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Generality of marine prostanoid biosynthesis by the 2-oxidopentadienylcation pathway
Tetrahedron Printed in
Letters,Vo1.28,No.37,pp Great Britain
GENERALITY
4247-4250,1987
0040-4039/87 $3.00 Pergamon Journals
OF MARINE PROSTANOID BIOSYNTHESIS OXIDOPENTADIENYL CATION PATHWAY
+ -00 Ltd.
BY THE 2-
E. J. Corey and Seiichi P. T. Matsuda Department
of Chemistry, Harvard University,
Cambridge, Massachusetts,
02138
Summaw: The prostanoid, preclavulone-A (5). which is produced by the Okinawan coral Clavularia viridis is also biosvnthesized by the unrelated Caribbean coral, Pseudoulexaura Dorosa. indicating that the biosvnthesis of 5 may be widespread in coral. The biogenesis of preclavulone:A from arachidonic acid &curs by lipoiygenation at C(8), migration of oxygen from C(8) to C(9) and ring closure, in a process (marine pathway) which contrasts sharply with the mammalian (endoperoxide) route. Preclavulone-A may be a key intermediate from which other more highly oxygenated, bioactive marine prostanoids are formed.
It is striking that in the enormous covering chemistry,
biosynthesis
literature on prostaglandins
(PG’s), with many thousands
and biology, there is only one clearly documented
case of a non-mammalian
source of PG’s, the Caribbean coral Plexaura horrwmalla . This abundant and distinctive highly-branched, weight)
bush-like)
or the 15-epimer
homomalla as a potential farming.
soft coral is extraordinarily (depending
on subspecies).
commercial-scale
of papers
(coffee-brown
in color,
rich in PGA, methyl ester acetate (1) (up to 2% of dry 1.2 Several years ago there was great interest in P.
source of PG’s either by pruning in natural habitat or by marine
(The coral grows well when planted on submerged
concrete
blocks at depths of lo-20 feet in the
Caribbean.) Our interests in Plexaura homomalla have been biosynthetic,
arising from evidence that the biosynthesis of
1 appeared to follow a totally different pathway from that established for the formation of PG’s in mammals (endoperoxide pathway).3 The delineation of the biosynthesis of PGA2 in P. homomalla has been complicated by several practical difficulties self digestion.
of research with this coral stemming mainly from the enormous
In the meantime,
another prostanoid, has been found eicosatetraenoic
speed of proteolytic
the mode of biosynthesis
of
clavulone I (2)4 produced by the Pacific coral Clavularia viridis (collected near Okinawa). that C. viridis converts
acid (4) (8(R)-HPETE)
a series of three hydroxylations oxygen.
however, progress has been made in determining arachidonic
acid (3) to 8(R)-hydroperoxy-5,11,14(Z),
and thence to preclavulone-A
(at C(4), C(7) and C(12)) followed
By analogy with the biosynthesis
(5), ~6 from which clavulone I can arise by by esterification
of the plant regulator cis-jasmonic
conversion
of 4 to 5 occurs by way of allene oxide (6) and oxidopentadienyl
mechanistic
feasibility
of the formation
and 7 recently has been demonstrated
of the preclavulone-A
and elimination
of C(7)
acid, 7.8 it appears probable that the cation (7) intermediates.
structure and stereochemistry
by a biomimetic chemical synthesis.9
4247
It
9(E)-
The
via intermediates
6
4248
Preclavulone-A totally synthetic
was identified by combined radiotracer-HPLC-chemical
reference
compounds.
The amounts of preclavulone-A
characterization
involved
techniques using
in this work were so small
(< IO-tsg) as to preclude the use of physical methods such as ‘H NMR and mass spectroscopy; absolute configuration
was not determined.
We suspected that the 8.lipoxygenation-oxidopentadienyl biosynthesis porosa
of marine prostanoids.
since it had previously
8(RJ-HPETEtu,*t
porosa
As a test of this idea we examined the Caribbean soft coral
was collected
(4 g.) was dissolved
in an oxygen atmosphere and chromatography12 no arachidonic analysis.
Pse1ufopk.n211n2
been reported that an acetone powder from this coral converts arachidonic acid to in February,
seconds after removal from the sea and thereafter. porosa
prostanoids.
