- Email: [email protected]
Ligularidine, a new pyrrolizidine alkaloid from Ligularia dentata
LIGULARIDINE,
A NEW PYRROLIZIDINE
FROM LIGULARIA Manabu HIKICHI, School of Pharmaceutical
The structure
Summary
significantly
Sciences,
reported
activity
aerial
pyrrollzldlne
parts of Llgularia
pyrrollzldlne
alkaloid,
The present id moiety
pyrrollzldlne
on carcinogenic
pyrrollzldlne
Hara(Japanese
name
and spectral obtained
using C6H6 AcOEt HN(Et)*
alkaloids
by the direct comparisons
of mixed m.ps
colorless
needles,
spectrum,
of which
131 5 show the presence
macrocyclic
let at 4 92(lH) and a broad singlet
cyclic
otonecine
(CD) curves3'7, acid moiety methyl
with a known
diester at 244nm
alkaloid
parts were chro-
system to afford
llgularldlne,
with the authentic
196.0" and [cI], -49 8'(EtOH), signals of carbons
specimen
by carbon
shows molecular
thirteen
by IR spectral
group in the neclne moiety
alkaloid5
resonance(PMR)
difference
at 5 11 and 4 38(5=12
as a twelve membered
by positive
Other assignable
1 45(3H,
methane
(AH=O 72ppm) and the coupling
at C-9, 1 IS classified
group,
group at C-15, respectively
the
a trip-
The signals of the gemlnal
at a pair of doublets
These facts are al';0 supported
s) for acetyl
of Ashows
to Cti3-N at N-4 position,
of the shift
(+0 84).
and the ethyll-
spectrum
A singlet at a(ppm) 2 11(3H),
proton at C-2, respectively
protons
absorption
circular
signals
0
con-
macro-
dlchrolsm
in the neclc
s) and 0 94(3H, d, J=6 OHz) for two
groups at C-12 and C-13 and 1 78(3H, d, J=8 OHz) and 6 79(lH, q, J=8 OHz) for trans-
ethylldene
for-
nuclear mag-
The signals at 193 7, 137 5, 134 1, 138 5 and
carbonyl
(AE +3 91) and 280nm
are at 2 00(3H,
and its necic ac-
and IR spectrum
are represented
the gemlnal
solvent
IS identical
at 6 16(lH) correspond
From the aojreciable
stant (J=l2 OHz) between
which
The proton magnetic
seco-pyrrollzldlne
at C-9 position
of llgularldlne
which are also ascertained
-COOR)
proton(-G-j-OCO-) at C-7 and an olefinic protons
together
signals at G(ppm) 171 9, 169 8 and 167 4 are showing the
of a,B-unsaturated
in the neclc acid moiety4
Hz each other)6
m p
carbons
cm-' 1740, 1730 and 1700(conJ
methylene
, [a],
407 196) and 21 detectable
of three ester carbonyl
twelve membered
plants,
from the roots and
of the roots and aerial
and cllvorine
dene group
in Compositae
evidences from the MeOH exts
on silica gel column
at vi::
alkaloids
determination
of several
presence
having
of the neclc acid
was isolated
Maruba-dakebukl)
the mixture
netic resonance(CMR)
108 Japan
llgularldlne(l),
and the configurations
matographed
Llgularldlne(L),
Tokyo,
cllvorlne(~)3
The crude alkaloids
mula C21H2g07N(M+
alkaloid,
named llgulandlne(~)
paper deals with the structural
by chemical
FURUYA*
Mlnato-ku,
were also determined
alkaloid,
dentata
University,
was elucidated
by Edwards*
In the course of the studies a new macrocyclic
DENTATA'
ASADA and Tsutomu
Kitasato
of a new macrocyclic
high mutagenic
and its enantlomer
Yoshihisa
ALKALOID
134
No. 14
The high resolution (C9H,402N),
mass spectral
152(C9H140N)
studies
and 151(C9H130N)
on 1 show that the fragment
arise fr;
ment ions at m/e*363(C20H2905N),
320(C,8H2604N),
C2H30)
group 1s located
indicate
that the acetoxy
C-12 and C-13 positions
