Pungent aromatic compound from New Zealand liverwort Hymenophyton flabellatum

Article abstract of DOI:10.1248/cpb.57.1015

Ether extract of the New Zealand liverwort Hymenophyton flabellatum produced a pungent principle. The structure has been identified as known compound, 1-(2,4,6-trimethoxy-phenyl)-but-2(E)-en-1-one by means of its spectral data, previously isolated from th

Full text of DOI:10.1248/cpb.57.1015

September 2009
Notes
Chem. Pharm. Bull. 57(9) 1015—1018 (2009)
1015
Pungent Aromatic Compound from New Zealand Liverwort
Hymenophyton flabellatum
a
Masao TOYOTA, ,a Ikuko OMATSU,a John BRAGGINS,b and Yoshinori ASAKAWA
*
a Institute of Pharmacognosy, Tokushima Bunri University; Yamashiro-cho, Tokushima 770–8514, Japan: and b Plant
Systematics, School of Biological Sciences, University of Auckland; Private Bag 92019, Auckland, New Zealand.
Received April 30, 2009; accepted June 19, 2009; published online June 22, 2009
Ether extract of the New Zealand liverwort Hymenophyton flabellatum produced a pungent principle. The
structure has been identified as known compound, 1-(2,4,6-trimethoxy-phenyl)-but-2(E)-en-1-one by means of its
spectral data, previously isolated from the fern Arachinoides standishii. Further isolation of the extract of this
species afforded eight aromatic compounds whose structures were determined by spectral analysis. Those com-
pounds were shown to be biogenetically and structurally related to the pungent compound of this species.
Key words Hepaticae; Hymenophyton flabellatum; pungent principle; liverwort
Bryophytes are phylogenetically placed between algae and shaded wet soil, humus and old logs in forest, and beside
the pteridophytes and are divided into three classes: Musci streams. Previous phytochemical work has resulted in the
(mosses), Hepaticae (liverworts) and Anthocerotae (horn- isolation of flavonoids from this species with division into
worts). We previously reported that chemical constituents two chemo types of the genus; however, the hot-tasting con-
among the three classes of bryophytes are totally different, stituent of Hymenophyton species has not yet been re-
with terpenoids and aromatic components found in liver- ported.10) In reality, H. flabellatum shows strong pungency
worts closely related to those found in Phaeophytes (brown when leaf fragments are chewed. We had an opportunity for
algae) in terms of chiroptical properties.1)
collection of this species in New Zealand, and further investi-
In the course of our investigation of bioactive substances gation of this species afforded a hot-tasting compound to-
in bryophytes, we found that some liverworts release pun- gether with four new aromatic compounds.
gent, hot-tasting substances. Five pungent compounds have
In order to identify the pungent principle, Hymenophyton
been isolated from liverworts, such as polygodial from flabellatum was extracted with ether. The ether extract pos-
Porella vernicosa,2) sacculatal from Trichocoleopsis saccu- sessed an incredibly strong pungent taste and was chro-
lata,3) plagiochilin A from Plagiochila yokogurensis,4) diplo- matographed on silica gel followed by preparative HPLC to
phyllolide from Chiloscyphus polyanthus and Diplophyllum give pure pungent-tasting compound 1-(2,4,6-trimethoxy-
albicans,5) and tulipinolide from Wiesnerella denudata6) (Fig. phenyl)-but-2(E)-en-1-one (1) (6.6% of the total extract).
1). Sacculatal and plagiochiline A are the characteristic pun- Isolation of 1 from the fern Arachinoides standishii11,12) and
gent compounds of liverworts, although polygodial is known from Dysophylla verticillata (Labiatae)13) has been previ-
as a hot-tasting constituent of higher plant Polygonum hy- ously reported. Furthermore, antifeeding activity of 1 in the
dropiper.7) Recently, we briefly reported the isolation and larvae of yellow butterfly, Eurema hecabe, has also been re-
identification of hot-tasting compound 1 from the liverwort ported.14)
Hymenophyton flabellatum (LABILL.).8) We now report in de-
Further purification of the ether extract gave new aromatic
tail the isolation and structural elucidation of the pungent compounds 2 (1.5%), 3 (0.5%), 6 (12.4%), and 7 (0.2%),
principle and four new aromatic compounds, together with together with known aromatic compounds 4 (3.0%),13)
5
four known compounds from New Zealand liverwort H. fla- (0.8%),15) 8 (1.4%)15,16) and 9 (1.8%).17)
bellatum.
