Diastereoselective reaction of 1,3-dihydroxy calixarene with acylisocyanates: New and easy approach for preparing inherently chiral calyx[4]arenes

Article abstract of DOI:10.1007/s11224-015-0706-5

The facile method of generating internal chirality into the calixarene with two hydroxy groups at the lower rim via an attached chiral substituent has been proposed. The reaction with acylisocyanates, catalyzed by a small amount of triethylamine, proceeds

Full text of DOI:10.1007/s11224-015-0706-5

Struct Chem
DOI 10.1007/s11224-015-0706-5
ORIGINAL RESEARCH
Diastereoselective reaction of 1,3-dihydroxy calixarene
with acylisocyanates: new and easy approach for preparing
inherently chiral calyx[4]arenes
1
1
1
2,3
•
V. I. Boyko
O. V. Shishkin
•
A. B. Rozhenko
,3
•
V. V. Pirozhenko
1
•
S. V. Shishkina
2
•
V. I. Kalchenko
Received: 14 November 2015 / Accepted: 17 November 2015
Ó Springer Science+Business Media New York 2016
Abstract The facile method of generating internal chi-
rality into the calixarene with two hydroxy groups at the
lower rim via an attached chiral substituent has been pro-
posed. The reaction with acylisocyanates, catalyzed by a
small amount of triethylamine, proceeds forming predom-
inantly one of the two possible calixarene carbamates. The
best diastereomeric excess (60 %) has been achieved in the
reaction of trichloroacyl isocyanates with 1,3-hydroxycal-
ixarene substituted with the chiral phenylethyl amide
moiety. The individual diastereomers of trichloroacetyl-
carbamoylcalix[4]arenas were isolated by crystallization,
and their absolute configuration was determined by X-ray
diffraction study. The most favored conformations pre-
dicted for 1,3-dihydroxy calixarene structures by quantum
chemical calculations possess very similar stability. How-
ever, the triethylamine molecule preferably connects to the
one hydroxyl group of the two available ones, providing
the most favorable adduct, which predominantly partici-
pates in the reaction with acylisocyanates. This gives rise
to the observed diastereomeric excess. The subsequent
treatment of the formed carbamoyl with n-propyl bromide
in presence of NaH and hydrolysis of the product of
alkylation easily provide a persistent internally chiral
calixarene.
Keywords Inherent chirality Á Calixarenes Á X-ray
structure determination Á Diastereomeric excess Á DFT
Introduction
Calixarenes are bowl-shaped macrocycles, which are of
great interest for designing highly efficient and selective
receptors for cations, anions and neutral molecules [1], as
well as self-assembling molecular capsules and well-de-
fined functional nanostructures [2]. Over the past two
decades, a considerable success has been achieved in the
design and synthesis of chiral calixarenes, which are
promising molecular platforms for the construction of
enantioselective catalysts and receptors [3]. Of particular
interest are inherently chiral calixarenes [4, 5] in which
chirality originates from asymmetric arrangements of
functional groups attached to the wide [6–11] and/or nar-
row rim [4, 12] of macrocycles. Generating inherent chi-
rality without using chiral reagents results in racemic
mixtures of both enantiomers, which are hardly separable
via chromatography on chiral stationary phases [12–15].
Using chiral auxiliary groups (1-phenylethyl, amino acid
ester, BINOL, menthyl, etc.) usually results in mixtures
with relations of diastereomers close to 1:1. They have
been separated by enantioselective high-performance liq-
uid chromatography [16–18], in some case, by kinetic
resolution [19, 20] and crystallization [21–23]. Only in few
cases, the formation of significant excesses of one of the
two diastereomers was observed directly in the reaction
[24–26].
&
&
1
A. B. Rozhenko
a_rozhenko@ukr.net
V. I. Kalchenko
vik@ioch.kiev.ua
Institute of Organic Chemistry, National Academy of
Sciences of Ukraine, Murmanska Str. 5, Kiev 02660, Ukraine
2
STC ‘‘Institute for Single Crystal’’, National Academy of
Sciences of Ukraine, Lenin Ave. 60, Kharkiv 61001, Ukraine
3
V.N. Karazin Kharkiv National University, 4 Svobody sq.,
Kharkiv 61077, Ukraine
123

Struct Chem
As we have found previously [27], acylation of 25,27-
dialkoxy-26,28-dihydroxy calix[4]arenes by acylisocyanates
proceeds under mild conditions with a participation of only
one hydroxyl group. If one substituent in 26,28-dihydrox-
ycalix[4]arenas is chiral, an asymmetrical induction is
expected in this reaction, which can result in a preferable
formation of one of the two diastereomers.
J = 7.2 Hz (3H, CH
J = 13.4 Hz (1H, e-Ar–CH
(3H, e-Ar-CH -Ar), 3.87 m (2H, OCH
J = 13.4 Hz (1H, e-Ar–CH –Ar), 4.21 d, J = 13.2 Hz
(2H, a-Ar–CH –Ar), 4.24 d, J = 13.2 Hz (1H, a-Ar–CH
Ar), 4.47 d, J = 15.4 Hz (1H, OCH C(O)), 4.53 d,
J = 15.4 Hz (1H, OCH C(O)), 5.23 m (1H, CH), 6.76 m
4H, PhH), 7.05 m (6H, PhH), 7.24 m (3H, PhH), 7.43 s
2
CH
3
), 1.8 m (2H, CH
–Ar), 3.35 d, J = 13.2 Hz
CH ), 4.14 d,
2 3
CH ), 3.28 d,
2
2
2
2
2
–
2
2
2
2
(
Experimental
(1H, OH), 7.45 s (1H, OH), 8.76 d, J = 8.0 Hz (1H, NH).
Calculated, %: s 80.34, H 8.63, N 1.64. C H NO . Found,
5
7
73
5
Acylisocyanates [28], monoalkoxycalix[4]arenes 1,2 [29]
and sulfocalix[4]arene 6 [27] were prepared using the
known procedures.
%: s 80.07, H 8.36, N 1.75.