A specimen of
1987, off Key Large, Florida, and frozen in dry ice a few An acetone powder (400 mg.) prepared’0
from frozen P.
in 200 ml. of pH 9.2 0.2 M borate buffer and stirred with 50 mg. of arachidonic acid
at 4’C for 3 h. After extractive isolation of acidic lipid, esterifrcation 3 mg. of pure preclavulone-A
methyl ester was obtained.
with diazomethane
Control experiments
in which
acid was added to the acetone powder preparation showed no detectible preclavulone-A
In addition
preclavulone-A.
HPLC analysis
As expected
of extracts
of P. porosa
itself
showed
from these results, incubation of 8(R)-HPETE
preparation from P. porosa led to its bioconversion Preclavulone-A
the
cation cyclization route might be general for the
(3), a clue that this coral might also be capable of synthesizing
Pseudoplexaura
consequently,
could be detected in extracts of C. viridis.
Also no preclavulone-A
no measurable
by HPLC amount
with the above described
of
enzyme
into preclavulone-A.
methyl ester was rigorously
identified
by the 500 MHz ‘H KMR spectrun~,13 infrared
absorption (carbonyl peaks at 1740 and 1711 cm:‘), ultraviolet absorption at 219 nm in ethanol, and mass spectrum: (electron impact) peaks at 332 (MC), 301 (M+ - OCH,), 222 (M+ - CHCH=CHC5Ht 1), 192 (M+ CHCH=CH(CH&COOCH$, preclavulone-A conversion
methyl ester with diazabicyclo[5.4.0]
with an authentic sample.s,n
undec-7-ene
in tetrahydrofuran
to the more stable isomer having trans ring appendages
preclavulone-A compared
and by HPLC comparison
methyl ester was characterized
Further, treatment of
at 23°C for 24 h. resulted in
(methyl ester of 8). The rran.s isomer of
by 500 MHz lH NMR, infrared, ultraviolet,
with those for a totally synthetic reference
and mass spectra as
sample,5 and also by identity of HPLC behavior with the
authentic sample. The finding
that two dissimilar
species
of coral from widely
separated
prostanoid signals the advisability of a broader program of research on marine-derived A (5) is quite possibly a precursor not only of clavulones, a “primary” marine prostanoid.
The identification
may well serve a crucial biochemical
cation + triggers
+ corresponding
PGAz + 1 ; or arachidonic oocyte
hpoxygenation
maturation pathway.
and role of these prostanoids
function in marine biology.
in P. homomallu occurs via the oxidopentadienyl acid -+ 8,15-his-HPETE
but of other prostanoids
produce
eicosanoids.
the same
Preclavulone-
as well, and thus may serve as is of unusual interest since they
A previous sumlise6 that the biosynthesis
of 1
cation route now seems even more plausible, e.g., arachidonic
8,9-allene oxide --f corresponding
acid +
in starfish’”
regions
preclavulone-A
provides
+ 1. The recent discovery
still another
Finally, from an evolutionary
9-oxido-8,Y,l0,11,12-pentadienyl
standpoint
reason
for interest
it is fascinating
mammals have evolved totally different biosynthetic paths to prostanoids.ts
that 8(R)-HETE
in the arachidonate
g-
that marine organisms
and
AcO
I
CiAc 1
2
3
8
i
t
4
5
OOH
6
7
4250
REFERENCE AND NOTES 1.
A. J. Weinheimer
and A. J. Spraggins, Tetruhedron
2.
W. P. Schneider, (1972).
3.
E. J. Corey, H. E. Ensley, Commun., 277 (1975).
4.
H. Kikuchi, Y. Tsukitani, K. Iguchi, and Y. Yamada, (1982); idem. ibid., 24, 1549 (1983).
5.
E. J. Corey, P. T. Lansbury, Jr. and Y. Yamada, Tetrahedron Letters, 26,417 1 ( 1985).
6.
E. J. Corey, M. d’Alarcao, S. P. T. Matsuda, P. T. Lansbury, Jr., and Y. Yamnda. .I. Chem. Sot., 109, 289 (1987).
7.
B. A. Vick and D. C. Zimmerman,
8.
B. A. Vick, P. Feng and D. C. Zimmerman,
9.
