Two new compounds from the roots of Ilex pubescens

Article abstract of DOI:10.1080/14786419.2011.598155

A new triterpenoid glycoside, heterobetulinic acid 3-O - D-glucopyranosyl(1→2) - D-xylopyranoside (1), together with a new phenylacrylic acid derivative, 3S,4-dihydroxyl-2-methylene-but-1-enyl caffeate (2), were isolated from the roots of Ilex pubescens. Their structures were elucidated by HR-ESI-MS, 1-D and 2-D NMR analyses and chemical methods. In addition, the absolute configuration of 2 was established by the application of a modified Mosher's method.

Full text of DOI:10.1080/14786419.2011.598155

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Two new compounds from the roots of
Ilex pubescens
Ting Wu a , Qing-Wen Zhang b , Xiao-Qi Zhang a c , Ge Liu a , Lei
Wang a , Miao-Miao Jiang d , Yi-Fan Feng d & Wen-Cai Ye a c
a Institute of Traditional Chinese Medicine and Natural Products,
College of Pharmacy, Jinan University , Guangzhou 510632 , P.R.
China
b Institute of Chinese Medical Sciences, University of Macau ,
Taipa , Macau
c Guangdong Province Key Laboratory of Pharmacodynamic
Constituents of TCM and New Drugs Research, Jinan University ,
Guangzhou 510632 , P.R. China
d Central Laboratory, Guangdong Pharmaceutical University ,
Guangzhou 510006 , P.R. China
Published online: 26 Aug 2011.
To cite this article: Ting Wu , Qing-Wen Zhang , Xiao-Qi Zhang , Ge Liu , Lei Wang , Miao-
Miao Jiang , Yi-Fan Feng & Wen-Cai Ye (2012) Two new compounds from the roots of Ilex
pubescens , Natural Product Research: Formerly Natural Product Letters, 26:15, 1408-1412, DOI:
10.1080/14786419.2011.598155
To link to this article: http://dx.doi.org/10.1080/14786419.2011.598155
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Natural Product Research
Vol. 26, No. 15, August 2012, 1408–1412
Two new compounds from the roots of Ilex pubescens
Ting Wua, Qing-Wen Zhangb, Xiao-Qi Zhangac, Ge Liua, Lei Wanga,
Miao-Miao Jiangd, Yi-Fan Fengd and Wen-Cai Yeac
*
aInstitute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan
University, Guangzhou 510632, P.R. China; Institute of Chinese Medical Sciences, University of
b
Macau, Taipa, Macau; cGuangdong Province Key Laboratory of Pharmacodynamic Constituents of
TCM and New Drugs Research, Jinan University, Guangzhou 510632, P.R. China; Central
Laboratory, Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China
d
(Received 6 June 2010; final version received 1 May 2011)
A new triterpenoid glycoside, heterobetulinic acid 3-O-ꢀ-D-glucopyranosyl
(1 ! 2)-ꢀ-D-xylopyranoside (1), together with a new phenylacrylic acid derivative,
30S,40-dihydroxyl-20-methylene-but-10-enyl caffeate (2), were isolated from the
roots of Ilex pubescens. Their structures were elucidated by HR–ESI–MS, 1-D
and 2-D NMR analyses and chemical methods. In addition, the absolute
configuration of 2 was established by the application of a modified Mosher’s
method.
Keywords: Ilex pubescens; triterpenoid glycoside; phenylacrylic acid derivative;
absolute configuration
1. Introduction
The plant Ilex pubescens Hook. et Arn. is widely distributed in the south of China.
The dried roots of the plant have been used as a traditional Chinese medicine for the
treatment of cardiovascular and cerebrovascular diseases and hypercholesterolemia
(Jiang et al., 2005; Wang, Zhou, Jiang, Wong, & Liu, 2008). Previous phytochemical
and pharmacological studies of this plant had led to the isolation of anticoagulant and
anti-inflammatory triterpenoid saponins (Han, Song, & Rhee, 1993; Wang, Zhou, Jiang, &
Liu, 2008), anti-platelet aggregating phenylacrylic acid compounds (Jiang et al., 2005), as
well as lignans and iridoid glycosides (Yang, Ding, & Zhang, 2007; Zhou, Wang, X.M. Li,
& X.Li, 2008). As a part of our investigation on bioactive constituents from the plants of
genus Ilex (Sun, Wang, Zhang, Zhao, & Ye, 2009; Sun, Zhang, et al., 2009; Wu, Zhang,
Wang, Ye, & Zhao, 2009), two new compounds including a triterpenoid glycoside (1) and
a phenylacrylic acid derivative (2) (Figure 1) were obtained from the roots of I. pubescens.
