Eremophilane glucosides from petasites japonicus

Article abstract of DOI:10.1002/hlca.201300368

Three new eremophilane glucosides, namely, petasitosides A-C, and seven known eremophilane-type sesquiterpenoids were isolated from the roots of Petasites japonicus. Their structures were elucidated by spectroscopic techniques including 1D- and 2D-NMR spectroscopy and mass spectrometry. This is the first report on eremophilane glycosides from the genus Petasites. Copyright

Full text of DOI:10.1002/hlca.201300368

Helvetica Chimica Acta – Vol. 97 (2014)
985
Eremophilane Glucosides from Petasites japonicus
a
b
c
a
a
by Guangyin Wang ), Junzeng Zhang ), Marianna Kulka ), Fujiang Guo* ), and Yiming Li* )
a) School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P. R.
China (phone: þ 86-21-51322191; fax: þ 86-21-51322193; e-mail: gfj@shutcm.edu.cn; ymlius@163.com)
b
)
Aquatic and Crop Resource Development, National Research Council of Canada, Halifax, NS, B3 H
3
Z1, Canada
c) National Institute of Nanotechnology, National Research Council Canada, Edmonton, AB, T6G2M9,
Canada
Three new eremophilane glucosides, namely, petasitosides A – C, and seven known eremophilane-
type sesquiterpenoids were isolated from the roots of Petasites japonicus. Their structures were
elucidated by spectroscopic techniques including 1D- and 2D-NMR spectroscopy and mass spectrometry.
This is the first report on eremophilane glycosides from the genus Petasites.
Introduction. – Petasites japonicus (Siebold & Zucc.) Maxim., also known as
Butterbur, is a herbaceous perennial plant in the family of Asteraceae. In China, the
whole plant has been used as a traditional Chinese medicine against tonsillitis,
carbuncle swollen boils, and poisonous snake bite [1]. It is also cultivated in Japan and
South Korea, where it is consumed as a common vegetable. The flower bud is baked
and used in traditional medicine as an expectorant or in the treatment of asthma in
Japan [2]. Sesquiterpenoids, especially eremophilanes [3 – 6], have been previously
reported as the main constituents of this plant. Pharmacological studies have suggested
that P. japonicus extracts possess a variety of biological features such as neuro-
protective [7 – 9], anti-allergic [2][10], antimutagenic, and cytotoxic [11 – 13] activities.
In an in vivo model of active systemic anaphylaxis (ASA), our preliminary
pharmacological experiments had revealed that the CHCl -soluble fraction of the 95%
3
EtOH extract taken from the rhizomes blocked type-I and type-IV allergic inflamma-
tion [14]. Further chemical investigation of this plant resulted in the isolation of three
new eremophilane sesquiterpenoid glucosides, 1 – 3, along with seven known sesqui-
terpenoids, 4 – 10 (Fig. 1).
Results and Discussion. – The CH Cl -soluble fraction from the 95% EtOH extract
2
2
of the roots of P. japonicus was subjected to column chromatography on silica gel (200 –
00 mesh), eluting with a gradient of petroleum ether/AcOEt. Further purification by
3
column chromatography using silica gel, Sephadex LH-20, and ODS yielded 4 – 8. The
BuOH-soluble fraction from the 95% EtOH extract of the roots of P. japonicus, was
subjected to column chromatography on silica gel (200 – 300 mesh) with a gradient of
CH Cl /MeOH 20 :1 to MeOH to afford 16 fractions. After further purification on
2
2
ODS, 1 – 3, 9, and 10 were obtained. Among the isolated compounds, the known com-
pounds 4 – 10, which have previously been reported from this genus, were identified as
ꢀ
2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 97 (2014)
Fig. 1. Chemical structures of 1 – 10
6
b-(angeloyloxy)-3b,8a-dihydroxyeremophil-7(11)-en-12,8b-olide (4) [4], 6b-(ange-
loyloxy)-3b,8b-dihydroxyeremophil-7(11)-en-12,8a-olide (5) [4], 3b-(angeloyloxy)er-
emophilenolide (6) [15], 6b-(angeloyloxy)-8-hydroxyeremophilenolide (7) [16], 6b-
(angeloyloxy)-8b-hydroxy-3-oxoeremophil-7(11)-en-12,8a-olide (8) [1], 3b,6b-dihy-
droxyeremophilenolide (9) [17], and 3b-hydroxy-8-oxoeremophil-6-en-12-oic acid
methyl ester (10) [18].