5,11,17,23-Tetra-tert-butyl-25-methoxy-26,28-dihydroxy-
7-menthyloxycarbonylmethoxycalix[4]arene 5 A solu-
2
5
,11,17,23-Tetra-tert-butyl-25-methoxy-26,28-dihydroxy-
7-(1-phenylethyl)aminocarbonylmethoxycalix[4]arene 3 To
solution of 0.5 g (0.75 mmol) monomethoxy-
tion of monomethoxycalix[4]arene 1 (1.02 g, 1.5 mmol)
and potassium carbonate (0.255 g, 0.415 mmol) in 100 ml
acetonitrile was stirred at 50 °C for 1 h. To the suspension
0.45 g (1.65 mmol) of menthyl ester of monobromoacetic
acid was added and the reaction mixture was boiled for 5 h.
Acetonitrile was removed under reduced pressure. The
reaction product was purified by column chromatography
2
a
calix[4]arene 1 0.057 g (0.415 mmol) potassium carbonate
was added in 75 ml acetonitrile. The mixture was stirred
for 1 h at 70 °C. 0.192 g (0.792 mmol) of S-(-)-1-pheny-
lamide of monobromoacetic acid was added and the reac-
tive mixture was boiled for 9 h. Acetonitrile was removed
under reduced pressure, then 25 ml of 5 % HCl was added.
The resulted mixture was extracted by chloroform
on silica gel using system ethylacetate–hexane (1–3) as
1
eluent. Yield 68 %, m.p. 109–112 °C. H NMR (CDCl
ppm: 0.91 s (9H, t-Bu), 0.98 s (9H, t-Bu), 1.30 s (18H, t-
), d,
3
(
3 9 15 ml). The organic phase was dried over Na SO ,
2 4
Bu), 0.76–1.91 m (18H, MentH), 3.32 d, J = 13.2 Hz (2H,
and the solution was removed at reduced pressure. In order
to remove the rest of water, the product was solved twice in
benzene (15 ml) that was distillated. Yield quantitative,
m.p. 126–129 °C. For the further reactions, the solution
e-Ar–CH
3.96 s (3H, OCH
Ar), 4.28 d, J = 13.2 Hz (1H, ax-Ar–CH
J = 13.2 Hz (1H, ax-Ar–CH –Ar), 4.78 d, J = 13.2 Hz
(1H, ax-Ar–CH –Ar), 4.67 s (2H, OCH ), 4.86 (1H, m,
2
–Ar), 3.33 d, J = 13.2 Hz (2H, eq-Ar–CH
), 4.27 d, J = 13.2 Hz (1H, ax-Ar–CH
–Ar), 4.44 d,
2
–Ar),
–
2
3
2
2
1
was used without an isolation of product 3. H NMR
2
2
(
CDCl ), d, ppm.: 0.99 s (9H, t-Bu), 1.01 s (9H, t-Bu),
.29 s (18H, t-Bu), 1.68 d, J = 7.1 Hz (3H, CHCH ), 3.36
3
MentH), 6.73 s (2H, ArH), 6.82 s (2H, ArH), 7.06 s (4H,
ArH), 7.09 s (1H, OH), 7.10 s (1H, OH). Calculated, %: s
3
1
d, J = 13.5 Hz (1H, eq-Ar–CH –Ar), 3.38 d, J = 13.1 Hz
2
79.68, H 9.15. C57
H O . Found, %: s 80.03, H 9.15.
78 6
(
1H, eq-Ar–CH –Ar), 3.39 d, J = 13.1 Hz (1H, eq-Ar–
2
5
,11,17,23-Tetra-tert-butyl-25-hydroxy-26-(1-phenylethyl)
CH –Ar), 3.40 d, J = 13.1 Hz (1H, eq-Ar–CH –Ar),
2
2
amino- carbonylmethoxy-27-trichloromethylcarbonylaminocar-
bonyloxy-28-methoxycalix[4]arene 7 (cS) To a solution of
calyx[4]arenamide 3 prepared from 1.43 g (2.15 mmol)
monomethoxycalix[4]arene in 5 ml diethyl ether, a solu-
tion of 0.51 g (2.69 mmol) trichloroacetyl isocyanate in
3
.77 s (3H, OCH ), 4.12 d, J = 13.5 Hz (1H, ax-Ar–CH –
3 2
Ar), 4.17 d, J = 13.1 (1H, Hz ax-Ar–CH –Ar), 4.22 d,
2
J = 13.1 Hz (1H, ax-Ar–CH –Ar), 4.29 d, J = 13.1 Hz
2
(
1H, ax-Ar–CH –Ar), 4.48 d, J = 14.8 Hz (1H, O–CH ),
2 2
4
.56 d, J = 14.8 Hz (1H, OCH ), 5.33 m (1H, CH), 6.85 d,
2
1
0 ml of diethyl ether was added. After cooling the mixture
J = 2.4 Hz (2H, ArH), 6.88 d, J = 2.4 Hz (2H, ArH), 6.90
d, J = 2.4 Hz (2H, ArH), 7.05 d, J = 2.4 Hz (2H, ArH),
down to 5 °C, one drop of TEA was added and kept the
reaction mixture at this temperature for 100 h. Diethyl
ether was distilled off. The residue was treated with 12 ml
of boiling methanol and cooled. The formed crystals were
7
.07 d, J = 2.4 Hz (2H, ArH), 7.10 d, J = 2.4 Hz (2H,
ArH), 7.34 m (3H, PhH), 7.49 s (1H, OH), 7.54 m (2H,
PhH), 7.57 s (1H, OH), 9.05 d, J = 8.2 Hz (1H, NH).
Calculated, %: s 80.16, H 8.44, N 1.70. C H NO Found,
separated by filtration. Overall yield 53 %, m.p.
20
5
5
69
5
221–223 °C
(decomp.).
1
3
[a]D = -42.86
(589 nm,
%
: s 79.80, H 8.80, N 2.00.
