Triggering of the Bergman cyclization by photochemical ring contraction. Facile cycloaromatization of benzannulated cyclodeca-3,7-diene-1,5-diynes

Article abstract of DOI:10.1021/ja064470q

Eleven-membered ring enediyne 1, which incorporates an α-diazo-β-diketone moiety, undergoes efficient light-induced ring contraction to produce two isomeric ten-membered ring enediyne compounds. The latter undergo spontaneous facile Bergman cyclization at

Full text of DOI:10.1021/ja064470q

Published on Web 03/13/2007
Triggering of the Bergman Cyclization by Photochemical Ring Contraction.
Facile Cycloaromatization of Benzannulated Cyclodeca-3,7-diene-1,5-diynes
Grigori V. Karpov and Vladimir V. Popik*
Department of Chemistry, the UniVersity of Georgia, Athens, Georgia 30602
Received June 23, 2006; E-mail: vpopik@uga.edu
Scheme 2. Synthesis of Diazodiketone 1a
The extreme cytotoxicity of natural enediyne antibiotics is
attributed to the ability of the (Z)-3-ene-1,5-diyne fragment to
undergo Bergman cyclization and produce a DNA-damaging
p-benzyne diradical.1,2 Photochemical triggering of this reaction
allows for the spatial and temporal control of enediyne reactivity.
Several examples of light-induced cycloaromatization of acyclic3,4
and cyclic5 enediynes, as well as of natural antibiotic Dynemicin
A,6 have been reported in literature. Our group explores an
alternative strategy of photoactivation: the in situ generation of a
reactive enediyne system, which subsequently undergoes the
cycloaromatization.7
Here we report the first example of triggering of the thermal
Bergman cyclization by the photochemical ring contraction. The
latter process causes substantial increase in the strain energy of
cyclic enediynes, thus triggering the cycloaromatization. It is known
that 11-membered ring enediynes are stable at ambient temperatures,
while 10-membered analogues undergo spontaneous cyclization.8
We have designed and synthesized 11-membered enediyne (1),
which incorporates an R-diazo-â-diketone moiety. Upon irradiation
or thermolysis, 1 undergoes Wolff rearrangement to produce
reactive 10-membered enediynes 3a and 3b. The latter undergo
spontaneous Bergman cyclization (Scheme 1).
a Reagents and conditions: (a) LDA/EtOAc, 90%; (b) TBDMS-Cl,
imidazole/DMAP, 90%; (c) K2CO3/MeOH, 97%; (d) I2/morpholine, ben-
zene, 50 °C, 91%; (e) DIBAL, 91%; (f) CrCl2/NiCl2, THF, 84%; (g) Dess-
Martin periodinane, 92%; (h) HF, MeCN 88%; (i) Dess-Martin periodinane,
84%; (j) DBU, TsN3, 84%.
(TIR) spectroscopy. Ketenes 2a and 2b, which are indistinguishable
at the resolution of the TIR instrument,9 are formed within 30 ns
after the laser pulse and decay with a lifetime of ca. 50 µs in the
presence of 5% methanol in CCl4. The 350 nm irradiation of 1
results in the efficient (Φ350 ) 0.36) dediazotization of the starting
material. However, dihydroanthracene derivatives 4a (54%) and
4b (31%), as well as small amounts of diketone 14 (<10%), were
the only isolated products upon photolysis in 2-propanol (R ) i-Pr,
Scheme 1). 4a and 4b are the major products even at low conversion
(5-10%) of 1. Low-temperature photolysis of 1 allowed us to
isolate unstable ketoester 3a, which undergoes clean cyclization to
4a with τ1/2 ) 5 h at 36 °C in 2-propanol. However, enediyne 3b
was not detected in the photolysate even at 0 °C. This observation
allows us to conclude that enediyne 3b is also formed in the photo-
Wolff reaction of 1 but undergoes rapid thermal Bergman cycliza-
tion to 4b. The lifetime of enediyne 3b (τ1/2 ) 4.5 min) was
measured by following the growth of absorbance of 4b at 248 nm
after 2 min of irradiation.
Scheme 1
The facile cycloaromatization of benzannulated 10-membered
ring cyclic enediynes 3a,b, which resembles that of the strained
nine-membered C-1027 chromophore,13 is rather unusual. Other
known derivatives of 3,4-benzocyclodeca-1,5-diyne (15, Scheme
3) are stable under ambient conditions and undergo slow Bergman
cyclization only at elevated temperatures.14 NMR data9 indicate that
ketoesters 3a, and presumably 3b, predominantly exist in the enol
form (i.e., 3Ea and 3Eb, correspondingly, Scheme 3). An additional
endocyclic double bond apparently reduces the barrier for the
Bergman cyclization. In fact, attempts to prepare 3,4-8,9-dibenzo-
cyclodeca-1,5-diyne produced only 5,12-dihydronaphthacene,15
while annulene 16 (Scheme 3), which can be generated photo-
The target 2-diazo-6,7-benzocycloundeca-4,8-diyn-1,3-dione (1)
was prepared by the diazo transfer reaction from tosyl azide onto
the â-diketone 14 (Scheme 2).9 The latter was in turn prepared by
