- Email: [email protected]
Isolation and structure determination of the mycotoxin chaetoglobosin C, a new [13] cytochalasin
TetrahedronLetters MO. 17, pp 1355 - 1356, 1976, Psrgamon Premr. Printed in Great Britain.
ISOLATION AND STRUCTURE CHAETOGLOBOSIN
DETERMINATION
C, A NEW [U]
OF THE MYCOTOXIN
CYTOCHALASIN
James P. Springer and Jon Clardy* Ames, Laboratory-USERDA and Department of Chemistry Iowa State University, Ames, Iowa 50011 John M. Wells Southeastern Fruit and Tree Nut Research Station P.O. Box 87, Byron, Georgia 31003 Richard J. Cole and Jerry W. Kirksey National Peanut Research Laboratory-USDA Dawson, Georgia 31742 R.D. Macfarlane and D.F. Torgerson Department of Chemistry, Texas A & M College Station, Texas 77843 (Receivedin Jappr 25 February 1976; received in UK for publication17 lkrch 1976) As part of our continuing program on the isolation and characterization
Of
fungal toxins we wish to report the structure of chaetoglobosin C (A), a [13 cytochalasin. In recent years the cytochalasins have received considerable scrutiny because of their wide range of biological effects especially cytostatic activity.l" BsC
Five isolates (ATCC #32000-32004) were taken of the fungus Penicillium aurantio-virens Biourge originally found on weevil infested pecans. The fungus was cultured on shredded wheat medium as previously describede3 The mycelium was extracted with chloroform and after concentration subjected to an elution series on a silica gel Column. Toxicity was found in the ethyl gradient elution (chloroform-ethyl acetate) was used for further purification.
1355
No. 17
13%
The crude toxin was crystallized Cf""-plasma
mp. 257-259*C.
from ethyl acetate
desorption
mass
ion 528) combined with microanalysis
indicated
spectra
3310,
(KBr) showed maxima
at 3460,
standard) 61.68
showed 6.92 d(3H), J=7
addition
to a number An X-ray
compound. structure
analysis
diffraction
Chaetoglobosin
four-circle
experiment
Hz; 61.17 m(5H);
s(3H;
68.44
s(lH) in
by the insolubility
elucidated
of the of the
the complete
background,
stereo-
effects,
was .035 usrng isotropic factors
group.
and C(8) being
The thirteen
double bonds and three ketone angle
The relative cytochalasins
distorted
(R factor)
containing
generated unit are
a lo-
drawing, cis
groups
boat
membered
conformation
ring contains
the
fused, and in ring.
with
from the least square plane
including
in the solid state between
stereochemistry
index
and anisotropic
ring is trans fused to the six-membered
.6Sb, respectively,
from c(4)-c(6)-c(7)-c(9).
observed
atoms.5'B
ring adopts a slightly .53 and
A).
series of programs.4 residual
as a [13]cytochalasin
rings of the isoindolone
the tMrteen-membered
The six membered
with
for Lorentz,
for the hydrogens
As can be seen in the computer
six and the five membered
correction
the unweighted
factors
for the remaining
can be described
(1.54178
CUKQ radiation
was solved using the MULTAN
temperature
reflections
on a fully automated
1531 (739) were considered
least squares refinements
The compound
technique
using monochromated
and polarization
routine
(indol-3-yl)
an z-scan
space group Pp1Z121
All unique
of data were taken and after
{(Fe)2 ) 30 (P,)"). T‘ne crystal structure
temperature
in the orthorhombic
and $ -25.578(4).
utilizing
diffractometer
A total of 2153 pieces
dihedral
1641, 1621,
in the high field portion
peaks
C (1) crystallizes _b =3.171(2),
28~ 114O were collected
addition
strong),
(de-IBIS0 with TlrlSas internal
d(3H), J=6
was frustrated
The ir
CsZH3eN205.
of ,1.
with a=13.020(4),
After
Hz; 6.93
of unresolved
A detailed
spectrum.
16%’ (broad,
65.8 - 6.2 m(2H); 67.0-7.6
s(3H); 64.95 m(lH);
(quasi molecular
the formula
The nmr spectra
1096, 1044, 930 and 731 cm-l.
to give s?lall needles,
spectrometry
C(5)
formed
two trans
an ct-diketo functionality.
these ad.jacent carbonyls
is the same as the previously
The
is 108'.
characterized
and related compounds.1-'2
There are two previous
reports
of cytochalasins
containing
the lO-(indol-
functionality.' The work of Natori, et al. is of particular interest. They presented structural proofs (without stereochemistry) for two mycotoxins called chaetoglobosin A (2) and B. The material we isolated has the same
j-yl)
formula and mp as the material they previously designated chaetoglobosin C.* Chaetoglobosin C is known to be one of the products derived from chaetoglobosin A (2) upon treatment with triethylamine or upon letting 2 stand in chloroform.
lOor17
It is easy to imagine a series of keto-enol tautomerizations that will convert A to C. Thus, this work, which defines the relative stereochemistry of chaetoglobosin C, combined with the work of Natori, et al. on chaetoglobosins A and B provides relative stereostructures for all three mycotoxins except for the configuration of the C(19) hydroxyl in A and B. Chaetoglobosin C may be formally derived from one molecule of tryptophan, nine acetates and three C1 residues from methionine.' Acknowledgments Jon Clardy wishes to thank the Alfred P. Sloan Foundation for a fellowship (1973-75) and the Camille and Henry Dreyfus Foundation for a grant (1972-77). References 1
M. G.
T.
