The synthesis and crystal structure of (4α,8β,13β,16β) -13-methyl-16,18-diol-17-norkaurane: A simultaneous reduction product of isosteviol

Article abstract of DOI:10.1007/s10870-010-9912-6

(4α,8β,13β,16β)-13-methyl-16,18-diol-17-norkaurane was synthesized by esterification and reduction of isosteviol, respectively. The structure of the title compound was established by spectral analysis and X-ray diffraction studies. The compound crystallizes in the orthorhombic space group P2₁2₁2₁ with unit cell parameters: a = 7.3705 (14) A, b = 13.508 (3) A, c = 20.139 (4) A, V = 2005.1 (7) A³, Z = 4. The conformation of rings A and B is chair, whereas the conformation of ring C is unsymmetrical distorted chair. The stereochemistry of the A/B and B/C ring junctions is trans, while the five-membered ring D adopts an envelope conformation. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s10870-010-9912-6

J Chem Crystallogr (2011) 41:519–522
DOI 10.1007/s10870-010-9912-6
ORIGINAL PAPER
The Synthesis and Crystal Structure of (4a,8b,13b,16b)-
13-Methyl-16,18-diol-17-Norkaurane: A Simultaneous
Reduction Product of Isosteviol
Junqing Chen
Meng Cao Wen Zhou
•
•
Min Sun
•
•
Jin Cai
Min Ji
•
Received: 21 February 2010 / Accepted: 17 November 2010 / Published online: 9 December 2010
Ó Springer Science+Business Media, LLC 2010
Abstract (4a,8b,13b,16b)-13-methyl-16,18-diol-17-nor-
kaurane was synthesized by esterification and reduction of
isosteviol, respectively. The structure of the title compound
was established by spectral analysis and X-ray diffraction
studies. The compound crystallizes in the orthorhombic
space group P2 2 2 with unit cell parameters: a = 7.3705
In the previous work, we have reported on the synthesis
0
of the benzoyloxymethyl ester, 4 -bromobutyl ester and
15a-bromo derivative of isosteviol [7–9]. In this study, a
simultaneous reduction product of isosteviol was synthe-
sized by facile route, and the crystal and molecular struc-
ture of it was also confirmed. The need for a definitive
proof of the crystal structure is due to the growing
importance in assessing the molecular arrangements known
for this type of compounds [10].
1
1 1
˚
˚
14) A, b = 13.508 (3) A, c = 20.139 (4) A, V = 2005.1
˚
(
(
3
7) A , Z = 4. The conformation of rings A and B is chair,
˚
whereas the conformation of ring C is unsymmetrical dis-
torted chair. The stereochemistry of the A/B and B/C ring
junctions is trans, while the five-membered ring D adopts
an envelope conformation.
The preparation of title compound is illustrated in
Scheme 1. Treatment of isosteviol 2 obtained by acid-
catalyzed hydrolysis of stevioside 1 with 2-bromopropane
and K CO in acetonitrile afforded the corresponding
2
3
Keywords Crystal Structure ꢀ Isosteviol ꢀ Chair ꢀ
Envelope ꢀ Reduction Product
isopropyl ester of isosteviol 3 in 95% yield [9]. Reduction
of compound 3 with LiAlH in tetrahydrofuran at 0 °C
4
afforded
(4a,8b,13b,16b)-13-methyl-16,18-diol-17-nor-
kaurane 4 in good yield. The structure of 4 was confirmed
1
13
Introduction
by MS, IR, H NMR, C NMR, elemental analysis, and
X-ray crystallography.
Isosteviol, (4a,8b,13b)-13-methyl-16-oxo-17-norkauran-
1
8-oic acid 2 obtained by acid-catalyzed hydrolysis of
stevioside 1, a constituent of Stevia rebaudiana, is a tetra-
cyclic diterpenoid with a beyerane skeleton, which is
commonly used as a noncaloric sugar substitute [1, 2]. It
has been found that isosteviol has good pharmacological
activity against broad spectrum significant diseases
including ischemia–reperfusion injury, hypertension, and
cancer [3–6].
Experimental
Melting points were determined on an RY-1 hot-stage
microscope with the thermometer uncorrected. Infrared
spectra were recorded in a Nicolet Impact 410 spectro-
1
13
photometer. H, C NMR spectra were recorded on a
Bruker Avance DPX-300 MHz instrument in DMSO-d6,
and chemical shifts (d) were reported in parts per million
(ppm) relative to TMS as an internal standard. Mass spectra
J. Chen ꢀ M. Sun ꢀ J. Cai ꢀ M. Cao ꢀ W. Zhou ꢀ 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
were recorded on Aglient 1100 LC–MS. Elementary
analyses were performed on Elementar Vario EL III
instrument. All reactions were monitored by TLC on silica
gel 60F-254 glass plates (E.Merk).
