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The stereochemistry of germacranolide sesquiterpenes
Tetrahedron
Letters
No.30,
~~72863-2866,
THE STEREOCHEMISTRY
1967.
Pergamon Press
Ltd.
Printed
in Great Britain.
OF GERMACRANOLIDE SESQUITERPENES
S. Morris Kupchan and John E. Kelsey Department
of Pharmaceutical Chemistry, University Madison, Wisconsin
of Wisconsin
and G. A. Sim Chemical Laboratory,
University
of Sussex, Brighton, England
(Received1 May 1967) All non-germacranolide
sesquiterpene
lished absolute configurations
In contrast, germacranolides
(I-11).
lactones with rigorously
appear to have C-7$-oriented of rigorously
have been represented with C-7 substituents We note here that the presently-used cranolides
is not unambiguous,
Furthermore,
those germacranolides
with C-7@-substituents,
Consequently, equivalent
each germacranolide structural formulae.
which have heretofore
been represented
and therefore fit the proposed biogenetic bear C-7p-substituents
as
formulae
generaliza-
(9).
sesquiterpenes;
namely,
that each germacranolide
be
with C-7 in the lower right corner and bearing a $-substituent.
The convention observation
germa-
is advanced to define a unique and consistent representa-
tion for germacranolide represented
for describing
may be equally well portrayed by equivalent
tion that all sesquiterpenes A convention
oriented either a or S. convention
by two configurationally
bearing C-7a-substituents
established configurations
because of the symmetry of the germacranolide
carbon skeleton about the C-2, C-7 axis. may be represented
estab-
substituents
thus defines
(a) the face of the molecule which is under
and (b) a unique and consistent numbering
system for the carbon
skeleton. A Dreiding model of elephantopin
(Ia, 12) was rotated 180' about the
C-2,C-7 axis and rotomer Ib, bearing a C-7B-substituent proposed
convention
defines structure and numbering
sentation of elephantopin. center is indicated Costunolide
The absolute configuration
tetrahydroacetylbalchanolide as bearing a C-7a-substituent equivalent
involving epimerization
(IVa, 4,161 were correlated
(VII)), and eupatoriopicrin (cf. IVa).
eupatoriopicrin's
formula, IVb.
interrelation
repre-
at each asymmetric
(III, 4,15) have well-established
By a series of reactions
(III) and eupatoriopicrin
the new convention,
The
(13). (II, 14) and balchanolide
absolute configurations. C-7, balchanolide
was obtained.
Ib as the preferred
Although
has been designated
However, it is proposed that, under
structure should be represented by the
epimerization
at C-7 was possible
of III and IV, both compounds bear C-7$-substituents.
olide (III) is a 6,7-lactone, whereas
at
(via
eupatoriopicrin
2863
in the Balchan-
(IVb) is a 7,8-lactone.
No.30
Ia
Ib
11
LT.1
Germacranolides of established configuration may, indeed, be regarded as conforming to the noteworthy biogenetic correlation that C-7 substituents in sesquiterpenes have a common absolute @-configuration (9b). If there is a common biogenetic origin for the guaianolides, santanolides, and germacranolides (cf. 91, then the numbering convention suggested here probably correctly identifies those carbons in the lo-membered ring compounds which become C-4 and C-lO,respectively, in the guaianolides and santanolides. No detailed biosynthetic information is yet available to test the hypothesis that the carbon atom designated as C-10 by this convention arises in all these compounds from a unique position in a farnesol-like precursor.
No.30
2865
0
IVa
IVb
. III
_,.OAc
=Q -0.H
/'
H;
b
0
VII
2866
No.30
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9.
10. 11. 12. 13. 14.
A. J. Haagen-Sm:.t,Fortschritte der Chemie Oryanischer Naturstoffe l.2, 1 (19551. T. Nozoe and ShiiI&, Ibid. 19, 32 (1960). F. germ, Ibid. 2-9, 1 (1960). F. germ and L. Izlejx, Guaianolides and Germacranolides, Editions Scientifiques Hcrmann, laris (1966). D. H. R. Barton and P. de Mayo, Quart. Rev. 11, 189 (1957). T. G. Halsall and D. W. Theobald, Ibid. 16, 101 (1962). F. germ, Angew. Chem. Intern. Ed. Engl. f~, 94 (1967). W. Cocker and T. B. H. McMurry, Tetrahedron 2, 181 (1960). a. J. B. Hendr:lckson,Tetrahedron p, 82 (1959); b. Ibid. 19, 1387 (1963). W. Herz and M. IJ.Laksbmikanthsm, Tetrahedron 2l, 1711 (1965). S. M. Kupchan, -1.C. Hemingway, J. M. Cassady, J. R. Knox, A. T. McPhail and G. A. Sim, :1.Am. Chem. Sot. g, 465 (1967). S. M. Kupchan, ‘1.Aynehchi, J. M. Cassady, A. T. McPhail, G. A. Sim, H. K. Schnoes, ,md A. L. Burlingsme, J. Am. Chem. Sot. 88, 3674 11966). R. S. Cahn, C. 'Cngold,and V. Prelog, Angew. Chem. Intern. Ed. Enpl. 2, 385 (1966). a. V. Herout and F. germ, Chem. Ind. (London) 1067 (1959); b. M. Suchy, V. Herout and F. germ, Collection Czech. Chem. Commun. 3& 2899 (1966).
15.
V. Herout, M. !+lch$ and F. germ, Ibid. 26, 2.612(1961).
16.
L. Dolejs and V. Herout, Ibid. 2, 2654 (1962). This work was slpported by grants from the National Cancer Institute (CA-04500) and the American Cancer Society (T-275). JEK was National Institutes of Health Predoctoral Fellow, 1965-1967.
