- Email: [email protected]
A total synthesis of (±)cerulenin
Tetrahedron Letters
Pergaizon Press.
No. 44, pp 3847 - 3850, 1977.
Printed
in Great Britain.
A TOTAL SYNTHESIS OF (+)-CERULENIN E. J. Corey and David R. Williams Department of Chemistry, (Received
Harvard University,
in USA 17 August 1977; received
Cambridge, Massachusetts
in UK for publication
02138, USA
16 September 19.77)
The antifungal antibiotic, cerulenin 3 was isolated from the culture filtrate of Cephalosporium 1 and shown to inhibit lipid biosynthesis of Escherichia coli by irreversibly binding P-ketoacyl-acyl caerulens, carrier protein synthetase, the enzyme which catalyzes the acylation of a malonyl thioester for the chain 2 3a The structure originally proposed for cerulenin on the basis lengthening reaction of fatty acid synthesis. 3b on the basis of a detailed nmr study. Very of chemical and spectroscopic data was revised to 1 in 1974 4 This communication recently two different synthetic routes to the racemic antibiotic have been reported. describes
concurrent work in these laboratories
which has led to a simple and convergent synthesis of
(+)-cerulenin. Treatment of 3-butyn -l-o1 with dihydropyran (1.2 equiv, CH2C12, O”, 2 hr) and a catalytic amount of toluenesulfonic acid gave the tetrahydropyranyl ether 2_ (bp 86-90” at 20mm) in 96% yield.
Hydrostannation of
the terminal acetylene proceeded smoothly with tri-n_butyltin hydride at 90” for 10 hr in the presence of a catalytic amount of the radical initiator,
azoisobutyronitrile,
to 0.6 &I with tetrahydrofuran and cooled to -78”.
affording the vinylstannane 3 which was diluted
Dropwise addition via syringe of 2.45 -M n-butyllithium in
hexane (1.1 equiv) generated a pale yellow solution of the corresponding vinyllithium reagent which was stirred 5 The mixture was at -78” for 2 hr and finally treated with 1.03 equiv of freshly distilled 1-bromo-2-butene. slowly warmed to 25” over 8 hr and worked up in the usual way.
Chromatography on silica gel with 10% ether
in hexane led to the isolation of pure tetrahydropyranyl ether 4 in 72% yield; however, this was routinely unnecessary
as direct treatment of the crude product mixture with aqueous acetic acid in tetrahydrofuran
(3:3:2 by volume) at 60” for 5 hr afforded the alcohol ; as a clear,
colorless
liquid after careful distillation
(bp 92-94” at 21mm) in 640/O overall yield from the acetylenic ether 2. Quantitative transformation to the w mesylate 5 (M&l, CH2C12, Et3N, 0” for 1 hr)6 and displacement with sodium iodide in dry acetone at 50” for 3 hr provided the sensitive iodide ‘7_in 80% yield.
Although iodide L did not survive chromatography or dis-
tillation, dissolution in pentane gave a faintly reddish solution which was easily decanted from dark insoluble impurities.
The addition of 1.8 M -- t-butyllithium (1.1 equiv) in pentane to a 0.04 M solution of iodide L in dry pentane at -78” effected halide-metal exchange. After stirring at -78” for 40 min, the colorless reaction mixture was transferred by cannula under positive argon pressure into a solution of epoxy anhydride 1,0~
3847
3848
(1.1
NQ. 44
equiv)
poured
in dry tetrahydrofuran
into ice water,
and esterified
acidified
upon addition
of ethereal
in hexane)
pale yellow
oils.
This combined
be raised
by further
addition
of two equivalents
arising
from
i-butyllithium species
with anhydride
treated
with a solution
in the isolation
Treatment
reagent
chloride
acetone
in chloroform.
