Synthesis and crystal structure of benzoyloxymethyl (4α,8β, 13β)-13-methyl-16-oxo-17-norkauran-18-carbonate Ester

Article abstract of DOI:10.1007/s10870-008-9435-6

Isosteviol derivative: benzoyloxymethyl (4α,8β,13β)-13- methyl-16-oxo-17-norkauran-18-carbonate ester was synthesized by esterification of isosteviol with chloromethyl benzoate and its crystal structure was determined by X-ray diffraction method. The compound crystallizes in the triclinic space group P1 with unit cell parameters: a = 8.784(3) A, b = 9.079(3) A, c = 15.950(6) A, α = 79.343(6)°, β = 79.061(5)°, γ = 89.849(5)°, Z= 2. The conformation of rings A and B is chair, whereas the conformation of ring C is unsymmetrical twist chair. The carbonyl group at the C20 is coplanar with the benzene ring. The fragment of the ester group occupying the pseudoaxial site of C1 position adopts a zigzag conformation.

Full text of DOI:10.1007/s10870-008-9435-6

J Chem Crystallogr (2009) 39:108–111
DOI 10.1007/s10870-008-9435-6
ORIGINAL PAPER
Synthesis and Crystal Structure of Benzoyloxymethyl
(4a,8b,13b)-13-methyl-16-oxo-17-norkauran-18-carbonate Ester
Jin Cai Æ Wen Zhou Æ Junqing Chen Æ
Min Sun Æ Min Ji
Received: 17 April 2007 / Accepted: 4 June 2008 / Published online: 25 June 2008
Ó Springer Science+Business Media, LLC 2008
Abstract Isosteviol derivative: benzoyloxymethyl (4a,8b,
13b)-13-methyl-16-oxo-17-norkauran-18-carbonate ester was
synthesized by esterification of isosteviol with chloromethyl
benzoate and its crystal structure was determined by X-ray
diffraction method. The compound crystallizes in the triclinic
[3–6]. However, study in the Sansom Institute has dem-
onstrated that isosteviol has a short half life for only
30 min and would be removed rapidly from the body,
probably owing to glucuronidation of carboxyl in isostev-
iol. Therefore, the benzoyloxymethyl ester of isosteviol,
benzoyloxymethyl (4a,8b,13b)-13-methyl-16-oxo-17-nor-
kauran-18-carbonate ester 6, was synthesized, which may
retain the pharmacological activity while having much
more desirable pharmacokinetic properties via hydrolyzed
by esterase under biological conditions to release isosteviol
step by step. The crystal and molecular structures of ben-
zoyloxymethyl ester was confirmed for future scientific
studies, and a conventional synthetic method was also
reported in this literature.
˚
space group P1 with unit cell parameters: a = 8.784(3) A,
˚
˚
b = 9.079(3) A, c = 15.950(6) A, a = 79.343(6)°, b =
79.061(5)°, c = 89.849(5)°, Z= 2. The conformation of rings
A and B is chair, whereas the conformation of ring C is
unsymmetrical twist chair. The carbonyl group at the C20 is
coplanar with the benzene ring. The fragment of the ester group
occupying the pseudoaxial site of C1 position adopts a zigzag
conformation.
Keywords Crystal structure Á Isosteviol Á
Benzoyloxymethyl ester
Experimental
Introduction
Synthesis
Isosteviol, (4a,8b,13b)-13-methyl-16-oxo-17-norkauran-
18-oic acid 2, is a tetracyclic diterpenoid with a beyerane
skeleton, obtained by acid-catalyzed hydrolysis of stevio-
side 1, a constituent of Stevia rebaudiana, which is
commonly used as a noncaloric sugar substitute [1, 2]. It
has been found that isosteviol has good pharmacological
activity against a number of significant diseases including
ischemia–reperfusion injury, hypertension, and cancer
The synthesis of benzoyloxymethyl ester involved con-
densation of benzoyl chloride and paraformaldehyde, to
yield chloromethyl benzoate 5, which was converted to
compound 6 by reacting with the sodium salt of isosteviol
(Scheme 1). The structure of 6 was confirmed by MS, IR,
1HNMR, 13CNMR, elemental analysis, and X-ray
crystallography.
Synthesis of Sodium Isosteviol
Isosteviol 2 was obtained by hydrolysis of stevioside 1 with
10% sulfuric acid at 95 °C for 7 h and recrystallization
from ethanol gave colorless crystals of 2 in 80% yield. To a
solution of sodium (0.2 g) in ethanol (20 mL), isosteviol 2
(2.8 g) was added. The mixture was stirred at reflux for
J. Cai Á W. Zhou Á J. Chen Á M. Sun Á M. Ji (&)
Institute of Pharmaceutical Engineering, School of Chemistry
and Chemical Engineering, Southeast University, 210096
Nanjing, People’s Republic of China
e-mail: jimin@seu.edu.cn
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J Chem Crystallogr (2009) 39:108–111
109
Scheme 1 The synthesis route
of compound 6
2 h. The precipitate was collected by filtration, giving pale
2917.91, 1743.42, 1716.42, 1600.71, 711.64 cm-1
;
yellow solid of 3 (3.6 g) in 95% yield.