17.
Letters
No.30,
~~72863-2866,
THE STEREOCHEMISTRY
1967.
Pergamon Press
Ltd.
Printed
in Great Britain.
OF GERMACRANOLIDE SESQUITERPENES
S. Morris Kupchan and John E. Kelsey Department
of Pharmaceutical Chemistry, University Madison, Wisconsin
of Wisconsin
and G. A. Sim Chemical Laboratory,
University
of Sussex, Brighton, England
(Received1 May 1967) All non-germacranolide
sesquiterpene
lished absolute configurations
In contrast, germacranolides
(I-11).
lactones with rigorously
appear to have C-7$-oriented of rigorously
have been represented with C-7 substituents We note here that the presently-used cranolides
is not unambiguous,
Furthermore,
those germacranolides
with C-7@-substituents,
Consequently, equivalent
each germacranolide structural formulae.
which have heretofore
been represented
and therefore fit the proposed biogenetic bear C-7p-substituents
as
formulae
generaliza-
(9).
sesquiterpenes;
namely,
that each germacranolide
be
with C-7 in the lower right corner and bearing a $-substituent.
The convention observation
germa-
is advanced to define a unique and consistent representa-
tion for germacranolide represented
for describing
may be equally well portrayed by equivalent
tion that all sesquiterpenes A convention
oriented either a or S. convention
by two configurationally
bearing C-7a-substituents
established configurations
because of the symmetry of the germacranolide
carbon skeleton about the C-2, C-7 axis. may be represented
estab-
substituents
thus defines
(a) the face of the molecule which is under
and (b) a unique and consistent numbering
system for the carbon
skeleton. A Dreiding model of elephantopin
(Ia, 12) was rotated 180' about the
C-2,C-7 axis and rotomer Ib, bearing a C-7B-substituent proposed
convention
defines structure and numbering
sentation of elephantopin. center is indicated Costunolide
The absolute configuration
tetrahydroacetylbalchanolide as bearing a C-7a-substituent equivalent
involving epimerization
(IVa, 4,161 were correlated
(VII)), and eupatoriopicrin (cf. IVa).
eupatoriopicrin's
formula, IVb.
interrelation
repre-
at each asymmetric
(III, 4,15) have well-established
By a series of reactions
(III) and eupatoriopicrin
the new convention,
The
(13). (II, 14) and balchanolide
absolute configurations. C-7, balchanolide
was obtained.
Ib as the preferred
Although
has been designated
However, it is proposed that, under
structure should be represented by the
epimerization
at C-7 was possible
of III and IV, both compounds bear C-7$-substituents.
olide (III) is a 6,7-lactone, whereas
at
(via
eupatoriopicrin
2863
in the Balchan-
(IVb) is a 7,8-lactone.
No.30
Ia
Ib
11
LT.1
Germacranolides of established configuration may, indeed, be regarded as conforming to the noteworthy biogenetic correlation that C-7 substituents in sesquiterpenes have a common absolute @-configuration (9b). If there is a common biogenetic origin for the guaianolides, santanolides, and germacranolides (cf. 91, then the numbering convention suggested here probably correctly identifies those carbons in the lo-membered ring compounds which become C-4 and C-lO,respectively, in the guaianolides and santanolides. No detailed biosynthetic information is yet available to test the hypothesis that the carbon atom designated as C-10 by this convention arises in all these compounds from a unique position in a farnesol-like precursor.
No.30
2865
0
IVa
IVb
. III
_,.OAc
=Q -0.H
/'
H;
b
0
VII
2866
No.30
REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9.
10. 11. 12. 13. 14.
A. J. Haagen-Sm:.t,Fortschritte der Chemie Oryanischer Naturstoffe l.2, 1 (19551. T. Nozoe and ShiiI&, Ibid. 19, 32 (1960). F. germ, Ibid. 2-9, 1 (1960). F. germ and L. Izlejx, Guaianolides and Germacranolides, Editions Scientifiques Hcrmann, laris (1966). D. H. R. Barton and P. de Mayo, Quart. Rev. 11, 189 (1957). T. G. Halsall and D. W. Theobald, Ibid. 16, 101 (1962). F. germ, Angew. Chem. Intern. Ed. Engl. f~, 94 (1967). W. Cocker and T. B. H. McMurry, Tetrahedron 2, 181 (1960). a. J. B. Hendr:lckson,Tetrahedron p, 82 (1959); b. Ibid. 19, 1387 (1963). W. Herz and M. IJ.Laksbmikanthsm, Tetrahedron 2l, 1711 (1965). S. M. Kupchan, -1.C. Hemingway, J. M. Cassady, J. R. Knox, A. T. McPhail and G. A. Sim, :1.Am. Chem. Sot. g, 465 (1967). S. M. Kupchan, ‘1.Aynehchi, J. M. Cassady, A. T. McPhail, G. A. Sim, H. K. Schnoes, ,md A. L. Burlingsme, J. Am. Chem. Sot. 88, 3674 11966). R. S. Cahn, C. 'Cngold,and V. Prelog, Angew. Chem. Intern. Ed. Enpl. 2, 385 (1966). a. V. Herout and F. germ, Chem. Ind. (London) 1067 (1959); b. M. Suchy, V. Herout and F. germ, Collection Czech. Chem. Commun. 3& 2899 (1966).
15.
V. Herout, M. !+lch$ and F. germ, Ibid. 26, 2.612(1961).
16.
L. Dolejs and V. Herout, Ibid. 2, 2654 (1962). This work was slpported by grants from the National Cancer Institute (CA-04500) and the American Cancer Society (T-275). JEK was National Institutes of Health Predoctoral Fellow, 1965-1967.
17.