E. J. Corey, K. Ritter, M. Yus and C. Najera, Terrahedron Letrers, in press.
R. D. Hamilton
Letters, 5185 (1969).
and L. E. Rhuland,
M. Hamberg,
J. Am. Chem. Sot., 94, 2122
and B. Samuelsson,
.1. Chem. Sot.
Tetrahedron
Biochem. Biophys. Res. Commr~.,
Letters,
Chern.
23, 5171
At71.
111. -ITO i1983).
Lipids, 15,468 (1980).
10.
G. L. Bundy, E. G. Nidy, D. E. Epps, S. A. Mizsak, and R. J. Wnuk, J. Biol. Chem., 261, 747 (1986).
11.
D. R. Doerge and M. D. Corbett, Experientia, 38,901 (1982)
12.
After an initial flash chromatographic purification (2:l hexane-ether on silica gel), HPLC separation was carried out on a 4.6 mm, x 25 cm. DuPont Zorbox silica column using 12:1 hexane-t-butyl methyl ether.
13.
lH NMR data (500 MHz in CDC13) for preclavulone-A methyl ester are as follows (6): 1.7 (m, 2H, carbon0.89 (t. J = 7, 3H, carbon-20), 1.2-1.4 (m. 6H, carbons-17,18,19), 3), 1.9-2.0 (m, 2H), 2.1-2.2 (m, 4H), 2.1-2.2 (m, 3H), 2.32 (t, J = 6, 2H, carbon-2) 2.5 (m, 2H, carbon 8, X), 3.05 (m, lH, carbon-12), 3.67 (s, 3H, OCH$, 5.35-5.55 (m, 4H. 7.68 (dd, J = 5.9, 2.9, lH, carbons-5,6,14,15), 6.19 (dd, J = 5.9, 1.6, lH, carbon-lo), carbon- 11).
14.
L. Meijer, A. R. Brash, R. W. Bryant, Chem., 261, 17040 (1986).
K. Ng, J. Maclouf
and H. Sprecher,
J. Riol.
1.5. This research was assisted financially by a grant from the National Science Foundation. We thank Dr. David Anderson for his help in the collection and identification of pse&o@cli4ru porosa (Received
in
USA 16 June
1987)
Letters,Vo1.28,No.37,pp Great Britain
GENERALITY
4247-4250,1987
0040-4039/87 $3.00 Pergamon Journals
OF MARINE PROSTANOID BIOSYNTHESIS OXIDOPENTADIENYL CATION PATHWAY
+ -00 Ltd.
BY THE 2-
E. J. Corey and Seiichi P. T. Matsuda Department
of Chemistry, Harvard University,
Cambridge, Massachusetts,
02138
Summaw: The prostanoid, preclavulone-A (5). which is produced by the Okinawan coral Clavularia viridis is also biosvnthesized by the unrelated Caribbean coral, Pseudoulexaura Dorosa. indicating that the biosvnthesis of 5 may be widespread in coral. The biogenesis of preclavulone:A from arachidonic acid &curs by lipoiygenation at C(8), migration of oxygen from C(8) to C(9) and ring closure, in a process (marine pathway) which contrasts sharply with the mammalian (endoperoxide) route. Preclavulone-A may be a key intermediate from which other more highly oxygenated, bioactive marine prostanoids are formed.
It is striking that in the enormous covering chemistry,
biosynthesis
literature on prostaglandins
(PG’s), with many thousands
and biology, there is only one clearly documented
case of a non-mammalian
source of PG’s, the Caribbean coral Plexaura horrwmalla . This abundant and distinctive highly-branched, weight)
bush-like)
or the 15-epimer
homomalla as a potential farming.
soft coral is extraordinarily (depending
on subspecies).
commercial-scale
of papers
(coffee-brown
in color,
rich in PGA, methyl ester acetate (1) (up to 2% of dry 1.2 Several years ago there was great interest in P.
source of PG’s either by pruning in natural habitat or by marine
(The coral grows well when planted on submerged
concrete
blocks at depths of lo-20 feet in the
Caribbean.) Our interests in Plexaura homomalla have been biosynthetic,
arising from evidence that the biosynthesis of
1 appeared to follow a totally different pathway from that established for the formation of PG’s in mammals (endoperoxide pathway).3 The delineation of the biosynthesis of PGA2 in P. homomalla has been complicated by several practical difficulties self digestion.
