C O M M U N I C A T I O N S
Scheme 3. Comparison of Diradical and Radical Anion Pathways
for the C1-C5 Cyclization of Parent Enediyne
A key feature of the new reaction is the likely involvement of
photoinduced electron transfer (PET) from an organic donor to the
excited enediyne. Further mechanistic studies, solvent, isotope, and
substituent effect studies as well as the application of this novel
reaction to DNA cleavage will be reported in a due course.
Acknowledgment. We thank Professor R. Clark for the deter-
mination of the X-ray structure of compound 3b, Professors J.
Saltiel, A. Kutateladze, and W. Herz for helpful discussions, Dr.
M. Manoharan for computational assistance. Mr. F. Bou-Hamdan
for performing NOE NMR experiments, and Professor R. Holton
for the use of NMR facilities. I.A. is grateful to Florida State
University for a First Year Assistant Professor Award.
Scheme 4. Possible Scheme for Formation of the Photochemical
Products
Supporting Information Available: Experimental procedures, 1H,
13C, 19F NMR spectra for all compounds, details of B3LYP/6-31G**
computations (PDF). An X-ray crystallographic file of indene 3b (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) (a) Nicolaou, K. C.; Smith, A. L. Acc. Chem. Res. 1992, 25, 497. (b)
Maier, M. E.; Bosse, F.; Niestroj, A. J. Eur. J. Org. Chem. 1999, 1, 1. (c)
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159. (e) Caddick, S.; Delisser, V. M.; Doyle, V. E.; Khan, S.; Avent, A.
G.; Vile, S. Tetrahedron 1999, 55, 2737. (f) Enediyne Antibiotics as
Antitumor Agents; Borders, D. B., Doyle, T. W., Eds.; Marcel Dekker:
New York, 1995.
(2) Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660. Bergman,
R. G. Acc. Chem. Res. 1973, 6, 25.
(3) Kagan, J.; Wang, X.; Chen, X.; Lau, K. Y.; Batac, I. V.; Tuveson, R. W.;
Hudson. J. B J. Photochem. Photobiol. B: Biol. 1993, 21, 135. Funk, R.
L.; Young, E. R. R.; Williams, R. M.; Flanagan, M. F.; Cecil, T. L. J.
Am. Chem. Soc. 1996, 118, 3291. Kaneko, T.; Takanashi, M.; Hirama,
M. Angew. Chem. 1999, 38, 1267. Jones, G. B.; Wright, J. M.; Plourde,
G., II; Purohit, A. D.; Wyatt, J. K.; Hynd, G.; Fouad F. J. Am. Chem.
Soc. 2000; 122, 9872. Choy, N.; Blanco, B.; Wen, J.; Krishan; A.; Russell,
K. C. Org. Lett. 2000, 2, 3761.
photoinduced electron transfer (PET) from 1,4-cyclohexadiene to
the singlet excited states of the enediynes 2a-c highly exothermic
(>25 kcal/mol). At this exothermicity, PET should be diffusion-
controlled and we do observe efficient quenching of fluorescence
of enediyne 3a by cyclohexadiene.9 Unlike the cyclization of neutral
enediynes, the C1-C5 cyclization of the enediyne radical anions
leads to an intermediate stabilized through resonance involving
cyclopentadienyl anion (Scheme 3), thus rendering this cyclization
mode possible.10
Taking into account the circumstantial evidence for the radical
anion pathway, we performed the photolysis in the presence of CH3-
OD and observed partial deuterium incorporation at both methylene
groups of indene 3a.
These observations suggest that C1-C5 ring closure with the
formation of a fulvene radical anion is initiated by electron transfer
from 1,4-cyclohexadiene to the enediyne excited singlet state. The
fulvene radical anion may either abstract a hydrogen atom from
1,4-cyclohexadiene or abstract a proton from the cyclohexadienyl
radical cation. Both pathways have precedents: hydrogen donor
activity of 1,4-cyclohexadiene is commonly used for quenching of
1,4-diradicals formed in Bergman cyclizations, whereas radical
cations are known to be very strong acids (e.g., pKa of toluene
radical cation in DMSO is -20).11 The relative timing and
regioselectivity of proton and H-atom abstraction are not clear at
this time. Although the protonation is likely to be fast, the possibility
of a H-atom abstraction in an intimate ion pair cannot be eliminated.
