J. Am. Chem. Soc. 1996, 118, 3291-3292
Scheme 1
3291
Photochemical Cycloaromatization Reactions of
ortho-Dialkynylarenes: A New Class of DNA
Photocleaving Agents
,
†
†
Raymond L. Funk,* Erick R. R. Young,
‡
‡
Robert M. Williams, Mark F. Flanagan, and
Tricia L. Cecil‡
Department of Chemistry
The PennsylVania State UniVersity
UniVersity Park, PennsylVania 16802
Department of Chemistry, Colorado State UniVersity
Fort Collins, Colorado 80523
ReceiVed June 30, 1995
in quantitative yield. These transformations proceeded more
slowly or not at all if lesser quantites of 1,4-cyclohexadiene
The fascinating class of enediyne-containing antitumor agents,
in particular, calicheamicin γ1 , dynemicin A, and neocarzi-
I
(10-0 equiv) in cyclohexane were employed, a result which is
nostatin chromophore have been the subject of extensive
research efforts primarily directed toward their synthesis and
the elucidation of their mechanism of action.1 It is now widely
appreciated that (1) DNA is targeted as a consequence of the
various recognition domains and that (2) evolutionary pressure
has ingeniously engineered these natural products to require a
nucleophilic- or redox-based bioactivation step in order to trigger
a facile, thermal cycloaromatization reaction leading to a lethal
biradical intermediate.
We are intrigued by the possibility of consolidating the
functional elements of the enediyne anticancer antibiotics,
thereby simplifying the task of synthesizing potential chemo-
therapeutic agents which operate by DNA cleavage pathways.
Thus, it was envisaged that certain polycyclic ortho-dialkyny-
larenes would intercalate into DNA and, moreover, the planar
π systems might be further exploited by facilitating photochemi-
cal, as opposed to thermal, cycloaromatization/cleavage reac-
tions.2 We report herein on the viability of this photochemical
transformation and the resultant new class of DNA photocleav-
ing agents.4
consistent with a reVersible cycloaromatization.7 Irradiation of
dialkynylpyrene 1 in THF-d (99.5%) afforded 6 with 33% D ,
8
2
37% D1
, and 30% D0 incorporation (mass spectral analysis)
and an attenuation of the intensity for the new aromatic (singlet)
resonance. A strained, cyclic dialkynylarene facilitates the
cycloaromatization, but is not obligate. Thus, irradiation of 9,-
10-dipropynylphenanthrene afforded 1,2-dimethyltriphenylene
(61% conversion) under conditions (hν, dioxane, cyclohexadi-
ene, Pyrex, 18 h) similar to those shown for the cyclization of
5.8
However, the photochemical cycloaromatizations of the
terminal acetylenic compounds, 9,10-diethynylphenanthrene and
,5-diethynylpyrene, were unsuccessful. Finally, the ben-
4
zylidene acetal of dialkynylphenanthrene 10, which possesses
a conformationally locked 10-membered ring, undergoes a
smooth photochemical cycloaromatization (hν, 18 h, 30 equiv
1
,4-cyclohexadiene, acetone, 47%) whereas the rate of the
analogous thermal cycloaromatization is markedly attenuated
190 °C, 17 h, 69% conversion) relative to the rate of thermal
cyclization of 5 (98 °C, t , 5 h).
3
(
1
/2
We next considered the preparation of a water soluble
dialkynylphenanthrene and/or dialkynylpyrene in order to
examine the DNA photocleaving properties of these compounds.
The dialkynylarenes 1-5 (Scheme 1) were prepared in order
to determine whether the photochemical counterpart of the
Bergman reaction was equally as effective as the thermal
5
6
(4) Selected examples of DNA photocleaving agents include the fol-
lowing. Radical precursors: (a) Hecht, S. M.; Levy, M. J.; Quada, J. C. J.
Am. Chem. Soc. 1993, 115, 12171. (b) Little, R. D.; Groppe, J.; Bregant,
T. M. Ibid. 1994, 116, 3635. (c) Saito, I.; Sakurai, T.; Kurimoto, T.;
Takayama, M. Tetrahedron Lett. 1994, 35, 4797 and references therein.
Poly(hetero)cyclic aromatic compounds: (d) Perrouault, L.; Asseline, U.;
Rivalle, C.; Thuong, N. T.; Bisagni, E.; Giovannangeli, C.; Le Doan, T.;
Helene, C. Nature 1990, 344, 358. (e) Tokuyama, H.; Yamago, S.;
Nakamura, E.; Shiraki, T.; Sugiura, Y. J. Am. Chem. Soc. 1993, 115, 7918.
(f) Schuster, G. B.; Armitage, B.; Yu, C.; Devadoss, C. Ibid. 1994, 116,
9847. (g) Saito, I.; Takayama, M.; Kawanishi, S. Ibid. 1995, 117, 5590
and references therein. Porphyrins: (h) Magda, D.; Wright, M.; Miller, R.