The structures of the new compounds were elucidated by using various spectro-
scopic methods. Compound 1 was obtained as white amorphous powder with the
molecular formula of C H O deduced from the HR-ESI mass spectrum (m/z 437.2164
21
34
8
þ
(
[M þ Na] )), indicating five degrees of unsaturation. The IR spectrum indicated the
presence of OH (3379 cm ), and C¼O (1716 cm ) groups. In the C-NMR spectrum
Table), the signals at d(C) 102.4, 76.9, 76.2, 73.4, 69.9, and 61.3 indicated the presence
of one glucosyl moiety. The glucosyl H-atom signals were detected at d(H) 4.32 (d, J ¼
ꢀ
1
ꢀ1
13
(
7
.6, 1 H), 3.84 (dd, J ¼ 11.9, 2.0, 1 H), 3.66 (dd, J ¼ 11.9, 5.8, 1 H), and 3.19 – 3.32
1
(overlapped, 4 H) in its H-NMR spectrum (Table). Acid hydrolysis and GC analysis of
13
1
confirmed the presence of d-glucose. The C-NMR and DEPT-135 data indicated
that the aglycon of 1 contained 15 C-atoms including those of three Me, four CH , five
2
CH groups, and three quaternary C-atoms. One C¼O signal at d(C) 210.0, two O-
bearing C-atom signals at d(C) 65.5 (CH) and 81.3 (CH), and the signals at d(C) 144.9
(
C) and 112.5 (CH ), ascribed to the C(11)¼C(12) bond, were observed. In the
2
1
H-NMR spectrum, there were three Me signals at high field (d(H) 1.85 (s), 1.09 (s),
and 0.82 (d, J ¼ 6.7)). Among them, the signal at d(H) 1.85 suggested that the
corresponding Me group was attached to an olefinic C-atom. These observations and
the HMBC analysis (Fig. 2) suggested that 1 had a typical eremophilane skeleton. In
the HMBC spectrum, long-range correlations were observed between HꢀC(1),
HꢀC(8), HꢀC(10), and C(9); HꢀC(1), HꢀC(3), and C(2); HꢀC(12), and C(11),

Helvetica Chimica Acta – Vol. 97 (2014)
987
Table. 1H- and 13C-NMR (400 and 100 MHz, resp., CD OD) Data of 1 – 3. d in ppm, J in Hz.