C = 0.504, CHCl ). H NMR (CDCl ), d, ppm: 0.63 (9H, s,
3
5
,11,17,23-Tetra-tert-butyl-25-propoxy-26,28-dihydroxy-
7-(1-phenylethyl)aminocarbonylmethoxycalix[4]arene 4 It
t-Bu), 0.82 s (9H, t-Bu), 1.27 s (9H, t-Bu), 1.31 s (9H, t-
Bu), 1.52 d, J = 7.1 Hz (3H, CH C), 2.96 d, J = 13.7 Hz
(1H, eq-Ar–CH –Ar), 3.22 d, J = 13.3 Hz (1H, eq-Ar–
CH –Ar), 3.29 d, J = 13.3 Hz (1H, eq-Ar–CH –Ar), 3.31
d, J = 13.7 Hz (1H, eq-Ar–CH –Ar), 3.75 s (3H, OCH ),
3.95 d, J = 13.7 Hz (1H, ax-Ar–CH –Ar), 3.98 d,
2
3
was prepared analogously to 3 from monopropoxy-
1
calix[4]arene 2. Yield 96 %, m.p. 93–95 °C. H NMR
2
2
2
(
CDCl ), d, ppm: 0.92 s (18H, t-Bu), 0.98 t, J = 7.2 Hz
2
3
3
(
3H, CH ), 1.31 s (9H, t-Bu), 1.31 s (9H, t-Bu), 1.65 d,
3
2
1
23

Struct Chem
J = 13.7 Hz (1H, ax-Ar–CH –Ar), 4.08 d, J = 13.3 Hz
2
NMR (CDCl ), d, ppm: 168.88, 153.41, 151.37, 150.87,
3
(
1H, ax-Ar–CH –Ar), 4.14 d, J = 14.8 Hz (1H, OCH ),
2
149.72, 146.81, 145.64, 145.49, 143.50, 142.43, 135.38,
134.53, 133.22, 132.66, 131.70, 131.62, 130.13, 128.21,
128.08, 126.75, 126.22, 125.72, 125.68, 125.61, 125.44,
125.22, 125.19, 125.16, 125.09, 124.76, 124.54, 77.20,
74.09, 62.82, 48.76, 34.21, 34.03, 33.84, 32.33, 31.80,
31.71, 31.45, 31.41, 31.17, 31.14, 31.09, 29.80, 23.62,
22.21, 10.46. Calculated, %: C 80.42, H 8.73, N 1.62.
C H NO . Found, %: C ? 80.51, H 8.60, N 1.73.
2
4
.18 d, J = 13.3 Hz (1H, ax-Ar–CH –Ar), 4.55 d,
2
J = 14.8 Hz (1H, OCH ), 5.12 m (1H, CH), 6.27 d,
2
J = 2.5 Hz (1H, ArH), 6.37 d, J = 2.5 Hz (1H, ArH),
6
.59–6.62 m (3H, PhH), 6.74 d, J = 8.5 Hz (1H, ArH),
.02 d, J = 2.4 Hz (1H, ArH), 7.06 dd, J = 2.4, 2.3 Hz
2H, ArH), 7.17–7.29 m (6H, OH ? PhH ? NH), 10.39 s
7
(
(
1
3
1H, C(O)NHC(O)). C NMR (CDCl ), d, ppm: 167.21,
3
58 75
5
1
1
1
1
1
3
6
%
59.39, 152.06, 150.76, 149.91, 149.63, 148.86, 147.20,
46.33, 144.03, 142.91, 142.17, 135.05, 134.78, 131.31,
31.26, 131.15, 128.71, 128.61, 128.18, 127.28, 127.02,
26.43, 126.00, 125.79, 125.68, 125.59, 125.34, 125.17,
24.95, 92.15, 75.30, 63.72, 48.91, 34.38, 33.90, 33.81,
3.56, 31.67, 31.46, 30.87, 30.72, 21.47. Calculated, %: C
8.80, H 6.87, Cl 10.50, N 2.77. C H Cl N O . Found,
5
2
1
,11,17,23-Tetra-tert-butyl-25-methoxy-26,28-dipropoxy-
7-(1-phenylethyl)aminocarbonylmethoxycalix[4]arene
1
7
Yield 0.078 g (8.7 %). M.p. 208–211 °C. H NMR
(CDCl ), d, ppm: 0.70 t, J = 7.2 Hz (3H, CH CH ), 0.86 t,
3
2
3
J = 7.2 Hz (3H, CH CH ), 0.87 s (9H, t-Bu), 0.90 s (9H,
2
3
t-Bu), 1.31 s (9H, t-Bu), 1.324 s (9H, t-Bu), 1.60 m (4H,
CH CH ), 1.71 d, J = 7.2 Hz (3H, CH CH), 3.22 d,
J = 13.0 Hz (3H, e-Ar–CH –Ar), 3.27 d, J = 13.0 Hz
5
8
69
3 2 7
2
3
3
: C 69.01, H 6.75, Cl 10.42, N 2.86.
2
Alkylation of calixarenecarbamate 7 (cS) The solution of
.00 g (0.988 mmol) of calix[4]arene 7 (cS) and 0.095 g
3.95 mmol) of NaH in 28 ml DMFA was stirred at room
temperature for 3 h. To the reaction mixture 0.304 g
0.225 ml, 2.469 mmol) of propylbromide was added and
stirred at 65 °C for 48 h. The mixture was poured into
00 ml of cold 5 % solution of HCl. The mixture was kept
(1H, e-Ar–CH –Ar), 3.50 s (3H, OCH ), 3.56 m (4H,
2
3
1
OCH CH ), 4.17 d, J = 13.0 Hz (1H, a-Ar–CH –Ar),
2 2 2
(
4.193 d, J = 13.0 Hz (1H, a-Ar–CH –Ar), 4.40 d,
2
J = 13.0 Hz (1H, a-Ar–CH –Ar), 4.41 d, J = 13.0 Hz
2
(
(1H, a-Ar–CH –Ar), 4.76 d, J = 15.6 Hz (1H, OCH
2
2
C(O)), 5.09 d, J = 15.6 Hz (1H, OCH C(O)), 5.52 m (1H,
2
1
CH), 6.52 m (4H, PhH), 7.08 s (2H, PhH), 7.09 s (2H,
PhH), 7.342 m (5H, PhH), 8.20 d, J = 8.6 Hz (1H, NH).
at 5 °C for 1 h, the liquid was decanted, the solid was
extracted with chloroform (3 9 15 ml), the organic phase
was washed with water (30 ml). After drying over Na SO
2
4
Details of calculations
chloroform was removed under reduced pressure. The
residue was treated with hexane (2 9 15 ml), and the
solvent was removed under reduced pressure. Reaction
products 16 and 17 were separated with the column chro-
matography on approx. 40 g silica gel, eluent ethylacetate–
hexane (1:5).