Although the mass
in every
the infrared
protons
attached
CHC13) revealed stable,
more
with silica spectra
to the oxirane
polar
as obtained
pyrrolin-2-ones the structure
favoring storage primary
moiety
(90%) yield
from
following
synthetic
material
material
to produce
several
of cerulenin
reports
greater
between
described
1, a substance which should be very useful nl 11 available l4 C-maleic anhydride.
9
internal
10
compounds. a smooth
con-
with 30%
at 3300 cm
a complex on silica
of crystalline, producing
-1
as well
set of signals
for the
gel (30% THF in of amide A to the
authentic
identical
temperature
and nmr spectra
cerulenin
infrared
and nmr
herein in further
is uniquely biochemical
of 5-hydroxy-3studies
In the case of cerulenin, in the hydroxylactam
forms
resulted
identical
the isolation
as well as synthetic
ring strain
the open and cyclic
days at room
infrared
and
to that of authentic
isomerization
concerning
of 2-alkylpyrroles,
acid and its derivatives.
the equilibrium
in ether;
4b).
in light of recent
the photo-oxygenation
amide A which exhibited The synthesis
@.
Treatment
of
at -100”
on Florisil
absorption
exhibited
three components
possibly
the organolithium
and pyridine
carbonyl
was identical
the partial
the
at -100” under argon resulting
chromatography
from
1:2:2).
of the same
is not surprising
would be expected
the open form),
resulting
products
can
from
fraction,
in tetrahydrofuran
hydroxyl
spectrum
Thin layer
12 (ratio
gave a mixture
broad
gel
12 as
12 resulting
to cerulenin, chloride
chromatography
of this material
resonance
with ether, on silica
at 25” for 3 hr provided
column
displayed
ring at C-2 and C-3.
of 5-aminodehydrolevulinic
of synthetic
spectrum
components
hydroxide
following
spectrum
CYand P-hydroxylactams
gel immediately
approach
with thionyl
amount of dialkylated
ammonium
and the proton
three equilibrating
This observation
epoxide
in excellent
region,
In an alternative
along with a considerable
was
on to (+)-cerulenin)
No condensation
1,1 (1.2 equiv) in tetrahydrofuran
of 1,2 and 12 with methanolic
carbonyl
chromatography
of a hydrocarbon
iodide 2.
anion of di-t_butylbipheny18
of the dimethylester
into C+)-cerulenin
as a broadened
extracted
80/oof lactone
amounts
of the starting
mixture
12 and 200/Oof the pseudo-la&one
was also obtained
2 (alcohol 2 was treated
with the radical
respect,
acid,
thin layer
ketoester
2 and considerable
reactions
version
cerulenin
the reaction
of 10% hydrochloric
Preparative
There
1,Owere observed.
of 1,2 in 30% yield
temperature
(42%) of lt and 12 (both of which can be carried
experimentation.
from
92%) by reaction
diazomethane.
yield
to room
addition
22% of the expected
and coupling
2 was generated
bp 80-84”;
afforded
of lithium
elimination
Upon warming
to pH 2 by careful
(30% ethyl acetate
doubtless
at -78”.
is in delicate
although the structures
balance.
in slow conversion
concerning
to the crystalline
to that of natural
suited
for the ready
studies,
starting
(thus
In fact
(+)-cerulenin. 14 synthesis of C-labeled
from
commercially
3849
2 u
BU3sNT~~
WX 3
&
CH300~OOCH3
2,
X=OTHP
2,
x=1
2,
X=OH
2,
X=Cl
6,
X=OS02CH3
2,
X=Li
+ OOCH,
l,o
3
?2
R RY3-0 12,
R = C8H13
3850
No. 44
References 1.
Y. Sano, S. Nomura, Y. Kamio, S. Omura, and T. Hata, 2. Antibiotics,
Ser. A.,
22, 344 (1967).
2.
G. D’Agnolo, I. S. Rosenfeld,
Biochim.
Biophys. Acta.,
32, 3.
J. Awaya, S. Omura, and P. R. Vagelos,
155 (1973).
