A new convergent approach to the polycyclic framework of dynemicin A

Full text of DOI:10.1021/jo9702047

3028
J . Org. Chem. 1997, 62, 3028-3029
Sch em e 1
A New Con ver gen t Ap p r oa ch to th e
P olycyclic F r a m ew or k of Dyn em icin A†
Sonia Escudero, Dolores Pe´rez,
Enrique Guitia´n,* and Luis Castedo
Departamento de Qu´ımica Orga´nica,
Universidad de Santiago y Unidad Asociada al CSIC,
15706 Santiago de Compostela, Spain
Received February 5, 1997
Sch em e 2a
Dynemicin A (1), a cyclic enediyne antibiotic isolated
from Micromonospora chersina,1 has been the subject of
intensive chemical and biological research owing to its
potent antibacterial and anticancer activities and its
unique molecular structure, which combines an enediyne
unit with the anthraquinone chromophore of the anthra-
cyclinones.2
Various structural features of dynemicin A are thought
to play important roles in its mechanism of action. The
anthraquinone moiety is believed to act both as delivery
system, allowing intercalation and binding of the molecule
at specific sites along the minor groove of DNA, and as
triggering device, undergoing a bioreduction that facili-
tates opening of the epoxide and Bergman cyclization of
the enediyne, which gives a diradical capable of hydrogen
abstraction and subsequent cleavage of the DNA.3 In
view of this, a general synthesis of the polycyclic skeleton4
of dynemicin A is of great interest not only as part of an
approach to this natural product and analogous ene-
diynes but also as a route to novel anthraquinones that
are potential DNA intercalators.
a
Key: (a) BnNH2, reflux; 68%; (b) CH(OCH3)3, PhNH2, AcOH,
DMF; 80%; (c) (for 5a ) NCCH2CO2Me, KOBut, DMF; 93%; (d) (for
5b) 6, 180 °C; 77%.
framework of dynemicin A and analogs with different
planar moieties (Scheme 1). This paper reports our
preliminary results.
Pyrones 5 were easily prepared in two or three steps
from acid 2 (Scheme 2).6 Condensation of 2 with benzyl-
amine afforded imide 3 in 68% yield. Reaction of 3 with
trimethyl orthoformate and aniline in DMF yielded
enamine 4, which upon treatment with methyl cyanoac-
etate and KOBut gave pyrone 5a in 74% overall yield
from 3. Pyrone 5b was obtained in 77% yield by reaction
of 3 with methyl 3-(dimethylamino)-2-methoxyacrylate
(6), which was prepared by a published procedure.7 The
dimethylamine eliminated in the condensation of 3 and
6 must be removed by passing a strong current of an inert
gas through the reaction vessel; otherwise, nucleophilic
attack on the pyrone by this amine causes decomposition.
Diels-Alder reaction of 5b with benzyne (generated
by thermal decomposition of benzenediazonium 2-car-
boxylate),8 followed by CO2 extrusion, afforded the tet-
rahydrobenzophenanthridine 8b in 77% yield; but pyrone
5a , with an ester group at position 3, proved to be less
reactive, giving compound 8a in only 42% yield, together
with unreacted 5a (76% yield on the basis of unrecovered
starting material). Attempts to consume all of the
starting 5a by adding an excess of benzyne resulted in a
competitive reaction involving addition of a second ben-
zyne unit to ring C of 8a .
In relation to our work on the synthesis of planar
antitumor benzophenanthridines by intermolecular Di-
els-Alder reaction of pyrones with benzyne,5 we sought
a similar approach to the synthesis of the polycyclic
* To whom correspondence should be addressed. E-mail:
qoenrgui@uscmail.usc.es.
† Dedicated to Prof. Eckehardt Winterfeldt on the occasion of his
65th birthday.
(1) (a) Konishi, M.; Ohkuma, H.; Matsumoto, K.; Tsuno, T.; Kamei,
H.; Miyaki, T.; Oki, T.; Kawaguchi, H.; VanDuyne, G. D.; Clardy, J . J .
Antibiot. 1989, 42, 1449. (b) Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki,
T.; VanDuyne, G. D.; Clardy, J . J . Am. Chem. Soc. 1990, 112, 3715.
(2) For selected references on the synthesis of dynemicin A and
model systems, see: (a) Danishefsky, S. J .; Shair, M. D. J . Org. Chem.
1996, 61, 16. (b) Shair, M. D., Yoon, T.-Y.; Danishefsky, S. J . Angew.
Chem., Int. Ed. Engl. 1995, 34, 1721. (c) Takahashi, T.; Sakamoto, Y.;
Yamada, H.; Usui, S.; Fukazawa, Y. Angew. Chem., Int. Ed. Engl. 1995,
34, 1345. (d) Nishikawa, T.; Ino, A.; Isobe, M. Tetrahedron 1994, 50,
1449. (e) Taunton, J .; Wood, J . L.; Schreiber, S. L. J . Am. Chem. Soc.
1993, 115, 10378. (f) Nicolaou, K. C.; Dai, W.-M.; Hong, Y. P.; Tsay, S.