respectively
l+ /CH3 :\OCOCH3 co I
3'C=C,CHTCH\
H'
i0 I
The significant
frag-
221(1Z,~H,~0~N) and 43(100%,
at C-12, two methyl
$H3 CH
the neclne moiety8
249(C14Hlg03N),
in the neclc acid moiety,
ions at m/e 168
groups are attached
(Fig
at
1)
FH3
CH
CH3 \C=C/CHP
3'C=C/CH~CH\C/CH3 H/ t0 a
)
H'
8;
h0 ;t;s'"
)
ZH3
m/e 407(7%)
m/e 320(17%)
m/e.221(21%)
\(L\ m/e 168(20%)
m/e 152(15%)
m/e 151(15%)
Figure 1
From the data mentloned
above,
the plane structure
of !, 1s shown to be 12-acetoxy-trans-15-
ethylidene-4,12,l3-tr~methyl-8-oxoc4.8-seco-senec-l-en~ne The absolute vealed by chemical successive
configurations
of asymmetric
hydrogenolysls
hydrolysis
carbons
and hydrolysis
gave (7R)-dlhydrodesoxyotoneclne,
On the other hand, alkaline
hydrolysis
with HCl to yield
hydrochlorlde(gum)',
+lO 5'(EtOH)
otoneclne
and C10H,404
s), 1 80(3H,
peaks) and the mass fragment
ethylidene-4,5-dimethylpentane-5-ollde with physical
constants
pentane-5-ollde
reported
configuration
of l_wlth
Adam's
b p 135"/lOmmHg(picrate,
catalyst
and
m p 220 0")8
neclne and neclc acid which were treated
and necic acid lactone(3),
m p
131 O", La],
The IR(v,!$~ cm-' 3500, 1750 and 1660), PMR
G(ppm)
d, J=8 OHz), 7 16(lH, q, J=8 OHz) and 2 0- 2 5(3H,
patterns
ofA
and furthermore
lndlcate
that 3 1s 5-carboxy-trans-2-
these physical
data are ln good agreememt
of (4R,5S)- or (4S,5R)-5-carboxy-trans-2-ethy~ldene-4,5-dlmethylby J
D
Edwards2
+O 26 at 262nm) and its dihydroneclc absolute
of lafforded
by mass spectrum
1 18(3H, d, J=6 OHz), 1 65(3H, complicated
in the neclne and the neclc acid were re-
Hydroqenetion
The positive
acid lactone
at C-5 In 2 1s (S)"
(~)(AE
Therefore
CD curves of
3_(AE+2
+3 99 at 225nm) 2 1s suggested
79 at 225nm and
indicate
that an
to be (4R,5S)-5-carboxy-
a-2-ethylidene-4,5-dlmethylpentane-5-ollde A further hydrogenation ligularldine
study was carried
out by the direct preparation
with Raney nickel catalyst by direct comparison
ylelded
of mixed m ps
l_which
of ifrom
1s identical
cllvorlne
(2)
with naturally
, [a],, and other spectral data (Fig
Partial
occurring 2)
tH, 3 cv Figure
From the spectral was elucidated senec-1-enlne (4R,5S)-acid
and the chemcal
data mentioned
above,
the structure
of ligulandine(L)
to be (12S,13R)-12-acetoxy-trans-15-ethy1~dene-4,12,13-tr~methy1-8-oxo-4,8-secoand (+)-acid and (-)-acid
lactone(2)
lactones
and (4S,5R)-acid
The necic acid moiety ethylldene
2
lactone",
in llgularldlne(L)
group at C-15 and unusual
reported
by Edwards2
were also concluded
to be
respectively
shows the charactenstlc
(S)-conflguratlon
structure
having trans-
at C-12 among many macrocycllc
secopyrro-
Now it became Just urgent to test the carcinogenic acexcept cllvot~ne(~)~ 13 12 showed high like as fuklnotoxln , because Land Its significant pyrrollc derlvatlve 14 mutagenic activities and more the tribe Senecloneae plants are widely used as foods and medl15 canal crude drugs in Japan. llzldlne
alkaloids
tivities
The tests of carclnogenlclty
Acknowledgements Medical
Faculty,
The authors
Palackj, University,
work was supported Science
-
and other blologlcal
wish to thank to Professor
for a gift of the authentic
in part by a Grant-In-Ald
and Culture,
Japan
activities
for Cancer
Research
are now in progress.