(a) S. Omura, M. Katagiri, A. Nakagawa, Y. Sano, S. Nomura, and T. Hata, -J. Antibiotics, 22, 349 (1967); (b) B. H. Arison and S. Omura, 2. Antibiotics,
4.
5.
92, 2805 (1977); (b) A. A. Jakubowski,
(a) R. K. Boeckman and E. W. Thomas, 2. -Am. Chem. s., F. S. Guziec, Jr.,
and M. Tishler,
Tetrahedron @&,
S. Winstein and W. G. Young, 2. -Am. Chem. e., mixture containing 200/Oof 3-bromo-1-butene;
Ser. A.,
27, 28 (1974).
2399 (1977).
52, 104 (1936).
l-Bromo-2-butene
consists of a
however, displacement of bromide occur preferentially
at the primary terminus. 6.
R. K. Crossland and K. L. Servis, 2. s.
7.
(a) G. B. Payne and P. H. Williams, Chem d-d)
and Indust
545 (1971).
Chem 3 35, 3195 (1970). -*
2. m.
Chem * 22, 54 (1959); (b) G. AIlan and A. N. Neogi, -*
Anhydride 1,Oexhibited ir peaks (CHC13) at 1810, 1110, 1035, 905 cm
and an nmr peak (CDC13) at t 4.33 (s, 2). 8.
(a) S. E. Wilson, Tetrahedron& Tetrahedron s,
9.
, 4651 (1975); (b) P. K. Freeman and L. L. Hutchinson,
1849 (1976).
(a) D. A. Lightner and L. K. Low, 2. Heterocyclic D. A. Lightner,
-.
9 167 (1972); (b) G. B. Quistad and , _,
Tetrahedron &&. , 4417 (1971).
10.
J. Awruch and B. Frydman, Tetrahedron &e&
, 4121 (1976).
11.
This study was assisted financially by the National Institutes of Health. Konrad BIoch for an authentic sample of cerulenin.
We are gratefuI tc Professor
-1
,
Pergaizon Press.
No. 44, pp 3847 - 3850, 1977.
Printed
in Great Britain.
A TOTAL SYNTHESIS OF (+)-CERULENIN E. J. Corey and David R. Williams Department of Chemistry, (Received
Harvard University,
in USA 17 August 1977; received
Cambridge, Massachusetts
in UK for publication
02138, USA
16 September 19.77)
The antifungal antibiotic, cerulenin 3 was isolated from the culture filtrate of Cephalosporium 1 and shown to inhibit lipid biosynthesis of Escherichia coli by irreversibly binding P-ketoacyl-acyl caerulens, carrier protein synthetase, the enzyme which catalyzes the acylation of a malonyl thioester for the chain 2 3a The structure originally proposed for cerulenin on the basis lengthening reaction of fatty acid synthesis. 3b on the basis of a detailed nmr study. Very of chemical and spectroscopic data was revised to 1 in 1974 4 This communication recently two different synthetic routes to the racemic antibiotic have been reported. describes
concurrent work in these laboratories
which has led to a simple and convergent synthesis of
(+)-cerulenin. Treatment of 3-butyn -l-o1 with dihydropyran (1.2 equiv, CH2C12, O”, 2 hr) and a catalytic amount of toluenesulfonic acid gave the tetrahydropyranyl ether 2_ (bp 86-90” at 20mm) in 96% yield.
Hydrostannation of
the terminal acetylene proceeded smoothly with tri-n_butyltin hydride at 90” for 10 hr in the presence of a catalytic amount of the radical initiator,
azoisobutyronitrile,
to 0.6 &I with tetrahydrofuran and cooled to -78”.
affording the vinylstannane 3 which was diluted
Dropwise addition via syringe of 2.45 -M n-butyllithium in
hexane (1.1 equiv) generated a pale yellow solution of the corresponding vinyllithium reagent which was stirred 5 The mixture was at -78” for 2 hr and finally treated with 1.03 equiv of freshly distilled 1-bromo-2-butene. slowly warmed to 25” over 8 hr and worked up in the usual way.
