Total Synthesis of Novel 6-Substituted Lavendamycin Antitumor Agents

Article abstract of DOI:10.1021/ol035381a

(Equation presented) Novel 6-substituted lavendamycins have been synthesized for the first time. The key step in these syntheses is a Pictet-Spengler condensation (Scheme 1). Efficient methods for the synthesis of each compound, including a novel reaction for the facile introduction of alkylamino groups at the C-6 position of the lavendamycin system, are discussed. Possible mechanisms for these reactions are also presented.

Full text of DOI:10.1021/ol035381a

ORGANIC
LETTERS
2004
Vol. 6, No. 4
473-476
Total Synthesis of Novel 6-Substituted
Lavendamycin Antitumor Agents
Hassan Seradj, Wen Cai, Noe O. Erasga, Darrell V. Chenault,
Kathryn A. Knuckles, Justin R. Ragains, and Mohammad Behforouz*
Department of Chemistry, Ball State UniVersity, Muncie, Indiana 47306
mbehforo@bsu.edu
Received July 23, 2003
ABSTRACT
Novel 6-substituted lavendamycins have been synthesized for the first time. The key step in these syntheses is a Pictet−Spengler condensation
(Scheme 1). Efficient methods for the synthesis of each compound, including a novel reaction for the facile introduction of alkylamino groups
at the C-6 position of the lavendamycin system, are discussed. Possible mechanisms for these reactions are also presented.
Lavendamycin (1), an antitumor antibiotic, was isolated from
the fermentation broth of Streptomyces laVendulae in 1981.1
Total syntheses of lavendamycin methyl ester (2) have been
reported by Kende,2a Boger,2b and our group.3a,b In 1993 and
1996, we introduced two short and efficient methods for the
synthesis of 2.3a,b Formal syntheses of 2 have also been
reported.2c
we were in need of analogues with various substituents at
the C-6 position. In this letter, we report for the first time
the synthesis of a number of these novel analogues (Table
1) via new and efficient methods. These compounds are the
first examples of C-6-substituted lavendamycins and are part
of a much larger series of derivatives with a wide range of
molecular reduction potentials and lipophilicity. Our ana-
logues will be the subject of future antitumor studies in
general and, in particular, an evaluation of a possible
correlation of reduction potential with antitumor activity.4
Analogues 6-18 in Table 1 are the 6-substituted derivatives
of our previously synthesized lavendamycins 2-5.3a-e Our
(2) (a) Kende, A. S.; Ebetino, F. H. Tetrahedron Lett. 1984, 21, 91. (b)
Boger, D. L.; Duff, S. R.; Panek, J. S.; Yasuda, M. J. Org. Chem. 1985,
50, 5790. (c) Rama Rao, A. V. Recent Prog. Chem. Synth. Antibiot.; Lukacs,
G., Ohno, M., Eds.; Springer: Berlin, 1990; p 497 and references therein.
(3) (a) Behforouz, M.; Gu, Z.; Cai, W.; Horn, M. A.; Ahmadian, M. J.
Org. Chem. 1993, 58, 7089. (b) Behforouz, M.; Haddad, J.; Cai, W.; Arnold,
M. B.; Mohammadi, F.; Sousa, A. C.; Horn, M. A. J. Org. Chem. 1996,
61, 6552. (c) Behforouz, M.; Haddad, J.; Cai, W.; Gu, Z. J. Org. Chem.
1998, 63, 343. (d) Fang, Y.; Linardic, C. M.; Richardson, D. A.; Cai, W.;
Behforouz, M.; Abraham, R. T. Mol. Cancer Ther. 2003, 517. (e) Behforouz,
M.; Merriman, R. L. U.S. Patent 5 525 611, June 11, 1996. (f) Behforouz,
M.; Cai, W.; Stocksdale, M. G.; Jung, J. Y. J. Med. Chem., accepted for
publication.
As part of our long-term research on the synthesis and
biological activity studies of lavendamycin antitumor agents,3
(1) (a) Doyle, T. W.; Balitz, D. M.; Grulich, R. E.; Nettleton, D. E.;
Gould, S. J.; Tann, C.-H.; Mews, A. E. Tetrahedron Lett. 1981, 22, 4595.
(b) Balitz, D. M.; Bush, J. A.; Bradner, W. T.; Doyle, T. W.; O’Herron, F.
A.; Nettleton, D. E. J. Antibiot. 1982, 35, 259.
(4) (a) Hodnett, E. M.; Wongwiechintana, C.; Dunn, W. J., III; Marrs,
P. J. Med. Chem. 1983, 26, 570. (b) Shaikh, I. A.; Johnson, F.; Grollman,
A. P. J. Med. Chem. 1986, 29, 1329.
10.1021/ol035381a CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/28/2004