123

5
20
J Chem Crystallogr (2011) 41:519–522
Table 1 Crystal data and other experimental details
CCDC number
765366
Crystal description
Crystal size
Colorless block
0.38 9 0.35 9 0.31 mm
Chemical formula
Molecular weight
Temperature
C
20
H
34
O
2
2
ꢀC H
5
OH
352.54
298(2) K
˚
Radiation, wavelength
Unit cell dimensions
Mo Ka, 0.71073 A
˚
a = 7.3705 (14) A
˚
b = 13.508 (3) A
˚
c = 20.139 (4) A
Crystal system
Orthorhombic
Space group
1 1 1
P2 2 2
Scheme 1 The synthesis route of compound 4
3
˚
2005.1 (7) A
Unit cell volume
No. of molecules per unit cell, Z
Absorption coefficient
Absorption correction
4
-1
0.075 mm
Synthesis of Isopropyl (4a,8b,13b)-13-methyl-16-oxo-
Multi-scan (Tmin = 0.9721
and Tmax = 0.9772)
1
7-norkauran-18-carbonate Ester (3)
F(000)
784
Isosteviol was obtained by hydrolysis of stevioside with
0% sulfuric acid at 95 °C for 7 h, and recrystallization
from ethanol gave colorless crystals of isosteviol in 80%
h range for entire data collection
Limiting indices
2.5–20.4°
-8 B h B9, -17 B k B 17,
1
-
26 B l B 22
yield. Isosteviol (5 g, 16 mmol), K CO (4.4 g, 32 mmol)
2
3
Reflections collected/unique
Reflections observed (I [ 2r (I))
Refinement
13,302/2,833
and 2-bromopropane (2 ml, 21 mmol) were dissolved in
1,812
1
5
00 ml acetonitrile. After reflux of the above mixture for
.5 h, the resulting mixture was cooled to room tempera-
2
Full-matrix least-squares on F
Data/restraints/parameters
2,833/0/230
0.0437
ture, and then distilled to one-third volume under reduced
pressure. The residue was poured into ice water, and the
resulting precipitates were collected by filtration. The
crude product was purified by recrystallization with ethanol
to afford 3 (5.4 g, 95%).
Final R-factor
2
wR(F )
0.1036
Goodness-of-fit
1.104
-
3
Final residual electron density
-0.172 \ Dq \ 0.153 e A˚
Synthesis of (4a,8b,13b,16b)-13-methyl-16,18-diol-
1
7-norkaurane (4)
CHOH), 4.07–4.11(t, 1H, CH OH, J = 5.31 Hz), 4.43–
2
1
.44(d, 1H, CHOH, J = 4.32 Hz); C NMR (300 MHz,
3
4
A mixture of LiAlH (0.9 g, 24 mmol) and 40 mL anhy-
4
DMSO-d ), d , ppm: 15.24, 17.65, 19.62, 19.78, 25.00,
6
C
drous tetrahydrofuran was stirred with ice bath cooling, and
compound 3 (1.8 g, 5 mmol) in 20 mL anhydrous tetrahy-
drofuran was slowly dropped into the mixture. The resulting
mixture was refluxed with stirring for 3 h and then cooled to
room temperature. After that, water (1.5 mL), 4 M NaOH
aq (3 mL), water (1.5 mL) were added dropwise slowly.
The mixture was then filtered and washed with tetrahy-
drofuran (10 mL). The filtrate was then evaporated and the
residue was purified by column chromatography on silica
27.49, 33.61, 35.19, 37.15, 38.13, 41.55, 41.59, 41.79,
42.85, 55.23, 56.36, 56.49, 62.76, 78.36; Anal. calcd for
C
H
O
ꢀ1/4H
O(%):C, 77.24; H, 11.18; Found: C 77.11,
2
20
34
2
H 11.03.
Crystal Structure Determination
Colorless block shaped single crystals of the title com-
pound were obtained by slow evaporation of a ethanol
solution. X-ray diffraction data were collected at 298 K on
a BRUKER SMART 1000 CCD diffractometer with
graphite monochromatized Mo Ka radiation (k = 0.71073
(
petroleum ether/ethyl acetate = 4:1, v/v) to give the title
compound (1.2 g, 78%). mp 142–143 °C. MS(EI): 307.3
? -1
M ? H] ; IR(KBr): v 3340.27, 2931.41, 1035.64 cm ;
[
1
˚
H NMR(300 MHz,DMSO-d ), d , ppm: 0.81(s, 3H, 20-
A). The crystal used for data collection was of dimensions
6
H
3
0.38 9 0.35 9 0.31 mm . Cell parameters were obtained
H ), 0.82(s, 3H, 17-H ), 0.84(s, 3H, 19-H ), 0.73–1.78(m,
3
3
3
2
1
3
0H, 1-H , 2-H , 3-H , 5-H, 6-H , 7-H , 9-H, 11-H , 12-H ,
2
from least-square fit of angular settings of 2,561 reflections
in the h range 2.5–20.4°. A semiempirical absorption cor-
rection (multi-scan, SADABS) was applied.