All the structures were first optimized using the TUR-
BOMOLE program set (version 6.4) [30], and the
implemented resolution of identity (RI) [31–33] algo-
rithm. The RI-B97-D functional [34] and standard triple-
zeta basis sets [35] (TZVP) were used. The contraction of
the basis functions was (14s9p)/[5s4p] ? {73,211/6111}
for S, (11s6p)/[5s3p] ? {62,111/411} for s, N, O and F
and (5s)/[3s] ? {311} for H. One set of (five) d-functions
was added for every non-hydrogen atom, and one set of
p-functions was used for H’s. For all the structures
vibrational analyses were performed computing numeri-
cally first- and second-order derivatives, checking the
equilibrium structures to be true local minima in energy.
No imaginary frequencies were found for the optimized
structures. For the calculation of DE and DG values, zero-
point energy and chemical potential, respectively, were
added to the total energy magnitudes using default scal-
ing. The solvent effects were taken into account using the
COSMO routine [36–38] implemented into the TURBO-
MOLE set of programs. For the COSMO-derived total
energy values correction magnitudes computed at the gas-
phase approximation were employed. The optimized
structures were pictured using the Jmol program [39].
5
,11,17,23-Tetra-tert-butyl-25-hydroxy-26-methoxy-27-
propoxy-28-(1-phenylethyl)aminocarbonylmethoxycalix
1
[
4]arene 16 Yield 0.372 g (43 %), m.p. 209–211 °C. H
NMR (CDCl ), d, ppm: 0.87 s (9H, t-Bu), 0.97 s (9H, t-
3
Bu), 1.02 t, J = 7.5 Hz (3H, CH CH ), 1.27 s (9H,t-Bu),
2
3
1
.31 s (9H, t-Bu), 1.70 d, J = 6.5 Hz (3H, CH CH ),
2 3
2
.09 m (2H, CH CH ), 3.08 d, J = 13.5 Hz (1H, eq-Ar–
2
3
CH –Ar), 3.23 d, J = 12.5 Hz (1H, Ar-eq-CH –Ar), 3.256
2
2
d, J = 12.4 Hz (1H, Ar-eq-CH –Ar), 3.38 d, J = 13.8 Hz
2
(
1H, Ar-eq-CH –Ar), 3.91 s (3H, OCH ), 3.92 m (2H,
2 3
OCH CH ), 4.05 d, J = 15.2 Hz (1H, OCH C(O)), 4.06 d,
2
2
2
J = 13.8 Hz (1H, ax-Ar–CH –Ar), 4.13 d, J = 13.5 Hz
2
(
1H, ax-Ar–CH –Ar), 4.36 d, J = 12.5 Hz (1H, Ar-ax-
2
CH –Ar), 4.38 d, J = 12.4 Hz (1H, Ar-ax-CH –Ar), 4.75
2
2
d, J = 15.2 Hz (1H, OCH C(O)), 5.31 m (1H, CH),
2
6
.63 m (3H, PhH), 6.75 d, J = 2.4 Hz (1H, PhH), 6.84 d,
J = 2.4 Hz (1H, PhH), 7.07 m (6H, PhH), 7.37 s (1H,
1
3
OH), 7.37 m (1H, PhH), 9.01 d J = 7.4 Hz (1H, NH).
C
123

Struct Chem
X-ray diffraction study
Result and discussion
X-ray diffraction studies were performed on an automatic
Chiral calix[4]arenes 3–6 were prepared by reaction of
appropriate monoalkoxycalix[4]arenes 1,2 with an
equimolar amount of chiral N-(1-phenylethyl)-2-bromoac-
etamide or menthylbromoacetate in boiling acetonitrile
using K CO as a base (Scheme 1). Compound 5 was
«
Xcalibur 3» diffractometer (graphite monochromated
MoKa radiation, CCD-detector, x-scanning). The struc-
tures were solved by direct method using SHELXTL
3
package [40]. The restrains for the Csp –Csp (1.54 A) and
3
˚
2
3
3
Csp –O (1.43 A) bond lengths in the n-alkyl substituents
˚
chromatographically purified on silica gel, whereas com-
pounds 3,4 were obtained in analytically pure form already
after evaporation of the solvent. 26,28-Dihydroxy-
calix[4]arene 6 was prepared from (1S)-10-camphorsul-
fonyl chloride and monoalkoxycalix[4]arene 1 in presence
of an organic base in toluene, according to the described
were applied during refinement of the structure 17. Posi-
tions of the hydrogen atoms were located from electron
density difference maps and refined by ‘‘riding’’ model
with Uiso = nUeq of the carrier atom (n = 1.5 for methyl
and hydroxyl groups and n = 1.2 for other hydrogen
atoms). Hydrogen atoms of the hydroxyl group and amide
fragment were refined using isotropic approximation in the
1
procedure [41]. In H NMR spectra, signals of protons of
hydroxyl groups of compounds 3–6 appear as two singlets.