F
Santavy), Chemcal
sample of cllvonne from the Ministry
Institute and this
of Education,
N?. 14
1236
References *All melting
points are uncorrected
lutlon mass spectrometer
and the molecular
and the analytical
formulae
were measured
values were In good agreement
by high reso-
with the calculated
values. 1.
Part IX in the series "Studies M. Hlklchl
and T
2.
J. D. Edwards,
3.
A. Klssek,
Jr. and T. Matsumoto,
P. Sedmera
K. B. Blrnbaum, ron Letters, 4
M. Tanaka, and H G
5. 6.
7.
C
L. Nelson,
R
C
C. J. Culvenor,
C
0. Cervinka,
K. Atal, C
11.
0
P
Sun,
reported althogh differ
D
H
C. J
Chem
This compound
14
Presented
Resonance
J
M. O'Donovan,
Chem
R. H
Furuya and M
for Organic
S
Shlmizu
Chemist",
, ZJ, 801(1967)
Russell
D
and R. N. Seelye,
Renwich and M
R. S. Sawney and L
Hlklchl,
Yamanaka,
Santavi, and C
W
M
Scopes,
Smith, Aus. J. Chem., 20, 805(1967).
Chem. Comm
., 1968, 261.
K. Atal [Phytochemlstry,
was the same plane structure
data of 0-acetylcrotaverrlne
Hikichi,
'I& 1061(1976)]
as llgulandlne(L),
and its necic acid lactone
the necic acid lactone(2) Chem. Pharm. Bull
1120(1976).
, Ifl,
from j_with Ac20 and pyrldlne
A. Hiram, M. Nagao, T
at 130"
Suglmura,
of the 7th Environment
Mutagen
T
Matsushlma,
Society,
14 (1978) T
S. Hashimoto,
5(1972).
Klyne, W. P. Mose, J
M bS. Bhatia
and T. Furuya at the Meeting
15
Tetrahed-
Pharm. Bull., 24, 3178(1976).
and spectral
was derived
by H
J. Saito, T. Mltsulshl,
Nuclear Magnetic
Candy,
Klisek and F
from those of Land
13
J
0-acetylcrotaverrlne
the physical
T. Furuya and M
and F. zantavi,
3653
R. S. Sawhney,
12.
Johnson
and L. W. Smith, Aust. J
Crout, W
Culvenor,
L. Hub, A
recently
B
G
and T. Furuya,
10.
F
2492
Sot (C), 1971,
9.
L
41(1972)
"Carbon-13
G. M. O'Donovan
Sot., 1965,
M. Hikichi
*
Chem. Comm., 35, 956(1970).
Snatzke,
K. Kanida,
, New York, Chap
C. Cambie,
Chem
G
See for Part VIII
767.
, 32, 1837(1967).
