Synthesis of fan-shaped C3 molecule with three glycyrrhetinic acid units and self-assembly properties

Article abstract of DOI:10.1002/cjoc.201190213

A novel fan-shaped C₃ molecule with three glycyrrhetinic acid units was synthesized via "click chemistry" in high yield and the self-assembly characteristics were studied in different mixed solvents.

Full text of DOI:10.1002/cjoc.201190213

FULL PAPER
Synthesis of Fan-Shaped C3 Molecule with Three Glycyrrhetinic
Acid Units and Self-Assembly Properties
Hu, Juna(胡君)
Yu, Libinga(于立冰)
Zhang, Menga(章萌)
Ju, Yong*,a,b(巨勇)
a Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua University, Beijing 100084, China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China
A novel fan-shaped C3 molecule with three glycyrrhetinic acid units was synthesized via “click chemistry” in
high yield and the self-assembly characteristics were studied in different mixed solvents.
Keywords terpenoids, C3 molecules, self-assembly
Introduction
Symmetry plays an important role in the chemical
topics such as chemical selectivity, supramolecular
self-assembly, chiral recognition, asymmetric synthesis
and catalysis.1-4 Among various symmetric organic
compounds, versatile and available C3 molecules are
widely used in organic nanotubes, redox active chro-
mophores and controlled self-assembly.5-8 As a repre-
sentative of C3 molecules, 1,3,5-triazine is well-known
in organic chemistry and is used in a variety of applica-
tions as 2,4,6-mono-, di- or trisubstituted derivatives
endowed with different substituents.9,10 Due to the high
reactivity of chlorine atoms in cyanuric chloride
(2,4,6-trichloro-1,3,5-triazine) toward nucleophiles, it is
generally used as the starting material for the prepara-
tion of different triazine derivatives,11 including den-
drimers in which the triazine ring acts as the construc-
tive core.12-15
Glycyrrhetinic acid (1, GA) is a facile pentacyclic
triterpenoid presenting in the form of aglycone or gly-
cosides from medicinal plants. It has always been noted
for the effect on anti-inflammation, anti-virus and
anti-tumor.16-21 Despite of chiral rigid skeleton, relative
low-toxicity and biocompatibility, there is few reports
about triterpenoids as the scaffolds in supramolecular
and recognition chemistry.22-28
Figure 1 Structure of novel fan-shaped C3 molecule with three
glycyrrhetinic acid units.
with sodium azide in DMF at 70 ℃, compound 4 was
synthesized (Scheme 1a). On the other hand, 2,4,6-
tris(prop-2-ynyloxy)-1,3,5-triazine (6) was obtained by
treating cyanuric chloride 5 with 2-propynyl alcohol in
the presence of potassium hydroxide in THF (Scheme
1b).31 Synthesis of the fan-shaped C3 molecules of
GA-triazole conjugate was described in Scheme 2 as the
following procedure:32 a solution of 4 and 6 (molar
ratio＝3∶1), 5 mol% CuSO4•5H2O and 20 mol% so-
dium ascorbate in t-BuOH-CH3OH-H2O (10∶2∶1,
volume ratio) was stirred at 65 ℃ for 6 h. Compound 7
was obtained after column chromatographic purification
with 75% yield.
To continue our previous work23,24,29,30 a new kind
fan-shaped C3 molecule with three GA units (Figure 1)
was synthesized and the self-assembly properties were
studied.
Results and discussion
GA (1) was esterified to 2, followed by treatment
with bromoacetyl bromide at r.t. to give 3. After reacting
*
E-mail: juyong@tsinghua.edu.cn; Tel.: 0086-010-62792795; Fax: 0086-010-62781695
Received October 13, 2010; revised January 4, 2011; accepted February 17, 2011.
Project supported by the National Natural Science Foundation of China (Nos. 20772071, 20972086) and the Specialized Research Fund for the Doc-
toral Program of Higher Education (No. 20090002110060).
Chin. J. Chem. 2011, 29, 1139— 1142
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Hu et al.
FULL PAPER
Scheme 1 Synthesis of (a) azides of glycyrrhetinic acid and (b) terminal alkynes
Reagents and conditions: (i) CH3I, K2CO3, THF, reflux; (ii) BrCOCH2Br, K2CO3, CH2Cl2, r.t.; (iii) NaN3, DMF, 70 ℃; (iv) 2-propynyl alcohol, KOH, THF.
Scheme 2 Synthesis of novel fan-shaped C3 molecule via “click chemistry”
The self-assembly behavior of 7 was studied in dif-
ferent mixed solvents. The primary results showed that
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Chin. J. Chem. 2011, 29, 1139—1142