1HNMR(CDCl3) d: 0.65(s, 3H, 20-H3), 0.95(s, 3H, 17-H3),
1.23(s, 3H, 18-H3), 0.85–1.91(m,18H, 1-H2, 2-H2, 3-Hax,
5-H, 6-H2, 7-H2, 9-H, 11-H2, 12-H2, 14-H2, 15-Hb), 2.19–
2.23(d, 1H, 3-Heq, J = 13.68 Hz), 2.42–2.50(dd, 1H, 15-
Ha, J = 18.72, 3.75 Hz), 5.97–6.03(q, 2H, OCH2O,
J = 6.17 Hz), 7.44–7.49(m, 2H, Ph-H), 7.59–7.63(t, 1H,
Ph-H, J = 7.49 Hz), 8.03–8.06(m, 2H, Ph-H) ppm; 13C-
NMR(CDCl3) d: 13.37, 18.77, 19.80, 20.27, 21.58, 28.65,
37.22, 37.79, 38.09, 39.36, 39.68, 41.43, 44.00, 48.24,
48.61, 54.24, 54.68, 57.09, 128.56, 128.92, 129.87, 133.73,
165.21, 176.12, 222.10 ppm; Anal. calcd for C28H36O5
(%):C, 74.31; H, 8.02; Found: C 74.48, H 7.81.
Synthesis of Chloromethyl Benzoate
A mixture of benzoyl chloride (12 mL, 0.1 mol), dry
paraformaldehyde (3 g), and a minute quantity of zinc
chloride were heated at 105 °C for 18 h. After cooling to
ambient temperature, the mixture was poured into ice water
and extracted with dichloromethane. The organic phase
was dried with sodium sulfate and the solvent was removed
by evaporation. Then the oil residue was chromatographed
on silica gel with ethyl acetate/petroleum ether, and 4 g
(23% yield)of chloromethyl benzoate 5 was obtained.
Crystal Structure Determination
Synthesis of Benzoyloxymethyl Ester
Colorless rhombic crystals of the title compound were
grown at room temperature from methanol by slow evap-
A mixture of sodium isosteviol 3 (3.4 g, 0.01 mol), chlo-
romethyl benzoate 5 (2 g, 0.012 mol), a minute quantity of
potassium iodide, and acetonitrile (30 mL) was heated at
reflux for 6 h. After cooling to ambient temperature, the
solvent was removed in a vacuum and water (20 mL) was
added. The organic phase was extracted with ethyl acetate
and dried with sodium sulfate, then the solvent was
removed by evaporation. Recrystallization from methanol
gave colorless crystals of 6 (2.8 g) in 62% yield, m.p. 106–
107 °C. The compound was characterized on the basis of
oration technique.
A single crystal of dimensions
0.46 9 0.45 9 0.37 mm was chosen for X-ray diffraction
studies. X-ray diffraction data were collected on a BRU-
KER SMART 1000 CCD diffractometer with graphite
monochromatized Mo–Ka radiation. The crystal data, data
collection details, and refinement parameters for the
structures are listed in Table 1.
The structure was solved by direct methods (program
SHELX-97) and refined by the full-matrix least-squares
method on all F2 data using the SHELXL-97 programs.
spectral data: MS(ES): [M + Na]+ 475.3; IR vmax
:
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J Chem Crystallogr (2009) 39:108–111
Table 1 Crystal data and other experimental details
CCDC number
CCDC-272526
Colorless rhombic
C28 H36 O5
452.57
Crystal description
Chemical formula
Molecular weight
Temperature (K)
298(2)
˚
Radiation, wavelength (A)
Crystal system
0.71073
Triclinic
Space group
P1
Unit cell dimensions
˚
a (A)
8.784(3)
˚
b (A)
9.079(3)
˚
c (A)
15.950(6)
79.343(6)
79.061(5)
89.849(5)
1226.6(7)
2
a (°)
b (°)
c (°)
Fig. 1 Thermal motion ellipsoids, shaving crystallographic atom
numbering
3
˚
Unit cell volume (A )
Z
Density (calculated) (mg/m3)
Absorption coefficient (mm-1
F(000)
1.225
)
0.083
488
h range for data collection (°)
Limiting indices
2.28–25.01
-10 B h B 10
-10 B k B 9
-16 B l B 18
6493/4264 [R(int) = 0.0336]
98.8%
Reflections collected/unique
Completeness to theta = 25.01
Absorption correction
Semi-empirical from
equivalents
Maximum and minimum
transmission
0.9701, 0.9630
Refinement method
Full-matrix least-squares on F2
4264/3/601
Data/restraints/parameters
Goodness-of-fit on F2
1.002
Final R indices [I [ 2sigma(I)]
R indices (all data)
R1 = 0.0547, wR2 = 0.1219
R1 = 0.0919, wR2 = 0.1410
0.189, -0.172
Largest different peak and hole
-3
˚
(eA
)
Fig. 2 The crystal packing diagram
The non-hydrogen atoms were refined anisotropically. The
hydrogen atoms were fixed at geometrically permitted
positions and were not refined.