Coll. Czech
Sedmera,
Nagata,
& Sons, Inc
L. H. Bnggs,
P
of Crude Drugs". 1978,
J. Org. Chem
zantavi,
Japan Analyst, 1,
J
Letters,
3421
Culvenor,
J. Chem 8.
1971,
S. Toda, T
L. Levy and G
C. J
and F
A. Klzsek,
Kigasawa,
John Wiley
on Constituents
Furuya, Tetrahedron
J
Syn
(Received II-I Japan 25 Decen.t,er 197e)
Org
Chem
Japan, 35, 653(1977)
I. Hlrono
Japan, Mishima,
October
A NEW PYRROLIZIDINE
FROM LIGULARIA Manabu HIKICHI, School of Pharmaceutical
The structure
Summary
significantly
Sciences,
reported
activity
aerial
pyrrollzldlne
parts of Llgularia
pyrrollzldlne
alkaloid,
The present id moiety
pyrrollzldlne
on carcinogenic
pyrrollzldlne
Hara(Japanese
name
and spectral obtained
using C6H6 AcOEt HN(Et)*
alkaloids
by the direct comparisons
of mixed m.ps
colorless
needles,
spectrum,
of which
131 5 show the presence
macrocyclic
let at 4 92(lH) and a broad singlet
cyclic
otonecine
(CD) curves3'7, acid moiety methyl
with a known
diester at 244nm
alkaloid
parts were chro-
system to afford
llgularldlne,
with the authentic
196.0" and [cI], -49 8'(EtOH), signals of carbons
specimen
by carbon
shows molecular
thirteen
by IR spectral
group in the neclne moiety
alkaloid5
resonance(PMR)
difference
at 5 11 and 4 38(5=12
as a twelve membered
by positive
Other assignable
1 45(3H,
methane
(AH=O 72ppm) and the coupling
at C-9, 1 IS classified
group,
group at C-15, respectively
the
a trip-
The signals of the gemlnal
at a pair of doublets
These facts are al';0 supported
s) for acetyl
of Ashows
to Cti3-N at N-4 position,
of the shift
(+0 84).
and the ethyll-
spectrum
A singlet at a(ppm) 2 11(3H),
proton at C-2, respectively
protons
absorption
circular
signals
0
con-
macro-
dlchrolsm
in the neclc
s) and 0 94(3H, d, J=6 OHz) for two
groups at C-12 and C-13 and 1 78(3H, d, J=8 OHz) and 6 79(lH, q, J=8 OHz) for trans-
ethylldene
for-
nuclear mag-
The signals at 193 7, 137 5, 134 1, 138 5 and
carbonyl
(AE +3 91) and 280nm
are at 2 00(3H,
and its necic ac-
and IR spectrum
are represented
the gemlnal
solvent
IS identical
at 6 16(lH) correspond
From the aojreciable
stant (J=l2 OHz) between
which
The proton magnetic
seco-pyrrollzldlne
at C-9 position
of llgularldlne
which are also ascertained
-COOR)
proton(-G-j-OCO-) at C-7 and an olefinic protons
together
signals at G(ppm) 171 9, 169 8 and 167 4 are showing the
of a,B-unsaturated
in the neclc acid moiety4
Hz each other)6
m p
carbons
cm-' 1740, 1730 and 1700(conJ
methylene
, [a],
407 196) and 21 detectable
of three ester carbonyl
twelve membered
plants,
from the roots and
of the roots and aerial
and cllvorine
dene group
in Compositae
evidences from the MeOH exts
on silica gel column
at vi::
alkaloids
determination
of several
presence
having
of the neclc acid
was isolated
Maruba-dakebukl)
the mixture
netic resonance(CMR)
108 Japan
llgularldlne(l),
and the configurations
matographed
Llgularldlne(L),
Tokyo,
cllvorlne(~)3
The crude alkaloids
mula C21H2g07N(M+
alkaloid,
named llgulandlne(~)
paper deals with the structural
by chemical
FURUYA*
Mlnato-ku,
were also determined
alkaloid,
dentata
University,
was elucidated
by Edwards*
In the course of the studies a new macrocyclic
DENTATA'
ASADA and Tsutomu
Kitasato
of a new macrocyclic
high mutagenic
and its enantlomer
Yoshihisa
ALKALOID
134
No. 14
The high resolution (C9H,402N),
mass spectral
152(C9H140N)
studies
and 151(C9H130N)
on 1 show that the fragment