Chromatography on silica gel with 10% ether
in hexane led to the isolation of pure tetrahydropyranyl ether 4 in 72% yield; however, this was routinely unnecessary
as direct treatment of the crude product mixture with aqueous acetic acid in tetrahydrofuran
(3:3:2 by volume) at 60” for 5 hr afforded the alcohol ; as a clear,
colorless
liquid after careful distillation
(bp 92-94” at 21mm) in 640/O overall yield from the acetylenic ether 2. Quantitative transformation to the w mesylate 5 (M&l, CH2C12, Et3N, 0” for 1 hr)6 and displacement with sodium iodide in dry acetone at 50” for 3 hr provided the sensitive iodide ‘7_in 80% yield.
Although iodide L did not survive chromatography or dis-
tillation, dissolution in pentane gave a faintly reddish solution which was easily decanted from dark insoluble impurities.
The addition of 1.8 M -- t-butyllithium (1.1 equiv) in pentane to a 0.04 M solution of iodide L in dry pentane at -78” effected halide-metal exchange. After stirring at -78” for 40 min, the colorless reaction mixture was transferred by cannula under positive argon pressure into a solution of epoxy anhydride 1,0~
3847
3848
(1.1
NQ. 44
equiv)
poured
in dry tetrahydrofuran
into ice water,
and esterified
acidified
upon addition
of ethereal
in hexane)
pale yellow
oils.
This combined
be raised
by further
addition
of two equivalents
arising
from
i-butyllithium species
with anhydride
treated
with a solution
in the isolation
Treatment
reagent
chloride
acetone
in chloroform.
Although the mass
in every
the infrared
protons
attached
CHC13) revealed stable,
more
with silica spectra
to the oxirane
polar
as obtained
pyrrolin-2-ones the structure
favoring storage primary
moiety
(90%) yield
from
following
synthetic
material
material
to produce
several
of cerulenin
reports
greater
between
described
1, a substance which should be very useful nl 11 available l4 C-maleic anhydride.
9
internal
10
compounds. a smooth
con-
with 30%
at 3300 cm
a complex on silica
of crystalline, producing
-1
as well
set of signals
for the
gel (30% THF in of amide A to the
authentic
identical
temperature
and nmr spectra
cerulenin
infrared
and nmr
herein in further
is uniquely biochemical
of 5-hydroxy-3studies
In the case of cerulenin, in the hydroxylactam
forms
resulted
identical
the isolation
as well as synthetic
ring strain
the open and cyclic
days at room
infrared
and
to that of authentic
isomerization
concerning
of 2-alkylpyrroles,
acid and its derivatives.
the equilibrium
in ether;
4b).
in light of recent
the photo-oxygenation
amide A which exhibited The synthesis
@.
Treatment
of
at -100”
on Florisil
absorption
exhibited
three components
possibly
the organolithium
and pyridine
carbonyl
was identical
the partial
the
at -100” under argon resulting
chromatography
from
1:2:2).
of the same
is not surprising
would be expected
the open form),
resulting
products
can
from
fraction,
in tetrahydrofuran
hydroxyl
spectrum
Thin layer
12 (ratio
gave a mixture
broad
gel
12 as
12 resulting
to cerulenin, chloride
chromatography
of this material
resonance
with ether, on silica
at 25” for 3 hr provided
column
displayed
ring at C-2 and C-3.
of 5-aminodehydrolevulinic
of synthetic
spectrum
components
hydroxide
following
spectrum
CYand P-hydroxylactams
gel immediately
approach
with thionyl
amount of dialkylated
ammonium
and the proton
three equilibrating
This observation
epoxide
in excellent
region,
In an alternative
along with a considerable
was
on to (+)-cerulenin)
No condensation
1,1 (1.2 equiv) in tetrahydrofuran
of 1,2 and 12 with methanolic
carbonyl
chromatography
of a hydrocarbon
iodide 2.
