Isolation and structure of striatenic acid from liverwort Cheilolejeunea serpentina and the absolute configuration by synthesis

Article abstract of DOI:10.1016/S0040-4020(00)00069-7

Striatenic acid has been isolated from the liverwort Cheilolejeunea serpentina collected in Malaysia and its structure was determined on the basis of extensive 2D NMR techniques. The absolute configuration was established by synthesis of the optically act

Full text of DOI:10.1016/S0040-4020(00)00069-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1655–1659
Isolation and Structure of Striatenic Acid from Liverwort
Cheilolejeunea serpentina and the Absolute
Configuration by Synthesis
*
Motoo Tori, Akihito Aiba, Hiroki Koyama, Toshihiro Hashimoto, Katsuyuki Nakashima,
Masakazu Sono and Yoshinori Asakawa
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
Received 13 December 1999; accepted 20 January 2000
Abstract—Striatenic acid has been isolated from the liverwort Cheilolejeunea serpentina collected in Malaysia and its structure was
determined on the basis of extensive 2D NMR techniques. The absolute configuration was established by synthesis of the optically active
methyl ester. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
column chromatography to isolate striatenic acid (1).
Because it has a carboxyl group (3200–2500, 1682 cmϪ1),
Liverworts are rich sources of terpenoids, which very often
show cytotoxic, anti-inflamatory, anti-fungal, or anti-micro-
bial activities.1–3 We have been studying the chemical
constituents of various liverworts collected in all over the
world. We have previously reported the metabolites of
Cheilolejeunea trifaria, i.e. trifarienols A–E (trifarane-
type sesquiterpenoids) having a bicyclo[3.3.1]nonane skele-
ton, which are very rare in the nature.4,5 We have collected
closely related Malaysian species Cheilolejeunea serpen-
tina and isolated a new striatane-type sesquiterpene. Now
we report the isolation, structure determination, and the
absolute configuration6 of striatenic acid (1) by synthesis
of the optically active methyl ester 2.
it was converted to a corresponding methyl ester
(1720 cmϪ1) by treatment with diazomethane.7 The ester 2
exhibited a molecular ion peak at m/z 248, whose molecular
formula was determined by HRMS to be C16H24O2. The 1H
NMR spectrum showed the existence of five olefinic
protons. The presence of a vinyl group was obvious from
the signals at dH 6.38 (1H, dd, Jˆ17.4, 10.4 Hz), 5.04 (1H,
d, Jˆ17.4 Hz), and 4.89 (1H, d, Jˆ10.4 Hz). The 13C NMR
showed seven sp2 carbons, one of which was due to an ester
(dC 167.9). Therefore, there are three double bonds, two of
which were trisubstituted olefins (Table 1). Since the degree
1
Table 1. The H and 13C NMR data of acid 1 and ester 2 (CDCl3)
1 (400 MHz)
2 (600 MHz)
No.
H
C
H
C
1
1.67 (m)
34.6
1.67 (m)
34.5
2a
2b
3
4
5
1.42 (m)
1.52 (m)
2.16 (m)
7.15 (t, 4.2)
–
25.9
–
1.42 (m)
1.52 (m)
2.16 (m)
6.91 (t, 4.2)
–
25.9
–
25.8
144.0
135.2
39.9
34.8
–
130.1
137.4
141.8
110.3
–
15.7
20.8
172.6
11.9
–
25.6
140.8
135.1
40.0
35.0
–
130.1
137.4
141.8
110.3
–
15.7
21.0
167.9
11.9
51.3
6
–
–
7a
7b
8
2.41 (dd, 15.9, 9.0)
2.82 (dd, 15.9, 6.0)
5.29 (dd, 9.0, 6.0)
–
6.34 (dd, 17.2, 10.8)
4.89 (d, 10.8)
5.04 (d, 17.2)
0.90 (d, 6.8)
1.16 (s)
2.41 (dd, 15.4, 8.0)
2.73 (dd, 15.4, 6.0)
5.26 (dd, 8.0, 6.0)
–
6.38 (dd, 17.4, 10.4)
4.89 (d, 10.4)
5.04 (d, 17.4)
0.89 (d, 6.6)
1.16 (s)
Results and Discussion
Isolation and structure
9
10
11a
11b
12
13
14
15
OMe
An ether extract of C. serpentina was subjected to silica gel
Keywords: carboxylic acids and derivatives; natural products; plants;
terpenes and terpenoids.
