Synthesis of novel chiral cholic acid-based molecular tweezers containing unsymmetrically disubstituted urea units using microwave irradiation

Article abstract of DOI:10.3184/174751912X13318994425202

An efficient procedure has been developed for the synthesis of new chiral cholic acid molecular tweezer artificial receptors by linking an unsymmetrically disubstituted urea to methyl deoxycholate via a carbonate chain using microwave irradiation. The structures of these new receptors were confirmed by 1H NMR, IR, MS spectra and elemental analysis. Their binding properties were examined by UV-Vis spectra titration. The preliminary results indicate that these molecular tweezers not only recognised anions, but also showed good enantioselectivity for D-amino acid methyl esters.

Full text of DOI:10.3184/174751912X13318994425202

206 RESEARCH PAPER
APRIL, 206–209
JOURNAL OF CHEMICAL RESEARCH 2012
Synthesis of novel chiral cholic acid-based molecular tweezers containing
unsymmetrically disubstituted urea units using microwave irradiation
Bitao Zenga,b, Zhigang Zhaob*, Lijun Zhoua and Qinghan Lib
aYiBin Vocational andTechnical College, Yibin 644003, P. R. China
bCollege of Chemistry and Environmental Protection Engineering, Southwest University for Nationalities, Chengdu 610041, P. R. China
An efficient procedure has been developed for the synthesis of new chiral cholic acid molecular tweezer artificial
receptors by linking an unsymmetrically disubstituted urea to methyl deoxycholate via a carbonate chain using
microwave irradiation. The structures of these new receptors were confirmed by 1H NMR, IR, MS spectra and elemen-
tal analysis. Their binding properties were examined by UV-Vis spectra titration. The preliminary results indicate that
these molecular tweezers not only recognised anions, but also showed good enantioselectivity for D-amino acid
methyl esters.
Keywords: molecular tweezer, microwave irradiation, deoxycholic acid, molecular recognition
The understanding of noncovalent intermolecular interactions
has become the central focus of supramolecular chemistry.1–3
The design and synthesis of molecular tweezer artificial
receptors to recognise substrates of biochemical significance
utilising these weak forces so that they mimic biological events
are of major interest in molecular recognition research.4–8 The
natural rigid concave structure and inherent asymmetry of
cholic acid suggests that it is an ideal building block for the
construction of molecular tweezers. In recent years, molecular
tweezers have been synthesised derived from steroidal cholic
acid.9–13 However, to our knowledge, the use of chiral unsym-
metrical disubstitued ureas as building blocks for the construc-
tion of deoxycholic acid molecular tweezer has not been
reported.
Furthermore, the application of microwave techniques for
organic synthesis has attracted considerable interest in recent
years.14–15 This is because this method can greatly reduce
reaction times, enhance conversions and simplify work-up.
In continuation of our ongoing program to synthesise tweezer
artificial receptors using microwave irradiation,16–18 we report
here a facile and rapid synthetic method for the preparation of
chiral unsymmetrically disubstituted urea type molecular
tweezer based on deoxycholic acid under microwave irradiation
which, to the best of our knowledge, has not been attempted
previously. At the sametime, we have made some preliminarily
studies of the recognition properties of this kind of molecular
tweezer for anions and chiral molecules. The synthetic route is
shown in Scheme 1.
were added, the absorbance value rose in a regular pattern. It
showed that these molecular tweezers possessed the ability to
form a complex with the guest molecules under examination.
The titration data were analysed by using the Hildebrand–
Benesi equation.19 Based on equation (1), when [G]0>>[H]0,
the plots of 1/[G]0 versus 1/∆A were measured. The plot gave
a straight line. We calculated with the association constants
(Ka) from the intercept and the slope of the line, we calculated
with the association constants (Ka). The free energy change
(–∆G0) was obtained according to equation (2). The association
constants (Ka) and free energy changes (–∆G0) for the inclusion
complexes of anions and D/L–amino acid methyl esters with
the molecular tweezers 9b, 9c, 9f are listed in Tables 2 and 3.