Synthesis of Fan-Shaped C3 Molecule with Three Glycyrrhetinic Acid Units
7 could form weak organogel in THF-methanol (V∶
V＝3∶1) with the MGC of 2.3 g/100 cm3 (MGC,
minimum gelator concentration at which gelation was
observed to restrict the flow of the medium28) and the
Tgel＝36 ℃ (Tgel, the required temperature for the or-
ganogel to collapse, was determined by the dropping
ball method at MGC33) (Figure 2a). To gain visual in-
sight into the aggregation mode of this weak gel, scan-
ning electron microscopy (SEM) was used to investigate
the gel structure (Figure 2b). The gel was dried in a
vacuum freeze dryer and then was coated with a thin
layer of gold before imaging. The SEM images revealed
that 7 could self-assemble into nanoscale fibrous struc-
tures with regular fiber diameters of ca. 40—100 nm in
THF-methanol. It is well known that the formation of
gels is based on self-assembly of organic molecules
driven by multiple weak interactions, such as di-
pole-dipole interaction, van der Waals forces and hy-
drogen-bonding.23,34 For this fan-shaped C3 molecule, it
might be driven by the weak π-π interactions and the
special skeleton. Meanwhile, it only self-assembled to
solid spheres with the diameters range of 300—800 nm
in THF-water (V∶V＝3∶1) (Figure 2c). The detailed
mechanism is still in progress.
(1.43 g, 10.4 mmol) and 2 (5 g, 10.3 mmol, which was
carried out by the reported method.35) were dissolved in
50 mL of anhydrous CHCl3, and bromoacetyl bromide
(1.1 mL, 12.4 mmol) was added slowly at 0 ℃. The
mixture was stirred for 22 h at r.t., then the crude was
washed with 10% citric acid, H2O, brine, dried by mag-
nesium sulfate and evaporated. Purification by flash
chromatography (n-hexane-EtOAc, V∶V＝4∶1) af-
forded 3 as a white solid, yield 93%. m.p. 244—246 ℃;
1H NMR (CDCl3, 300 MHz) δ: 5.63 (s, 1H, 12-H), 4.54
(dd, J1＝11.67 Hz, J2＝5.13 Hz, 1H, 3-H), 3.80 (dd, J1
＝18.87 Hz, J2＝12.00 Hz, 2H, O2CCH2Br), 3.65 (s, 3H,
CO2CH3), 0.77, 0.88, 1.09, 1.11, 1.13, 1.33 (7×s,
7×3H, 23, 24, 25, 26, 27, 28, 29-CH3); 13C NMR
(CDCl3, 75 MHz) δ: 200.00 (11-C), 176.95 (CO2CH3),
169.39 (13-C), 166.09 (O2CCH2Br), 128.53 (12-C),
82.96 (3-C), 61.71, 55.07, 51.84, 48.45, 45.45, 44.09,
43.26, 41.13, 38.73, 38.39, 37.80, 36.96, 32.71, 31.89,
31.19, 28.60, 28.39, 28.07, 26.53, 26.42, 23.42, 18.7＋4,
17.38, 16.67,＋16.47; ESI-MS (＋) m/z: 607 [M＋H] ,
629 [M＋Na] .
3-Azidoacetate-GA methyl ester (4) NaN3 (43
mg, 0.66 mmol) and 3 (200 mg, 0.33 mmol) were dis-
solved in 10 mL of anhydrous DMF, and the mixture
was stirred for 7 h at 70 ℃. The crude was poured into
water and filtrated. The solid was purified by flash
chromatography (dichloromethane-methanol, V∶V＝
70∶1) afforded 4 as a white solid, yield 96%. m.p. 207
1
—210 ℃; H NMR (CDCl3, 300 MHz) δ: 5.59 (s, 1H,
12-H), 4.56 (dd, J1＝11.34 Hz, J2＝5.16 Hz, 1H, 3-H),
3.80 (s, 2H, O2CCH2Br), 3.62 (s, 3H, CO2CH3), 0.73,
0.84, 1.06, 1.08, 1.14, 1.30 (7×s, 7×3H, 23, 24, 25, 26,
27, 28, 29-CH3); 13C NMR (CDCl3, 75 MHz) δ: 199.92
(11-C), 176.90 (CO2CH3), 169.41 (13-C), 166.18
(O2CCH2Br), 128.46 (12-C), 82.87 (3-C), 61.61, 55.00,
50.62, 48.40, 45.40, 44.05, 43.23, 41.09, 38.72, 38.13,
37.78, 36.92, 32.66, 31.87, 31.14, 28.57, 28.34, 28.13,
26.49, 26.42, 23.57, 23.39, 18＋.70, 17.39, 16.7＋8, 16.44;
