Synthesis and crystal structure of 2-acetoxy-3-(3,4-diacetoxyphenyl) propanoic acid

Article abstract of DOI:10.3184/174751916X14531217100725

2-Acetoxy-3-(3,4-diacetoxyphenyl)propanoic acid has been synthesised as a derivative of 2-hydroxy-3-(3,4-dihydroxyphenyl)propanoic acid (danshensu) to improve its chemical stability and liposolubility. It was readily hydrolysed to release the bioactive da

Full text of DOI:10.3184/174751916X14531217100725

JOURNAL OF CHEMICAL RESEARCH 2016
VOL. 40 FEBRUARY, 95–96
RESEARCH PAPER 95
Synthesis and crystal structure of 2-acetoxy-3-(3,4-diacetoxyphenyl)
propanoic acid
Lei Chena, Bin xiao Sub, Jing wen Wanga, Jin yi Caoa, Shan bo Maa, Ai dong Wena and Yang Lic*
aDepartment of Pharmacy, Xijing Hospital Fourth Military Medical University, Xi’an 710032, Shaanxi Province, P.R. China
bDepartment of Anesthesiology, Xijing Hospital Fourth Military Medical University, Xi’an 710032, Shaanxi Province, P.R. China
cCollege of Life Sciences, Northwest University, Biomedicine Key Laboratory of Shaanxi Province, Xi’an 710069, Shaanxi Province, P.R. China
2-Acetoxy-3-(3,4-diacetoxyphenyl)propanoic acid has been synthesised as a derivative of 2-hydroxy-3-(3,4-dihydroxyphenyl)propanoic
acid (danshensu) to improve its chemical stability and liposolubility. It was readily hydrolysed to release the bioactive danshensu. Its
crystal structure and stereochemistry were determined by X-ray single crystal diffraction analysis.
Keywords: 2-acetoxy-3-(3,4-diacetoxyphenyl)propanoic acid, crystal structure, X-ray diffraction analysis
2-Hydroxy-3-(3,4-dihydroxyphenyl)propanoic
acid,
also
Suitable crystals of triacetyl danshensu were selected after
examination under polarising microscope. Diffraction
called danshensu, is an active component of the root of Salvia
miltiorrhiza used as a traditional herb in China and other Asian
countries. Danshensu exhibits well-known pharmacological
activities, such as dilating coronary arteries, inhibiting platelet
aggregation, improvement of microcirculation and protection of
myocardium from reperfusion injury.1–4 Although danshensu is
widely used, it does not easily enter into cells by crossing the
cell membranes due to its phenolic hydroxyl group and so is
poorly soluble in lipidic matrices.5 Thus, there is a great need to
find new danshensu derivatives with potent biological activity,
good stability and liposolubility.
Over the past several decades, many danshensu derivatives
have been designed and synthesised to increase their stability
and liposolubility.6–8 These derivatives were expected to exhibit
similar biological activity to danshensu due to both the ester
and ether linkages, which are easily hydrolysed to release
bioactive danshensu.
a
data were collected at 296(2) K on a Bruker Smart CCD
diffractometer with Mo-Kα radiation (λ = 0.71073 Å). The
data integration and reduction were processed with SAINT
software.9 The structures were solved by the direct method
using SHELXTL and subject to a full-matrix least-squares
refinement on F2 with the SHELXL-97 program.10 All non-
hydrogen atoms were refined anisotropically. All hydrogen
atoms were determined via difference Fourier maps and refined
with isotropic atomic displacement parameters. The X-ray
crystal structure of triacetyl danshensu showing the atom
numbering and molecular packing in the crystal is shown in
Figs 2 and 3 respectively.
The crystal of triacetyl danshensu is monoclinic, with
space group P 2(1) and unit cell parameters: a = 11.428(3) Å,
b = 6.1995(17) Å, c = 12.737(4) Å, α = 90°, β = 105.794(6)°,
γ = 90° and V = 868.3(4) Å3. Two molecules (one triacetyl
danshensu, one water of crystallisation) form the asymmetric
unit. A total of 4401 reflections had their intensities integrated
and scaled (1.85 ≤ θ ≤ 25.09), of which 2914 were considered
significant [Rint = 0.05]. Completeness to theta (25.09°) = 99.5%.
X-ray crystallography has been increasingly used to
determine the molecular structure of organic compounds.
However, the crystal structure of danshensu derivatives is rarely
reported. Here, we have synthesised successfully an important
danshensu
derivative,
2-acetoxy-3-(3,4-diacetoxyphenyl)
propanoic acid, named triacetyl danshensu (Fig. 1). The
structure and stereochemistry were determined by X-ray single
crystal diffraction analysis for the first time.
Results and discussion
Triacetyl danshensu was synthesised by reaction of danshensu
and acetic anhydride in the presence of a catalytic amount of
perchloric acid.
RO
COOH
OR
H
RO
:
:
=
R
Danshensu
Triacetyl danshensu R =Ac
Fig. 2 Molecular structure and ORTEP drawing of triacetyl danshensu,
showing the atomic numbering. Thermal ellipsoids are drawn at 50%
probability.
Fig. 1 Structures of danshensu and triacetyl danshensu.
* Correspondent. E-mail: ly2011@nwu.edu.cn