The visually largest effect of the asymmetrical center in the
substituent was observed for compound 3: in this case not
1
6 and 17 structures. The crystallographic data and
experimental parameters are listed in Table 1. Final atomic
coordinates, geometrical parameters and crystallographic
data have been deposited at the Cambridge Crystallo-
graphic Data Centre, 11 Union Road, Cambridge, CB2
only the protons in CH C(O) group, but also the protons in
2
the conjunctive methylene fragments of the calixarene
scaffold and the phenyl hydrogens turned out to be dia-
stereotopic. Even the proton signals of tert-butyl groups at
the upper rim of the macrocycle were influenced in the
1
EZ, UK (fax: ?44 1223 336033; e-mail: deposit@ccdc.-
cam.ac.uk). The deposition numbers are given in Table 1.
Table 1 Crystallographic data
Parameter
7
16
17
and experimental parameters for
compounds 7, 16 and 17
Unit cell dimensions
˚
a (A)
14.578(1)
15.7730(7)
24.191(2)
90.0
13.9136(5)
16.4396(6)
23.234(1)
90.0
15.4675(2)
18.0847(3)
19.1762(3)
90.0
˚
b (A)
˚
c (A)
a (°)
b (°)
c (°)
90.0
90.0
90.0
90.0
90.0
90.0
3
˚
V (A )
5562.6(7)
2152
5314.3(4)
1880
5364.1(1)
1976
F(000)
Crystal system
Space group
Z
Orthorhombic
Orthorhombic
Orthorhombic
P2
4
1
2
1
2
1
P2
4
1 1
2 2
1
P2 2 2
1 1 1
4
T (K)
100
100
100
-
1
l (mm
)
0.217
1.209
70
0.067
1.083
55
0.070
1.125
55
3
D
calc (g/cm )
2H
max (°)
Measured reflections
124,753
23,922
0.034
21,441
11,448
0.028
7772
23,217
11,553
0.025
8399
Independent reflections
R
int
Reflections with F [ 4r(F)
Parameters
18,698
719
600
652
R
1
0.039
0.042
0.099
0.941
0.045
0.123
1.011
wR
2
0.098
S
0.995
CCDC number
631,504
815,331
815,332
1
23

Struct Chem
Table 2 Experimentally
observed diastereomeric excess
Calixarene
Product
Alk
R*
Ac
d.e. (%)
(
d.e.) of one of the isomers for
3
5
6
3
3
3
3
4
a
7
8
CH
CH
CH
CH
CH
CH
CH
3
CH
CH
2
C(O)NHCHMePh(-)
C(O)Ment(-)
CCl
CCl
CCl
3
3
3
C(O)
C(O)
C(O)
60
calixarene carbamates 7–14 in
reaction of calixarenes 3–6 with
acylisocyanates Ac-NCO
3
3
3
3
3
3
2
0
9
SO
CH
CH
CH
CH
CH
2
Camph(?)
No reaction
10
11
12
13
14
2
C(O)NHCHMePh(-)
C(O)NHCHMePh(-)
C(O)NHCHMePh(-)
C(O)NHCHMePh(-)
C(O)NHCHMePh(-)
CF
p-F-C
p-CH
(CH
CCl
3
C(O)
50
2
2
2
2
6
H
4
C(O)
20
3
C
6
H
4
SO
a
2
20
3
)
3
CC(O)
No reaction
30
n-C
3
H
7
3
C(O)
3
The reaction proceeded by using NaH instead of Et N, but no d.e. was observed
Scheme 1 Treatment of 1,2 with chiral bromides
spectrum registered in CDBr solution, while they were
3
in presence of a catalytic amount of triethylamine (TEA).
After evaporation of solvent the cS to cR diastereomeric
ratio was determined in the crude mixture integrating the
corresponding proton signals of NH protons or protons of
separated from the asymmetrical center by 11 bonds. The
ratio of the formed cS and cR diastereomers by acylation of
chiral calix[4]arenes 3–6 by acylisocyanates (Scheme 2)
depends on the nature of the chiral substituent R*, size of
alkyl groups and type of isocyanate reacted.
1
tert-Bu groups in H NMR spectra (Table 2). It turned out
that 6 did not react under used conditions with tri-
chloroacetyl isocyanate. In the case of 5, an equimolar
mixture of diastereomers resulted from the reaction with
trichloroacetyl isocyanate. Finally, in the reaction of cal-
ixarene 3 with trichloroacetyl isocyanate, a noticeable
diastereomeric excess (d.e.) (60 %) was obtained for 7(cS)
versus 7(cR). By treatment of the crude mixture of isomers
7(cS) and 7(cR) product with hot methanol, a minor
In order to estimate the effect of the attached asym-
metrical inductor on diastereoselectivity of acylation, we
studied the reaction of trichloroacetyl isocyanate with
methoxycalix[4]arenes bearing (S)-(1-phenyl)ethylamide
(
(
3), (1R,2S,5R)-menthol (5), or (1S)-10-camphorsulfonyl
6) chiral groups in the distal position. The acylation of
compounds 3–6 was carried out in diethyl ether at 0–5 °C
Scheme 2 Treatment of 3–6 with acetyl isocyanates
123

Struct Chem
diastereomer 7(cR) partially dissolved and diastereomeric
purity of isomers 7(cS) grew to 90–92 %. Then it was
easily increased to 98 % by crystallization from a mixture
hexane–dichloromethane. It was expected that the
increased size of the alkyl substituent R neighboring to the
chiral reactive center would also increase stereoselectivity
of the reactions. However, the replacement of the methoxy
moiety by n-propoxy substituent (structure 4) reduced d.e.
from 60 to 30 %.
C2ÁÁÁC7 and C23ÁÁÁC28 are nearly parallel (the corre-
sponding dihedral angle is 11.3°), and rings C9ÁÁÁC14 and
C23ÁÁÁC28 are oriented almost orthogonally (the corre-
sponding dihedral angle value is 84.0°). Hydroxyl O1–H
forms an intramolecular hydrogen bond with O4, the
oxygen atom of the methoxy group, while NH of the
trichloroacetamide fragment (H4) is involved in bifurcated
hydrogen bonding with O1 and O2. It is confirmed by the
analysis of the electron density distribution within the
Bader’s theory [42]. According to this theory (3, -1), bond
critical point (BCP) of the electron density distribution is
found between hydrogen atom and acceptor of proton for
these intramolecular hydrogen bonds. Moreover, the
energy of the hydrogen bond can be estimated using the
characteristics of the (3, -1) critical point in accordance
with the Espinosa’s formula [43]. The energy values cal-
culated for the O1–HÁÁÁO4, N2–HÁÁÁO2 and N2–HÁÁÁO1
hydrogen bonds are 6.78, 4.90 and 3.01 kcal/mol, respec-
tively. It is noteworthy that the proton of one methylene
bridge (H8B) and the aromatic proton H5 face the phenyl
ring of the (S)-a-phenylacetamido group (ring C49ÁÁÁC54).