These show that these molecular tweezers possessed the
ability to form a complex with these guest molecules. The
supramolecular complexes consisted of 1:1 host and guest
molecules. The association constants of molecular tweezer
9f, for example, are 507.25, 16862.00, 13670.56 L mol−1 for
NO3−, H2PO4−, CH3COO−, respectively. At the same time, these
receptors showed good chiral recognition for D-amino acid
methyl esters, the maximum KD /KL of molecular tweezer 9c
reaches 4.02 for D/L–His–OMe. The details of molecular
recognition of these molecular tweezers are under further
studies.
(1)
(2)
Results and discussion
Experimental
As shown in Table 1, the microwave-enhanced method when
compared with the conventional heating method, has the
following advantages: (1) the reaction avoids the use of the
very toxic phosgene, and reduces pollution of the environment;
(2) the reaction rate increased 27–33 times, and greatly
shortened the reaction time; (3) the yields of molecular
tweezers have increased from 57–65% to 86–94%. Hence, the
microwave assisted method is a safe, fast, efficient and green
synthesis method for chiral molecular tweezers based on
deoxycholic acid.
Melting points were determined on a micro-melting point apparatus
and were uncorrected. IR spectra were obtained on 1700 Perkin-Elmer
FTIR using KBr disks. H NMR spectra were recorded on a Varian
1
INOVA 400 MHz spectrometer using TMS as internal standard. Mass
spectra were determined on Waters Q-TOF Premier instrument.
Elemental analysis was performed on a Carlo-Erba-1106 auto analy-
ser. Optical rotation was measured on a Wzz-2B polarimeter. All reac-
tions were performed in a commercial microwave reactor (XH-100A,
100-1000 W, Beijing Xianghu Science and Technology Development
Co. Ltd, Beijing, P. R. China). All the solvents were purified before
use. Intermediates 3 and 7 was prepared according to reported
procedures.20–21 The physical constants of intermediates 3a–f and 7 are
listed in Table 4.
The recognition of molecular tweezers 9b, 9c, 9f for anions
and D/L –amino acid methyl esters has been investigated by
UV-Vis spectra titration in CHCl3 at 25 °C. We added aromatic
amines and D/L –amino acid methyl esters solution of different
Microwave method for the preparation of molecular tweezers 9a–f
Triphosgene (0.11 g, 0.37 mmol) was added to a solution of interme-
diate 7 (0.29 g, 0.5 mmol) in dry CH2Cl2 (10 mL) and dry pyridine
(0.2 mL) at room temperature. Then the solution was placed in the
microwave oven and the reaction mixture was irradiated for 10 min at
200 W. Intermediate 8 was formed and, without separation, the inter-
mediate 3 (1.5 mmol) and dry pyridine (0.2 mL) were added directly
concentrations to 9b, 9c, 9f of fixed concentration of 1×10−4
~
10×10−4 mol L−1, and measured the characteristic absorbance
value of the host–guest complexes. As the guest molecules
* Correspondent. E-mail: zzg63129@yahoo.com.cn

JOURNAL OF CHEMICAL RESEARCH 2012 207
Scheme 1 Reagents and conditions (i) CH3OH, SOCl2; (ii) aniline, triphosgene, DIEA, CH2Cl2; (iii) NaBH4, THF, H2O;
(iv) CH3OH, CH3COCl; (v) triphosgene, pyridine, MWI; (vi) m-nitroaniline, pyridine, MWI; (vii) triphosgene, CH2Cl2, pyridine, MWI;
(viii) CH2Cl2, pyridine, MWI.

208 JOURNAL OF CHEMICAL RESEARCH 2012
Table 1 Synthetic comparison of molecular tweezers 9a–f
1H, PhNHCO), 8.41–6.85 (m, 9H, ArH), 6.17 (d, J = 8.0 Hz, 1H,
CONH), 4.91 (brs, 1H, 123β-H), 4.67–4.59 (m, 1H, 3β-H), 4.12–3.93
(m, 3H, NCH + OCH2), 3.55 (s, 3H, COOCH3), 1.10 (d, J = 6.4 Hz,
3H, CH3), 0.92 (s, 3H, 19-CH3), 0.78 (d, J = 6.4 Hz, 3H, 21-CH3),
0.70 (s, 3H, 18-CH3); HRMS (ESI) m/z Calcd for C43H58 N4O10:
790.4153. Found: 791.4219 [M+H]+. Anal. Calcd for C43H58 N4O10: C,
65.30; H, 7.39; N, 7.08. Found: C, 65.20; H, 7.40; N, 7.06%.
between microwave irradiation and conventional heating
a
Compd.