arise fr;
ment ions at m/e*363(C20H2905N),
320(C,8H2604N),
C2H30)
group 1s located
indicate
that the acetoxy
C-12 and C-13 positions
respectively
l+ /CH3 :\OCOCH3 co I
3'C=C,CHTCH\
H'
i0 I
The significant
frag-
221(1Z,~H,~0~N) and 43(100%,
at C-12, two methyl
$H3 CH
the neclne moiety8
249(C14Hlg03N),
in the neclc acid moiety,
ions at m/e 168
groups are attached
(Fig
at
1)
FH3
CH
CH3 \C=C/CHP
3'C=C/CH~CH\C/CH3 H/ t0 a
)
H'
8;
h0 ;t;s'"
)
ZH3
m/e 407(7%)
m/e 320(17%)
m/e.221(21%)
\(L\ m/e 168(20%)
m/e 152(15%)
m/e 151(15%)
Figure 1
From the data mentloned
above,
the plane structure
of !, 1s shown to be 12-acetoxy-trans-15-
ethylidene-4,12,l3-tr~methyl-8-oxoc4.8-seco-senec-l-en~ne The absolute vealed by chemical successive
configurations
of asymmetric
hydrogenolysls
hydrolysis
carbons
and hydrolysis
gave (7R)-dlhydrodesoxyotoneclne,
On the other hand, alkaline
hydrolysis
with HCl to yield
hydrochlorlde(gum)',
+lO 5'(EtOH)
otoneclne
and C10H,404
s), 1 80(3H,
peaks) and the mass fragment
ethylidene-4,5-dimethylpentane-5-ollde with physical
constants
pentane-5-ollde
reported
configuration
of l_wlth
Adam's
b p 135"/lOmmHg(picrate,
catalyst
and
m p 220 0")8
neclne and neclc acid which were treated
and necic acid lactone(3),
m p
131 O", La],
The IR(v,!$~ cm-' 3500, 1750 and 1660), PMR
G(ppm)
d, J=8 OHz), 7 16(lH, q, J=8 OHz) and 2 0- 2 5(3H,
patterns
ofA
and furthermore
lndlcate
that 3 1s 5-carboxy-trans-2-
these physical
data are ln good agreememt
of (4R,5S)- or (4S,5R)-5-carboxy-trans-2-ethy~ldene-4,5-dlmethylby J
D
Edwards2
+O 26 at 262nm) and its dihydroneclc absolute
of lafforded
by mass spectrum
1 18(3H, d, J=6 OHz), 1 65(3H, complicated
in the neclne and the neclc acid were re-
Hydroqenetion
The positive
acid lactone
at C-5 In 2 1s (S)"
(~)(AE
Therefore
CD curves of
3_(AE+2
+3 99 at 225nm) 2 1s suggested
79 at 225nm and
indicate
that an
to be (4R,5S)-5-carboxy-
a-2-ethylidene-4,5-dlmethylpentane-5-ollde A further hydrogenation ligularldine
study was carried
out by the direct preparation
with Raney nickel catalyst by direct comparison
ylelded
of mixed m ps
l_which
of ifrom
1s identical
cllvorlne
(2)
with naturally
, [a],, and other spectral data (Fig
Partial
occurring 2)
tH, 3 cv Figure
From the spectral was elucidated senec-1-enlne (4R,5S)-acid
and the chemcal
data mentioned
above,
the structure
of ligulandine(L)
to be (12S,13R)-12-acetoxy-trans-15-ethy1~dene-4,12,13-tr~methy1-8-oxo-4,8-secoand (+)-acid and (-)-acid
lactone(2)
lactones
and (4S,5R)-acid
The necic acid moiety ethylldene
2
lactone",
in llgularldlne(L)
group at C-15 and unusual
reported
by Edwards2
were also concluded
to be
respectively
shows the charactenstlc
(S)-conflguratlon
structure
having trans-
at C-12 among many macrocycllc
secopyrro-
Now it became Just urgent to test the carcinogenic acexcept cllvot~ne(~)~ 13 12 showed high like as fuklnotoxln , because Land Its significant pyrrollc derlvatlve 14 mutagenic activities and more the tribe Senecloneae plants are widely used as foods and medl15 canal crude drugs in Japan. llzldlne
alkaloids
tivities
The tests of carclnogenlclty
Acknowledgements Medical
Faculty,
The authors
Palackj, University,
work was supported Science
-
and other blologlcal
wish to thank to Professor
for a gift of the authentic
in part by a Grant-In-Ald
and Culture,
Japan
activities
for Cancer
Research
are now in progress.
