Dual reactivity of a photochemically-generated cyclic enyne-allene

Article abstract of DOI:10.1039/b911871c

A reactive ten-membered ring enyne-allene (τ_{25 °C} = 5-6 min) is efficiently generated (Φ_{300 nm} = 0.57) by UV irradiation of a thermally stable precursor in which a triple bond is masked as a cyclopropenone moiety.

Full text of DOI:10.1039/b911871c

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Dual reactivity of a photochemically-generated cyclic enyne–allenew
Alexander V. Kuzmin and Vladimir V. Popik*
Received (in College Park, MD, USA) 17th June 2009, Accepted 27th July 2009
First published as an Advance Article on the web 14th August 2009
DOI: 10.1039/b911871c
A reactive ten-membered ring enyne–allene (s25 1C = 5–6 min) is
efficiently generated (U300 nm = 0.57) by UV irradiation of a
thermally stable precursor in which a triple bond is masked as a
cyclopropenone moiety.
cyclopropenone. The p-system of the cyclopropenone moiety
in the enyne–allene precursor 1 is orthogonal to the plane of
the ring, therefore, cyclopropenone 1 lacks the crucial in-plane
overlap of p-orbitals that is required for cycloaromatization.
Photochemical decarbonylation of cyclopropenones is usually
1
5
Natural enediyne antibiotics are arguably the most potent
1
antineoplastic agents ever discovered. Their cytotoxicity
an efficient process and has been successfully employed for
11a,b
the generation of reactive enediynes.
Thus, irradiation of
is attributed to the ability of the (Z)-3-hexene-1,5-diyne
cyclopropenone 1 results in the loss of carbon monoxide
and regeneration of the triple bond, making the substrate
susceptible to the Myers–Saito cyclization (Scheme 1).
(
enediyne) and (Z)-1,2,4-heptatrien-6-yne (enyne–allene)
fragments to undergo cycloaromatization, producing cytotoxic
2
benzenoid diradicals. The lack of anti-tumor selectivity of this
class of natural products results in high general toxicity
and hampers their clinical applications. Photo-triggering of
the cycloaromatization reaction opens the possibility for the
selective treatment of cancerous tissues in a fashion similar to
1
,3,4
5
photodynamic therapy.
The direct irradiation of acyclic
6
and cyclic enediynes, enyne–allenes/cummulenes, as well as
8
of natural antibiotic Dynemicin A, induces the formation of
7
various diradical species albeit with rather low efficiency. The
quantum yield of the photochemical Bergman cyclization
can be substantially improved by adjusting the electronic
Scheme 1 Photochemical generation of enyne–allene 2.
The crucial cyclopropenone moiety was synthesized in
a two step procedure (Scheme 2).w First, the addition of
difluorocarbene, which was generated by the thermolysis of
9
properties of substituents and/or using different modes of
1
excitation energy transfer, such as MLCT.
0
1
6
Our group has developed an alternative strategy for the
trimethylsilyl fluorosulfonyldifluoroacetate, to the acetylene
4 produced 1,1-difluorocyclopropene 5. Then, the latter was
hydrolyzed on wet silica gel to give cyclopropenone 6. The
presence of the cyclopropenone moiety in synthetic inter-
mediate 6 limits the range of reagents and reaction conditions
that can be employed, since cyclopropenones readily form
salts with Lewis acids and give ring-opening products with
photo-triggering of the cycloaromatization reaction: the in situ
1
1
generation of reactive enediynes. However, the rate of the
Bergman cyclization of even highly strained nine-membered
1
1a
ring enediynes (t25 1C B 2 h) is not fast enough to allow for
the temporal and spatial resolution of p-benzyne generation
in biological systems. In order to enhance the rate of the
formation of cytotoxic 1,4-diradicals, we turned our attention
to compounds containing a (Z)-1,2,4-heptatrien-6-yne structural
fragment, i.e., enyne–allenes. Myers–Saito cyclization of these
substrates produces a,3-didehydrotoluene analogs, which are
responsible for the cytotoxicity of natural antibiotics of the
1
7
various nucleophiles. Conversion of 6 into 2,2-dimethyl-1,3-
1
8
propanediyl acetal 7 allows us to circumvent these difficulties.
The second acetylenic substituent was introduced using
conventional Stille coupling conditions (8, Scheme 2).
Simultaneous saponification of the acetate and removal of
the trimethylsilyl protecting group to give 9 was achieved using
potassium carbonate in aqueous methanol. Iodination of
1
2
neocarzinostatin family.
undergo spontaneous cyclization under ambient conditions,
while cyclic enyne–allenes are virtually unknown apparently
Acyclic enyne–allenes usually
1
3
1
9
terminal acetylene with an iodine–morpholine system,
20
followed by Dess–Martin oxidation gave iodoaldehyde 11.
11c,14
due to their ability to undergo very rapid cycloaromatization.
Here we report the first example of the direct photochemical
Macrocyclization to form ten-membered cycle 12 was achieved
2
1
generation of ten-membered ring cyclic enyne–allene 2
under Nozaki–Hiyama–Kishi conditions. The key step in the
synthesis of enyne–allene precursor 1 is the acetylene–allene
rearrangement. Several enyne–allenes were prepared by
isomerization of propargyl alcohol employing Mitsunobu
(
Scheme 1). To synthesize a thermally stable photo-precursor
of enyne–allene 2 we decided to mask the triple bond as a
2
2
reaction with 2-nitro-benzenesulfonyl hydrazide. Acetal 12,
Department of Chemistry, University of Georgia, Athens,
Georgia 30602, USA. E-mail: vpopik@uga.edu;
however, is not stable under Mitsunobu conditions and we
2
3
had to adopt an alternative procedure. The reaction of
propargylic mesylate 13 with EtMgBr in the presence of an
excess of CuCN and LiCl led to the exclusive formation
of the desired allene (14). Acetal deprotection was achieved
Fax: +1 (706) 542-9454; Tel: +1 (706) 542-1953
w Electronic supplementary information (ESI) available: Preparation
1
of cyclopropenone 1, detailed experimental procedures, H and
13
C
spectra of newly synthesized compounds. See DOI: 10.1039/b911871c
This journal is ꢀc The Royal Society of Chemistry 2009
Chem. Commun., 2009, 5707–5709 | 5707