The distance between hydrogen atoms and the nearest
The influence of the nature of isocyanate on stereose-
lectivity of the acylation reaction was studied using cal-
ixarene 3 as starting material. The best (d.e. 60 %) was
achieved in the reaction of 3 with trichloroacetyl iso-
cyanate. In the reactions of 3 with sulfonylisocyanate and
p-fluorobenzoyl isocyanate, only minor stereoselectivity
was observed (20 %), but it was higher in case of trifluo-
roacetyl isocyanate (d.e. 50 %) (Table 2). Noteworthy, the
reaction of calixarene 3 with the more bulky trimethy-
lacetylisocyanate in presence of TEA did not proceed, and
by using more basic NaH as catalyst no d.e. was observed
for the formed carbamate.
The absolute structure of 7(cS) was determined by X-ray
crystallography. Stable crystals suitable for single-crystal
X-ray diffraction studies were grown by crystallization
from a mixture hexane/CH Cl . In the crystal, 7(cS) adopts
˚
aromatic carbons is 1.79 A for the C8-H8bÁÁÁC49 interac-
˚
tion and 3.13 A for the C5–H5ÁÁÁC53 interaction. The
existence of the BCP between the H8bÁÁÁC49 and H5ÁÁÁC53
atoms clearly indicates C–HÁÁÁp attractions. Their energies
2
2
a pinched cone conformation (Fig. 1), the aromatic rings
Fig. 1 Molecular structure of
compound 7(cS). Hydrogen
atoms are omitted for clarity
with the exception of those
taking part in the formation of
hydrogen bonds. Carbon atoms
of the t-Bu groups at C11 and
C18 are disordered. The most
˚
important distances (in A) and
angles (in degrees) for hydrogen
bonds: O1ÁÁÁO4 2.825(1),
N2ÁÁÁO1 2.915(1), N2ÁÁÁO2
2
.903(1), O1-H2ÁÁÁO4 162(2),
N2-H4ÁÁÁO1 117(1), N2-H4ÁÁÁO2
1
42(1)
1
23

Struct Chem
are about 1.79 and 0.71 kcal/mol, which can be estimated
from the BCP’s characteristics. As indicated by inter-
molecular distances, the (S)-a-phenylacetamido group
indicates weak intermolecular attractions to the carbon and
chlorine atoms of the neighboring 7(cS) molecule.
Since the studied stereoselective reaction is catalyzed by
a small amount of TEA, in the low-polar solvent like
diethyl ether, one of the two hydroxyl groups probably
forms a weakly bonded ionic pair with TEA, instead its
deprotonation. The adduct participates in such form in the
reaction with acetyl isocyanate. Within the number of the
conformational isomeres optimized at the RI-B97-D/TZVP
level of theory, the lowest total energy possesses the
structure 3TEA-1 (S) (Fig. 3), which is approx. 0.8 kcal/
mol more favored than 3TEA-2 (S). The slightly larger
energy preference for 3TEA-1 (S) (*1.0 kcal/mol) is
predicted by taking solvent effects into account using the
COSMO routine [36–38]. One may expected that the OH
group attached to the TEA molecule possesses higher
nucleophilicity and reacts more easily with the isocyanate
molecule than the hydroxyl at the opposite position of the
calixarene lower rim. The reaction of the coordinated
hydroxyl group in 3TEA-1 (S) with trichloroacetyl iso-
cyanate yields the major product 7(cS). The proposed
explanation of the observed d. e. is only plausible. The
comprehensive computational study of the mechanism
would require locating the corresponding transition state
structures and comparing their energies. Unfortunately, this
is prevented by the large size of the studied molecules.
In particular, high stereoselectivity of the reaction with
trichloroacetyl isocyanate compared with other isocyanates
can be attributed to the combination of electronic and steric
factors in the structures corresponding to the transition
states. As one can see from structure 3TEA-1 (S), the
reaction center is surrounded by other atoms and groups
forming a cavity. tert-Bu substituent in t-BuC(O)NCO is
probably too bulky to fit this cavity. A special role of
hydrogen bonds stabilizing conformations 3(S)-1 and 3(S)-
2 is supported by the fact that the diastereoselectivity of the
reaction disappears by using stronger bases. Probably, in
this case the alkali cation is solvated by diethyl ether and
The diastereoselectivity induced in 7 by the chiral
-phenylethyl amide moiety we have previously referred to
1
the slightly different thermodynamic stability of the cor-
responding isomeric reaction products, 7(cS) and 7(cR)
[
44]. However, such a diastereoselectivity is rather driven
by different energies of isomeric reaction intermediates or
activation energies of the corresponding transition states,
determining different reaction rates of acylisocyanates with
the two available hydroxyl groups. The d.e. experimentally
found for 7(cS) and 7(cR) (60 %) requires the difference in
energy of approx. 0.8 kcal/mol. This value is practically
beyond accuracy of DFT approaches, and therefore the
more superior RI-B97-D/TZVP approach [34, 35] that
allows taking the electron dispersion effects into account
was chosen to provide information on the origin of the
observed effect. Geometry optimization predicted for 3
(
(
S) two most favored conformations, 3-1 (S) and 3-2
S) (Fig. 2). They are fixed by intramolecular hydrogen
bonds with the different directions, clockwise and coun-
terclockwise. The specific reactivity could be determined
by rigid conformations of the calixarene, due to the
NHÁÁÁOH bonding and NCHÁÁÁO=C short contact. 3-2
(
S) possesses a slightly lower energy (DE is about
-
0.7 kcal/mol) compared to the isomeric 3-1 (S), but the
difference becomes negligible (*0.2 kcal/mol) by com-
paring the calculated DG values. Thus, while in these
structures one of the OH groups is sterically more shielded
against the attack by the acylating agent than another one,
the two conformations exist in the solution in almost equal
concentrations and probably cannot determine the observed
d.e. in the reaction with trichloroacetyl isocyanates.