Conventional method Microwave method tc/tw
Time/min
Yield/%
Time/min Yield/%
9a
9b
9c
9d
9e
9f
600
600
660
660
720
780
57
60
63
65
61
58
21
22
23
20
24
25
93
94
90
93
87
86
29
27
29
33
30
31
9b: Pale yellow solid, yield 94%, m.p. 109–111 °C, [α]2D0+39.0
(c 1.6, CH2Cl2); IR (KBr)(cm−1): 3385, 2870, 1736, 1596, 1441, 1227,
1
1061; H NMR (400 MHz, DMSO-d6) δ: 10.12 (s, 1H, 3-OCONH),
8.46 (s, 1H, PhNHCO), 8.42–6.87 (m, 9H, ArH), 6.18 (d, J = 8.4 Hz,
1H, CONH), 4.91 (brs, 1H, 123β-H), 4.67-4.60 (m, 1H, 3β-H), 4.18–
4.14 (m, 1H, NCH), 4.09–3.73 (m, 2H, OCH2), 3.55 (s, 3H, COOCH3),
0.91 (s, 3H, 19-CH3), 0.87–0.82 (m, 7H, CH(CH3)2), 0.77 (d, J = 6.4
Hz, 3H, 21-CH3), 0.69 (s, 3H, 18-CH3); HRMS(ESI) m/z Calcd for
C45H63N4O10: 819.4544. Found: 819.4554 [M]+. Anal. Calcd for
C45H63N4O10: C, 65.91; H, 7.74; N, 6.83. Found: C, 65.70; H, 7.72; N,
6.81%.
a tC, Conventional heating method needs time; tMW, microwave
method needs time.
Table 2 Association constants (Ka) and Gibbs free energy
changes (–∆G°) for the inclusion complexes of anions with
molecular tweezers 9b, 9c, 9f in CHCl3 at 25 °C
9c: Pale yellow solid, yield 90%, m.p. 82–83 °C, [α]2D0+53.3 (c 1.3,
CH2Cl2); IR (KBr)(cm−1): 3387, 2869, 1737, 1598, 1447, 1225, 1065;
1H NMR (400 MHz, DMSO-d6) δ: 10.06 (s, 1H, 3-OCONH), 8.46
(s, 1H, PhNHCO), 8.40–6.84 (m, 14H, ArH), 6.23 (d, J = 8.0 Hz, 1H,
CONH), 4.92 (brs, 1H, 123β-H), 4.65–4.59 (m, 1H, 3β-H), 4.18–3.99
(m, 3H, NCH + OCH2), 3.55 (s, 3H, COOCH3), 2.82–2.72 (m, 2H,
PhCH2), 0.92 (s, 3H, 19-CH3), 0.79 (d, J = 6.4 Hz, 3H, 21-CH3), 0.68
(s, 3H, 18-CH3); HRMS(ESI) m/z Calcd for C49H62N4O10: 866.4466.
Found: 867.4551 [M+H]+. Anal. Calcd for C49H62 N4O10: C, 67.88; H,
7.21; N, 6.46. Found: C, 67.71; H, 7.18; N, 6.48%.