3
Position
1
1
2
3
d(H)
d(C) d(H)
d(C) d(H)
d(C)
1.44 – 1.51 (m),
29.6 1.38 – 1.46 (m),
1.58 – 1.63 (m)
26.4 1.51 – 1.62 (m),
1.63 – 1.67 (m)
26.6
2.21 – 2.26 (m)
2
3
3.95 – 4.04 (m)
1.29 – 1.38 (m),
65.5 1.53 – 1.60 (m)
38.5 3.64 – 3.71 (m)
26.9 1.56 – 1.61 (m)
69.9 3.73 – 3.78 (m)
26.9
69.9
1.68 – 1.71 (m)
4
5
6
7
8
9
1.48 – 1.54 (m)
–
1.82 – 1.84 (m)
2.56 (dt, J ¼ 11.9, 4.3)
4.56 (d, J ¼ 11.9)
–
31.6 1.85 – 1.91 (m)
44.6 1.87 – 1.95 (m)
44.6
40.2
158.8
136.3
199.5
40.7
39.8
–
39.8
–
39.6 6.61 (s)
155.6 6.78 (s)
47.1
81.3
–
–
138.2
199.8
–
–
210.0 2.20 (dd, J ¼ 17.3, 2.1),
40.4 2.27 (dd, J ¼ 17.1, 2.2),
2
.74 (dd, J ¼ 17.3, 4.5)
2.77 (dd, J ¼ 17.3, 4.3)
1
1
1
0
1
2
2.67 (d, J ¼ 3.2)
–
4.90 (br. s),
55.3 2.03 – 2.09 (m)
144.9 2.94 – 3.03 (m)
112.5 3.41 (dd, J ¼ 7.0, 9.4),
3.92 (dd, J ¼ 6.5, 9.4)
35.3 2.06 – 2.10 (m)
35.5
142.8
70.4
32.7
–
72.9 4.34 (d, J ¼ 12.6),
4.94 (br. s)
4.54 (d, J ¼ 12.6)
1
3
1.85 (s)
18.4 1.11 (d, J ¼ 7.0)
15.7 5.21 (d, J ¼ 1.5),
115.8
5
.34 (d, J ¼ 1.5)
1
1
4
5
0.82 (d, J ¼ 6.7)
1.09 (s)
20.2 1.00 (d, J ¼ 7.0)
14.3 1.24 (s)
6.3 1.00 (d, J ¼ 7.0)
6.3
24.1
24.4 1.29 (s)
Glc
1’
2’
3’
4’
5’
6’
4.32 (d, J ¼ 7.6)
102.4 4.24 (d, J ¼ 7.8)
73.4 3.16 (dd, J ¼ 9.1, 7.8)
76.2 3.26 (overlapped)
69.9 3.25 (overlapped)
76.9 3.34 (overlapped)
61.3 3.67 (dd, J ¼ 11.9, 5.5),
3.88 (dd, J ¼ 11.9, 1.6)
103.1 4.27 (d, J ¼ 7.8)
73.8 3.17 (dd, J ¼ 9.1, 7.8)
76.5 3.24 (overlapped)
70.4 3.24 (overlapped)
76.7 3.34 (overlapped)
61.6 3.64 (dd, J ¼ 11.9, 5.4),
3.87 (dd, J ¼ 11.9, 1.4)
101.6
73.7
76.5
70.4
76.9
61.6
3.24 (overlapped)
3.32 (overlapped)
3.30 (overlapped)
3.19 (overlapped)
3.66 (dd, J ¼ 11.9, 5.8),
3.84 (dd, J ¼ 11.9, 2.0)
Fig. 2. Key HMBCs (H ! C) of 1 – 3
C(13), and C(7). These data confirmed the presence of the C(11)¼C(12) bond and the
C(9)¼O group, and the two OH groups were at C(2) and C(8). The position of the
sugar residue was also determined from the HMBC experiment, in which there were
cross-peaks between the anomeric H-atom signals at d(H) 4.32 (HꢀC(1’)) and d(C)

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Helvetica Chimica Acta – Vol. 97 (2014)
8
1.3 (C(8)). The b-anomeric configuration of the d-glucose unit was determined based
1
13
on its coupling constant (J ¼ 7.6 ) . All H- and C-NMR signals (Table) were assigned
1
1
on the basis of the HMBC, HSQC, and H, H-COSY correlations. The relative
configuration of 1 was determined by the NOESY correlations shown in Fig. 3. The
NOE cross-peak HꢀC(10)/Me(15) suggested a cis-junction of the A/B rings. The NOE
correlations between H ꢀC(2) and H ꢀC(4), and H ꢀC(8) and H ꢀC(10) implied that
a
a
b
b
the OH groups at C(2) and C(8) were b- and a-oriented, respectively [19]. The
configuration at C(7) was deduced from the coupling constant of 11.9 Hz between
HꢀC(7) and HꢀC(8), indicating their trans diaxial orientation [20]. The structure of 1
was thus elucidated as (2b,8a)-2-hydroxy-9-oxoeremophil-11-en-8-yl b-d-glucopyrano-
side and named petasitoside A.
