 mg, 5 mmol) was added. The mixture
was stirred for 24 h. If some precipitate was formed, dichlorometh-
ane was added to dissolve it, and the solution was directly poured
onto the top of a chromatographic column (silica gel). The chroma-
tography proceeded with 5–10% acetone in dichloromethane as the
eluent. The product was then dissolved in a minimal volume of hot
acetone, after which the same volume of water was added and ace-
tone was slowly removed on a rotary evaporator to yield a white
powder which was filtered off and dried in vacuo.
4.1.1. Synthesis of esters 5b–d,f–h: general procedure
To a solution of Boc protected amino acid (10 mmol) in dichlo-
romethane (50 mL) at 0 °C was added the appropriate alcohol
(20 mmol) followed by EDCI (11 mmol) and DMAP (1 mmol). The
mixture was allowed to reach room temperature and was stirred
for 12 h. It was then concentrated to ca. 20 mL on a rotary evapo-
rator. Ethyl acetate (80 mL) was added, and the organic phase was
washed with 10% NaHSO4 (2 ꢂ 50 mL), saturated NaHCO3
(2 ꢂ 50 mL) and brine (20 mL). The organic phase was then dried
over magnesium sulfate and concentrated. Isopropyl and n-butyl
esters were sufficiently pure enough to be used in the next step,
while benzyl esters 5d,h were purified by chromatography (silica
gel, hexanes/ethyl acetate 7:3) to remove the excess of benzyl
alcohol.
Boc-Val-OiPr 5b: colourless oil (1.92 g, 74%), dH (500 MHz,
DMSO) 7.06 (1H, d, J = 8.0 Hz), 4.91 (1H, sept, J = 6.4 Hz), 3.84–
3.63 (1H, m), 2.13–1.83 (1H, m), 1.39 (9H, s), 1.19 (3H, d,
J = 6.3 Hz), 1.17 (3H, d, J = 6.2 Hz), 0.87 (6H, d, J = 6.7 Hz); dC
(126 MHz, DMSO) 171.4, 155.7, 78.1, 67.5, 59.5, 29.5, 28.2, 21.6,
21.5, 18.9, 18.3. HRMS (ESI, [M+Na]+): calc for (C13H25NO4+Na+)
4.1.3. Synthesis of receptors 1b–d,f–h,i: general procedure
Caution: All operations with phosgene should be carried in a well
ventilated hood, and the rotary evaporator should be equipped with
a water jet pump to adsorb the gaseous phosgene in water.
The appropriate Boc protected amino acid ester (6 mmol) was
dissolved in 4 M HCl in dioxane (10 mL) and stirred for 2 h at rt.
It was then concentrated, and deprotected hydrochloride was sus-
pended in dichloromethane (20 mL), cooled to 0 °C. Next, 10%
aqueous NaHCO3 (20 mL) was added and the phases were stirred
vigorously. After complete dissolution of the starting material,
the stirring was stopped and phosgene (1.93 M solution in toluene,
6 mL) was added. Stirring was continued at 0 °C for 10 min. The
phases were separated in a separatory funnel and the water phase
was further extracted with dichloromethane (10 mL). The com-
bined organic phases were dried over MgSO4, and concentrated
on a rotary evaporator. The resulting isocyanate was dissolved in
dichloromethane and o-phenylenediamine (2 mmol) was added.
The mixture was stirred for 24 h. If some precipitate was formed,
hot dichloromethane was added until the solution was clear. The
solution was then poured onto the top of a chromatographic col-
umn (silica gel), and the chromatography proceeded with 5–10%
acetone in dichloromethane as the eluent. The product was then
dissolved in the minimal volume of hot acetone, after which the
same volume of water was added and acetone was slowly removed
on a rotary evaporator to yield a white powder which was filtered
and dried in vacuo.
282.16758, found: 282.16777, [
a
]
D
20 = ꢀ34.8 (c 1.2, MeOH).
Boc-Val-OnBu 5c: colourless oil (2.02 g, 74%), dH (500 MHz,
DMSO) 7.11 (1H, d, J = 8.2 Hz), 4.11–3.97 (2H, m), 3.81 (1H, dd,
J = 8.2, 6.7 Hz), 2.00 (1H, oct, J = 6.7 Hz), 1.63–1.45 (2H, m), 1.38
(9H, s), 1.38–1.28 (2H, m), 0.95–0.79 (9H, m); dC (126 MHz, DMSO)
172.0, 155.7, 78.1, 63.8, 59.5, 30.2, 29.5, 28.2, 19.0, 18.6, 18.4, 13.5.