successive Dess-Martin oxidations of 1,3-diol 11. The crucial
cyclization step has been achieved using the Nozaki-Hiyama-
Kishi procedure (Scheme 2).10
The photo-Wolff reaction11 of diazodiketone 1 was expected to
produce two isomeric â-ketoketenes 2a and 2b, which should
rapidly react with the hydroxylic solvents (τH O ∼ 1 µs)12 to give
2
â-ketoesters 3a and 3b (Scheme 1).
In fact, the formation of a characteristic ketene band at 2212
cm-1 in laser flash photolysis of 1 was detected by transient IR
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C O M M U N I C A T I O N S
chemically or using flash vacuum pyrolysis, is a short-lived transient
at room temperature16 and is relatively stable only in cryogenic
matrices.17
Scheme 3
Figure 1. Light-induced cleavage of æX174 DNA in the presence of 1.
Lanes 1-5: DNA irradiated for 0, 15, 45, 180, and 480 s. Lanes 6-9:
DNA + 1 (1787 µM), irradiated for 0, 15, 45, and 180 s. Lanes 10-14:
DNA + 1 (488 µM), irradiated for 0, 15, 45, 180, and 480 s. Lanes 15-
19: DNA + 1 (82 µM), irradiated for 0, 15, 45, 180, and 480 s. Lane 20:
DNA incubated with PSt-I restriction enzyme for 1 h at 37 °C. Lane 21:
DNA alone.
The reactivity difference between regioisomeric enediynes 3a
and 3b is also quite remarkable. We believe that this phenomenon
is caused by the electronic influence of the substituent at the vinylic
terminus of the π-conjugated system. The electron-rich hydroxyl
group in 3Eb donates electron density to the out-of-plane π-orbitals,
thus increasing the aromatic stabilization of the Bergman cyclization
transition state.18 The electron-withdrawing carbonyl group in 3Ea,
on the other hand, retards the cycloaromatization reaction.
In addition, the photochemistry of R-diazo-â-diketone 1 provides
us with the first direct experimental comparison of migratory
aptitudes of sp3- and sp-hybridized carbon atoms in the Wolff
rearrangement. â-Ketoesters 4a and 4b, which are formed by the
migration of alkyl and acetylenic substituents, correspondingly, are
obtained in the ratio of 7:4. This observation indicates the
preferential migration of the alkyl versus alkynyl substituents in
the Wolff rearrangement. Thermolysis of 1 at 100 °C in ethanol in
the presence of 1,4-cyclohexadiene produces 4a and 4b (R ) Et)
in a similar ratio.
An initial evaluation of the DNA cleavage ability of photoge-
nerated 10-membered ring enediynes 3a and 3b was carried out
using supercoiled plasmid DNA cleavage assays. Three forms of
this DNA [native (RF I), circular relaxed (RF II, produced by single-
strand cleavage), and linear (RF III, formed by scission of both
strand in close proximity)] are readily separated by the agarose gel
electrophoresis.
Solutions containing various concentrations of 1 and æX174
supercoiled circular DNA (30 ng/µL) were irradiated at 351.1 nm
using an argon ion laser at ca. -5 °C. Diazodiketone 1 induces
substantial single-strand cleavage (RF II) of æX174 DNA upon
irradiation, while the linearized form (RF III) was observed only
at higher concentrations of the cleaving agent (>500 µM) and
prolonged irradiation (Figure 1). The relatively high concentrations
of 1, which are required to achieve double-strand DNA photoscis-
sion, indicate that 1 has low affinity to a dDNA molecule. In order
to improve the photonuclease activity of enediyne 1, it is being
conjugated with a dDNA minor-groove binding moiety. It is also
interesting to note that irradiation of 1 in the presence of æX174
produces a new modification of DNA with lowest electrophoretic
mobility (Figure 1). The nature of this band, which was preliminar-
ily attributed to the covalently cross-linked dimer, is under
investigation.
termini of the extended π-system have pronounced effect on the
reactivity of the dienediyne system.
Acknowledgment. We thank the NIH (CA91856-01A1) and
the NSF (CHE-0449478) for the support of this project, and
Professor R.M. Wilson and Dr. E.T. Mack for the assistance in
conducting DNA photocleavage experiments.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
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In conclusion, the photoswitchable enediyne compound, which
is stable in the dark but converted into a very reactive form by
light-induced ring contraction, has been designed and synthesized.
Benzannulated 10-membered ring enediynes containing an ad-
ditional endocyclic double bond undergo facile cycloaromatization
even at 0 °C. The electronic properties of substituents at the alkene
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