The electron ionization-mass spectrum (EI-MS) of 1
Endemic to New Zealand and Australia,9) the liverwort H. showed a molecular ion peak at m/z 236. IR spectral analysis
flabellatum, belonging to Hymenophytaceae, grows on indicated the presence of an unsaturated carbonyl and an
1
aromatic ring. The H-NMR spectrum of 1 showed three
methoxyl groups and a di-substituted olefinic proton at d
6.50 and 6.66, which displayed trans configuration by mutual
coupling constant (Jꢀ15.5 Hz). Analysis of heteronuclear
multiple quantum coherence (HMQC) and heteronuclear
multiple bond correlation (HMBC) spectra supported the
structural assignment determined as 1-(2,4,6-trimethoxy-
phenyl)-but-2(E)-en-1-one. Whereas the 13C-NMR data of 1
was identical to that of compound 1 found in the fern Arachi-
noides standishii,11,12) it was not identical to that of vertinone
(1)13) isolated from D. verticillata (Labiatae). For this reason,
we attempted to synthesize 1 and directly compare the 13C-
NMR data between natural and synthetic materials. The reac-
tion of 1,3,5-trimethoxybenzene with crotonyl chloride using
Fig. 1. Hot-Tasting Substances Found in the Liverworts
aluminum chloride as catalyst gave 1-(2,4,6-trimethoxy-
© 2009 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: toyota@ph.bunri-u.ac.jp

1016
Vol. 57, No. 9
phenyl)-but-2(E)-en-1-one, whose 13C-NMR data was com-
Compound 6, [a]D20 ꢁ64.8 (cꢀ2.82, CHCl3), showed opti-
pletely identical to that of natural product 1 as well as litera- cally active and absorption bands at 3565 (OH), 1620 (CꢀO)
ture values.12) It was apparent from the above evidence that and 1592 (aromatic ring) cmꢁ1 in its IR spectrum. The ab-
the assignment of 13C-NMR data in the literature13) was in- sorption band at 3565 cmꢁ1 in the IR spectrum and a proton
correct.
signal at d 13.79 (1H, s) in the 1H-NMR spectrum suggested
IR spectrum of 2 showed absorption bands for hydroxyl, the presence of intramolecular hydrogen bonding. The UV
carbonyl groups and an aromatic ring at 3585, 1643, 1624 absorption maximum at 288 nm (log e, 4.16) and mutually
and 1595 cmꢁ1. UV absorption data at 318 nm (log e, 4.25) spin coupled proton signals at d 5.92 (1H, d, Jꢀ2.5 Hz) and
provided further evidence for the presence of an aromatic 6.07 (1H, d, Jꢀ2.5 Hz) exhibited the presence of 1,2,4,6-
ring. The EI-MS of 2 exhibited an ion peak at m/z 208 and tetrasubstituted aromatic ring. Further HMBC spectral
1
base peak at m/z 193. H-NMR spectral analysis showed a analysis of 6 confirmed the structure as 1-(2-hydroxy-4,6-
prominent signal at d 14.11, indicating the presence of hy- dimethoxyphenyl)-3-hydroxy-1-butanone.
