Synthesis, structural determination of a new ocotillol derivative and its epimer

Article abstract of DOI:10.2174/157017811799304377

Epimeric 20S, 24-epoxy-dammarane-3β, 6α, 12β, 25-tetraol acetic ester was synthesized from 20(S)-protopanaxatriol in the presence of acetic anhydride and the product oxidated by m-CPBA. 20S, 24R-epoxy dammarane-3β, 6α, 12β, 25-tetraol (ocotillol derivative) and its epimer were synthesized by saponification in the presence of sodium hydroxide in 1:1 molar ratio. The structures of the two compounds were characterized by X-ray diffraction method. The results showed the configuration of C-24 of two epimers as S-form (4, ocotillol derivative) and R-form (3, epimer), respectively.

Full text of DOI:10.2174/157017811799304377

682
Letters in Organic Chemistry, 2011, 8, 682-685
Synthesis, Structural Determination of a New Ocotillol Derivative and its
Epimer
Meng Qingguo*,a, Bi Yia, Wang Lianga, Jiang Naicaiv, Jiang Yongtaoa, Zhang Jiangfenga,
Yi Songtaob and Sun Haijuna
aSchool of Pharmacy, Yantai University, Yantai 264005, P.R. China;
bYantai Zozo Pharmaceuticals Co.Ltd, Yantai 264005, P.R. China
Received April 19, 2010: Revised September 14, 2010: Accepted December 06, 2010
Abstract Epimeric 20S, 24-epoxy-dammarane-3ꢀ, 6ꢁ, 12ꢀ, 25-tetraol acetic ester was synthesized from 20(S)-
protopanaxatriol in the presence of acetic anhydride and the product oxidated by m-CPBA. 20S, 24R-epoxy dammarane-
3ꢀ, 6ꢁ, 12ꢀ, 25-tetraol (ocotillol derivative) and its epimer were synthesized by saponification in the presence of sodium
hydroxide in 1:1 molar ratio. The structures of the two compounds were characterized by X-ray diffraction method. The
results showed the configuration of C-24 of two epimers as S-form (4, ocotillol derivative) and R-form (3, epimer),
respectively.
Keywords: Ocotillol, derivative, epimer, synthesis, structure determination.
INTRODUCTION
MS, 1H NMR, 13C NMR, ESI-MS, HSQC and/or HMBC,
DEPT 90, DEPT 135 and X-ray diffraction. According to the
literature, the difference of 20 (S)- and 20 (R)- isomer in
ocotillol-type saponin may be observed from the carbon
signal of C-21 (S: ꢀ28ꢁ1; R: ꢀ20ꢁ1) in 13C NMR
spectra [4], The results showed that the configuration of C-
24 of two epimers as S-form (4, ocotillol derivative) and R-
form (3, epimer), respectively. Single crystals of 3 and 4
were obtained from acetone, and X-ray crystallography
clearly showed that 20, 24-epoxy fraction and a pair of
epimers had been synthesized [5]. The crystal data are
illustrated in Tables 1 to 3. ORTEP representations are
shown in Figs. (1 and 2) together with the numbering
scheme adopted. Hydrogen bonds for 3 and 4 were
illustrated in Fig. (3). The X-ray crystal structure confirms
the configuration of C-24 of two epimers as S-form (4,
ocotillol derivative) and R-form (3, epimer), respectively.
Both Panax ginseng and Panax quinquefolium, belonging
to the Araliaceae, are well-known traditional medicinal
herbs. They are used as tonics for the treatment of diseases,
such as tumor and myocardial ischemia. Panax ginseng
contains a number of saponins, called ginsenoside, including
an oleanolic acid-type saponin in addition to the major
protopanaxadiol and protopanaxatriol-type saponins [1].
However, Panax quinquefolium contains an ocotillol-type
(20S, 24R-epoxyside) saponin with high anti-tumor activity
[2], as well as oleanolic acid-type saponin, protopanaxadiol
and protopanaxatriol-type saponins. Yu et al. have found that
ocotillol, 20S, 24S-epoxy-dammarane-3ꢀ, 6ꢁ, 12ꢀ, 25-
tetraol, possesses cardioprotective effect on myocardial
injury induced by isoproterenol in rats [3]. However,
ocotillol can only be degraded and isolated from Panax
quinquefolium L. in poor yield. Therefore, to obtain the
ocotillol-type saponin by modifying protopanaxatriol and
protopanaxadiol-type saponins is an interesting study and
has uses in diseases especially tumor and myocardial
ischemia. Based on this, herein, we report the synthesis and
characterization of ocotillol derivative 4 and its epimer 3
derived from 20(S)-protopanaxatriol. Epimeric acetic 20S,
24-epoxy-dammarane-3ꢀ, 6ꢁ, 12ꢀ, 25-tetraol ester, 2, was
synthesized by reaction of 20 (S)-protopanaxatriol and acetic
anhydride in pyridine at room temperature and oxidation of
the resulting 1 using m-CPBA.
SYNTHESIS
Synthesis of 3ꢀ, 6ꢁ, 12ꢀ-triacetyl-20 (S)-protopanaxatriol
(1)
To a solution of 20 (S)-protopanaxatriol (7.2 g, 2.646
mmol), N, N-dimethylaminopyridine (0.192 g, 1.57 mmol)
and pyridine (90 mL) in a round-bottomed flask, acetic
anhydride (8.64 mL, 7.52 mmol) was added and the reaction
was stirred for 24 h at room temperature. The solution was
evaporated to dry under pressure, and the resulting solid was
extracted with ethyl acetate. The organic phase was washed
with dilute hydrochloric acid, water and saturated sodium
chloride solution and dried over Na2SO4. The ethyl acetate
was evaporated in vacuo, yielding a semi-solid. Flash
chromatography (1:1 EtOAc-petroleum ether) yielded the
product as colorless semi-solid (4.59 g, 57.63% yield). ESI-
MS, m/z: 585.5 [M-H2O+H]+, 525.48 [M-H2O-
CH3COOH+H]+, 465.44 [M-H2O-2CH3COOH+H]+, 405.40
[M-H2O-3CH3COOH+H]+. Compared to spectra data of 20
20S, 24S-epoxy dammarane-3ꢀ, 6ꢁ, 12ꢀ, 25-tetraol
(ocotillol derivative) and its epimers are prepared by reaction
of epimeric 20S, 24-epoxy-dammarane-3ꢀ, 6ꢁ, 12ꢀ, 25-
tetraol acetic ester 2 and sodium hydroxide in methanol and
water in 1:1 molar ratio (Scheme 1). The structures of
ocotillol derivative and its epimer were confirmed by ESI-
*Address correspondence to this author at the School of Pharmacy, Yantai
University, Yantai 264005, P.R. China; Tel: +86-535-6706022;
Fax: +86-535-6706066; E-mail: mqg@ytu.edu.cn
1875-6255/11 $58.00+.00
© 2011 Bentham Science Publishers