of research with this coral stemming mainly from the enormous
In the meantime,
another prostanoid, has been found eicosatetraenoic
speed of proteolytic
the mode of biosynthesis
of
clavulone I (2)4 produced by the Pacific coral Clavularia viridis (collected near Okinawa). that C. viridis converts
acid (4) (8(R)-HPETE)
a series of three hydroxylations oxygen.
however, progress has been made in determining arachidonic
acid (3) to 8(R)-hydroperoxy-5,11,14(Z),
and thence to preclavulone-A
(at C(4), C(7) and C(12)) followed
By analogy with the biosynthesis
(5), ~6 from which clavulone I can arise by by esterification
of the plant regulator cis-jasmonic
conversion
of 4 to 5 occurs by way of allene oxide (6) and oxidopentadienyl
mechanistic
feasibility
of the formation
and 7 recently has been demonstrated
of the preclavulone-A
and elimination
of C(7)
acid, 7.8 it appears probable that the cation (7) intermediates.
structure and stereochemistry
by a biomimetic chemical synthesis.9
4247
It
9(E)-
The
via intermediates
6
4248
Preclavulone-A totally synthetic
was identified by combined radiotracer-HPLC-chemical
reference
compounds.
The amounts of preclavulone-A
characterization
involved
techniques using
in this work were so small
(< IO-tsg) as to preclude the use of physical methods such as ‘H NMR and mass spectroscopy; absolute configuration
was not determined.
We suspected that the 8.lipoxygenation-oxidopentadienyl biosynthesis porosa
of marine prostanoids.
since it had previously
8(RJ-HPETEtu,*t
porosa
As a test of this idea we examined the Caribbean soft coral
was collected
(4 g.) was dissolved
in an oxygen atmosphere and chromatography12 no arachidonic analysis.
Pse1ufopk.n211n2
been reported that an acetone powder from this coral converts arachidonic acid to in February,
seconds after removal from the sea and thereafter. porosa
prostanoids.
A specimen of
1987, off Key Large, Florida, and frozen in dry ice a few An acetone powder (400 mg.) prepared’0
from frozen P.
in 200 ml. of pH 9.2 0.2 M borate buffer and stirred with 50 mg. of arachidonic acid
at 4’C for 3 h. After extractive isolation of acidic lipid, esterifrcation 3 mg. of pure preclavulone-A
methyl ester was obtained.
with diazomethane
Control experiments
in which
acid was added to the acetone powder preparation showed no detectible preclavulone-A
In addition
preclavulone-A.
HPLC analysis
As expected
of extracts
of P. porosa
itself
showed
from these results, incubation of 8(R)-HPETE
preparation from P. porosa led to its bioconversion Preclavulone-A
the
cation cyclization route might be general for the
(3), a clue that this coral might also be capable of synthesizing
Pseudoplexaura
consequently,
could be detected in extracts of C. viridis.
Also no preclavulone-A
no measurable
by HPLC amount
with the above described
of
enzyme
into preclavulone-A.
methyl ester was rigorously
identified
by the 500 MHz ‘H KMR spectrun~,13 infrared
absorption (carbonyl peaks at 1740 and 1711 cm:‘), ultraviolet absorption at 219 nm in ethanol, and mass spectrum: (electron impact) peaks at 332 (MC), 301 (M+ - OCH,), 222 (M+ - CHCH=CHC5Ht 1), 192 (M+ CHCH=CH(CH&COOCH$, preclavulone-A conversion
methyl ester with diazabicyclo[5.4.0]
with an authentic sample.s,n
undec-7-ene
in tetrahydrofuran
to the more stable isomer having trans ring appendages
preclavulone-A compared
and by HPLC comparison
methyl ester was characterized
Further, treatment of
at 23°C for 24 h. resulted in
(methyl ester of 8). The rran.s isomer of
by 500 MHz lH NMR, infrared, ultraviolet,
with those for a totally synthetic reference
and mass spectra as
sample,5 and also by identity of HPLC behavior with the
authentic sample. The finding
that two dissimilar
species
of coral from widely
separated
prostanoid signals the advisability of a broader program of research on marine-derived A (5) is quite possibly a precursor not only of clavulones, a “primary” marine prostanoid.