drogen bonding in the molecule. The mutually spin–spin
Racemic compound 6 has been reported as a synthetic in-
coupled proton signals at d 6.00 (1H, d, Jꢀ2.2 Hz) and 5.92 termediate of 1-(2,4,6-trimethoxy-phenyl)-but-2(E)-en-1-one
(1H, d, Jꢀ2.2 Hz) exhibited the presence of 1,2,4,6-tetrasub- (1) and 4.18) Since compound 6 from H. flabellatum showed
stituted aromatic ring in 2. 13C-NMR spectral analysis optical activity as described earlier, we attempted to deter-
demonstrated the resonances of 11 carbons, including a car- mine the absolute configuration of the hydroxyl group in 6
bonyl carbon at d 193.1. The presence of trans-2-buten-1- by X-ray crystallographic analysis of a halogenated deriva-
one as a partial structure was apparent by further resonance tive. Bromination with N-bromosuccinimide afforded 10,
at dH 1.97 (3H, dd, Jꢀ6.9, 1.5 Hz), 7.07 (1H, dq, Jꢀ15, whose EI-mass spectrum showed ion peaks at m/z 396 [Mꢃ]
6.9 Hz) and 7.21 (1H, dq, Jꢀ15, 1.5 Hz) in its 1H-NMR, and (intensity 3.6%), 398 [Mꢃꢃ2] (7.2%) and 400 [Mꢃꢃ4]
dC 18.7 (q), 142.7 (d), and 131.9 (d) in the 13C-NMR spectra. (3.7%). This provided evidence for the presence of two
Furthermore, there is only one possible position, C-6ꢂ, for the bromine atoms in 10. Since two aromatic proton signals at d
attachment of the methoxyl group, since the Nuclear Over- 5.92 (d, Jꢀ2.5 Hz) and 6.07 (d, Jꢀ2.5 Hz) of 6 were missing
hauser Enhancement Spectroscopy (NOESY) of 2 showed a in the 1H-NMR spectrum of 10, the structure was clearly de-
correlation between the methoxyl proton and H-2 proton. termined. The absolute configuration of the hydroxyl group
Consideration of the spectral data established the structure of 6 was clarified by X-ray crystallographic analysis of crys-
of 2 as 1-(2,4-dihydroxy-6-methoxy-phenyl)-but-2(E)-en-1- tals of 10 obtained from ether solution. Finally, the absolute
one.
structure of 6 was established as 1-(2-hydroxy-4,6-di-
The structure of 3 was deduced by comparing its spectral methoxyphenyl)-3(R)-hydroxy-1-butanone by ORTEP draw-
data with that of 1. Since coupling constant 11.5 Hz was ob- ing (Fig. 3).
served at d 6.34 and 6.21 in the 1H-NMR spectrum of 3, it is
A glycoside of 6 has not only been isolated from ferns
clear that the double bond in the a,b-unsaturated ketone was Arachinoides standishii12) and Diplazium nipponicum,19) but
cis configuration. The structure of 3 was determined to be 1- 6 has also been obtained as an intermediate product in the
(2,4,6-trimethoxy-phenyl)-but-2(Z)-en-1-one.
synthesis of 1 and 4.18) This is the first example of the isola-
tion of 6 as a natural product. Assignment of NMR data for 6
is illustrated in Table 1. Furthermore, the absolute configura-
tion at C-3 of an aglycone 6 ([a]D ꢃ7.4)19) derived from
onioside, 1-(2-hydroxy-4,6-dimethoxyphenyl)-3(S)-hydroxy-
1-butanone 3-O-b-D-glucopyranoside isolated from the fern
Fig. 3. A Computer Generated Drawing of the Final X-Ray Model of
Fig. 2. The Structures of Compounds 2—10
Compound 10

September 2009
1017
Table 1. NMR Data for Compounds 2, 3, 6, and 7 in CDCl3
2
3
6
7
No.
1H
13C
1H
13C
1H
13C
1H
13C
1
2
—
193.1
131.9
—
193.7
130.8
—
205.0
52.2
—
194.6
46.4
7.21 (dq, 15, 1.5)
6.34 (dq, 11.5, 1.6)
3.05 (dd, 18, 9)
3.22 (dd, 18, 2.5)
4.35 (ddddd, 6.5,
6.5, 6.5, 9, 2.5)
1.27 (d, 6.5)
—
2.85 (d, 17)
2.93 (dd, 17, 2)
—
3
7.07 (dq, 15, 6.9)
142.7
6.21 (dq, 11.5, 7)
141.5
64.1
100.7
4 (CH3)
1ꢂ
2ꢂ
3ꢂ
4ꢂ
1.97 (dd, 6.9, 1.5)
—
—
6.00 (d, 2.2)
—
5.92 (d, 2.2)
—
—
14.11 (s)
—
18.7
105.8
167.8
96.6
162.5
90.9
163.3
—
—
—
—
55.7
2.10 (dd, 7, 1.6)
—
15.7
113.9
158.7
90.7a)
162.8
90.7a)
158.7
55.9a)
—
22.4
105.9
167.7
93.7
166.3
91.0
162.9
—
1.73 (s)
—
—
6.07 (d, 2.5)
—
5.98 (d, 2.5)
—
28.6
102.4
163.9
94.9
167.9
95.0
159.5
—
—
—
6.11a) (s)
—
6.07 (d, 2.5)
—
5.92 (d, 2.5)
—
—
13.79 (s)
3.83 (s)
5ꢂ
6ꢂ
6.11a) (s)
—
2-OCH3
2ꢂ-OH
4ꢂ-OCH3
4ꢂ-OH
3.78a) (s)
—
—
—
55.6
—
11.95 (s)
3.83 (s)
—
—
55.7
3.83 (s)
—
55.4
5.70 (bs)
—
—
3.86 (s)
6ꢂ-OCH3 3.88 (s)
3.78 a) (s)
55.9a)
55.6
—
—
Measured at 600 MHz for 1H and 150 MHz for 13C. a) Overlapped signals.