Synthesis, Structural Determination of a New Ocotillol Derivative and its Epimer
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
683
OH
H3C
CH3
CH3
24
CH3
HO
OH
HO
OAc
O
OAc
a
b
HO
AcO
AcO
2
OH
20(S)-Protopanaxatriol
OAc
OAc
1
OH
OH
H3C
CH3
H3C
O
CH3
24
24
O
OH
c
OH
+
HO
HO
4
3
OH
OH
Ocotillol derivate
epimer
Scheme 1. synthetic route for the preparation of the two epimers. Reagents: a) (CH3CO)2O, DMAP. Pyridine; b) m-CPBA, CH2Cl2; c) NaOH,
CH3OH, H2O.
Table 1. Selected Crystal Data for Compound 3 and 4
Parameter
3
4
Empirical formula
C30H52O5
492.72
C30H52O5
492.72
Formula weight
Crystal size /mm3
0.54ꢀ0.50ꢀ0.50
Orthorhombic
P2 (1) 2 (1) 2 (1)
1.27918 (6)
1.37842 (7)
1.60902 (8)
90
0.38ꢀ0.20ꢀ0.18
Orthorhombic
P2 (1) 2 (1) 2 (1)
1.29341 (18)
1.37677 (19)
1.6074 (2)
90
Crystal system
Space group
a/nm
b/nm
c/nm
ꢀ/(°)
ꢁ/(°)
90
90
ꢂ/(°)
90
90
V/nm3
2.8371 (2)
1.154
2.8623 (7)
1.143
Dx/(g·cm-1)
F (000)
1088
1088
Absorportion coefficiention/mm-1
0.076
0.075
ꢃ for data collection/(°)
1.95~26.02
0.0416
1.95~25.50
0.0528
Final R indices
wR2
S
0.1107
0.0991
1.046
0.979