Fig. 2 JMol plots of two most
favored conformations of 3
(S) (color codes: carbons in
gray, hydrogens in white,
nitrogen in blue, oxygen in red)
(
Color figure online)
123

Struct Chem
Fig. 3 JMol plots of two most
favored conformations of 3TEA
(
S) (color codes: carbons in
gray, hydrogens in white,
nitrogen in blue, oxygen in red,
the dashed lines mark O–
HÁÁÁTEA bonding) (Color
figure online)
the deprotonated form of calixarene 3a reacts non-
selectively.
propyl moiety are also diastereotopic, but appear in the
spectrum as a complex multiplet at 3.92 ppm.
Alkylation of compound 7(cS) with propyl bromide at
An exact position of the propyl substituent in 16 was
established by the X-ray diffraction study of monocrystal
(Fig. 5). In solid state, 16 exists in the irregular cone con-
formation, in which benzene rings C1ÁÁÁC6, involving amide
moiety, and C15ÁÁÁC20, substituted with the methoxy group,
are almost parallel (the corresponding dihedral angle is
17°). At the same time, aromatic rings with attached pro-
poxy (C8ÁÁÁC13) and hydroxy groups (C22ÁÁÁC27) are
almost orthogonal to each other (the corresponding angle is
88°). The cone conformation of the calixarene is addition-
ally stabilized by the formation of intramolecular hydrogen
bonds between the hydroxyl group and oxygen atom of the
6
0 °C in dry dimethylformamide in presence of NaH as a
base led to a mixture of 5,11,17,23-tetra-tert-butyl-25-
methoxy-26-hydroxy-27-(1-phenyl)ethylamino-carbonyl-
methoxy-28-propoxycalix[4]arene 16 (major product)
and
25-methoxy-26,28-dipropoxy-27-(1-phenyl)ethy-
laminocarbonylmethoxycalix[4]arene 17 (Scheme 3),
which were separated by column chromatography. One
can suggest that the reaction of calixarene 7(cS) proceeds
on the free hydroxyl group forming tetrafunctionalized
calixarene 15. Similarly to other O-phenylcarbamates, it
decomposes forming isocyanate and hydroxycalixarene
˚
1
6. A partial alkylation of 16 yields the minor derivative
7.
methoxy substituent [O5-H5ÁÁÁO4, d(HÁÁÁO) = 2.01(2) A,
1
\O–HÁÁÁO = 173(2)°] and between the amide NH and
oxygen of the hydroxy group [N1–H1ÁÁÁO5, d(HÁÁÁO) =
1
H NMR spectrum of 16 (Fig. 4) exhibits four signals of
˚
tert-butyl groups at 0.892, 0.991, 1.263 and 1.312 ppm.
Protons of methylene bridges appear in the NMR spectrum
as four AB spin systems with chemical shift differences 0.7
2.39(2) A, \N–HÁÁÁO = 147(2)°]. The energies of these
hydrogen bonds estimated from BCPs’ characteristics are
6.48 and 3.20 kcal/mol, respectively. The a-phenylethyl
amide substituent is located in ?sc-conformation rela-
tively the C1–C6 bond of the C1ÁÁÁC6 aromatic ring [the
C45–O1–C6–C1 torsion angle is 67.3(2)°] and the planar
to 1.3 ppm. Methylene protons of the –OCH C(O)– group
2
are diastereotopic and become apparent as AX doublets
(
J = 15.2 Hz, Dd = 0.72 ppm). Protons of the –OCH – of
2
PrBr, NaH
-
CCl3C(O)NCO
PrBr,
NaH
7
(cS)
O
o
O
O O
O
DMF, 60 C
O
+CCl3C(O)NCO
O O
CH3 H
O
O O
O
CH3
CH3
Y
HN
O
HN
O
HN
O
Ph
H
CH3
Ph
H
Ph
H
CH3
CH3
1
6
17
15 Y = -C(O)NHC(O)CCl3
Scheme 3 Alkylation of 7(cS) with propyl bromide
1
23

Struct Chem
1
Fig. 4 Full H NMR spectrum
of calyx[4]arene 16 (295 K,
4
3
00 MHz, CDCl ). In the inset,
the fragment 3.0–5.5 ppm is
presented
Fig. 5 Molecular structure of
diastereomer 16. Hydrogen
atoms are omitted for clarity
with the exception of those
taking part in the formation of
the O5-H5ÁÁÁO4, N1–H1ÁÁÁO5
and N1ÁÁÁH28A-C28
intramolecular hydrogen bonds
methylenecarbamide fragment is turned relatively the C6–
O1 bond (the C6–O1–C45–C46 torsion angle is
?ac-conformation relatively to the C46–N1 bond (the
C46–N1–C47–C48 torsion angle is 148.7(2)°), and the
phenyl ring is almost orthogonal to the C46–N1 bond and
is turned relatively to the N1–C47 bond [the C46–N1–
C47–C49 and N1–C47–C49–C50 torsion angles are
84.3(2)° and 92.1(3)°, respectively]. It can assume that
such disposition of the a-phenylethyl amide substituent is
-132.6(2)°). Such disposition of methylenecarbamide
fragment is stabilized additionally by the weak
N1ÁÁÁH28A-C28 intramolecular hydrogen bond [d(NÁÁÁ
˚
H) = 2.54 A, \C–HÁÁÁN = 165°) with the energy
2
.37 kcal/mol. The methyl group of this substituent has
123

Struct Chem
stabilized by stacking interactions between C49ÁÁÁC54
aromatic ring of substituent and C22ÁÁÁC27 aromatic ring
of the macrocycle. In favor of this suggestion is the dis-
located in –sc-conformation relatively to the C1–C6 bond
[the C45–O1–C6–C1 torsion angle is -60.6(2)°], and the
planar methylenecarbamide fragment is turned relatively to
the C6–O1 bond (the C6–O1–C45–C46 torsion angle is
-132.9(2)°] which is stabilized by the N1–HÁÁÁO3
˚
tance between them (3.4 A). The propyl substituent is
almost orthogonal to the C8ÁÁÁC13 aromatic ring (the
C55–O2–C13–C8 torsion angle is 93.2(2)°) and has ap–
ap-conformation [the C13–O2–C55–C56 and O2–C55–
C56–C57 torsion angles are 171.3(2)° and -173.3(2)°,
respectively].