* Corresponding author. Tel.: ϩ81-88-622-9611 (ext. 5631); fax: ϩ81-88-
655-3051; e-mail: tori@ph.bunri-u.ac.jp
–
–
1.73 (br s)
–
1.72 (br s)
3.68 (s)
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00069-7

1656
M. Tori et al. / Tetrahedron 56 (2000) 1655–1659
NOESY spectrum (Fig. 2). Because H-15 had an NOE
into H-7, and H-8 into H-10, the geometry of the double
bond at C-8 and C-9 should be E. The NOE’s between H-12
and H-13 and between H-1 and H-7 were observed to
suggest the cis orientation of H-12 and H-13. Thus, the
stereostructure was established as depicted in the formula
2. The absolute configuration was left undetermined.
Figure 1. The HMBC correlations for ester 2.
Synthesis of the optically active methyl ester 2
In order to establish the absolute configuration of striatenic
acid (1), we have planned to synthesize the optically active
methyl ester 2. We have previously reported the total
synthesis of trifarienols A and B starting from the optically
active keto ester 3, which was prepared from (R)-pulegone
through the chiral Michael addition reaction using (S)-(Ϫ)-
phenylethylamine with high de and ee.8 Thus, this
compound is easily accessed as a starting material. The
ketone 38 was protected as an acetal, and the side chain
was elongated with one carbon to afford ketone 6 by
addition of MeLi to the corresponding carboxylic acid 5.
The triflate was derived from ketone 6 with KHMDS and
triflic imide at rt for 5 days.9–13 The mixture of E and Z enol
triflate, 7E and 7Z (1:10), which could be separated by
HPLC, was obtained in 46% yield. The E/Z isomers were
Figure 2. The selected NOE’s for ester 2.
of unsaturation was five, the ester 2 must be a monocyclic
compound. The HMQC spectrum showed that the proton at
dH 5.26 (1H, dd, Jˆ8, 6 Hz) was attached to the carbon at dC
130.1 and that at dH 6.91 (1H, t, Jˆ4.2 Hz) to dC 140.8. The
HMBC spectrum indicated the carbon connectivities
between H-15 and C-8, C-9, C-10; H-12 and C-1, C-2, C-
6; H-13 and C-1, C-6, C-7, C-5; H-4 and C-14 (Fig. 1).
Therefore, compound 2 was determined to be the
striatane-type sesquiterpene methyl ester as depicted in
the formula. The stereochemistry was determined by the
Scheme 1. (a) HOCH2CH2OH, TsOH, PhH, reflux, 1 day, 83%; (b) 10% aq. KOH, MeOH, rt, 1 h, 90%; (c) MeLi, Et2O, 0ЊC, 1 h, 74%; (d) KHMDS, PhNTf2,
n
THF, rt, 5 days, 46% (E:Zˆ1:10); (e) Bu3SnCHˆCH2, Pd(PPh3)4, LiCl, THF, reflux, overnight; (f) TsOH, acetone–H2O (5:1), rt, overnight; then SiO2–
AgNO3; (g) tBuLi, PhNTf2, THF, Ϫ20ЊC, 14 days; (h) CO, Pd(OAc)2, PPh3, NEt3, DMF, MeOH, rt, 1 day, 21% (2 steps).