voucher specimen has been deposited at Institute of Pharmacognosy,
Tokushima Bunri University.
Diplazium nipponicum has been established as S-configura-
tion by modified Horeau’s method. The present work estab-
lished the configuration as R at C-3 of the naturally occurring
compound 6 from the liverwort. This is the first example in
which compounds from both the liverwort and fern have an
enantiomeric relationship.
Specimen was extracted with Et2O for 2 weeks. The ether extract
(340.3 mg; yield 5.4%) was chromatographed on silica gel to divide into 11
frs. (fr. 1—11). Fraction 9 (74.6 mg) was rechromatographed on Sephadex
LH-20 and further purified by prep HPLC on silica gel column (10 mm i.d.
ꢄ250 mm) using n-hexane–ethyl acetate (4 : 1, v/v) to give hot-tasting com-
pound, 1-(2,4,6-trimethoxy-phenyl)-but-2(E)-en-1-one (1) (22.4 mg; 6.6% of
total extract), compounds 2 (5.2 mg; 1.5%), 5 (2.7 mg; 0.8%), and 7 (0.8 mg;
0.2%). Fraction 8 (8.2 mg) was purified by prep HPLC on silica gel column
(10 mm i.d. ꢄ250 mm) using n-hexane–ethyl acetate (7 : 3, v/v) to give com-
pound 3 (1.8 mg; 0.5%). Fraction 10 (63.1 mg) was purified by prep HPLC
to give 6 (42.2 mg; 12.4%). Fractions 3 (25.3 mg), 6 (17.1 mg) and 11
(12.8 mg) were further purified by prep HPLC to give 4 (10.2 mg; 3.0%), 8
(4.6 mg; 1.4%), and 9 (6.0 mg; 1.8%), respectively.
Compound 7 (EI-MS [M]ꢃ m/z 224) showed absorption at
3586 cmꢁ1 for a hydroxyl group and 1640 cmꢁ1 for an unsat-
urated carbonyl group in the IR spectrum. UV spectral analy-
sis of 7 exhibited a maximum absorption band at 287 nm
(log e, 4.59) indicating the presence of an aromatic ring.
NMR spectral data revealed a singlet signal at dH 1.73 (s,
3H) which correlated to a hemiketal carbon at dC 100.7 and a
methylene carbon at dC 46.4 in the HMBC of 7. The correla-
1-(2,4,6-Trimethoxy-phenyl)-but-2(E)-en-1-one (1) 1H-NMR (200
MHz, CDCl3) d: 6.34 (1H, dq, Jꢀ15, 1.5 Hz), 6.67 (1H, dq, Jꢀ15, 6.9 Hz),
tion of the methylene protons at dH 2.85 and 2.93 between 1.90 (3H, dd, Jꢀ6.9, 1.5 Hz), 6.12 (2H, s), 3.75 (6H, s), 3.83 (3H, s). 13C-
NMR (50 MHz, CDCl3) d: 194.7 (C-1), 134.2 (C-2), 145.2 (C-3), 18.3 (C-
the carbonyl carbon at dC 194.6 and a quaternary aromatic
4), 111.8 (C-1ꢂ), 158.5 (C-2ꢂ, 6ꢂ), 90.7 (C-3ꢂ, 5ꢂ), 162.2 (C-4ꢂ), 55.9 (2ꢂ, 6ꢂ-
carbon at dC102.4 apparently exhibited the presence of C4
chain unit attached to aromatic ring, similar to previous com-
pounds 1—6. Further observation of aromatic proton signals
at d 5.98 and 6.07 (each, d, Jꢀ2.5 Hz) indicated that 1,2,4,6-
tetrasubstituted aromatic ring partially existed in 7. Extensive
1H- and 13C-NMR analysis (Table 1) allowed us to define the
structure of 7 as 2,5-dihydroxy-7-methoxy-2-methylchro-
man-4-one. Measurement of the optical rotation was not fea-
sible due to the small sample size.