HRMS (ESI, [M+Na]+): calcd for (C14H27NO4+Na+): 296.18323,
found: 296.18332, [
a]
D
20 = ꢀ29.2 (c 1.82, MeOH).
Boc-Val-OBn 5d: colourless oil (1.41 g, 46%), dH (600 MHz,
DMSO) 7.40–7.29 (5H, m), 7.21 (1H, d, J = 8.0 Hz), 5.16 (1H, d,
J = 12.5 Hz), 5.09 (1H, d, J = 12.5 Hz), 3.88 (1H, dd, J = 8.0, 6.7 Hz),
2.02 (1H, oct, J = 6.8 Hz), 1.38 (9H, s), 0.86 (3H, d, J = 6.8 Hz), 0.85
(3H, d, J = 6.8 Hz); dC (151 MHz, DMSO) 171.9, 155.8, 142.5,
136.0, 128.3, 128.0, 127.9, 127.6, 126.6, 126.4, 78.2, 65.7, 62.9,
59.5, 29.6, 28.2, 19.0, 18.4. HRMS (ESI, [M+Na]+): calcd for (C17H25-
NO4+Na+): 330.16758, found: 330.16895, [
a]
20 = ꢀ31.8 (c 1.1,
D
MeOH) (Lit.:29 ꢀ29.7).
Boc-Phe-OiPr 5f: colourless oil (1.96 g, 64%) dH (600 MHz,
DMSO) 7.80–7.04 (6H, m), 4.86 (1H, sept, J = 6.2 Hz), 4.08 (1H,
ddd, J = 9.3, 8.1, 5.8 Hz), 2.95 (1H, dd, J = 13.7, 5.6 Hz), 2.86
(1H, dd, J = 13.5, 9.8 Hz), 1.34 (9H, s), 1.17 (3H, d, J = 6.2 Hz), 1.08
(3H, d, J = 6.2 Hz); dC (151 MHz, DMSO) 171.5, 155.3, 137.6,
129.1, 128.1, 126.4, 78.2, 67.8, 55.5, 36.4, 28.1, 21.5, 21.3; HRMS
(ESI, [M+Na]+): calcd for (C17H25NO4+Na+): 330.16758, found:
330.16722, [
a
]
20 = ꢀ5.1 (c 1.1, MeOH).
D
Boc-Phe-OnBu 5g: colourless oil (2.02 g, 63%), dH (500 MHz,
Compound 1a white powder (717 mg, 85%), mp 152–155 °C, dH
(500 MHz, DMSO) 7.92 (2H, s), 7.51 (2H, dd, J = 5.9, 3.6 Hz), 6.97
DMSO) 7.37–7.16 (6H, m), 4.15 (1H, ddd, J = 9.5, 8.5, 5.6 Hz),

F. Ulatowski, J. Jurczak / Tetrahedron: Asymmetry 25 (2014) 962–968
967
(2H, dd, J = 6.0, 3.5 Hz), 6.91 (2H, d, J = 8.3 Hz), 4.17 (2H, dd, J = 8.2,
5.6 Hz), 3.66 (6H, s), 2.05 (2H, oct, J = 7.0 Hz), 0.92 (6H, d,
J = 7.0 Hz), 0.90 (6H, d, J = 7.0 Hz); dC (126 MHz, DMSO) 172.8,
155.7, 131.1, 123.3, 123.2, 57.9, 51.6, 30.5, 19.0, 18.0. HRMS (ESI,
[M+Na]+): calc for (C20H30N4O6+Na+) 445.205207, found:
Compound 1i grey crystals, (357 mg, 65%), mp 146–147 °C, dH
(400 MHz, CD3CN) 7.57 (s, 2H); 7.35–7.33 (m, 2H); 7.11–7.03 (m,
2H); 5.85 (2H, t, J = 5.5 Hz); 4.14 (4H, q, J = 7.1 Hz); 3.86 (4H, d,
J = 5.9 Hz); 1.22 (6H, t, J = 7.1 Hz). dC (100 MHz, CD3CN) 170.5;
156.9; 130.8; 126.8; 119.7; 61.2; 43.5; 14.7, elemental analysis:
calcd: C-52.45; H-6.05; N-15.29, found: C-52.32; H-6.25; N-14.76.
445.205210, [
a
]
D
20 = ꢀ2.8 (c 0.5, MeCN).