˚
intramolecular hydrogen bond [d(HÁÁÁO) = 2.34 A, \N–
HÁÁÁO = 155°) with the energy 3.29 kcal/mol. The methyl
group has ?ac-conformation relatively the C46–N1 bond
similar to molecule 16 (the C46–N1–C47–C48 torsion angle
is 104.1(2)°). In contrast to 6, the phenyl ring of substituent
in the molecule 16 is located in –ac-conformation relatively
the C46–N1 bond and is considerably less turned with
respect to the N1–C47 bond (the C46–N1–C47–C49 and
N1–C47–C49–C50 torsion angles are -127.4(2)° and
38.6(3)°, respectively). The difference in the conformation
of this substituent is probably determined by the substitution
of the hydroxy group by propoxy substituent. In this case, the
specific attraction of dispersion nature between the opposite
tert-butyl groups comes to fore, introducing a distortion in
the calixarene scaffold (see the inset in Fig. 6). The propyl
group C59ÁÁÁC61 is orthogonal to the aromatic ring
C22ÁÁÁC27 (the C59–O4–C27–C26 torsion angle is 93.7(2)°)
and has ?ac- and ?sc-conformations (the C27–O4–C59–
C60 and O4–C59–C60–C61 torsion angles are 150.4(2)°
and 61.7(3)°, respectively). The propyl group C55ÁÁÁC57 is
disordered over two positions with equal population due to
rotation around C13–O2 bond.
While compound 17 is not inherently chiral, the asym-
metrical carbon atom in the amide moiety induces prochi-
1
rality of protons in the OCH C(O) group. It appears in H
2
NMR spectrum as AB spin system with Dd 0.341 ppm and
JHH 15.4 Hz. Equatorial and axial protons of the methylene
2
unit at the calixarene’s lower rim are also non-equivalent,
2
and the spectrum displays four pairs of doublets with J
HH
1
2.9, 12.9, 12.8 and 13.1 Hz. Even tert-Bu groups on the
opposite side of the macrocycle give four signals at 0.868,
.902, 1.307 and 1.325 ppm. In solid state, the macrocycle
0
of the compound 17 has the irregularly flattened cone con-
formation (Fig. 6). The C8ÁÁÁC13 and C22ÁÁÁC27 aromatic
rings substituted by propyl groups are parallel (the dihedral
angle between them is 1°) and slightly shifted to each other.
Two remaining aromatic rings (C1ÁÁÁC6 and C15ÁÁÁC20) are
turned to each other by the dihedral angle 115°. The con-
formation of the a-phenylethyl amide substituent in 17
slightly differs from that in structure 16. This substituent is
Fig. 6 Molecular structure of
1
7. Hydrogen atoms are omitted
for clarity except of the H atom
taking part in the formation of
the N–HÁÁÁO intramolecular
hydrogen bond. In the inset,
another projection of the
structure is shown
1
23

Struct Chem
9
. Fraschetti C, Letzel MC, Paletta M et al (2012) Cyclochiral
resorcin[4]arenes as effective enantioselectors in the gas phase.
J Mass Spectrom 47:72–78. doi:10.1002/jms.2028
Conclusion
We have demonstrated the possibility of using the asym-
metric induction for preparing macrocyclic structures with
a prescribed order for the substituents at the calixarene
basis (intrachiral calyx[4]arenes). A significant influence of
the chiral center ((1-phenyl)ethylaminocarbonylmethoxy
moiety) at the lower rim of calixarene on the proton
chemical shifts and reactivity of the hydroxyl groups in the
reaction with acylisocyanates has been shown. Quantum
chemical (DFT) calculations have predicted two almost
equal in energy conformations for the starting dihydroxy-
calixarene, 1-1 (S) and 1-2 (S). The corresponding adducts
with TEA, 9-1 (S) and 9-2 (S) possess noticeably different
total energies and can determine the d.e. for the product
1
0. Li SY, Xu YW, Liu JM, Su CY (2011) Inherently chiral cal-
ixarenes: synthesis, optical resolution, chiral recognition and
asymmetric catalysis. Int J Mol Sci 12:429–455. doi:10.3390/
ijms12010429
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substitution of calixarenes: direct way to inherently chiral
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2. Li SZ, Yang K, Liu HB et al (2013) Inherently chiral biscal-
ixarene cone–cone conformers consisting of calix[4]arene and
calix[5]arene subunits. Tetrahedron Lett 54:5901–5906. doi:10.
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016/j.tetlet.2013.08.091
13. Luo J, Shen LC, Chung WS (2010) Inherently chiral bis-
calix[4]arenes: design and syntheses. J Org Chem 75:464–467.
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4. Talotta C, Gaeta C, Troisi F et al (2010) Absolute configuration
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2(S) observed in the experiment. The reaction of 7(cS) with
propyl bromide in presence of NaH as base yields intra-
1
021/ol101098x
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Acknowledgments A. B. Rozhenko thanks the Alexander von
Humboldt Foundation (Germany) for generous donating the hardware
for calculations and license to TURBOMOLE set of programs. The
team of the SKIT computer cluster at the V.M. Glushkov Institute of
Cybernetics of NAS of Ukraine, Kyiv, is gratefully acknowledged for
providing computational resources for TURBOMOLE calculations.
1
1
2
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