M. Tori et al. / Tetrahedron 56 (2000) 1655–1659
1657
determined by the NOE experiments. The E/Z mixture was
treated with Pd(PPh3)4, LiCl, and nBu3SnCHvCH2 in THF
under reflux to afford a mixture of dienes 8E and 8Z (3:1) in
95% yield. The acetal in the dienes 8E and 8Z was depro-
tected with TsOH in acetone–H2O (5:1) to afford a mixture
of ketones 9E and 9Z, which was purified by AgNO3-
impregnated silica gel column chromatography to give
pure 9E (Scheme 1). It was very interesting to note that
the pure E-triflate 7E gave the pure E-diene 8E, while the
pure Z-triflate 7Z afforded a mixture of E- and Z-dienes, 8E
was treated with diazomethane for 1 h at 0ЊC. The excess
diazomethane was decomposed by AcOH (0.5 mL). The
reaction mixture was evaporated to give a residue
(25 mg), which was purified by preparative TLC (hexane–
EtOAc, 20%) to afford ester 2 (12.2 mg). 1: [a]2D0ˆϩ43.5
(cˆ2.7, CHCl3); MS (EI) m/z 234 (Mϩ), 153 (base), 135,
125, 107. HRMS Obs. m/z 234.1603; Calcd for C15H22O2
234.1620; UV (EtOH) lmax nm (log e): 216 (4.08), 233
(4.38); IR (FT) 3200–2500, 1682, 1634, 1271 cmϪ1. 2:
[a]2D0ˆϩ49.9 (cˆ0.77, CHCl3); MS m/z 248 (Mϩ), 167
(base); HRMS Obs. m/z 248.1758; Calcd for C16H24O2
1
and 8Z (E:Zˆ3:1, from the H NMR spectrum). These
results are presumably explained by the the isomerization
of 8Z into 8E owing to Pd present in the mixture after the
C–C bond formation. When ketone 9E was treated with
LDA and triflic imide in THF overnight, complete recovery
of the starting ketone was observed. Thus, the triflate was
248.1776; IR (FT) 1720 cmϪ1
.
Acetalization of keto ester 3
A mixture of keto ester 3 (2.8 g, 13 mmol), TsOH (370 mg),
and ethyleneglycol (8.0 mL, 130 mmol) in PhH (310 mL)
was refluxed overnight with the aid of the Dean–Stark water
separator. The mixture was washed with sat. NaHCO3 and
brine, dried (MgSO4), and was evaporated to give a residue,
which was purified by silica gel column chromatography
(elution with hexane–EtOAc, 20%) to afford acetal 4
(2.8 g, 83%); oil; [a]D23ˆϪ25 (cˆ0.3, CHCl3); IR (FT)
t
derived from ketone 9E by treatment with BuLi and triflic
imide in THF for 14 days. Although the yield was very low
1
(judging from the H NMR spectrum), the final carbonyl-
ation was carried out with Pd(OAc)2, PPh3, NEt3, CO, and
MeOH in DMF to afford ester 2 in 21% in two steps.9–13 The
spectral data of ester 2 was completely identical with those
of the natural product. The specific rotation of the synthetic
ester 2 was [a]Dˆϩ45.7 (natural one [a]Dˆϩ49.9). There-
fore, the absolute configuration of ester 2 was established as
depicted in the formula.
1
1740 cmϪ1; H NMR (200 MHz, CDCl3) d 0.84 (3H, d,
Jˆ7 Hz), 0.91 (3H, s), 3.65 (3H, s), 3.92 (4H, br s); 13C
NMR (50 MHz, CDCl3) d 15.9 (CH3), 16.2 (CH3), 22.4
(CH2), 29.6 (CH2), 29.7 (CH2), 30.4 (CH2), 30.7 (CH2),
35.4 (CH2), 43.3 (C), 51.4 (CH3), 54.1 (CH2), 113.8
(CH2), 175.4 (C); MS (CI-CH4) m/z 257 (MϩH)ϩ, 241,
225, 195, 183, 141, 113, 99 (base); HRMS Obs. 257.1769
(MϩH)ϩ. Calcd for C14H25O4 257.1752.
As a conclusion, we have isolated striatenic acid (1) from
the liverwort C. serpentina and the structure was determined
to have a striatane-type, a rearranged monocyclofarnesane,
on the basis of 2D NMR data. Furthermore, the absolute
configuration was established by synthesis of the optically
active ester 2 starting from the easily accessible ketone 3.