Host
Guest
Ka/L mol−1
–∆G°/kJ mol−1
9b
NO3−
H2PO4−
238.04
12808.29
1691.34
13.55
23.43
18.42
CH3COO−
9c
9f
NO3−
2479.88
14720.01
11053.51
19.36
23.78
23.07
H2PO4−
CH3COO−
NO3−
507.25
16862.00
13670.56
15.43
24.10
23.59
H2PO4−
9d: Pale yellow solid, yield 93%, m.p. 104–106 °C, [α]2D0+89.7
CH3COO−
(c 1.6, CH2Cl2); IR (KBr)(cm−1): 3354, 2889, 1742, 1591, 1438, 1217,
1
1077; H NMR (400 MHz, DMSO-d6) δ: 10.12 (s, 1H, 3-OCONH),
8.45 (s, 1H, PhNHCO), 8.40–6.89 (m, 9H, ArH), 6.13 (d, J = 8.4 Hz,
1H, CONH), 4.92 (brs, 1H, 123β-H), 4.68–4.60 (m, 1H, 3β-H), 4.15–
4.11 (m, 1H, NCH), 4.03–3.94 (m, 2H, OCH2), 3.55 (s, 3H, COOCH3),
1.10 (d, J = 6.4 Hz, 3H, CH3), 0.92 (s, 3H, 19-CH3), 0.87–0.82
(m, 7H, CH(CH3)2), 0.79 (d, J = 6.4 Hz, 3H, 21-CH3), 0.71 (s, 3H,
18-CH3); HRMS(ESI) m/z Calcd for C46H64N4O10: 832.4622. Found:
833.4711 [M+H]+. Anal. Calcd for C46H64N4O10: C, 66.32; H, 7.74; N,
6.73. Found: C, 66.20; H, 7.76; N, 6.76%.
Table 3 Association constants(Ka) and Gibbs free energy
changes (−∆G0) for the inclusion complexes of amino acid
methyl esters with molecular tweezers 9b, 9c, 9f in CHCl3 at
25 °C
Host
Guest
Ka/L mol−1 –∆G0/kJ mol−1
KD/KL
9b
D-Try-OMe
L-Try-OMe
D-His-OMe
L-His-OMe
D-Try-OMe
L-Try-OMe
D-His-OMe
L-His-OMe
D-Try-OMe
L-Try-OMe
D-His-OMe
L-His-OMe
268.12
113.56
586.17
164.34
301.06
121.65
858.78
213.41
286.42
107.66
645.48
268.91
13.85
11.72
15.78
12.63
14.13
11.89
16.73
13.28
14.01
11.59
16.02
13.85
2.36
9e: Pale yellow solid, yield 87%, m.p. 94–96 °C, [α]2D0+122.4 (c 1.3,
CH2Cl2); IR (KBr)(cm−1): 3348, 2948, 1738, 1590, 1468, 1221, 1090;
1H NMR (400 MHz, DMSO-d6) δ: 10.14 (s, 1H, 3-OCONH), 8.46 (s,
1H, PhNHCO), 8.43–6.86 (m, 9H, ArH), 6.23 (d, J = 8.4 Hz, 1H,
CONH), 4.91 (brs, 1H, 123β-H), 4.68–4.57 (m, 1H, 3β-H), 4.25–4.18
(m, 1H, NCH), 4.07–3.98 (m, 2H, OCH2), 3.55 (s, 3H, COOCH3),
2.57–2.36 (m, 4H, CH2CH2S), 2.08 (s, 3H, SCH3), 0.92 (s, 3H,
19-CH3), 0.79 (d, J = 6.4 Hz, 3H, 21-CH3), 0.70 (s, 3H, 18-CH3);
HRMS(ESI) m/z Calcd for C45H62N4O10S: 850.4187. Found: 851.4268
[M+H]+. Anal. Calcd for C45H62N4O10S: C, 63.51; H, 7.34; N, 6.58.
Found: C, 63.37; H, 7.32; N, 6.59%.