Scheme 1 a
Table 1. 6-Substituted Lavendamycins and
Demethyllavendamycins
a Conditions: (a) Dry p-xylene or anisole, 3-19 h, reflux, argon.
Yields: 3, 79%; 5, 54%; 6, 45%; 7, 41%; 8, 32%; 9, 59%; 10,
49%; 11, 36%; 12, 56%; 13, 26%; 14, 53%.
preparation of 29.3a A controlled amount of bromine must
be used in the bromination of 21.6
Scheme 2 a
studies have shown 2-5 to be highly active antitumor
agents.3d,e
The key step in these syntheses is a Pictet-Spengler
condensation of the corresponding aldehydes with the
appropriate tryptophans (Scheme 1). Previously, we have
reported efficient syntheses of compounds 33a,b and 53e via
this condensation reaction.
a Conditions: (a) HNO3/H2SO4 (70% v/v), 3 h, rt. (b) Pd-C 10%,
H2 (40 psi), HCl, H2O, 24 h, rt. (c) FeCl3, CHCl3, H2O, 24 h, rt.
(d) Br2, HOAc, NaOAc, 24 h, rt, argon. (e) NaN3, H2O, THF, 4 h,
rt, argon. (f) PtO2, H2 (50 psi), dry MeOH, 10 h, rt. (g) SeO2,
p-dioxane, H2O, 21 h, reflux, argon.
Novel carbaldehyde 25 required for the synthesis of 6-8
was prepared according to Scheme 2.
7-Amino-6-methoxy-2-methylquinoline-5,8-dione (24) was
prepared 5 and then oxidized to the desired aldehyde 25 via
a method similar to that previously reported by us for the
Carbaldehyde 29 necessary for the synthesis of analogues
15-18 was prepared according to Scheme 3,3a and the novel
(5) (a) Liao, T. K.; Nyberg, H.; Cheng, C. C. J. Heterocycl. Chem. 1976,
13, 1063. (b) Boger, D. L.; Duff, S. R.; Panek, J. S.; Yasuda, M. J. Org.
Chem. 1985, 50, 5782.
(6) Use of more than 1.25 equiv of bromine lowers the yield of 22 and
produces undesired side products.
474
Org. Lett., Vol. 6, No. 4, 2004