Hydrolysis of ester 4
A solution of methyl ester 4 (3.1 g, 12 mmol) in MeOH
(30 mL) was treated with 10% aqueous KOH (90 mL) at
rt for 1 h. Methanol was removed and the residue was
extracted with ether. The aqueous layer was acidified with
1 M HCl at 0ЊC and the mixture was extracted with ether.
The ethereal solution was washed with brine, dried
(MgSO4), and evaporated to afford acid 5 (2.6 g, 90%);
Experimental
General
The IR spectra were measured with a JASCO FT/IR-5300
spectrophotometer. The 1H and 13C NMR spectra were
taken with a Varian Unity 200 (200 MHz), a Unity 600
(600 MHz), or a JEOL JNM GX400 (400 MHz) spectro-
meter. The mass spectra including high resolution mass
spectra were taken with a JEOL JMS AX-500 spectrometer.
Chemcopak Nucleosil 50-5 (10×250 mm) was used for
HPLC (JASCO pump system). Silica gel 60 (70–
230 mesh, Merck) was used for column chromatography
and silica gel 60 F254 plates (Merck) were used for TLC.
1
oil; IR (FT) 3400–2400, 1700 cmϪ1; H NMR (200 MHz,
CDCl3) d 0.84 (3H, d, Jˆ6.8 Hz), 0.92 (3H, s), 3.92 (4H, br
s); 13C NMR (50 MHz, CDCl3) d 15.8 (CH3), 16.1 (CH3),
22.3 (CH2), 29.3 (CH2), 29.7 (CH2), 30.2 (CH2), 30.6 (CH2),
35.3 (CH2), 43.3 (C), 64.0 (CH2), 113.8 (CH2), 181.4 (C);
MS (CI-CH4) m/z 243 (MϩH)ϩ, 225, 181, 171, 141, 127,
113, 99 (base), 86; HRMS Obs. 243.1591 (MϩH)ϩ, Calcd
for C13H23O4 243.1596.
Isolation procedure
Preparation of ketone 6
The liverwort (20.2 g) was collected at Langkawi Island,
Malaysia in 1992 and was identified by Dr M. Mizutani.
The voucher specimen was deposited in the herbarium of
Faculty of Pharmaceutical Sciences, Tokushima Bunri
University. The liverwort was pulverized and was extracted
with ether to afford the extract (490.5 mg), which was sepa-
rated by silica gel column chromatography (hexane–
EtOAc, in gradient) to yield 5 fractions. The second fraction
was further separated by silica gel chromatography
(hexane–EtOAc, gradient) to afford striatenic acid (1)
(53.2 mg). A solution of acid 1 (20 mg) in ether (2 mL)
A solution of acid 5 (1.5 g, 6.2 mmol) in ether (100 mL) was
treated with MeLi (1.09 M in ether, 12.5 mL, 14 mmol) at
0ЊC for 1 h. Wet ether was added and the ether layer was
separated. The organic layer was washed with brine, dried
(MgSO4), and evaporated to give a residue, which was puri-
fied by silica gel column chromatography (elution with
hexane–EtOAc, in gradient) to afford ketone 6 (1.1 g,
74%); oil; [a]2D3ˆϪ24.2 (cˆ1.6, CHCl3); IR (FT)
1
1710 cmϪ1; H NMR (200 MHz, CDCl3) d 0.84 (3H, d,
Jˆ6.8 Hz), 0.91 (3H, s), 2.13 (3H, s), 3.91 (4H, s); 13C
NMR (50 MHz, CDCl3) d 15.8 (CH3), 16.3 (CH3), 22.3

1658
M. Tori et al. / Tetrahedron 56 (2000) 1655–1659
(CH2), 27.9 (CH2), 29.7 (CH2), 30.0 (CH2), 30.2 (CH2), 35.4
(CH), 40.1 (CH3), 43.1 (C), 64.0 (C), 113.8 (CH2), 209.9
(C); MS (CI-CH4) m/z 241 (MϩH)ϩ, 223, 209, 183 (base),
161, 141, 113, 99, 86; HRMS Obs. 241.1788 (MϩH)ϩ.