Herein we report the isolation and structural elucidation of the new compounds.
2. Results and discussion
Compound 1 was obtained as colourless needles. The HR–ESI–MS of 1 exhibited a quasi-
molecular ion at m/z 749.4465 [M ꢀ H]ꢀ (Calcd for C41H65O12, 749.4482), consistent with
a molecular formula C41H66O12. The IR spectrum showed absorptions at 3389 (OH), 1698
(C¼O) and 1601 (C¼C) cmꢀ1. Acid hydrolysis of 1 yielded D-glucose and D-xylose, which
*Corresponding author. Email: chywc@yahoo.com.cn
ISSN 1478–6419 print/ISSN 1478–6427 online
ß 2012 Taylor & Francis
http://dx.doi.org/10.1080/14786419.2011.598155
http://www.tandfonline.com

Natural Product Research
1409
30
20
29
21
22
19
12
26
18
13
17
11
25
O
OH
COOH
28
1
4
7
14
5'
2
S
3'
HO
HO
OH
16
2
1
9
3
4
2'
1'
8
10
O
9
15
4'
8
3
27
4'
5'
7
O
O
5
6
HO
O
6
HO
OH
5
2'
3'
1'
24
23
4''
O
HO
HO
3''
OH
1
2
Figure 1. Chemical structures of compounds 1 and 2.
were identified by gas chromatography of their aldononitrile peracetate derivatives using
1
authentic samples as references (Section 3). The H-NMR spectrum of 1 displayed the
signals for seven methyl groups at ꢁH 0.84 (3H, s, H-25), 1.05 (3H, s, H-23), 1.06 (3H, s,
H-27), 1.10 (3H, s, H-26), 1.12 (3H, d, J ¼ 6.6 Hz, H-29), 1.29 (3H, s, H-24) and 1.73 (3H,
s, H-30), an oxygenated methine proton at ꢁH 3.30 (1H, dd, J ¼ 11.6, 4.1 Hz, H-3), two
anomeric protons at ꢁH 4.87 (1H, d, J ¼ 6.8 Hz, H-1 of xylose) and 5.38 (1H, d, J ¼ 7.6 Hz,
H-1 of glucose), as well as an olefinic proton at ꢁH 5.48 (1H, m, H-21). The 13C-NMR and
DEPT spectra showed 41 carbon signals including 7 methyls and 2 olefinic carbon signals.
All the above data indicated that 1 was an urs-20-en type triterpenoid glycoside.
Comparison of the NMR data of 1 with those of heterobetulinic acid (3ꢀ-hydroxy-urs-20-
en-28-oic acid) revealed that the aglycone of 1 was heterobetulinic acid (Lobo-Echeverri
et al., 2005). The sequence and glycosylation position of the sugar chain could be deduced
by an HMBC experiment. Thus, in the HMBC spectrum, correlations between H-1
(ꢁH 5.38) of glucose and C-2 (ꢁC 83.4) of xylose as well as between H-1 (ꢁH 4.87) of xylose
and C-3 (ꢁC 88.8) of aglycone were observed. Hence, the structure of 1 was elucidated as
heterobetulinic acid 3-O-ꢀ-D-glucopyranosyl(1 ! 2)-ꢀ-D-xylopyranoside.