Binder and Ch. Tamm An ew Chem. Inter. Edit., 12, 370 (1973); mchi, Y. Kitaura, &=&z--' H.migrJ. mardy, A.L. Demain, Glinsukon, N. Hunt, and G.N. Gogan, 2. Amer. Chem. &., a, 5423 (1973).
2.
s. ~_ Sekita, K. Yoshihira, S. Natorf, and H. Kuwano, Tetrahedron m., 2109 (1973); A.F. Cameron A.A. Freer, B. Hesp, and C.J. St rawson, J* Chem. Sot. Perkin II, 1741 (1974). --
3.
J.W. Ktrksey and R.J. Cole, Mycopath. et Mycol. Appl., 2,
4.
G. Germain, P. Main, and M.M. Woolfson, Acta Crgst., m,
5.
The following crystallographic programs were used: W.R. Busing, K-0. Martin, .. and H.A. Levy, "ORFLS, A Fortran Crystallographic LeastSquares Program", USAEC Report ORNL-TM-305, Oak Ridge National Laboratory, Oak Ridge Tenn., 1965. C. Johnson "ORTEP, A Fortran Thermal-Ellipsoid Plot ProgramA, U.S. Atomic Energy Commission Report ORNL-3794, Oak Ridge National Laboratory, 3ak Ridge, Tenn., 1965.
291 (19741 274 (1970).
1358
6.
7.
No. 17
Fractional coordinates, bond distances, bond angles and observed and calculated structure factors is available as a eupplement to Publication. To obtain a microfiche copy of the Supp,lement to Publication, contact the P'noto Service, Iowa State University, Ames, Iowa 50011; requesting Supplement to Publication for this article and submitting $0.50 in the form of chez, cash, or money order. Give your name and complete address (including zip code) for mailing. See accompanying authentic sample
papers by S. Natori, et al. We thank Dr. of chaetoglobosin C and spectral data.
Natori
for
an
hcti6)
b
Cfl6‘)
O(207
Figure
1.
A computer generated perspecttve drawing of chaetoglobosin C (I). Hydrogens are not shown for clarity and the absolute ConfiguraTion is drawn to conform with other cytocha1asLns.l
ISOLATION AND STRUCTURE CHAETOGLOBOSIN
DETERMINATION
C, A NEW [U]
OF THE MYCOTOXIN
CYTOCHALASIN
James P. Springer and Jon Clardy* Ames, Laboratory-USERDA and Department of Chemistry Iowa State University, Ames, Iowa 50011 John M. Wells Southeastern Fruit and Tree Nut Research Station P.O. Box 87, Byron, Georgia 31003 Richard J. Cole and Jerry W. Kirksey National Peanut Research Laboratory-USDA Dawson, Georgia 31742 R.D. Macfarlane and D.F. Torgerson Department of Chemistry, Texas A & M College Station, Texas 77843 (Receivedin Jappr 25 February 1976; received in UK for publication17 lkrch 1976) As part of our continuing program on the isolation and characterization
Of
fungal toxins we wish to report the structure of chaetoglobosin C (A), a [13 cytochalasin. In recent years the cytochalasins have received considerable scrutiny because of their wide range of biological effects especially cytostatic activity.l" BsC
Five isolates (ATCC #32000-32004) were taken of the fungus Penicillium aurantio-virens Biourge originally found on weevil infested pecans. The fungus was cultured on shredded wheat medium as previously describede3 The mycelium was extracted with chloroform and after concentration subjected to an elution series on a silica gel Column. Toxicity was found in the ethyl gradient elution (chloroform-ethyl acetate) was used for further purification.
1355
No. 17
13%
The crude toxin was crystallized Cf""-plasma
mp. 257-259*C.
from ethyl acetate
desorption
mass
ion 528) combined with microanalysis
indicated
spectra
3310,
(KBr) showed maxima
at 3460,
standard) 61.68
showed 6.92 d(3H), J=7
addition
to a number An X-ray
compound. structure
analysis
diffraction
Chaetoglobosin
four-circle
experiment
Hz; 61.17 m(5H);
s(3H;
68.44
s(lH) in
by the insolubility
elucidated
of the of the
the complete
background,
stereo-
effects,
was .035 usrng isotropic factors
group.
and C(8) being
The thirteen
double bonds and three ketone angle
The relative cytochalasins
distorted
(R factor)
containing
generated unit are
a lo-
drawing, cis
groups
boat
membered
conformation
ring contains
the
fused, and in ring.