2
2
2
2
2
2
4-H , 15-H ), 3.08-3.13(q, 1H, CH OH, J = 5.36 Hz),
2
2
2
.45-3.54(q, 1H, CH OH, J = 5.31 Hz), 3.62–3.69(m, 1H,
2
1
23

J Chem Crystallogr (2011) 41:519–522
521
The structure was solved by direct methods using
SHELX-97, and refined by the full-matrix least-squares
2
method on all F data using the SHELXL-97 programs. All
Results and Discussion
Selected bond distances, bond angles and torsion angles are
listed in Table 2. In all essential details, the molecular
geometry of (4) in terms of the bond lengths and angles are
in good agreement with standard values. However, the C5–
C15–C1 and C15–C1–C17 bond angles of 118.03 (19) and
113.3(2)° have been increased to minimize the steric
interactions between the methyl group at C5 and the O
atoms of the hydroxyl group at C17.
H atoms were placed in geometrical positions and con-
strained to ride on their parent atoms with C–H distances in
˚
the range 0.96–0.98 A, with U (H) = 1.5U (C) for
iso
eq
methyl H and 1.2U (C) for other H atoms. The final
eq
refinement cycles converged to an R = 0.044 and
2
wR(F ) = 0.104 for the observed data. Residual electron
-
3
˚
densities ranged from -0.17 to 0.15 e A . The crystal
data, data collection details, and structure refinement
details are summarized in Table 1.
An ORTEP [11] view of the title compound with atomic
labeling is shown in Fig. 1. The title compound has two
˚
Table 2 Selected bond lengths (A), bond angle (°) and torsion angles (°) for non-hydrogen atoms
(
a) Bond lengths
O1–C10
C1–C17
C2–C3
1.429(3)
1.526(3)
1.518(4)
1.565(3)
1.532(3)
1.530(3)
1.550(3)
1.523(3)
1.472(4)
O2–C17
C1–C18
C5–C19
C6–C7
1.435(3)
1.535(4)
1.533(3)
1.534(4)
1.530(4)
1.539(3)
1.528(3)
1.526(3)
C1–C2
1.537(4)
1.560(3)
1.553(3)
1.549(3)
1.523(4)
1.533(3)
1.546(3)
1.416(3)
C1–C15
C5–C15
C6–C12
C9–C16
C10–C11
C12–C16
O3–C21
C5–C6
C7–C8
C8–C9
C9–C20
C11–C12
C13–C14
C21–C22
C9–C10
C12–C13
C14–C15
(
b) Bond angles
C2–C1–C17
C2–C1–C15
C3–C2–C1
110.9(2)
108.8(2)
113.7(2)
108.1(2)
112.2(2)
108.84(19)
112.4(2)
113.8(2)
112.4(2)
115.1(2)
111.56(19)
114.8(2)
113.8(2)
114.87(19)
112.7(2)
C2–C1–C18
C17–C1–C15
C2–C3–C4
107.3(2)
113.3(2)
111.4(2)
113.3(2)
108.31(19)
114.3(2)
114.3(2)
109.9(2)
112.9(2)
105.7(2)
109.3(2)
112.9(2)
109.7(2)
118.03(19)
110.5(2)
C17–C1–C18
C18–C1–C15
C3–C4–C5
108.0(2)
108.3(2)
113.8(2)
C19–C5–C4
C19–C5–C6
C7–C6–C12
C8–C7–C6
C19–C5–C15
C4–C5–C6
C4–C5–C15
C15–C5–C6
C12–C6–C5
C16–C9–C8
C16–C9–C10
O1–C10–C11
C10–C11–C12
C6–C12–C16
C16–C12–C11
C14–C15–C5
C9–C16–C12
108.18(19)
106.65(19)
116.61(19)
108.6(2)
C7–C6–C5
C9–C8–C7
C16–C9–C20
C8–C9–C10
O1–C10–C9
C13–C12–C6
C13–C12–C11
C14–C13–C12
C14–C15–C1
O2–C17–C1
C8–C9–C20
C20–C9–C10
C11–C10–C9
C13–C12–C16
C6–C12–C11
C13–C14–C15
C5–C15–C1
O3–C21–C22
98.8(2)
111.6(2)
106.66(19)
107.12(19)
100.22(19)
110.3(2)
103.3(2)
(
c) Torsion angles
C17–C1–C2–C3
C3–C4–C5–C6
-75.3(3)
-167.1(2)
-73.3(3)
53.6(3)
C18–C1–C2–C3
C19–C5–C6–C7
C12–C6–C7–C8
C16–C9–C10–O1
C20–C9–C10–C11
C7–C6–C12–C11
C19–C5–C15–C1