Compound 2 was obtained as amorphous powder. The molecular formula of 2 was
determined as C14H16O6 on the basis of a quasi-molecular ion at m/z 279.0796 [M ꢀ H]ꢀ
(Calcd for C14H15O6, 279.0784) in the HR–ESI–MS. The IR spectrum showed absorptions
1
at 3405 (OH), 1692 (C¼O), 1630 (C¼C), 1605 and 1447 (Ar) cm–1. The H-NMR and
1H–1H COSY spectra indicated the presence of a set of aromatic protons [ꢁH 7.06 (1H, d,
J ¼ 1.7 Hz, H-2), 7.00 (1H, dd, J ¼ 8.1, 1.7 Hz, H-6) and 6.76 (1H, d, J ¼ 8.1 Hz, H-5)], a
couple of trans-olefinic protons [ꢁH 7.50 (1H, d, J ¼ 15.9 Hz, H-7) and 6.29 (1H, d,
J ¼ 15.9 Hz, H-8)], an oxygenated methine [ꢁH 4.05 (1H, m, H-30)], two oxygenated
methylenes [ꢁH 4.67 (2H, br s, H-50) and 3.42 (2H, m, H-40)], and an exo-methylene [ꢁH 5.18
(1H, br s, H-10a) and 5.10 (1H, br s, H-10b)]. The 13C- and DEPT-NMR spectra displayed
14 carbon signals. The above data indicated that 2 was a caffeate derivative with a 3,4-
dihydroxyl-2-methylene-1-but-enyl moiety (Jiang et al., 2005). The HMBC correlation
between H-50 (ꢁH 4.67) and C-9 (ꢁC 166.1) demonstrated that the isoprene unit was
connected to C-9 through an oxygen atom. To determine the absolute configuration of C-
30, a modified Mosher’s method was applied (Su et al., 2002). The differences of proton
chemical shift values (Dꢁ ¼ ꢁS ꢀ ꢁR, ppm) between (S)-MTPA ester (2a) and (R)-MTPA
ester (2b) (Supplementary Figure S1 – online only) suggested the presence of S

1410
T. Wu et al.
configuration at C-30 in 2. Therefore, 2 was identified as 30S,40-dihydroxyl-20-methylene-
but-10-enyl caffeate.
3. Experimental
3.1. General experimental procedures
Melting points were determined on an X-5 melting point apparatus. Optical rotations were
measured on a JASCO P-1020 digital polarimeter. IR spectra were recorded on a JASCO
FT/IR-480 Plus spectrometer in KBr pellets. The NMR data were obtained on a
BRUKER AV-400 spectrometer using TMS as an internal standard. HR–ESI–MS data
were determined on an Agilent 6210 LC/MSD TOF mass spectrometer. Column
chromatographies were run on silica gel (200–300 mesh, Qingdao Marine Chemical
Group Co. Ltd, P.R. China), Sephadex LH-20 (Pharmacia, Sweden) and ODS (YMC,
Japan). TLC analyses were carried out using precoated silica gel GF254 plates (Qingdao
Marine Chemical Group Co. Ltd, P.R. China). (S)- and (R)-ꢂ-methoxy-ꢂ-(trifluoro-
methyl) phenylacetic chloride were purchased from Alfa-Aesar Chemicals Ltd. (Tianjin,
China). All solvents used in column chromatographies and HPLC chromatography were
of analytical grade (Shanghai Chemical Plant, Shanghai, P.R. China) and chromato-
graphic grade (Fisher Scientific, New Jersey, USA), respectively.
3.2. Plant material
The roots of I. pubescens were collected from Conghua city, Guangdong province of
China, in July of 2007. The plant was identified by Prof. Guang-Xiong Zhou of College of
Pharmacy, Jinan University. A voucher specimen (No. 2008071101) was deposited in the
Institute of Traditional Chinese Medicine and Natural Products, Jinan University,
Guangzhou, P.R. China.
3.3. Extraction and isolation
The air-dried and powdered roots (5.0 kg) were extracted with 70% EtOH at room
temperature. After the removal of EtOH under reduced pressure, the remaining aqueous
solution was chromatographed over D101 macroporous resin using H2O, 20%, 50% and
95% EtOH as eluents. The 50% EtOH fraction (120.0 g) was subjected to silica gel eluted
with CHCl3:MeOH (100:0 to 50:50) to give 20 subfractions (1–20). Subfraction 14
(300 mg) was further purified over an ODS column (50% MeOH) and a Sephadex
LH-20 column (MeOH) to yield 1 (3.0 mg). The 95% EtOH fraction (266.0 g) was
chromatographed on silica gel with a gradient elution by CHCl3:MeOH (100:0 to 50:50) to
afford 2 (5.0 mg).