F
Santavy), Chemcal
sample of cllvonne from the Ministry
Institute and this
of Education,
N?. 14
1236
References *All melting
points are uncorrected
lutlon mass spectrometer
and the molecular
and the analytical
formulae
were measured
values were In good agreement
by high reso-
with the calculated
values. 1.
Part IX in the series "Studies M. Hlklchl
and T
2.
J. D. Edwards,
3.
A. Klssek,
Jr. and T. Matsumoto,
P. Sedmera
K. B. Blrnbaum, ron Letters, 4
M. Tanaka, and H G
5. 6.
7.
C
L. Nelson,
R
C
C. J. Culvenor,
C
0. Cervinka,
K. Atal, C
11.
0
P
Sun,
reported althogh differ
D
H
C. J
Chem
This compound
14
Presented
Resonance
J
M. O'Donovan,
Chem
R. H
Furuya and M
for Organic
S
Shlmizu
Chemist",
, ZJ, 801(1967)
Russell
D
and R. N. Seelye,
Renwich and M
R. S. Sawney and L
Hlklchl,
Yamanaka,
Santavi, and C
W
M
Scopes,
Smith, Aus. J. Chem., 20, 805(1967).
Chem. Comm
., 1968, 261.
K. Atal [Phytochemlstry,
was the same plane structure
data of 0-acetylcrotaverrlne
Hikichi,
'I& 1061(1976)]
as llgulandlne(L),
and its necic acid lactone
the necic acid lactone(2) Chem. Pharm. Bull
1120(1976).
, Ifl,
from j_with Ac20 and pyrldlne
A. Hiram, M. Nagao, T
at 130"
Suglmura,
of the 7th Environment
Mutagen
T
Matsushlma,
Society,
14 (1978) T
S. Hashimoto,
5(1972).
Klyne, W. P. Mose, J
M bS. Bhatia
and T. Furuya at the Meeting
15
Tetrahed-
Pharm. Bull., 24, 3178(1976).
and spectral
was derived
by H
J. Saito, T. Mltsulshl,
Nuclear Magnetic
Candy,
Klisek and F
from those of Land
13
J
0-acetylcrotaverrlne
the physical
T. Furuya and M
and F. zantavi,
3653
R. S. Sawhney,
12.
Johnson
and L. W. Smith, Aust. J
Crout, W
Culvenor,
L. Hub, A
recently
B
G
and T. Furuya,
10.
F
2492
Sot (C), 1971,
9.
L
41(1972)
"Carbon-13
G. M. O'Donovan
Sot., 1965,
M. Hikichi
*
Chem. Comm., 35, 956(1970).
Snatzke,
K. Kanida,
, New York, Chap
C. Cambie,
Chem
G
See for Part VIII
767.
, 32, 1837(1967).
Coll. Czech
Sedmera,
Nagata,
& Sons, Inc
L. H. Bnggs,
P
of Crude Drugs". 1978,
J. Org. Chem
zantavi,
Japan Analyst, 1,
J
Letters,
3421
Culvenor,
J. Chem 8.
1971,
S. Toda, T
L. Levy and G
C. J
and F
A. Klzsek,
Kigasawa,
John Wiley
on Constituents
Furuya, Tetrahedron
J
Syn
(Received II-I Japan 25 Decen.t,er 197e)
Org
Chem
Japan, 35, 653(1977)
I. Hlrono
Japan, Mishima,
October