3.57
2.47
4.02
2.66
2.40
9c
9f
9f: Pale yellow solid, yield 86%, m.p. 115–117 °C, [α]2D0+218.2
(c 1.2, CH2Cl2); IR (KBr)(cm−1): 3349, 2868, 1738, 1599, 1442, 1223,
Table 4 The physical constants of intermediates 3a–f and 7
1
1054; H NMR (400 MHz, DMSO-d6) δ: 10.90 (s, 1H, indole-NH),
Compd
Formula
M.p./ °C
[α]2D0/ °C
10.01 (s, 1H, 3-OCONH), 8.52 (s, 1H, PhNHCO), 8.40–6.90 (m, 14H,
ArH), 6.22 (d, J = 8.4 Hz, 1H, CONH), 4.91 (brs, 1H, 123β-H),
4.64–4.57 (m, 1H, 3β-H), 4.26–4.20 (m, 1H, NCH), 4.18–4.13 (m,
2H, OCH2), 3.52 (s, 3H, COOCH3), 2.94–2.85 (m, 2H, indole-CH2),
0.94 (s, 3H, 19-CH3), 0.77 (d, J = 6.4 Hz, 3H, 21-CH3), 0.69 (s, 3H,
18-CH3); HRMS(ESI) m/z Calcd for C51H63N5O10: 905.4575. Found:
906.4648 [M+H]+. Anal. Calcd for C51H63N5O10: C, 67.60; H, 7.01; N,
7.73. Found: C, 67.43; H, 7.03; N, 7.70%.
3a
3b
3c
3d
3e
3f
C10H14N2O2
C12H18N2O2
C16H18N2O2
C13H20N2O2
C12H18N2O2S
C18H19N3O2
C32H46N2O7
125–127
103–104
133–134
88–90
–8.0 (c 0.5 CH2Cl2)
–44.0 (c 0.5 CH2Cl2)
–20.0 (c 0.5 CH2Cl2)
–28.0 (c 0.5 CH2Cl2)
+ 18.4 (c 0.5 CH2Cl2)
+ 35.6 (c 0.5 CH2Cl2)
+ 85.7 (c 0.5 CH2Cl2)
95–97
167–168
184–185
7
Conventional method for the preparation of molecular tweezers 9a–f
Triphosgene (0.11 g, 0.37 mmol)was added to a solution of intermedi-
ate 7 (0.29 g, 0.5 mmol) in dry CH2Cl2 (20 mL) and dry pyridine
(0.2 mL) at room temperature. Then the solution was refluxed for 5 h.
Intermediate 8 was formed and, without separation, intermediate 3
(1.5 mmol) and dry pyridine (0.2 mL) were added directly to the mix-
ture which was refluxed for a further 5–8 h. The solvent was removed
and the residue was diluted with ethyl acetate (20 mL) and washed
with 10% NaHCO3 (15 mL×3), brine (15 mL×3) and finally dried
over anhydrous Na2SO4. The solvent was evaporated to give the crude
product. The crude product was purified by column chromatography
on silica gel H with dichloromethane/ethyl acetate as the eluant.
to the mixture and the irradiation continued for 10–15 min at the same
power. The solvent was removed and the residue was diluted with
ethyl acetate (20 mL) and washed with 10% NaHCO3 (15 mL×3),
brine (15 mL×3), and finally dried over anhydrous Na2SO4. The
solvent was evaporated to give the crude product. The crude product
was purified by column chromatography on silica gel H with dichlo-
romethane/ethyl acetate as the eluant. The physical and spectra data of
the compounds 9a–f are as follows.
9a: Pale yellow solid, yield 93%, m.p. 82–84 °C, [α]2D0+74.4 (c 1.3,
CH2Cl2); IR (KBr)(cm−1): 3349, 2868, 1738, 1599, 1442, 1223, 1054;
1H NMR (400 MHz, DMSO-d6) δ: 10.09 (s, 1H, 3-OCONH), 8.46 (s,

JOURNAL OF CHEMICAL RESEARCH 2012 209
6
7
J. Leblond and A. Petitjean, ChemPhysChem, 2011, 12, 1043.
J. Leblond, H. Gao, A. Petitjean and J.C. Leroux, J. Am. Chem. Soc., 2010,
132, 8544.
Z.G. Zhao, X.L. Liu, Q.H. Li and S.H. Chen, Chin. J. Org. Chem., 2009,
29, 1336 (in Chinese).
This work was supported by the Science and Technology Key
Project of YiBin City (No. 2010SF027), the Fundamental
Research Funds for Central University, Southwest University
for Nationalities (No. 11NZYTH05) and the Project of
Postgraduate Degree Point Construction, Southwest University
for Nationalities (No. 2011XWD-S0703).
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Received 29 January 2012; accepted 18 February 2012
Paper 1201135 doi: 10.3184/174751912X13318994425202
Published online: 17 April 2012
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