684 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Table 2. Hydrogen-Bonds Geometry for 3 (Å,˚)
Qingguo et al.
D-H...A
D-H
H...A
D...A
D-H…A
O(2)-H(2)...O(5)
0.82
0.82
1.95
2.41
2.697(2)
2.882(3)
152.1
117.4
O(1)-H(1A)...O(2)
Symmetry code: x, y, z+1.
Table 3. Hydrogen-Bonds Geometry for 4 (Å,˚)
D-H...A
d (D-H)
d (H...A)
d (D...A)
D-H…A
O2-H2...O5 i
O1-H1A...O2 ii
O2-H2A...O4
O1-H1...O3iii
0.82
0.82
0.82
0.82
1.90
1.95
1.87
2.04
2.693 (3)
2.763 (2)
2.671 (2)
2.858 (2)
163.7
169.6
166.0
172.2
Symmetry codes: (i) x, y, z +1; (ii) -x, y-1/2, -z +3/2; (iii) x-1/2, -y +1/2, -z +1.
Fig. (1). ORTEP of 3 with thermal ellipsoids shown at 30% probability.
Fig. (2). ORTEP of 4 with thermal ellipsoids shown at 30% probability.
(S)-protopanaxatriol reported in literature [6], the
assignments based on 1H NMR and 13C NMR data showed
that hydroxyls connected to C-3, C-6, C-12 had been
acetylated, 20 (S)-hydroxyl had not been acetylated at all.
Synthesis of epimeric 20S, 24-epoxy-dammarane-3ꢀ, 6ꢁ,
12ꢀ, 25-tetraol acetic ester (2)
A
mixture of 3ꢀ, 6ꢁ, 12ꢀ-triacetyl-20 (S)-
protopanaxatriol (3.830 g, 6.362 mmol) in methylene
chloride was cooled to -3oC, and then m-CPBA was