Compound 1b white powder (411 mg, 43%), mp 120–123 °C; dH
(500 MHz, DMSO) 7.96 (2H, s), 7.57–7.44 (2H, m), 6.99–6.93 (2H,
m), 6.84 (2H, d, J = 8.4 Hz), 4.95 (2H, sept, J = 6.3 Hz), 4.11
(2H, dd, J = 8.4, 5.3 Hz), 2.05 (2H, td, J = 13.7, 6.8 Hz), 1.25–1.19
(12H, m), 0.93 (6H, s, J = 6.8 Hz), 0.90 (6H, d, J = 6.9 Hz); dC
(126 MHz, DMSO) 171.7, 155.7, 131.1, 123.2, 123.2, 67.8, 57.9,
30.5, 21.6, 21.6, 18.9, 17.9. HRMS (ESI, [M+Na]+): calcd for
4.2. Competitive titration
Competitive titrations19 were conducted in MeCN-d3 (0.05%
H2O, Eurisotop, packed in a vial with a septum) on a mixture of chi-
ral host (ꢁ0.01 m) and achiral reference 1i (ꢁ0.005 M); the differ-
ences in concentrations enabled the unambiguous assignment of
the signals. To this mixture, aliquots of homochiral guest solutions
were added in several steps until [G]0 ꢃ [H] + [Href]. Changes in the
chemical shifts of the inner urea protons were followed. The ratio
of the association constants were calculated according to the
equation:
(C24H38N4O6+Na+) 501.26836, found: 501.26922, [
0.5, MeCN).
a
]
D
20 = ꢀ9.1 (c
Compound 1c white powder (405 mg, 40%), mp 134–136 °C, dH
(500 MHz, DMSO) 7.93 (2H, s), 7.51 (2H, dd, J = 5.7, 3.6 Hz), 6.97
(2H, dd, J = 5.8, 3.6 Hz), 6.87 (2H, d, J = 8.3 Hz), 4.29–3.91 (6H, m),
2.05 (2H, oct, J = 6.3 Hz), 1.69–1.46 (4H, m), 1.47–1.25 (4H, m),
1.02–0.79 (18H, m); dC (126 MHz, DMSO) 172.3, 155.7, 131.1,
123.3, 64.0, 57.9, 30.5, 30.2, 19.0, 18.6, 18.0, 13.5. HRMS (ESI,
[M+Na]+): calcd for (C26H42N4O6+Na+): 529.29966, found:
max
D
d
ref
ꢀ 1
ꢀ 1
KH
D
dref
Krel
¼
¼
Kref
D
D
dmHax
dH
20 = +1.6 (c 0.5, MeCN).
D
where
D
dmax corresponds to the chemical shift of the pure super-
529.30038, [a]
max
ref
Compound 1d white powder (367 mg, 32%), mp 150–152 °C, dH
(600 MHz, DMSO) 7.97 (2H, s), 7.50 (2H, dd, J = 5.9, 3.6 Hz), 7.44–
7.30 (10H, m), 6.97 (2H, dd, J = 6.0, 3.6 Hz), 6.93 (2H, d, J = 8.3 Hz),
5.19 (2H, d, J = 12.4 Hz), 5.13 (2H, d, J = 12.4 Hz), 4.21 (2H, dd,
J = 8.3, 5.4 Hz), 2.07 (2H, d, J = 6.8 Hz), 0.91 (6H, d, J = 6.8 Hz), 0.88
(6H, d, J = 6.8 Hz); dC (151 MHz, DMSO) 172.2, 155.8, 135.9, 131.1,
128.4, 128.1, 128.1, 123.3, 123.2, 109.5, 65.9, 58.0, 30.4, 19.0,
17.9. HRMS (ESI, [M+Na]+): calcd for (C32H38N4O6+Na+)
molecule (host fully saturated with guest).
anions were determined by classical NMR titration.
D
d
values for both
D
dmHax and Krel
were fitted to obtain the best match between calculated and exper-
imental values by OriginÒ software§ curve fitting algorithm:
Krel
ꢄ
D
dmHax
D
dH
¼
max
ref
D
d
Krel
þ
ꢀ 1
D
dref
597.26835, found: 597.26448, [a]
20 = +2.0 (c 0.45, MeCN).