Compound 2, obtained as white amorphous powder, was assigned the molecular
þ
formula C H O according to its HR-ESI-MS (m/z 437.2150 ([M þ Na] )). The IR
21
34
8
ꢀ
1
ꢀ1
spectrum indicated that an OH (3386 cm ) and a C¼C group (1658 cm ) were
1
13
present. There was a glucosyl moiety as revealed by H- and C-NMR (Table) and acid
1
hydrolysis. In the H-NMR spectrum, signals of three tertiary Me groups were observed
d(H) 1.24, 1.11, and 1.00). The H-NMR spectrum also revealed the presence of one
1
CHꢀO (d(H) 3.64 – 3.71) and one CH O group (d(H) 3.41 and 3.92). The aglycon
2
structure of 2 was determined as 3,12-dihydroxy-8-oxoeremophil-6-ene according to
1
13
HMBC analysis (Fig. 2). The H- and C-NMR spectra of the aglycone moiety were
similar to those of 3b-hydroxy-8-oxoeremophil-6-en-12-oic acid methyl ester [18],
except that the C(12)OOH group was reduced to a primary alcohol in the former. The
HMBC between the signals at d(H) 4.24 (HꢀC(1’)) and d(C) 72.9 (C(12)) revealed that
the glucosyl moiety was at C(12). All H- and C-atom signals (Table) were assigned
1
1
based on HMBC, HSQC, and H, H-COSY correlations. The relative configuration of
was determined by the NOESY correlations shown in Fig. 3. In the NOESY
2
spectrum, the correlations H ꢀC(10)/Me(15), HꢀC(6)/H ꢀC(3), and HꢀC(6)/
b
a
H ꢀC(4) suggested that the Me(15) group was cis to HꢀC(10), and the OH group at
a
C(3) was b-oriented [18][20]. Thus, the structure of 2 was elucidated as 3b-hydroxy-8-
oxoeremophil-6-en-12-yl b-d-glucopyranoside and named petasitoside B.
Compound 3 was white amorphous powder with a molecular formula C H O
8
2
1
32
þ
based on the HR-ESI-MS (m/z 435.1996 ([M þ Na] )), indicating six degrees of
unsaturation. The IR spectrum indicated that OH (3386 cm ) groups and a C¼C bond
1662 cm ) were present. There was glucosyl moiety revealed by H-
ꢀ1
ꢀ1
1
(
a
13
1
13
and C-NMR (Table) and acid hydrolysis. The H- and C-NMR spectra of 3 were
similar to those of 2, except that the Me(13) group was replaced by a CH (13)¼ group
2
1
13
(
d(C) 115.8). All H- and C-NMR signals (Table) were assigned on the basis of
Fig. 3. Key NOE correlations of 1 – 3

Helvetica Chimica Acta – Vol. 97 (2014)
989
1
1
HMBC, HSQC, and H, H-COSY correlations. The relative configuration of 3 was
determined by the NOESY correlations shown in Fig. 3. Therefore, 3 was deduced as
3
b-hydroxy-8-oxoeremophila-6,11(13)-dien-12-yl b-d-glucopyranoside, named as pe-
tasitoside C.
Eremophilane-type sesquiterpenes belong to the bicyclic sesquiterpene group,
whose basic skeletal structure contains two six-membered rings and four Me groups.
These compounds often occur in oxygenated forms such as eremophilane alcohols,
eremophilane acids, eremophilane lactones, furanoeremophilanes, or rare eremophi-
lane glycosides [21][22] in nature. Some special structures such as noreremophilanes
[
3], secoeremophilanes [22], and eremophilane dimers [23] also have been found.