3.3.1. Heterobetulinic acid 3-O-ꢀ-D-glucopyranosyl(1 ! 2)-ꢀ-D-xylopyranoside (1)
Colourless needles, m.p. 290–292ꢁC; IR (KBr) ꢃmax: 3389, 2944, 1698, 1601, 1455, 1117,
1079 and 1042 cmꢀ1; HR–ESI–MS: m/z 749.4465 [M ꢀ H]ꢀ (Calcd for C41H65O12,
749.4482); 1H (400 MHz, C5D5N) ꢁ: 5.48 (1H, d, J ¼ 6.8 Hz, H-21), 5.38 (1 H, d, J ¼ 7.6 Hz,
H-100), 4.87 (1 H, d, J ¼ 6.8 Hz, H-10), 4.50 (1H, m, H-600b), 4.48 (1H, m, H-600a), 4.39 (1H,
m, H-400), 4.32 (1H, m, H-50a), 4.27 (1H, m, H-300), 4.25 (1H, m, H-30), 4.24 (1H, m, H-20),
4.18 (1H, m, H-40), 4.14 (1H, m, H-200), 3.94 (1H, m, H-500), 3.70 (1H, m, H-50b), 3.30 (1H,
dd, J ¼ 11.6, 4.1 Hz, H-3), 2.84 (1H, m, H-13), 2.64 (1H, dd, J ¼ 15.2, 7.2 Hz, H-22b), 2.46
(1H, m, H-19), 2.33 (1H, d, J ¼ 9.8 Hz, H-12b), 2.20 (1H, m, H-2b), 2.02 (1H, m, H-22a),
1.92 (1H, m, H-2a), 1.81 (1H, m, H-15b), 1.78 (1H, m, H-16b), 1.73 (3H, s, H-30), 1.68
(1H, m, H-1a), 1.56 (1H, m, H-11b), 1.52 (1H, m, H-12a), 1.47 (1H, m, H-6b), 1.45 (1H, m,

Natural Product Research
1411
H-7b), 1.36 (1H, dd, J ¼ 11.2, 6.4 Hz, H-9), 1.35 (1H, m, H-18), 1.33 (1H, m, H-7a), 1.30
(1H, m, H-6a), 1.29 (3H, s, H-24), 1.26 (1H, m, H-11a), 1.25 (1H, m, H-16a), 1.17 (1H, m,
H-15a), 1.12 (3H, d, J ¼ 6.6 Hz, H-29), 1.10 (3H, s, H-26), 1.06 (3H, s, H-27), 1.05 (3H, s,
H-23), 0.94 (1H, m, H-1b), 0.84 (3H, s, H-25) and 0.75 (1H, d, J ¼ 10.2 Hz, H-5); 13C-
NMR (100 MHz, C5D5N) ꢁ: 178.1 (C-28), 143.1 (C-20), 117.9 (C-21), 106.1 (C-100), 105.7
(C-10), 88.8 (C-3), 83.4 (C-20), 78.3 (C-500), 78.0 (C-30, 300), 77.1 (C-200), 71.7 (C-400), 71.0 (C-
40), 66.7 (C-50), 62.7 (C-600), 56.0 (C-5), 50.9 (C-9), 49.4 (C-18), 49.1 (C-17), 42.3 (C-14),
41.3 (C-8), 39.8 (C-4), 39.4 (C-13), 39.2 (C-1), 38.5 (C-22), 37.8 (C-19), 37.1 (C-10), 34.7
(C-7), 33.7 (C-12), 29.6 (C-16), 28.0 (C-24), 27.9 (C-15), 27.0 (C-2), 23.7 (C-29), 22.2 (C-
30), 21.9 (C-11), 18.5 (C-6), 16.6 (C-25), 16.5 (C-23), 16.4 (C-26) and 15.0 (C-27).