The latter equation does not include any variable referring to
D
Compound 1e white powder (787 mg, 76%), mp 141–143 °C, dH
(600 MHz, DMSO) 7.98 (2H, s), 7.47–7.40 (2H, m), 7.32–7.18 (10H,
m), 6.99–6.94 (2H, m), 6.92 (2H, d, J = 7.8 Hz), 4.51 (2H, ddd,
J = 13.6, 7.6, 5.7 Hz), 3.62 (6H, s), 3.04 (2H, dd, J = 13.8, 5.8 Hz),
2.97 (2H, dd, J = 13.6, 7.6 Hz); dH (151 MHz, DMSO) 172.7, 172.6,
155.3, 136.9, 131.0, 129.18, 129.15, 128.30, 128.25, 126.61,
126.54, 123.41, 123.36, 54.2, 51.8, 37.5; HRMS (ESI, [M+Na]+):
calcd for (C28H30N4O6+Na+) 541.20576, found: 541.21088,
the concentrations of the reagents, therefore mixtures of any (even
unknown) compositions may be used. This eliminates the common
errors that arise from errors in concentrations. Also the lower pur-
ity of the hosts and guest does not affect the results (if only the
impurities do not significantly change the chemical shifts). The
lowest error is obtained for data-points with 0.1 <
The uncertainty of a single competitive titration was calculated
by Origin fitting algorithm. The uncertainty of enantioselectivity
Dd/Dd
max < 0.9.
[
a]
D
20 = +7.2 (c 0.45, MeCN).
was calculated according to the formula:
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
Compound 1f white powder (436 mg, 38%), mp 115–118 °C, dH
D
a=a
¼
ðD
KrSel=KrSelÞ2 þ ð
D
KrRel=KrRelÞ2:
(600 MHz, DMSO) 7.99 (2H, s), 7.45 (2H, dd, J = 5.8, 3.6 Hz), 7.29
(4H, t, J = 7.3 Hz), 7.26–7.19 (6H, m), 6.96 (2H, dd, J = 5.8, 3.6 Hz),
6.89 (2H, d, J = 7.7 Hz), 4.85 (2H, sept, J = 6.2 Hz), 4.45 (2H, dt,
J = 7.7, 6.8 Hz), 2.99 (2H, s), 2.98 (2H, s), 1.16 (6H, d, J = 6.2 Hz),
1.08 (6H, d, J = 6.2 Hz); dC (151 MHz) 171.6, 155.3, 136.8, 131.1,
129.3, 128.2, 126.6, 123.4, 109.5, 68.0, 54.3, 37.7, 21.6, 21.4. HRMS
(ESI, [M+Na]+): calcd for (C32H38N4O6+Na+) 597.26836, found:
4.3. HPLC analyses
Enantiomers of receptors 1e and 1f were resolved using AS-H
(Daicel ChiralpakÒ, i.d. 4.6 mm, length 200 mm) column with an
isocratic elution: 35% actone/65% n-hexane. tR for 1e: 6.85 min
597.26923, [a]
20 = +16.3 (c 0.5, MeCN).
D
(L
); 9.10 min (
D); tR for 1f 3.90 min (L); 4.55 min (D).
Compound 1g white powder (481 mg, 40%), mp 123–126 °C, dH
(600 MHz, DMSO) 7.99 (2H, s), 7.48–7.41 (2H, m), 7.29 (4H, t,
J = 7.4 Hz), 7.25–7.19 (6H, m), 7.01–6.94 (2H, m), 6.91 (2H, d,
J = 7.8 Hz), 4.49 (2H, q, J = 7.5 Hz), 4.05–3.97 (4H, m), 3.03–2.95
(4H, m), 1.51–1.44 (4H, m), 1.29–1.18 (4H, m), 0.85 (6H, t,
J = 7.4 Hz); dC (151 MHz, DMSO) 172.2, 155.3, 136.8, 131.1, 129.2,
128.3, 126.6, 123.4, 64.1, 54.3, 37.7, 30.1, 18.5, 13.5; HRMS (ESI,
[M+Na]+): calcd for (C34H42N4O6+Na+) 625.29966, found:
Acknowledgements
This work was co-financed by the European Union form the
European Regional Development Fund, Grant Ventures-4-2009/4
administrated by Foundation for Polish Science.
References
625.30061, [a]
20 = +4.0 (c 0.5, MeCN).
D
Compound 1h white powder (442 mg, 33%), mp 142–144 °C, dH
(500 MHz, DMSO) 8.00 (2H, s), 7.47–7.12 (22H, m), 7.00–6.90 (4H,
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