Synthesis, Structural Determination of a New Ocotillol Derivative and its Epimer
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
685
Fig. (3). Hydrogen bonds for 3 and 4 (dashed lines).
(dissolved in 10 mL methylene chloride) added slowly. After
2 h, the organic solution was washed with water and
saturated sodium chloride solution and dried over Na2SO4.
The CH2Cl2 was evaporated in vacuo, yielding a white solid.
Flash chromatography (1:1 EtOAc-petroleum ether) and
crystallization from EtOAc yielded the product as white
China (No. J07WE26), Shandong Provincial Natural Science
Foundation, China (No. Y2007C138) for financial support.
The authors thank Mr. Liandong Liu (School of Chemistry,
Shandong Normal University, Jinan, 250014 P R China) for
his invaluable support in X-ray data collection. We also
gratefully acknowledge Mr. Jiyong Chen and Ms. Li Shen
for the measurement of ESI-MS and NMR.
o
needle-like crystal (3.20 g, 81.38% yield). mp 205~206 C.
ESI-MS, m/z: 619.54 [M+H]+, 559.50 [M-CH3COOH+H]+,
499.45
[M-2CH3COOH+H]+,
481
[M-2CH3COOH-
REFERENCES AND NOTES
H2O+H]+, 439.40 [M-3CH3COOH+H]+, 421.39 [M-
3CH3COOH-H2O+H]+. Chemical shift values of C-24, C-25
in compounds 1 and 2 were quite different [7], showing that
C-24 and C-25 of compound 2 were connected to hydrogen
atom, and C-24 and C-25 of compound 2 were alkene atom.
[1]
Shibata, S.; Tanaka, L.; Shoji, L.; Saito, H. Chemistry and
pharmacology of panax. Econ. Med. Res. 1985, 1, 217-284.
Takano, K.; Midori, T.; Eiichiro, I.; Teruo, M. ; Harukuni, T. ;
Hoyoku, N. ; Nguyen, M. D.; Ryoji, K.; Kazuo, Y. Cancer
chemopreventive activity of majonoside-R2 from Vietnamese
ginseng, Panax vietnamensis Cancer Lett. 1999, 147, 11-16.
Yu, C.; Fu, F.-H.;Yu, X.; Han, B.; Zhu, M. Cardioprotective effect
of ocotillol, a derivate of pseudoginsenoside F11, on myocardial
injury induced by isoproterenol in rats . Arzneimittelforschung.
2007, 57(9): 568-572.
[2]
[3]
Synthesis of 20S, 24S-epoxy-dammarane-3ꢀ, 6ꢁ, 12ꢀ, 25-
tetraol (4) and 20S, 24R-epoxy-dammarane-3ꢀ, 6ꢁ, 12ꢀ,
25-tetraol (3)
[4]
[5]
Seiji, F.; Ryoji, K.; Kazuhiro, O.; Kazuo, Y.; Chiu, M. H.; Nie, R.
L.; Osamu, T. Dammarane Glycosides from aerial part of
Neoalsomitra IntegrifoliolaꢀPhytochemistry, 1995, 39(3): 591-602.
Data collection
The epimeric 20S, 24-epoxy-dammarane-3ꢀ, 6ꢁ, 12ꢀ, 25-
tetraol acetic ester 2 (2.480 g, 4.53 mmol) and methanol 24
ml were stirred at room temperature, and pH was adjusted
12 with 1 mol/L potassium hydroxide solution. After 2
h, the resulting mixture was diluted with water 200 mL,
the precipitate formed and filtered off, washed with
water, and dried in vacuo. Flash chromatography (EtOAc)
and crystallization from acetone yielded compound 3 as
white pellet-like crystal (0.80 g, 34.90% yield), mp 249~250
oC and compound 4 as white lump-like crystal (0.778 g,
34.62% yield), mp 263~264 oC.
Bruker SMART CCD area-detetor 4474 independent reflections
diffractometer
4355 reflections with I >2ꢂ (I)
ꢃ and ꢄ scans
Rint=0.026
Absorption correction: multi-scan
ꢅmax= 25.0˚
(SADABS; Breker, 2000)
h= -12 ꢀ 13
k= -12 ꢀ14
l= 0 ꢀ 14
Tmin=0.513, Tmax=0.872
8908 measured reflections
Refinement
Refinement on F2
R[(F2>2ꢁ (F2)]=0.100
wR (F2)=0.226
H-atom parameters constrained
2
w= 1/[ꢂ2 (Fo ) + 102.4837P]
where P = (Fo2 + 2Fc2)/3
(ꢂ/ꢂ)max< 0.001
S = 1.15
4474 reflections
483 parameters
ꢂꢆmax = 2.49e Å -3
ACKNOWLEDGEMENTS
ꢂꢆmin = -1.23e Å -3
The authors are grateful to the Faculty of Pharmacy of
Yantai University, National Natural Science Foundation of
China (No.81001358), Scientific Reasearch Foundation of
the Higher Education Institutions of Shandong Province,
[6]
[7]
Lin, M. C.; Wang, K. C.; Lee, S. S. Transformation of
Ginsenosides Rg1 and Rb1, and Crude Sanchi Sapo Nins by
Human Intestinal Microflora. Journal of the Chinese Chemical
Society, 2001, 48: 113-120.
C-24: 125.0 (1), 85.5 (2); C-25: 131.2 (1), 70.2 (2).