96 JOURNAL OF CHEMICAL RESEARCH 2016
Fig. 3 Molecular packing of triacetyl danshensu, viewed
along the b-axis. The dashed lines represent hydrogen
bonds.
Table 1 Hydrogen bond data for triacetyl danshensu
Synthesis of triacetyl danshensu; general procedure
A catalytic amount (0.2 g) of perchloric acid was added to a mixture
of danshensu (10.0 g, 50.0 mmol) in acetic anhydride (20 mL). The
reaction mixture was stirred at 60 °C for 6 h. After the reaction was
finished, the mixture was cooled to room temperature, poured into icy
water and extracted with ethyl acetate. The organic layer was shaken
with brine, dried over Na2SO4 and then evaporated to leave a crude
material, which was purified by chromatography on a silica gel column
yielding the compound as a white solid (8.9 g). Then the solid was
purified by crystallisation from acetic acid.
D–H..A
d(D–H)/Å
0.82
d(H..A)/Å
d(D..A)/Å
∠DHA/°
O(8)-H(8B)...O(9)a
1.78
2.05(2)
2.03(3)
2.558(6)
2.870(6)
2.847(6)
156.9
171(8)
168(8)
O(9)-H(9A)...O(7)b 0.83(2)
O(9)-H(9B)...O(7)c 0.83(2)
Symmetry transformations used to generate equivalent atoms:
a: –x + 1, y–3/2, –z + 1.
b: –x + 1, y + 1/2, –z + 1.
c: x, y + 1, z – 1.
The goodness-of-fit on F2 is 0.908. Final indices were R1 =
0.0577, wR2 = 0.1357 [I > 2 σ (I)]. The largest difference
between peak and hole was 0.189 and –0.177 e Å–3. The bond
lengths and bond angles of triacetyl danshensu were found to be
quite normal: C–C lengths range from 1.341(8) Å [C(6)–C(7)]
to 1.533(7) Å [C(11)–C(12)] and C–O lengths range from
1.168(8) Å [O(4)–C(4)] to 1.438(6) Å [O(5)–C(12)] while
angles range from 106.6(4)° [O(5)–C(12)–C(11)] to 128.8(7)°
[O(4)–C(4)–C(3)].
2-Acetoxy-3-(3,4-diacetoxyphenyl)propanoic acid: White solid; yield
22
D
55%;
= +81.67 (c = 1,CH3OH). IR (KBr, cm–1): 3504 (–OH),
[α]
3061–3085 (ArH), 2855–2929 (C–H), 1774 (C=O); 1H NMR (500 MHz,
CDCl3) δ13.20 (s, 1H, –COOH), 7.15–7.18 (m, 3H, ArH), 5.07–5.09 (m,
1H, –CH), 3.02–3.16 (m, 2H, –CH2), 2.02– 2.50 (m, 9H, –CH3);
13C NMR (125 MHz, DMSO-d6): δ 170.38, 169.82, 168.24, 168.18,
141.62, 140.74, 135.26, 127.34, 124.33, 124.30, 72.16, 39.61, 20.39, 20.40;
MS (ESI) m/z: 347.0741 [M + Na]+. Anal. calcd for C15H16O8∙H2O: C,
52.63; H, 5.30; found: C, 52.62; H, 5.19%.
The crystal packing of triacetyl danshensu is ensured through
a complex network of hydrogen bonds occurring between
neighbouring molecules. The carboxyl group is engaged in