anion of di-t_butylbipheny18
of the dimethylester
into C+)-cerulenin
as a broadened
extracted
80/oof lactone
amounts
of the starting
mixture
12 and 200/Oof the pseudo-la&one
was also obtained
2 (alcohol 2 was treated
with the radical
respect,
acid,
thin layer
ketoester
2 and considerable
reactions
version
cerulenin
the reaction
of 10% hydrochloric
Preparative
There
1,Owere observed.
of 1,2 in 30% yield
temperature
(42%) of lt and 12 (both of which can be carried
experimentation.
from
92%) by reaction
diazomethane.
yield
to room
addition
22% of the expected
and coupling
2 was generated
bp 80-84”;
afforded
of lithium
elimination
Upon warming
to pH 2 by careful
(30% ethyl acetate
doubtless
at -78”.
is in delicate
although the structures
balance.
in slow conversion
concerning
to the crystalline
to that of natural
suited
for the ready
studies,
starting
(thus
In fact
(+)-cerulenin. 14 synthesis of C-labeled
from
commercially
3849
2 u
BU3sNT~~
WX 3
&
CH300~OOCH3
2,
X=OTHP
2,
x=1
2,
X=OH
2,
X=Cl
6,
X=OS02CH3
2,
X=Li
+ OOCH,
l,o
3
?2
R RY3-0 12,
R = C8H13
3850
No. 44
References 1.
Y. Sano, S. Nomura, Y. Kamio, S. Omura, and T. Hata, 2. Antibiotics,
Ser. A.,
22, 344 (1967).
2.
G. D’Agnolo, I. S. Rosenfeld,
Biochim.
Biophys. Acta.,
32, 3.
J. Awaya, S. Omura, and P. R. Vagelos,
155 (1973).
(a) S. Omura, M. Katagiri, A. Nakagawa, Y. Sano, S. Nomura, and T. Hata, -J. Antibiotics, 22, 349 (1967); (b) B. H. Arison and S. Omura, 2. Antibiotics,
4.
5.
92, 2805 (1977); (b) A. A. Jakubowski,
(a) R. K. Boeckman and E. W. Thomas, 2. -Am. Chem. s., F. S. Guziec, Jr.,
and M. Tishler,
Tetrahedron @&,
S. Winstein and W. G. Young, 2. -Am. Chem. e., mixture containing 200/Oof 3-bromo-1-butene;
Ser. A.,
27, 28 (1974).
2399 (1977).
52, 104 (1936).
l-Bromo-2-butene
consists of a
however, displacement of bromide occur preferentially
at the primary terminus. 6.
R. K. Crossland and K. L. Servis, 2. s.
7.
(a) G. B. Payne and P. H. Williams, Chem d-d)
and Indust
545 (1971).
Chem 3 35, 3195 (1970). -*
2. m.
Chem * 22, 54 (1959); (b) G. AIlan and A. N. Neogi, -*
Anhydride 1,Oexhibited ir peaks (CHC13) at 1810, 1110, 1035, 905 cm
and an nmr peak (CDC13) at t 4.33 (s, 2). 8.
(a) S. E. Wilson, Tetrahedron& Tetrahedron s,
9.
, 4651 (1975); (b) P. K. Freeman and L. L. Hutchinson,
1849 (1976).
(a) D. A. Lightner and L. K. Low, 2. Heterocyclic D. A. Lightner,
-.
9 167 (1972); (b) G. B. Quistad and , _,
Tetrahedron &&. , 4417 (1971).
10.
J. Awruch and B. Frydman, Tetrahedron &e&
, 4121 (1976).
11.
This study was assisted financially by the National Institutes of Health. Konrad BIoch for an authentic sample of cerulenin.
We are gratefuI tc Professor
-1
,