Many of them possess biological or therapeutic properties including antitumor,
antibacterial, and anti-inflammatory activities. Although a series of eremophilane
sesquiterpenes were isolated previously, this is the first report of eremophilane
glycosides from this genus.
This work was supported by the National Natural Science Foundation of China (the CanadaꢀChina
Joint Health Research Initiatives Grant 81261120567), the ꢀXing-linꢁ Scholar Program of SHUTCM, and
the Eastern Scholar Program (2012-90).
Experimental Part
General. TLC: HSGF254 silica gel plates (SiO ; 10 – 40 mm; Yantai Jiangyou, P. R. China). Column
2
2
chromatography (CC): SiO (100 – 200, 200 – 300, or 300 – 400 mesh; Qingdao Haiyang Chemical
Company, P. R. China), Sephadex LH-20 (GE Healthcare Bio-Sciences AB, Sweden), and ODS-A-HG
(
(
S-50 mm; YMC Co., Ltd., Japan). GC: Thermo TRACE DSQ apparatus equipped with a TR-5 column
length, 60 m ꢁ 0.25 mm, thickness of liquid phase, 0.25 nm). Optical rotations: PerkinElmer 341
polarimeter. UV Spectra: Agilent 8453 spectrometer (Agilent, Santa Clara, USA); l in nm. IR Spectra:
max
ꢀ1 1
Nicolet-Magna-750-FT-IR spectrometer (ThermoFisher, Madison, USA); KBr pellets; ˜n in cm . H-,
13
1
13
C- and 2D-NMR spectra: Bruker AV-400 instrument ( H: 400 and C: 100 MHz); d in ppm rel. to Me Si
4
as internal standard, J in Hz. ESI- and HR-ESI-MS: Finnigan LCQ Deca XP equipped with an
electrospray ionization source mass ion-trap spectrometer and Waters Micromass Q-TOF ultima Globe
spectrometer, resp.; in m/z.
Plant Materials. Roots of P. japonicus were collected in March 2011 from Bozhou area, Anhui
Province, P. R. China, and identified by Prof. Xiujia Zhou at Shanghai University of Traditional Chinese
Medicine. Avoucher sample (20110301) was deposited with the School of Pharmacy, Shanghai University
of Traditional Chinese Medicine, P. R. China.
Extraction and Isolation. Dried and milled roots of P. japonicus (20.0 kg) were extracted three times
(
2 h each) under reflux in 95% EtOH (20 l each). The solvent was evaporated under reduced pressure to
yield a crude extract (2.4 kg), which was suspended in H O (5 l), and then partitioned with petroleum
2
ether (PE; 15 l), CH Cl (15 l), and BuOH (15 l), to afford 325 g of CH Cl -soluble fraction and 100 g of
2
2
2
2
BuOH-soluble fraction.
The CH Cl -soluble fraction was then subjected to CC (SiO (200 – 300 mesh); PE/AcOEt 19 :1 to
2
2
2
1
:1) to give seven fractions, Frs. 1 – 7. Compounds 4 and 5 (15 g) were crystallized as a mixture in CH Cl /
2 2
MeOH from Fr. 5. Fr. 3 was subjected repeatedly to CC (SiO (300 – 400 mesh); PE/AcOEt 10 :1 to 1:1),
2
followed by CC (Sephadex LH-20 (MeOH) and ODS (80% MeOH)) to furnish 6 (15 mg), 7 (10 mg),
and 8 (12 mg).
The BuOH-soluble fraction was subjected to CC (SiO (200 – 300 mesh); CH Cl /MeOH 20 :1 to
2
2
2
MeOH) to afford 16 fractions, Frs. 1 – 16. Fr. 4 was decolorized by CC (MCI gel (CHP20P, Mitsubishi
Chemical Corp., Japan). The fraction eluted from 40% MeOH was subjected to CC repeatedly
(
Sephadex LH-20 (MeOH) and ODS (55% MeOH)) to afford 9 (11 mg). Fr. 9 also was subjected to CC

9
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Helvetica Chimica Acta – Vol. 97 (2014)
on MCI for decolorization, and its 20, 40, and 60% MeOH eluting fractions were further purified by a
combination of CC (SiO (CH Cl /MeOH 15 :1 to 6 :1), Sephadex LH-20 (MeOH), and ODS (40%
2
2
2
MeOH)) to yield 10 (27 mg), 1 (29 mg), 2 (5 mg), and 3 (4 mg).