the hydrogen bonds with hydroxyl groups of lattice water.
The water molecule is serving as a hydrogen bonding hub by
a bifurcated donor hydrogen bond to two hydroxyl groups, as
represented by O(9)–H(9A)...O(7) and O(9)–H(9B)...O(7) and
by a bifurcated acceptor hydrogen bond from one hydroxyl
group as represented by O(8)–H(8B)...O(9) (Table 1). These
intermolecular interactions result in the formation of chains
of molecules and the adjacent chains interact as shown in the
lattice structure. CCDC1433400 contains the supplementary
crystallographic data for this paper. The data can be obtained
free of charge from the Cambridge Crystallographic Data
Centre via www.cam.ac.uk/data_request.cif.
This work was financially supported by the National Natural
Science Foundation of China (No. 31200253) and the Shaanxi
Provincial Education Department (No. 2013JK0810). Lei Chen,
Bin xiao Su and Yang Li contributed equally to this study.
Received 3 November 2015; accepted 19 December 2015
Paper 1503688 doi: 10.3184/174751916X14531217100725
Published online: 27 January 2016
References
1
2
3
4
L. Wu, H. Qiao, Y. Li and L. Li, Phytomedicine., 2007, 14, 652.
L.N. Chen and X.X. Zhu, J. Chin. Materia. Medica., 2005, 30, 630.
B. Husna, T. On and Y.Z. Zhu, J. Pharmacol. Sci., 2007, 104, 202.
J. Zhang, X.Y. Zeng, Y. Yang and Z.F. Liu, Basic. Clin. Med., 2005, 25,
1054.
Experimental
5
6
C.N. Dong, Y. Wang and Y.Z. Zhu, Bioorg. Med. Chem., 2009, 17, 3499.
Y. Jia, X. Dong, P. Zhou, X. Liu, L. Pan, H. Xin, Y.Z. Zhu and Y. Wang,
Eur. J. Med. Chem., 2012, 55, 176.
The elemental analysis was performed by on an Elementar Vario
EL III elemental analyser. Optical rotations were measured with a
PerkinElmer 343 polarimeter. IR spectra were recorded on a FTIR-
8400S spectrophotometer. 1H NMR and 13C NMR spectra were
recorded on a Bruker Avance 500 MHz spectrometer. Mass spectra
were obtained using a Bruker micro TOF-Q II spectrometer. X-ray
single crystal diffraction was carried out on a Bruker Smart CCD
diffractometer. All the reagents were of analytical grade.
7
8
S. Seetapun, J. Yaoling, Y. Wang and Y.Z. Zhu, Biosci. Rep., 2013, 33, 677.
Q.B. Cui, Y.H. Chen, M.J. Zhang, L.C. Shan, Y.W. Sun, P. Yu, G.X. Zhang,
D.Y. Wang, Z.C. Zhao, Q. Xu, B.H. Xu and Y.Q. Wang, Chem. Biol. Drug
Des., 2014, 84, 282.
9
Y. Li, Y. Zhao, Y.M. Zhang, M.J. Wang and W.J. Sun, Carbohyd. Res.,
2009, 344, 2270.
10 G.M. Sheldrick, Acta Crystallogr. A., 2008, 64, 112.