OCH3), 55.4 (4ꢂ-OCH3). EI-MS m/z (rel. int.): 236 [Mꢃ] (83), 221 (38), 195
(100), 181 (25). IR (CHCl3) cmꢁ1: 1649, 1607, 1590. UV lmax (EtOH) nm
(log e): 291 (3.52), 223 (4.22), 211 (4.33).
Synthesis of 1-(2,4,6-Trimethoxy-phenyl)-but-2(E)-en-1-one (1) To a
solution of crotonyl chloride (0.76 g) in CS2 (15 ml), aluminum chloride
(0.77 g) and 1,3,5-trimethoxybenzene (0.4 g) was added and the mixture was
heated under reflux for 4 h. Excess water and CHCl3 were added to the reac-
tion mixture. The organic layer was washed with 10% Na2CO3 and then with
water. The organic layer was dried over Na2SO4, and the solvent was evapo-
rated under reduced pressure to give a residue (0.61 g). The residue was pu-
rified by Sephadex LH-20 using CH2Cl2–MeOH (1 : 1, v/v) and prep HPLC,
affording pure 1 (17.3 mg).
1-(2,4-Dihydroxy-6-methoxy-phenyl)-but-2(E)-en-1-one (2) NMR
data were described in Table 1. EI-MS m/z (rel. int.): 208 [Mꢃ] (11), 193
(100), 178 (16), 167 (24), 69 (11). IR (CHCl3) cmꢁ1: 3585, 1643, 1624,
1595, 1574, 1429, 1339. UV lmax (EtOH) nm (log e): 318 (4.25), 250 (sh)
(3.95), 209 (4.31).
We have focused on the bioactive constituents and the
chemosystematics of bryophytes and pteridophytes as well as
the evolutionary relationship between terrestrial spore-form-
ing green plants and algae using their characteristic chemical
indicators. The bryophytes are phylogenetically placed be-
tween the algae and pteridophytes. Compound 1 and bis-
bibenzyls7,20) were elaborated from both liverworts and ferns
as chemical indicators that could provide an evolutionary
1-(2,4,6-Trimethoxy-phenyl)-but-2(Z)-en-1-one (3) NMR data were
described in Table 1. EI-MS m/z (rel. int.): 236 [Mꢃ] (87), 205 (38), 195
(100), 168 (44), 137 (17). IR (CHCl3) cmꢁ1: 1607, 1466, 1414, 1157, 1132.
link between liverworts and ferns. On the basis of this result, UV lmax (EtOH) nm (log e): 297 (3.64), 227 (4.15), 204 (4.58).
1-(2-Hydroxy-4,6-dimethoxyphenyl)-3(R)-hydroxy-1-butanone (6)
it is clear that some ferns and liverworts produce similar
compounds and appear to be closely related chemically.
NMR data were described in Table 1. mp 67—68 °C. [a]D20 ꢁ64.8 (cꢀ2.82,
CHCl3). EI-MS m/z (rel. int.): 240 [Mꢃ] (8.5), 207 (23.5), 181 (100), 154
Experimental
(13.6). IR (CHCl3) cmꢁ1: 3565, 1620, 1592, 1418, 1160, 1116. UV lmax
(EtOH) nm (log e): 325 (3.88), 288 (4.16), 211 (4.65).
Plant Material Hymenophyton flabellatum (LABILL.) DUM. ex TREV.