A.; Sessler, J. L.; Sansom, P. I. Ibid. 1995, 117, 3629 and references therein.
Metal Complexes: (i) Nielsen, P. E.; Hiort, C.; Sonnichsen, S. H.; Buchardt,
O.; Dahl, O.; Norden, B. Ibid. 1992, 114, 4967. (j) Mascharak, P. K.;
Farinas, E.; Tan, J. D.; Baidya, N. Ibid. 1993, 115, 2996. (k) Barton, J.
K.; Sitlani, A.; Dupureur, D. M. Ibid. 1993, 115, 12589 and references
therein. (l) Riordan, C. G.; Wei, P. Ibid. 1994, 116, 2189.
(5) The preparation and thermal cycloaromatization reactions of dialky-
nylarenes 1-5 will be reported separately. We thank Kay M. Brummond
and Kim S. Para for the initial preparation of 2, 3, and 4, 5, respectively.
All new compounds reported herein exhibit satisfactory spectral (IR, UV,
NMR, HRMS) characteristics.
(6) Semiempirical calculations (PM3) show that the coefficients and nodal
properties of the HOMO/LUMO’s for 2, 4, and 5 are significantly different
than those for 3. Arene analogs of stilbenes also show this contrasting
photochemical behavior. For a theoretical explanation, see: Tinnemans,
A. H. A.; Laarhoven, W. H.; Sharafi-Ozeri, S.; Muszkat, K. A. Recl. TraV.
Chim. Pays-Bas 1975, 94, 239.
variant. Indeed, all of the dialkynylarenes except 3 underwent
a photochemical cycloaromatization upon irradiation (Hanovia
50 W, Pyrex, Et2O, 18 h) in the presence of 1,4-cycloheaxdiene
30 equiv). The cyclization of the dialkynylpyrene 1 to the
benzpyrene 6 was the most efficient of the substrates 1-5 and,
moreover, could be effected in sunlight (CH3CN, 3 h, Pyrex)
4
(
*
Author to whom correspondence should be addressed.
The Pennsylvannia State University.
Colorado State University.
†
‡
(
1) For reviews, see: (a) Nicolaou, K. C. Angew. Chem., Int. Ed. Engl.
991, 30, 1387. (b) Nicolaou, K. C.; Smith, A. L. Acc. Chem. Res. 1992,
1
2
5, 497. (c) Maier, M. E. Synlett 1995, 13.
(
2) DNA cleavage by bona fide photocycloaromatization reactions have
not yet been reported. However, for DNA cleavage by enediyne and related
compounds by photochemically triggered, thermal cycloaromatization
reactions, see: (a) Nicolaou, K. C.; Dai, W. M.; Wendeborn, S. V.; Smith,
A. L.; Torisawa, Y.; Maligres, P.; Hwang, C. K. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1032. (b) Wender, P. A.; Zercher, C. K.; Beckham, S.;
Haubold, E.-M. J. Org. Chem. 1993, 58, 5867. (c) Wender, P. A.; Beckham,
S.; O’Leary, J. G. Synthesis 1994, 1278. (d) Nakatani, K.; Isoe, S.;
Maekawa, S.; Saito, I. Tetrahedron Lett. 1994, 35, 605. DNA photocleavage
by dynemicin A involves an initial photoreduction step, see: (e) Shiraki,
T.; Sugiura, Y. Biochemistry 1990, 29, 9795. DNA photocleavage by
esperamicin and neocarzinostatin chromophore has also been reported,
see: (f) Sugiura, Y.; Kuwahara, J.; Vesawa, Y. Biochem. Biophys. Res.
Comm. 1989, 164, 903. The latter undergoes a Norrisch Type II cleavage
to produce a fulvene derivative which may be responsible for the DNA
cleavage, see: (g) Hirama, M.; Nehira, T.; Fujiwara, K.; Gomibuche, T.
Tetrahedron Lett. 1993, 34, 5753.
(7) For related observations in thermal cycloaromatizations, see: (a)
Semmelhack, M. F.; Neu, T.; Foubelo, F. J. Org. Chem. 1994, 59, 5038.
(b) Yoshida, K.-i.; Minami, Y.; Otani, T.; Tada, Y.; Hirama, M. Tetrahedron
Lett. 1994, 35, 5253.
(
3) This and related work was presented at the following: 204th National
ACS Meeting Washington, D.C., August, 1992. 33rd National Organic
Chemistry Symposium Bozeman, MO, June, 1993. 34th National Organic
Chemistry Symposium Williamsburg, VA, June, 1995.
(8) The photochemical cycloaromatization of 1,2-di(1-pentynyl)benzene
has recently been reported to proceed in low yield (10-40%), see: Turro,
J. J.; Evenzahav, A.; Nicolaou, K. C. Tetrahedron Lett. 1994, 35, 8089.
0
002-7863/96/1518-3291$12.00/0 © 1996 American Chemical Society