with
from the least square plane
including
in the solid state between
stereochemistry
index
and anisotropic
ring is trans fused to the six-membered
.6Sb, respectively,
from c(4)-c(6)-c(7)-c(9).
observed
atoms.5'B
ring adopts a slightly .53 and
A).
series of programs.4 residual
as a [13]cytochalasin
rings of the isoindolone
the tMrteen-membered
The six membered
with
for Lorentz,
for the hydrogens
As can be seen in the computer
six and the five membered
correction
the unweighted
factors
for the remaining
can be described
(1.54178
CUKQ radiation
was solved using the MULTAN
temperature
reflections
on a fully automated
1531 (739) were considered
least squares refinements
The compound
technique
using monochromated
and polarization
routine
(indol-3-yl)
an z-scan
space group Pp1Z121
All unique
of data were taken and after
{(Fe)2 ) 30 (P,)"). T‘ne crystal structure
temperature
in the orthorhombic
and $ -25.578(4).
utilizing
diffractometer
A total of 2153 pieces
dihedral
1641, 1621,
in the high field portion
peaks
C (1) crystallizes _b =3.171(2),
28~ 114O were collected
addition
strong),
(de-IBIS0 with TlrlSas internal
d(3H), J=6
was frustrated
The ir
CsZH3eN205.
of ,1.
with a=13.020(4),
After
Hz; 6.93
of unresolved
A detailed
spectrum.
16%’ (broad,
65.8 - 6.2 m(2H); 67.0-7.6
s(3H); 64.95 m(lH);
(quasi molecular
the formula
The nmr spectra
1096, 1044, 930 and 731 cm-l.
to give s?lall needles,
spectrometry
C(5)
formed
two trans
an ct-diketo functionality.
these ad.jacent carbonyls
is the same as the previously
The
is 108'.
characterized
and related compounds.1-'2
There are two previous
reports
of cytochalasins
containing
the lO-(indol-
functionality.' The work of Natori, et al. is of particular interest. They presented structural proofs (without stereochemistry) for two mycotoxins called chaetoglobosin A (2) and B. The material we isolated has the same
j-yl)
formula and mp as the material they previously designated chaetoglobosin C.* Chaetoglobosin C is known to be one of the products derived from chaetoglobosin A (2) upon treatment with triethylamine or upon letting 2 stand in chloroform.
lOor17
It is easy to imagine a series of keto-enol tautomerizations that will convert A to C. Thus, this work, which defines the relative stereochemistry of chaetoglobosin C, combined with the work of Natori, et al. on chaetoglobosins A and B provides relative stereostructures for all three mycotoxins except for the configuration of the C(19) hydroxyl in A and B. Chaetoglobosin C may be formally derived from one molecule of tryptophan, nine acetates and three C1 residues from methionine.' Acknowledgments Jon Clardy wishes to thank the Alfred P. Sloan Foundation for a fellowship (1973-75) and the Camille and Henry Dreyfus Foundation for a grant (1972-77). References 1
M. G.
T.
Binder and Ch. Tamm An ew Chem. Inter. Edit., 12, 370 (1973); mchi, Y. Kitaura, &=&z--' H.migrJ. mardy, A.L. Demain, Glinsukon, N. Hunt, and G.N. Gogan, 2. Amer. Chem. &., a, 5423 (1973).
2.
s. ~_ Sekita, K. Yoshihira, S. Natorf, and H. Kuwano, Tetrahedron m., 2109 (1973); A.F. Cameron A.A. Freer, B. Hesp, and C.J. St rawson, J* Chem. Sot. Perkin II, 1741 (1974). --
3.
J.W. Ktrksey and R.J. Cole, Mycopath. et Mycol. Appl., 2,
4.
G. Germain, P. Main, and M.M. Woolfson, Acta Crgst., m,
5.
The following crystallographic programs were used: W.R. Busing, K-0. Martin, .. and H.A. Levy, "ORFLS, A Fortran Crystallographic LeastSquares Program", USAEC Report ORNL-TM-305, Oak Ridge National Laboratory, Oak Ridge Tenn., 1965. C. Johnson "ORTEP, A Fortran Thermal-Ellipsoid Plot ProgramA, U.S. Atomic Energy Commission Report ORNL-3794, Oak Ridge National Laboratory, 3ak Ridge, Tenn., 1965.
291 (19741 274 (1970).
1358
6.
7.
No. 17
Fractional coordinates, bond distances, bond angles and observed and calculated structure factors is available as a eupplement to Publication. To obtain a microfiche copy of the Supp,lement to Publication, contact the P'noto Service, Iowa State University, Ames, Iowa 50011; requesting Supplement to Publication for this article and submitting $0.50 in the form of chez, cash, or money order. Give your name and complete address (including zip code) for mailing. See accompanying authentic sample
papers by S. Natori, et al. We thank Dr. of chaetoglobosin C and spectral data.
Natori
for
an
hcti6)
b
Cfl6‘)
O(207
Figure
1.
A computer generated perspecttve drawing of chaetoglobosin C (I). Hydrogens are not shown for clarity and the absolute ConfiguraTion is drawn to conform with other cytocha1asLns.l