3.3.2. 30S,40-Dihydroxyl-20-methylene-but-10-enyl caffeate (2)
Amorphous powder, m.p. 170–171ꢁC, [ꢂ]25 D ¼ þ2.3ꢁ (c ¼ 0.13, MeOH); IR (KBr) ꢃmax
:
3405, 1692, 1630, 1605, 1447, 1208, 1162 cmꢀ1; HR–ESI–MS: m/z 279.0796 [M – H]–
1
(Calcd for C14H15O6, 279.0784); H (400 MHz, DMSO-d6) ꢁ: 7.50 (1H, d, J ¼ 15.9 Hz, H-
7), 7.06 (1H, d, J ¼ 1.7 Hz, H-2), 7.00 (1H, dd, J ¼ 8.1, 1.7 Hz, H-6), 6.76 (1H, d,
J ¼ 8.1 Hz, H-5), 6.29 (1H, d, J ¼ 15.9 Hz, H-8), 5.18 (1H, br s, H-10a), 5.10 (1H, br s, H-
10b), 4.67 (2H, br s, H-50), 4.05 (1H, m, H-30), and 3.42 (2H, m, H-40); 13C-NMR
(100 MHz, DMSO-d6) ꢁ: 166.1 (C-9), 148.6 (C-4), 145.6 (C-3), 145.5 (C-20), 145.3 (C-7),
125.3 (C-1), 121.4 (C-6), 111.9 (C-10), 115.7 (C-5), 114.7 (C-2), 113.6 (C-8), 72.7 (C-30), 65.2
(C-40) and 63.5 (C-50).
3.4. Acid hydrolysis and identification of sugars for 1
Compound 1 (2.0 mg) was heated in an ampoule with 5.0 mL of 2N HCl (MeOH–H2O,
1:1) at 80ꢁC for 10 h. The aglycone was extracted with CHCl3 for three times and the water
layer was evaporated under reduced pressure. Pyridine (1 mL) and 3 mg of NH2OHꢂHCl
were added to the residue, and the mixture was heated at 100ꢁC for 1 h. Followed by the
addition of Ac2O (2.0 mL), the mixture was incubated in a water bath at 100ꢁC for 1 h and
partitioned using CHCl3 as solvent. The CHCl3 layer was concentrated for GC analysis
(front inlet 250ꢁC, column temperature 80ꢁC ! 230ꢁC, 5ꢁC minꢀ1) using standard
aldononitrile peracetates as reference samples. The monosaccharides of 1 were identified
as D-xylose [tR (min): 20.956 (from 1); 20.977 (reference D-xylose aldononitrile peracetate
derivative)] and D-glucose [tR (min): 35.626 (from 1); 35.662 (reference D-glucose
aldononitrile peracetate derivative), 37.501(reference L-glucose aldononitrile peracetate
derivative)].
3.5. Preparation of MTPA esters for 2
Compound 2 (1.5 mg) was treated with (R)-ꢂ-methoxy-ꢂ-(trifluoromethyl) phenylacetic
chloride (10 mL) in 0.5 mL of dried and deuterated pyridine. After being stirred at room
temperature for 10 h, the mixture was then evaporated to dryness. The residue was poured
into water (5 mL) and extracted with EtOAc (5 mL). The EtOAc extract was further
purified by silica gel column chromatography eluted with n-hexane:EtOAc (70:30) to yield
(S)-MTPA ester (2a, 1.6 mg). (R)-MTPA ester (2b, 1.7 mg) was obtained using the same
method by treatment of 2 (1.5 mg) with (S)-ꢂ-methoxy-ꢂ- (trifluoromethyl) phenylacetic
chloride.
3.5.1. (S)-MTPA ester (2a)
1H-NMR (400 MHz, Pyridine-d5) ꢁ: 6.32 (1H, m, H-30), 5.58 (1H, m, H-10a), 5.55 (1H, m,
H-10b), 5.09 (1H, m, H-40a), 5.03 (2H, br s, H-50) and 4.82 (1H, m, H-40b).

1412
T. Wu et al.
3.5.2. (R)-MTPA ester (2b)
1H-NMR (400 MHz, Pyridine-d5) ꢁ: 6.17 (1H, m, H-30), 5.47 (1H, m, H-10a), 5.33 (1H, m,
H-10b), 5.13 (1H, m, H-40a), 4.94 (2H, br s, H-50) and 4.82 (1H, m, H-40b).
Supplementary material
Figure S1 relating to this article is available online.
Acknowledgements
This study was supported by the National Natural Science Foundation for Outstanding Young
Scholars (No. 30625039), the Program for Changjiang Scholars (to Dr Ye), the Team Project of
Natural Science Foundation of Guangdong Province (No. 8351063201000003) and Macao Science
and Technology Development Fund (013/2008/A1). Ting Wu and Xiao-Qi Zhang contributed
equally to this study.
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