The title molecule consists of three six-membered ali-
phatic rings A, B, and C, and a five-membered aliphatic
ring D. The rigid molecular skeleton coincides with that
of the parent isosteviol 2 [7]. The conformation of rings A
and B is chair, whereas the conformation of ring C is
unsymmetrical twist chair and the values of the torsion
angles C12–C6–C7–C8, C6–C7–C8–C9, C6–C12–C16–
C9, and C8–C9–C16–C12 show some significant devia-
tion from the ideal value of 60°. Distortion in ring C is
because of strain at the junction with the five-membered
D ring.
Results and Discussion
1
1
The MS, IR, HNMR, CNMR and elemental analysis for
the product were in good agreement with the title com-
pound 6. Figure 1 shows the molecular structure of the
compound 6. Packing diagram of the compound 6 in a unit
cell is shown in Fig. 2. The selected bond lengths and bond
angles are listed in Table 2.
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J Chem Crystallogr (2009) 39:108–111
111
˚
Table 2 Selected bond lengths (A), bond angle (°) and torsion angles (°) for non-hydrogen atoms
(a) Bond lengths
O(1)–C(10)
1.217(7)
1.421(7)
1.195(7)
1.393(8)
1.366(11)
O(2)–C(18)
O(4)–C(20)
C(1)–C(17)
C(20)–C(21)
C(22)–C(23)
1.204(7)
1.368(7)
1.559(8)
1.472(9)
1.374(10)
O(3)–C(18)
O(4)–C(19)
C(1)–C(18)
C(21)–C(22)
C(23)–C(24)
1.352(7)
O(3)–C(19)
1.414(7)
1.508(8)
1.375(8)
1.371(11)
O(5)–C(20)
C(21)–C(26)
C(24)–C(25)
(b) Bond angles
C(18)–O(3)–C(19)
C(2)–C(1)–C(17)
C(17)–C(1)–C(15)
O(3)–C(18)–C(1)
O(5)–C(20)–C(21)
C(22)–C(21)–C(20)
C(25)–C(24)–C(23)
(c) Torsion angles
C12–C6–C7–C8
C8–C9–C16–C12
O1–C10–C9–C28
C18–O3–C19–O4
C19–O3–C18–C1
117.3(5)
107.4(5)
109.2(4)
112.5(5)
125.5(7)
119.0(6)
119.8(8)
C(20)–O(4)–C(19)
C(18)–C(1)–C(2)
C(18)–C(1)–C(15)
O(2)–C(18)–O(3)
O(4)–C(19)–O(3)
O(4)–C(20)–C(21)
C(26)–C(21)–C(20)
115.6(5)
109.6(5)
116.0(4)
121.7(5)
108.2(4)
112.0(6)
122.4(6)
C(18)–C(1)–C(17)
O(2)–C(18)–C(1)
O(5)–C(20)–O(4)
C(22)–C(21)–C(26)
C(23)–C(22)–C(21)
C(24)–C(25)–C(26)
106.3(5)
125.7(6)
122.5(6)
118.6(6)
120.3(7)
120.2(8)
-47.3(6)
70.0(5)
C6–C7–C8–C9
46.0(7)
-57.6(6)
7.7(7)
C6–C12–C16–C9
C7–C6–C12–C16
C20–O4–C19–O3
C19–O4–C20–C21
C19–O3–C18–O2
-73.8(5)
62.2(5)
C7–C8–C9–C16
C19–O3–C18–O2
C19–O4–C20–O5
C19–O4–C20–O5
-31.3(9)
91.3(5)
77.3(6)
7.2(8)
-172.1(4)
7.7(7)
-174.8(4)
7.2(8)
˚
The C10–O1 bond, 1.217(7) A, has a normal value for a
carbonyl group. The carbonyl group at the C20 is coplanar
with the benzene ring (torsion angle: O5–C20–C21–
C26 = 177.2(6)°, O5–C20–C21–C22 = -4.0(9)°), so the
of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data request/cif.
Acknowledgments We are very grateful to the China Ministry of
Health Foundation for Scientific Research (project no. WKJ2005-2-
022) for financial supports.
˚
C20–O5 distance, 1.195(7) A, is shorter than normal
because of its conjugation with the benzene ring. The
torsion angle O1–C10–C9–C28 is -31.3(9)°, minimizing
steric interaction. The C1 position is at one top of the chair
in ring A, methyl C17 is in the pseudoequatorial site, while
carbonyl C18 is in the pseudoaxial site. The C18–O3–C19–
O4–C20 fragment of the ester group adopts a zigzag con-
formation; the corresponding dihedral angles are given in
Table 2. The methylene C19 is almost the same torsion
angle from two oxygens of the carbonyl groups at C18 and
C20 (the torsion angles: C19–O4–C20–O5 = 7.2(8)°,
C19–O3–C18–O2 = 7.7(7)°).
The preliminary biological test showed that the title
compound exhibited acute antihyperglycemic effect. The
compound 6 is found to be more active than isosteviol on
depressing the blood glucose during IVGTT in SD rats,
respectively at 15.6 lM/kg.
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Supplementary Material
CCDC–272526 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free
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