Determination of Sugar Components. Compounds (0.5 mg each) were refluxed in 10% HCl/dioxane
1
:1 (2 ml) for 2 h, and the solvent was evaporated under N . The residue was dissolved in pyridine
2
(
100 ml), 0.1m l-cysteine methyl ester hydrochloride (200 ml) was added, and the mixture was warmed and
kept at 608 for 1 h. The trimethylsilylation reagent HMDS-TMCS (hexamethyldisilazane/Me SiCl/
3
pyridine 2 :1:10) was added, and the mixture was kept at 608 for another 30 min. The thiazolidine
derivatives were subjected to GC analysis. d-Glucose (t 41.31 min) was identified by comparison with an
R
authentic sample.
Petasitoside A (¼(2b,8a)-2-Hydroxy-9-oxoeremophil-11-en-8-yl b-d-Glucopyranoside ¼ (2R,3R,
4
aR,5S,7R,8aS)-Decahydro-7-hydroxy-4a,5-dimethyl-3-(1-methylethenyl)-1-oxonaphthalen-2-yl b-d-
2
5
Glucopyranoside; 1). Amorphous powder. [a] ¼ þ32.3 (c ¼ 0.10, MeOH). UV (MeOH): 212, 242.
D
1
13
IR (KBr): 3379, 1716, 1643, 1078, 1030. H- and C-NMR: see the Table. ESI-MS (pos.): 415 ([M þ
þ
þ
þ
þ
8
H] ), 437 ([M þ Na] ). HR-ESI-MS: 437.2164 ([M þ Na] , C H NaO ; calc. 437.2151).
21
34
Petasitoside B (¼ 3b-Hydroxy-8-oxoeremophil-6-en-12-yl b-d-Glucopyranoside ¼ 2-[(4aR,7S,8R,
aR)-3,4,4a,5,6,7,8,8a-Octahydro-7-hydroxy-8,8a-dimethyl-3-oxonaphthalen-2-yl]propyl b-d-Glucopyra-
8
2
5
noside; 2). Amorphous powder. [a] ¼ ꢀ55.0 (c ¼ 0.10, MeOH). UV (MeOH): 209, 239. IR (KBr):
D
1
13
þ
3
4
386, 1658, 1078, 1032. H- and C-NMR: see the Table. ESI-MS: 415 ([M þ H] ). HR-ESI-MS:
þ
þ
37.2150 ([M þ Na] , C H NaO
8
; calc. 437.2151).
21
34
Petasitoside C (¼ 3b-Hydroxy-8-oxoeremophila-6,11(13)-dien-12-yl b-d-Glucopyranoside ¼ 2-
(4aR,7S,8R,8aR)-3,4,4a,5,6,7,8,8a-Octahydro-7-hydroxy-8,8a-dimethyl-3-oxonaphthalen-2-yl]prop-2-
[
25
en-1-yl b-d-Glucopyranoside; 3). Amorphous powder. [a]
D
¼ ꢀ70.7 (c ¼ 0.09, MeOH). UV (MeOH):
1
13
2
11, 239. IR (film): 3386, 1662, 1080, 1034. H- and C-NMR: see the Table. ESI-MS (pos.): 413 ([M þ
þ
þ
þ
þ
H] ), 435 ([M þ Na] ). HR-ESI-MS: 435.1996 ([M þ Na] , C H NaO ; calc. 435.1995).
21
32
8
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Received October 10, 2013