C17–C1–C15–C5
C18–C1–C17–O2
167.0(2)
55.2(3)
C3–C4–C5–C19
C4–C5–C6–C7
71.2(3)
-64.0(3)
-179.8(2)
45.3(3)
C19–C5–C6–C12
C7–C8–C9–C10
C20–C9–C10–O1
C9–C10–C11–C12
C19–C5–C15–C14
C18–C1–C15–C14
C2–C1–C17–O2
-49.0(3)
159.8(2)
156.8(2)
-44.5(3)
-71.2(3)
75.9(3)
C7–C8–C9–C20
C8–C9–C10–O1
O1–C10–C11–C12
C10–C11–C12–C16
C17–C1–C15–C14
C18–C1–C15–C5
C15–C1–C17–O2
-79.6(3)
-9.7(3)
63.6(2)
-135.5(2)
-20.4(3)
-56.9(3)
-164.3(2)
164.0(2)
62.9(3)
-73.2(3)
44.1(3)
123

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J Chem Crystallogr (2011) 41:519–522
Fig. 1 ORTEP view of the molecule, showing the atom-labelling
scheme. Displacement ellipsoids are drawn at the 30% probability
level
hydroxyl groups and a fairly rigid structure consisting of
three-six-membered aliphatic rings A, B, C, and a five-
membered aliphatic ring D. The A/B ring and B/C junction
are trans-fused at C5–C15 and C6–C12, respectively. Ring
D is fused at C9–C16–C12 to ring C. The shapes and
conformations of the rings can be judged from the Cremer
and Pople Parameters [12] listed in Table 3. Rings A and B
adopt chair conformations, while ring C is in a distorted
Fig. 2 The packing diagram of the title compound
˚
Table 4 Hydrogen-bond geometry (A, °)
D–HꢀꢀꢀA
D–H
HꢀꢀꢀA
DꢀꢀꢀA
D–HꢀꢀꢀA
a
b
c
O1–H1ꢀꢀꢀO3
O2–H2ꢀꢀꢀO1
O3–H3ꢀꢀꢀO2
0.82
0.82
0.82
1.99
1.97
1.98
2.811(3)
2.774(3)
2.794(3)
175
167
173
chair conformation with puckering amplitude Q = 0.652
˚
(
3) A, h = 18.1 (3)° and /2 = 262.0(8)°. The distortion
may be attributed to the narrowing of the C9–C16–C12
bond angle to 103.3 (2)°. The five-membered ring D adopts
an envelope conformation with atom C16 displaced
a
b
Symmetry code: -1/2 ? x, 3/2-y, 1-z; 1-x, -1/2 ? y, 1/2-z;
c
-x, -1/2 ? y, 1/2-z
2
˚
from the C9/C10/C11/C12 plane by 0.281 (5) A. The C17–
Supplementary Material
C1–C2–C3 torsion angle of -75.3 (3)° describes the
b-orientation of the hydroxymethyl group with respect to
the ent-kaurane nucleus. The C20–C9–C10–O1 torsion
angle of -79.6 (3)° describes the b-orientation of the
hydroxyl groups at C10 with respect to the methyl C20.
Packing diagram of the title compound in a unit cell is
shown in Fig. 2. As indicated in Fig. 2, the structure con-
tains three hydrogen bonding interactions, which occur
between species comprising the asymmetric unit. The
ethanol solvent molecule forms an O3–H3ꢀꢀꢀO2 hydrogen
bond to the hydroxyl groups at C17 and accepts an
O1–H1ꢀꢀꢀO3 hydrogen bond from the hydroxyl groups at
C10. In the crystal structure, intermolecular O2–H2ꢀꢀꢀO1
hydrogen bonds help to consolidate the crystal packing.
The geometry of hydrogen bonding is given in Table 4.
CCDC-765366 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif
Acknowledgments We are grateful to the China Ministry of Health
Foundation for Scientific Research (project No. WKJ2005-2-022) for
financial support.
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1
0.532(3)
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1
23