Calcd. for C14H25O3 241.1804.
silica gel chromatography (hexane–EtOAc, 2%) to give
pure 8E (12 mg, 80%).
Reaction of pure 7Z
n
A solution of 7Z (50 mg, 0.16 mmol), Bu3SnCHvCH2
Preparation of ketone 9
(0.08 mL, 0.24 mmol, 1.5 equiv.), Pd(PPh3)4 (10 mg,
5 mol%), and LiBr (20 mg, 0.48 mmol, 3 equiv.) in THF
(5 mL) was heated under reflux overnight. Work-up as
above afforded a residue, which was purified by silica gel
chromatography (hexane–EtOAc, 2%) to give a mixture of
8E and 8Z (38.1 mg, 95%, 3:1).
A mixture of ketone 6 (1.2 g, 5.0 mmol), KHMDS (0.5 M in
toluene, 14.5 mL, 7 mmol), Tf2NPh (5 g, 14 mmol), and
THF (50 mL) was stirred at rt for 5 days. Aqueous NaOH
solution (10%) was added at 0ЊC and the solvent was
removed. The residue was extracted with ether and the
organic layer was washed with brine, dried (MgSO4), and
was evaporated to give a residue, which was purified by
silica gel column chromatography (elution with hexane–
EtOA, 1%) to afford a mixture of 7E and 7Z (840 mg,
Preparation of methyl striatenate 2
A solution of ketone 9E (37 mg, 0.18 mmol) in THF
(3.5 mL) was treated with tBuLi (1.6 M, 0.4 mL,
0.54 mmol) and Tf2NPh (190 mg, 0.54 mmol) at Ϫ20ЊC
for 14 days. After 10% NaOH aq. was added, the solvent
was evaporated and the residue was extracted with ether.
The organic layer was washed with brine, dried (MgSO4),
and was evaporated to give crude triflate 10 (149.3 mg); 1H
NMR (200 MHz, CDCl3) d 0.92 (3H, d, Jˆ7 Hz), 1.04 (3H,
s), 1.55 (3H, br s), 4.97 (1H, d, Jˆ10 Hz), 5.12 (1H, d,
Jˆ18 Hz), 5.36 (1H, t, Jˆ6 Hz), 5.79 (1H, t, Jˆ4 Hz),
6.38 (1H, dd, Jˆ18, 10 Hz). A mixture of crude triflate 10
(166 mg), PPh3 (180 mg, 0.7 mmol), Pd(OAc)2 (70 mg,
0.3 mmol), DMF (1 mL), NEt3 (0.2 mL, 1.4 mmol), and
MeOH (2 mL) was stirred at rt under CO atmosphere over-
night. Water was added and the mixture was extracted with
ether. The organic layer was washed with brine, dried
(MgSO4), and was evaporated to give a residue. The residue
was purified by silica gel column chromatography (elution
with hexane–EtOAc, 2%) to afford a crude product
(149.3 mg), which was further purified by HPLC (Nucleosil
50-5, 10×250 mm, hexane–EtOAc 10%) to afford pure
methyl striatenate (2) (9.2 mg, 21% from 9E);
1
46%, 1:10); 7E: H NMR (200 MHz, CDCl3) d 0.82 (3H,
d, Jˆ6.8 Hz), 0.95 (3H, s), 2.03 (3H, br s), 3.92 (4H, m),
1
5.89 (1H, t, Jˆ7.4 Hz). 7Z: H NMR (400 MHz, CDCl3) d
0.82 (3H, d, Jˆ7 Hz), 0.94 (3H, s), 2.05 (3H, br s), 3.90 (4H,
m), 5.62 (1H, t, Jˆ6.6 Hz); 13C NMR (100 MHz, CDCl3) d
15.8 (CH3×2), 19.8 (CH3), 22.5 (CH2), 29.9 (CH2), 30.2
(CH2), 30.6 (CH2), 36.2 (CH), 44.4 (C), 64.1 (CH2), 64.2
(CH2), 113.3 (C), 120.7 (CH), 143.9 (C). A solution of a