C.; Baldridge, K. K.; Siegel, J . S. J . Am. Chem. Soc. 1993, 115, 7944.
(g) Wender, P. A.; Zercher, C. K.; Beckham, S.; Haubold, E.-M. J . Org.
Chem. 1993, 58, 5867.
(3) (a) Semmelhack, M. F.; Gallagher, J .; Cohen, D. Tetrahedron Lett.
1990, 31, 1521. (b) Langley, D. R.; Doyle, T. W.; Beveridge, D. L. J .
Am. Chem. Soc. 1991, 113, 4395.
(4) For references on the synthesis of the anthraquinone subunit,
see: (a) Chikashita, H.; Porco, J . A., J r.; Stout, T. J .; Clardy, J .;
Schreiber, S. L. J . Org. Chem. 1991, 56, 1692. (b) Nicolaou, K. C.; Gross,
J . L.; Kerr, M. A.; Lemus, R. H.; Ikeda, K.; Ohe, K. Angew. Chem., Int.
Ed. Engl. 1994, 33, 781. (c) Okita, T.; Isobe, M. Tetrahedron 1994, 38,
11143.
It has been suggested that the presence of one nitrogen
and two oxygen atoms with a particular relative geometry
can determine the mode of binding of benzophenan-
(5) Pe´rez, D.; Guitia´n, E.; Castedo, L. J . Org. Chem. 1992, 57, 5911.
(6) Grewe, R.; Mondon, A. Chem. Ber. 1948, 279.
(7) Schmidt, R. R.; Betz, R. Synthesis 1982, 748.
(8) (a) Logullo, F. M.; Seitz, A. H.; Friedman, L. Org. Synth. 1968,
48, 12. (b) For
cycloadditions, see: Atanes, N.; Castedo, L.; Guitia´n, E.; Saa´, C.; Saa´,
J . M.; Suau, R. J . Org. Chem. 1991, 56, 2984.
a general procedure for intermolecular benzyne
S0022-3263(97)00204-1 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 10, 1997 3029
Sch em e 3
Sch em e 4a
thridines and other intercalating antitumor alkaloids to
DNA.9 With this in mind, we reacted 3,4-(methylene-
dioxy)benzyne (7b) with 5a and 5b, obtaining the corre-
sponding tetrahydrobenzophenanthridines 8c and 8d in
68 and 69% yield, respectively.
a
Key: (a) POCl3, 60 °C; 58%; (b) H2, 10% Pd/C, NaOAc; 100%.
Reaction of 5a and 5b with 2,3-naphthalyne afforded
complex reaction mixtures, which is attributable to the
increased reactivity toward dienophiles of the anthracene
system in the monoadduct 9 (Scheme 3). In keeping with
this, we detected mono- and diadducts 9 and 10 in around
15% yields.
Encouraged by the above results, we attempted the
synthesis of our main synthetic target, the anthraquinone
framework of dynemicin A, using a similar methodology.
It was envisaged that reaction of dienophiles, quinones
11, with pyrones 5, followed by extrusion of CO2 and air
oxidation, would give the desired polycyclic system
(Scheme 4). Quinones 11b10 and 11c11 were prepared
from commercially available 5,8-dihydroxynaphthoquino-
ne (11a ) by published procedures. Heating diacetate 11b
with 5b in nitrobenzene at 180 °C for 24 h afforded
compound 12b in 11% yield. A major byproduct was 12a
(resulting from acetate cleavage of 12b), and partial
decomposition of 11b was also observed. Compound 11a
did not react with 5b to afford 12a .
afforded compound 14 in quantitative yield. Methylated
anthraquinones 13 and 14 could be advanced intermedi-
ates in the total synthesis of 1, and we obtained them in
only four and five steps, respectively, from acid 2 and in
significantly better overall yields than previously pub-
lished procedures.
In conclusion, this paper describes a new convergent
approach to the pentacyclic nucleus of dynemicin A that
is based on Diels-Alder reaction between an R-pyrone
and a quinone. The use of arynes instead of quinones
as dienophiles allowed the synthesis of polycyclic com-
pounds that could serve as precursors to dynemicin
analogs with different intercalating moieties. Work
aimed at the construction of the enediyne system on these
molecules is in progress.
Ack n ow led gm en t. Financial support from the DGI-
CYT (PB93-0533) is gratefully acknowledged. S.E. and
D.P. thank the Spanish Ministry of Education for the
award of research grants.
Reaction of 5b with 5,8-dimethoxynaphthoquinone
(11c) afforded 12c in a remarkable 57% yield. Refluxing
12c with POCl3 gave chloroimine 13 in 58% yield, and
hydrogenolysis of 13 over Pd/C in the presence of NaOAc
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
and experimental procedures for the synthesis of compounds
3, 4, 5a ,b, 8a -d , 12a -c, 13, and 14 (5 pages).
(9) Cheng, C. C.; Zee-Cheng, R. K. Y. Heterocycles 1981, 15, 1275.
J O9702047