A possible sequence of further steps accounting for the formation
of the observed products is outlined in Scheme 4.
(4) Turro, N. J.; Evenzahav, A.; Nicolaou, K. C. Tetrahedron Lett. 1994, 15,
8089. Evenzahav, A.; Turro, N. J. J. Am. Chem. Soc. 1998, 120, 1835.
(5) Artamkina G. A.; Kovalenko S. V.; Beletskaya I. P.; Reutov O. A. Russ.
J. Org. Chem. 1990, 26, 225. For fluoride-induced reaction of organo-
silicon compounds with electron-deficient aromatic substrates see also:
(a) RajanBabu T. V.; Fukunaga T. J. Org. Chem. 1984, 49, 4571. (b)
RajanBabu, T. V.; Reddy, G. S.; Fukunaga, T. J. Am. Chem. Soc. 1985,
107, 5473. (c) Artamkina, G. A.; Kovalenko, S. V.; Beletskaya I. P.;
Reutov, O. A. Russ. J. Organomet. Chem., 1987, 329, 139. (d) Kovalenko,
S. V.; Artamkina, G. A.; Beletskaya, I. P.; Reutov O. A. J. Organomet.
Chem. 1988, 1, 125.
(6) Indenes 3a-c and 4c were isolated by HPLC and completely characterized
by spectral methods and, in the case of 3b, by X-ray crystallography (See
the Supporting Information for the details and Figure 1 for the X-ray
structure). Products of radical addition to cyclohexadiene are also present
in the reaction mixture as confirmed by GC-MS. The overall reaction
mass balance is high, but the isomeric reaction products are hard to
separate. This accounts for the low isolated product yields.
(7) Fulvenes are easily reduced: Tacke, M.; Fox, S.; Cuffe, L.; Dunne, J. P.;
Hartl F.; Mahabiersing, T. J. Mol. Struct. 2001, 559, 331.
(8) Prall, M.; Wittkopp, A.; Schreiner, P. A. J. Phys. Chem. A 2001, 105,
9265.
(9) The exothermicity has been calculated using the Rehm-Weller equation
and reduction potentials of enediynes 2 vs SCE in CH3CN (ca. -1.1 V).
ox
Rehm, D.; Weller, A. Isr. J. Chem. 1970, 8, 59. ∆GPET ) F(E1/2
-
red
E1/2 - e/ꢀR) - E0,0 where the Coulombic attraction term Fe/ꢀR is
estimated as 1.3 kcal mol-1 (see Mangion, D.; Kendall, J.; Arnold D. R.
Org. Lett. 2001, 3, 45) Oxidation potential of 1,4-cyclohexadiene in CH3-
CN was taken as 1.74 (Shono, T.; Ikeda, A.; Hayashi, J.; Hakozaki, S. J.
Am. Chem. Soc. 1975, 97, 4261.)
(10) The importance of the aromatic resonance structure in Scheme 3 is
supported by nuclear independent chemical shift (NICS) calculations that
show increased aromatic ring current in this radical anion and by natural
bond orbital analysis of its electronic structure. Benzannelation and
benzylic conjugation with terminal aromatic system are likely to decrease
the activation energy further and make this reaction exothermic. Alabugin,
I. V.; Manoharan, M. Manuscript in preparation.
To summarize, we have found a new mechanistically interesting
C1-C5 cyclization of enediynes. Unlike the Bergman cycloaro-
matization pathway, which involves two H-atom abstractions, the
new reaction is accompanied by four formal H-atom abstractions
(or two H-atom/two proton abstractions) and thus may provide a
new DNA-damaging warhead for use in biochemical applications.12
(11) Bordwell F. G., Cheng J.-P. J. Am. Chem. Soc. 1989, 111, 1792.
(12) Potentially, such warheads can target either DNA sugar residues or
nucleobases (e.g., guanine). Armitage, B. Chem. ReV. 1998, 98, 1171.
JA026630D
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