ESI-MS (＋) m/z: 568 [M＋H] , 590 [M＋Na] .
Figure 2 (a) Photograph of the gel 7 in THF-methanol (V∶ V＝
3∶ 1); (b) SEM image of 7 in THF-methanol (V∶ V＝ 3∶ 1); (c)
SEM image of 7 in THF-water (V∶ V＝ 3∶ 1).
Conclusion
A novel fan-shaped C3 molecule with three glycyr-
rhetinic acid units was synthesized via “click chemistry”,
and the self-assembly properties were studied in differ-
ent mixed solvents. It might give significant clue for the
potential applications in the field of biological and me-
dicinal chemistry.
2,4,6-Tris(prop-2-ynyloxy)-1,3,5-triazine
(6)
Compound 6 was prepared according to the previous
literature.31 The purity of 6 was verified by NMR spec-
troscopy, thin-layer chromatography and mass spec-
troscopy. All the experimental data of the isolated prod-
ucts were coincident with those previously reported.31
m.p. 69—71 ℃; 1H NMR (CDCl3, 300 MHz) δ: 2.52 (t,
J＝2.4 Hz, 3×1H, C≡CH), 5.01 (d, J＝2.4 Hz, 3×2H,
OCH2); 13C NMR (CDCl3, 75 MHz) δ: 172.52 (triaz-
ine-C), 77.05 (C≡CH), 75.95 (C≡CH), 55.97 (OCH2);
ESI-MS (＋) m/z: 266 [M＋Na]＋.
Experimental
General procedure
1H NMR and 13C NMR spectra were obtained with a
JEOL JNM-ECA 300/600 instrument. Chromato-
graphic purifications were conducted by column chro-
matography with the use of 0.06—0.20 mm silica gel.
TLC analysis was facilitated by the use of UV light (254
nm) with fluorescent-indicating plates. Chemicals and
solvents were either purchased from commercial sup-
pliers or purified by standard techniques.
Fan-shaped C3 molecule (7) A solution of 4 (350
mg, 0.62 mmol) and 6 (48 mg, 0.2 mmol) in
t-BuOH-CH3OH (V∶ V＝5∶1, 12 mL) was stirred at
55 ℃ for 15 min. Then CuSO4•5H2O (5 mol% in 0.5
mL of H2O) and sodium ascorbate (20 mol% in 0.5 mL
of H2O) were added. The reaction mixture was stirred at
65 ℃ for 6 h. The solvent was evaporated under re-
duced pressure to afford a crude product. It was dis-
3-Bromoacetate-GA methyl ester (3)
K2CO3
Chin. J. Chem. 2011, 29, 1139—1142
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Hu et al.
FULL PAPER
solved in CH2Cl2, washed with saturated brine, dried
with magnesium sulfate and filtered, followed by the
removal of the solvent under vacuum. Finally, the crude
product was purified by column chromatography on
silica gel (dichloromethane-methanol, V∶ V＝40∶1) to
obtain pure fan-shaped molecules 7 as white solid, yield
75%. m.p. 212—214 ℃; 1H NMR (CDCl3, 300 MHz) δ:
7.92 (s, 3×1H, triazole-H), 5.62 (s, 3×1H, 12-H), 5.56
(s, 3×2H, OCH2-triazole), 5.15 (s, 3×2H, O2CCH2-
triazole), 4.55—4.59 (m, 3×1H, 3-H), 3.65 (s, 3×3H,
CO2CH3), 0.69, 0.76, 0.79, 1.08, 1.09, 1.11, 1.32
(3×7×s, 3×7×3H, 23, 24, 25, 26, 27, 28, 29-CH3);
13C NMR (CDCl3, 75 MHz) δ: 198.92 (11-C), 175.93
(CO2CH3), 171.75 (triazine-C), 168.50 (13-C), 164.84
(O2CCH2-triazole), 141.52 (triazole-C), 127.39 (12-C),
124.69 (triazole-C), 82.52 (3-C), 60.57, 60.22, 53.85,
50.78, 50.11, 47.36, 44.35, 43.02, 42.19, 40.04, 37.58,
37.03, 36.72, 35.82, 31.56, 30.81, 30.10, 27.52, 27.31,
27.03, 25.44, 25.36, 22.37, 17.63, 16.29, 15.45, 15.37;
ESI-MS (＋) m/z: 1970 [M＋Na]＋.
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We thank Prof. Li Guang Tao for discussion.
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Chin. J. Chem. 2011, 29, 1139— 1142