The identification
may well serve a crucial biochemical
cation + triggers
+ corresponding
PGAz + 1 ; or arachidonic oocyte
hpoxygenation
maturation pathway.
and role of these prostanoids
function in marine biology.
in P. homomallu occurs via the oxidopentadienyl acid -+ 8,15-his-HPETE
but of other prostanoids
produce
eicosanoids.
the same
Preclavulone-
as well, and thus may serve as is of unusual interest since they
A previous sumlise6 that the biosynthesis
of 1
cation route now seems even more plausible, e.g., arachidonic
8,9-allene oxide --f corresponding
acid +
in starfish’”
regions
preclavulone-A
provides
+ 1. The recent discovery
still another
Finally, from an evolutionary
9-oxido-8,Y,l0,11,12-pentadienyl
standpoint
reason
for interest
it is fascinating
mammals have evolved totally different biosynthetic paths to prostanoids.ts
that 8(R)-HETE
in the arachidonate
g-
that marine organisms
and
AcO
I
CiAc 1
2
3
8
i
t
4
5
OOH
6
7
4250
REFERENCE AND NOTES 1.
A. J. Weinheimer
and A. J. Spraggins, Tetruhedron
2.
W. P. Schneider, (1972).
3.
E. J. Corey, H. E. Ensley, Commun., 277 (1975).
4.
H. Kikuchi, Y. Tsukitani, K. Iguchi, and Y. Yamada, (1982); idem. ibid., 24, 1549 (1983).
5.
E. J. Corey, P. T. Lansbury, Jr. and Y. Yamada, Tetrahedron Letters, 26,417 1 ( 1985).
6.
E. J. Corey, M. d’Alarcao, S. P. T. Matsuda, P. T. Lansbury, Jr., and Y. Yamnda. .I. Chem. Sot., 109, 289 (1987).
7.
B. A. Vick and D. C. Zimmerman,
8.
B. A. Vick, P. Feng and D. C. Zimmerman,
9.
E. J. Corey, K. Ritter, M. Yus and C. Najera, Terrahedron Letrers, in press.
R. D. Hamilton
Letters, 5185 (1969).
and L. E. Rhuland,
M. Hamberg,
J. Am. Chem. Sot., 94, 2122
and B. Samuelsson,
.1. Chem. Sot.
Tetrahedron
Biochem. Biophys. Res. Commr~.,
Letters,
Chern.
23, 5171
At71.
111. -ITO i1983).
Lipids, 15,468 (1980).
10.
G. L. Bundy, E. G. Nidy, D. E. Epps, S. A. Mizsak, and R. J. Wnuk, J. Biol. Chem., 261, 747 (1986).
11.
D. R. Doerge and M. D. Corbett, Experientia, 38,901 (1982)
12.
After an initial flash chromatographic purification (2:l hexane-ether on silica gel), HPLC separation was carried out on a 4.6 mm, x 25 cm. DuPont Zorbox silica column using 12:1 hexane-t-butyl methyl ether.
13.
lH NMR data (500 MHz in CDC13) for preclavulone-A methyl ester are as follows (6): 1.7 (m, 2H, carbon0.89 (t. J = 7, 3H, carbon-20), 1.2-1.4 (m. 6H, carbons-17,18,19), 3), 1.9-2.0 (m, 2H), 2.1-2.2 (m, 4H), 2.1-2.2 (m, 3H), 2.32 (t, J = 6, 2H, carbon-2) 2.5 (m, 2H, carbon 8, X), 3.05 (m, lH, carbon-12), 3.67 (s, 3H, OCH$, 5.35-5.55 (m, 4H. 7.68 (dd, J = 5.9, 2.9, lH, carbons-5,6,14,15), 6.19 (dd, J = 5.9, 1.6, lH, carbon-lo), carbon- 11).
14.
L. Meijer, A. R. Brash, R. W. Bryant, Chem., 261, 17040 (1986).
K. Ng, J. Maclouf
and H. Sprecher,
J. Riol.
1.5. This research was assisted financially by a grant from the National Science Foundation. We thank Dr. David Anderson for his help in the collection and identification of pse&o@cli4ru porosa (Received
in
USA 16 June
1987)