â-Methyltryptophan methyl ester (for compounds 7, 9, 15,
16, and 3, Scheme 1) was prepared according to our own
procedure.7b Tryptophan isoamyl ester (for compound 12,
Scheme 1) was prepared in 82% yield by the Fischer
esterification reaction in the presence of HCl gas followed
by the neutralization of the resulting salt with ammonium
hydroxide and EtOAc extraction. The remaining tryptophan
derivatives were prepared by the neutralization of the
commercially available salts.
Scheme 3 a
7-Acetamido-6-alkylaminolavendamycins (15-18) were
synthesized using a novel and simple method recently
developed in our laboratory. Direct addition of aziridine or
pyrrolidine to compounds 3 or 5 under very mild reaction
conditions resulted in the formation of almost 100% pure
products (Scheme 5). No transamination occurs at the C-2′
Scheme 5 a
a Conditions: (a) Pd-C 5%, H2 (30 psi), HCl, H2O, 15 h, rt. (b)
Ac2O, NaOAc, Na2SO3, 2.5 h, rt f 0 °C then MeOH, H2O, reflux,
30 min. (c) K2Cr2O7, AcOH, H2O, 24 h, rt. (d) HCl (gas), dry
MeOH, 22 h, 60 °C. (e) SeO2, p-dioxane, H2O, reflux, 19-23 h.
aldehyde 31 required for the synthesis of analogues 9-14
3c
was obtained by the oxidation of chlorodione 30 via a
method similar to that used for 29.3a
7-Acetamidoquinoline-5,8-dione 28 was converted to
chloroquinone 30 in a sequence of reactions shown in
Scheme 4.3c Acid-catalyzed methanolysis of 28 first gave
a Conditions: (a) Aziridine, CHCl3 or CHCl3/EtOH, 24-48 h,
rt. (b) Pyrrolidine, CHCl3 or DMF, 2 h, rt.
Scheme 4
amide and ester linkages or even at the vinylogous C-7 amide
function during the course of this reaction.
The literature lacks efficient methods for the synthesis of
8,9
6,7-diaminoquinolinediones. The use of dihalodiones or
9
their methoxy derivatives as the starting materials for the
amination of this system gives a mixture of 6- and 7-amino
products and not the desired diamino compound. This may
be due to the fact that once the replacement of either the
C-6 or the C-7 groups occurs by an amine, the resulting
quinone system becomes deactivated toward the second
Michael addition of another amine molecule as we have
observed in compound 32.
the aminodione derivative 32. A Michael addition of HCl to
aminodione 32 produced the intermediate hydroquinone 33,
which then oxidized to the final 6-chloroquinone 30. A
possible mechanism for the 1,4-addition of HCl to 32 has
already been reported.3c
(7) (a) Tolstikov, V. V.; Holpnekozlova, N. V.; Oreshkina, T. D.;
Osipova, T. V.; Preobrazhenskaya, M. N.; Sztarisckai, F.; Balzarini, J.;
Declercq, E. J. Antibiot. 1992, 45, 1020. (b) Behforouz, M.; Zarrinmayeh,
H.; Ogle, M. E.; Riehle, T. J.; Bell, F. W. J. Heterocycl. Chem. 1988, 25,
1627.
(8) Choi, H. Y.; Kim, D. W.; Chi, D. Y.; Yoon, E. Y.; Kim, D. J. J.
Org. Chem. 2002, 67, 5390 and references therein.
Tryptophan pyrrolidine amide (for compound 11, Scheme
1) was prepared according to the method of Tolstikov et al.7a
(9) Yoo, K. H.; Yoon, E. Y.; Park, Y. Y.; Park, S. W.; Lee, C.-O.; Lee,
W. K.; Chi, D. Y.; Kim, D. J. Bull. Korean Chem. Soc. 2001, 22, 1067.
Org. Lett., Vol. 6, No. 4, 2004
475

This novel and efficient method produces the 6-amino-
methoxy activating groups. Although dione 32 resists ami-
nation, it should be noted that it undergoes an efficient HCl
addition (Scheme 4). The ease of this transformation may
be due to the intermediacy of activated species such as 35
and 36.3c
10
lavendamycins as well as the 6,7-diaminodiones
in
excellent yields at room temperature. The proposed mech-
anism for this reaction is presented in Scheme 6. In contrast
Scheme 6
Interestingly, the spontaneous and complete reoxidation
of the intermediate 34 to its corresponding quinoline-5,8-
dione occurs during the reaction workup. In contrast, the
conversion of chlorohydroquinone 33 to its dione 30 results
in only partial air oxidation during the reaction workup and
ferric chloride is needed to complete the reaction.3c
In summary, efficient syntheses of first examples of
6-substituted lavendamycins have been reported, and a novel
method for the facile introduction of an amino group at the
C-6 position of the lavendamycin system has been intro-
duced.
Acknowledgment. Financial support for this study by the
National Institutes of Health and the American Cancer
Society is greatly appreciated. We thank Professor David
R. Williams of Indiana University and the staff at the Indiana
University Mass Spectrometry Laboratory for their help in
obtaining mass spectra.
to the unreactivity of aminoquinolinedione 32 toward the
amination reaction at the C-6 position, acetylamino com-
pounds 3 and 5 undergo this reaction very efficiently. It
appears that placement of an acetyl group on the C-7 nitrogen
of the amino function sufficiently decreases its electron-
donating ability and thus activates the system at its C-6
position toward a facile Michael addition reaction of the
amines with no necessity for the presence of halogen or
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds (6-
18, 25 and 31). This material is available free of charge via
the Internet at http://pubs.acs.org.
(10) Work on the addition of a variety of aliphatic and aromatic amines
at the C-6 positions of lavendamycins and aminoquinolinediones is ongoing
in our laboratories, and the results will be the subject of future reports.
OL035381A
476
Org. Lett., Vol. 6, No. 4, 2004