mixture of triflates 7E and 7Z (657 mg, 1.9 mmol) in THF
(50 mL) was treated with LiCl (240 mg, 6.0 mmol),
Pd(PPh3)4 (2 mol%), and nBu3SnCHvCH2 (0.72 mL,
2.6 mmol) under reflux overnight. Aqueous ammonia
(28%) was added and the solvent was removed. The residue
was extracted with ether and the organic layer was washed
with brine, dried (MgSO4), and was evaporated to give a
residue, which was purified by silica gel column chroma-
tography (elution with hexane–EtOAc, 2%) to afford dienes
8E and 8Z (450 mg, 95%, 3:1). The mixture of dienes 8E
and 8Z (400 mg) was treated with TsOH (10 mg) in acetone
(50 mL) and H2O (10 mL) at rt overnight. The solvent was
evaporated and the residue was extracted with ether. The
organic layer was washed with sat. NaHCO3 and brine, dried
(MgSO4), and was evaporated to give a residue, which was
purified by silica gel column chromatography to afford
dienes (263 mg). This sample was further purified by
AgNO3-impregnated silica gel column chromatography
(elution with hexane–EtOAc, 0–15%) to give pure 9E
(37.2 mg, 12%) and a mixture of 9E and 9Z (39.9 mg).14
[a]2D5ˆϩ45.7 (cˆ0.9, CHCl3); IR (FT) 1720 cmϪ1
;
1H
NMR (200 MHz, CDCl3) d 0.89 (3H, d, Jˆ6.8 Hz), 1.16
(3H, s), 1.72 (3H, s), 2.15 (2H, m), 2.40 (1H, dd, Jˆ14.6,
8.3 Hz), 2.75 (1H, dd, Jˆ14.6, 6.3 Hz), 3.68 (3H, s), 4.89
(1H, d, Jˆ10.6 Hz), 5.04 (1H, d, Jˆ17.2 Hz), 5.26 (1H, t,
Jˆ6.3 Hz), 6.34 (1H, dd, Jˆ17.2, 10.6 Hz), 6.91 (1H, t,
Jˆ4 Hz); 13C NMR (50 MHz, CDCl3) d 11.9, 15.7, 21.0,
25.6, 25.9, 34.6, 35.0, 40.1, 51.2, 110.3, 130.1, 135.1, 137.4,
140.8, 141.9, 167.9; MS (EI) m/z 248 (Mϩ), 217, 189, 167,
135 (base), 107, 93, 79.
1
9E: [a]2D0ˆϪ12.2 (cˆ1.0, CHCl3); IR (FT) 1720 cmϪ1; H
NMR (200 MHz, CDCl3) d 0.91 (3H, d, Jˆ6.8 Hz), 1.02
(3H, s), 1.76 (3H, br s), 4.93 (1H, d, Jˆ10 Hz), 5.08 (1H, d,
Jˆ18 Hz), 5.40 (1H, t, Jˆ6 Hz), 6.35 (1H, dd, Jˆ18 Hz,
10); 13C NMR (50 MHz, CDCl3) d 12.0, 15.7, 19.1, 24.2,
29.2, 34.8, 38.4, 38.6, 52.7, 110.6, 135.2, 138.5, 141.5,
215.3; MS (EI) m/z 206 (Mϩ), 191, 163, 149, 135, 126,
111, 93, 81 (base), 69, 55; HRMS Obs. 206.1653 (Mϩ).
Calcd for C14H22O 206.1670.
Acknowledgements
We thank Dr M. Mizutani, The Hattori Botanical Labora-
tory, Nichinan, Japan, for identification of the liverwort. The
600 MHz NMR and MS spectra were measured by Dr M.
Tanaka and Ms Y. Okamoto, Tokushima Bunri University,
respectively, to whom many thanks are due.
Reaction of pure 7E
A
solution of pure 7E (24 mg, 0.06 mmol),
nBu3SnCHvCH2 (0.025 mL, 1.3 equiv.), Pd(PPh3)4
(1.3 mg, 2 mol%), and LiBr (7.6 mg, 3 equiv.) in THF
(2 mL) was heated under reflux overnight. Work-up as
above afforded a residue (49.8 mg), which was purified by
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