(Herbarium specimen No. NZ-64; dry weight 6.25 g) was collected in De-
Bromination of 6 with N-Bromosuccinimide N-Bromosuccinimide
cember 2000 near the Haast river, on the south island of New Zealand. A (10 mg) was added to a solution of 6 (5.9 mg) in CCl4 (0.4 ml), and the reac-

1018
Vol. 57, No. 9
tion mixture was refluxed for 1 h. After cooling, the reaction mixture was
passed through a short column on celite, then purified by prep HPLC to give
10 (3.8 mg). 10: [a]D20 ꢁ23.4 (cꢀ0.38, CHCl3). EI-MS m/z (rel. int.): 400
(3.7), 398 (7.2), 396 [Mꢃ] (3.6), 367 (47.9), 365 (100), 363 (50.1), 341
(41.1), 339 (86.1), 337 (46.2). 1H-NMR (CDCl3; 300 MHz): 1.29 (d, 3H,
Jꢀ6.3 Hz), 3.22 (dd, Jꢀ18.4, 8.5 Hz), 3.34 (dd, Jꢀ18.4, 3 Hz), 3.92 (s), 3.96
(3H, s), 4.41 (1H, m).
5) Asakawa Y., Toyota M., Takemoto T., Suire C., Phytochemistry, 18,
1007—1009 (1979).
6) Asakawa Y., Matsuda R., Takemoto T., Phytochemistry, 19, 567—569
(1980).
7) Asakawa Y., “Progress in the Chemistry of Organic Natural Products,”
Vol. 42, ed. by Herz W., Kirby G. W., Moore R. E., Steglich W., Tamm
Ch., Springer, Vienna, 1982.
Crystal Data for 1-(3,5-dibromo-2-hydroxy-4,6-dimethoxyphenyl)-
3(R)-hydroxy-1-butanone (10) All diagrams and calculations were per-
formed using maXus (Bruker Nonius, Delft & MacScience, Japan). MoKa
(lꢀ0.71073). Orthorhombic P212121, aꢀ4.484 (2) Å, bꢀ14.4210 (8) Å,
mꢀ5.684 10) Markham K. R., Porter L. J., Campbell E. O., Chopin J., Bouillant M.-
mmꢁ1, final residuals R(all)ꢀ0.0750, R(gt)ꢀ0.0580, and S(ref)ꢀ1.084.
L., Phytochemistry, 15, 1517—1521 (1976).
2,5-Dihydroxy-7-methoxy-2-methyl-chroman-4-one (7) NMR data 11) Tanaka N., Maehashi H., Saito S., Murakami T., Saiki Y., Chen C.-M.,
were described in Table 1. EI-MS m/z (rel. int.): 224 [Mꢃ] (91), 209 (66),
Iitaka Y., Chem. Pharm. Bull., 27, 2874—2876 (1979).
207 (79), 182 (21), 167 (100) 140 (28). IR (CHCl3) cmꢁ1: 3586, 1640, 1578, 12) Tanaka N., Maehashi H., Saito S., Murakami T., Saiki Y., Chen C.-M.,
8) Asakawa Y., Toyota M., Oiso Y., Braggins J. E., Chem. Pharm. Bull.,
49, 1380—1381 (2001).
9) Allison K. W., Child J., “The Liverworts of New Zealand,” University
of Otago Press, Dunedin, 1975, p. 245.
cꢀ22.102 (5) Å, Vꢀ1429.2 (8) Å3, Zꢀ4, Dxꢀ1.850 mg mꢁ3
,
1315, 1157, 1073. UV lmax (EtOH) nm (log e): 325 (sh) (3.88), 287 (4.59),
212 (4.65).
Iitaka Y., Chem. Pharm. Bull., 28, 3070—3077 (1980).
13) Chakrabarti A., Chakraborty D. P., Phytochemistry, 27, 3683—3684
(1988).
Acknowledgement We thank Dr. M. Tanaka (Tokushima Bunri Univer- 14) Numata A., Katsuno T., Yamamoto K., Nishida T., Takemura T., Seto
sity) for his measurement using 600 MHz NMR. This work was supported K., Chem. Pharm. Bull., 32, 325—331 (1984).
by a Grand-in-Aid for Scientific Research (B) (No. 14403014) from the 15) Ahluwalia, V. K., Kumar D., Indian J. Chem., 15B, 514—518 (1977).
Ministry of Education, Culture, Sports, Science and Technology.
16) Tsui W.-Y., Brown Geoffrey D., Phytochemistry, 43, 871—876 (1996).
17) Morimoto M., Tanimoto K., Nakano S., Ozaki T., Nakano A., Komai
K., J. Agric. Food Chem., 57, 389—393 (2003).
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