View Article Online
Scheme 2 Reagents and conditions: (a) NaF, TFDA, 120 1C; (b) wet SiO
2
, 85% over two steps; (c) Et
3
OBF
4
, neopentylglycol, Et
3
N, 80%;
, 95%;
(
d) Pd(PPh
3
)
4
, Bu
3
SnCRCSiMe
3
, 90 1C, 72%; (e) K
2
CO
3
, MeOH (aq.), 84%; (f) I –morpholine, 72%; (g) DMP, 73%; (h) CrCl
2
2
, NiCl
2
s
i) MsCl, 90%; (j) CuCN, LiCl, EtMgBr, 83%; (k) Amberlyst 15, acetone, 75%.
(
s
using Amberlyst 15 in aqueous acetone to produce target
The outcome of the cyclization reaction, on the other hand,
strongly depends on the solvent. In THF, in the presence
of 1,4-cyclohexadiene, 9-ethyl-1,2,3,4-tetrahydroanthracene (3)
is formed as a major product (Scheme 3). This compound is
the expected product of the Myers–Saito cyclization and is
apparently formed via double hydrogen abstraction by the
diradical 15 (Scheme 3). In 2-propanol, however, insertion of
the solvent into the O–H bond, which produces 9-ethyl-1-
isopropoxy-1,2,3,4-tetra-hydroanthracene (17), is a predominant
process (Scheme 3). Minor amounts of 10-ethyl-1,2-dihydro-
anthracene were also isolated in both solvents.
7
-ethyl-6-dehydro-2,3,4-trihydro-1H-benzo[a]cyclo-propa[c]-
cyclode-cen-1-one (1, Scheme 2).
The UV spectrum of cyclopropenone 1 shows three close
lying absorbance bands at 237 nm (log e = 4.3), 267 nm
(
log e = 3.8), and 317 nm (log e = 3.4). Irradiation of
cyclopropenone 1 with 300 or 350 nm light results in the
efficient decarbonylation (F300 nm = 0.57 Æ 0.03) and formation
of the target ten-membered ring enyne–allene (2, Scheme 1).
The latter is quite reactive and undergoes facile spontaneous
Myers–Saito cyclization. The accurate rate measurements of
cycloaromatization of the enyne–allene 2 were conducted by
UV spectroscopy following the growth of the characteristic
2
32 nm band of tetrahydroanthracenes 3 or 17 (Scheme 3). As
shown in Fig. 1, the reaction shows first order kinetics.
The rate of the cycloaromatization at 25 Æ 0.1 1C was
À3
À1
in 2-propanol and
k = (2.735 Æ 0.046) Â 10
s
À3 À1
k = (3.41 Æ 1.01) Â 10
s
in THF containing 0.05 M
1
,4-cyclohexadiene (Fig. 1).
Scheme 3
The formation of ether 17 is inconsistent with the
conventional diradical mechanism of the Myers–Saito cyclization.
In 2-propanol, the s,p-diradical 15 is expected to abstract
hydrogen from the secondary carbon of the alcohol, since this
C–H bond is much weaker than the O–H bond. The O–H
insertion observed in 2-propanol suggests a polar, rather than
a radical, pathway of the cycloaromatization in that medium
(
16, Scheme 3). Similar ‘‘dual reactivity’’ has been reported
for acyclic enyne–allenes and was initially explained by the
‘
‘polar’’ nature of the a,3-didehydrotoluene, which can be
24
described as a resonance between a zwitterion and a diradical.
This hypothesis was later rejected on the basis of quantum
mechanical calculations since frontier orbitals in these two
electronic forms of a,3-didehydrotoluene are strictly orthogonal
Fig. 1 Cycloaromatization of the photo-generated enyne–allene 2 in
THF–1,4-cyclohexadiene (open circles) and in 2-propanol (filled circles)
at 25 1C. Solid lines represent fitting of the experimental data to a
single exponential equation.
2
5
and can not be mixed. Carpenter et al. proposed the
formation of O–H insertion product via a non-adiabatic
2
5b
It is interesting to note that the life-time of enyne–allene 2
shows little sensitivity to the reaction media (t25 1C B 5–6 min).
pathway.
The analysis of the reactivity of acyclic enyne–
allenes is complicated by the presence of conformational
5
708 | Chem. Commun., 2009, 5707–5709
This journal is ꢀc The Royal Society of Chemistry 2009

View Article Online
equilibrium. The position of the equilibrium, which should
depend on the solvent polarity, controls the rate, and potentially
the mechanism, of the cycloaromatization reaction. Enyne–
allene 2, on the other hand, is locked in the most reactive
conformation and allows us to focus the investigation of
enyne–allene reactivity on electronic factors.
3 R. Ackroyd, C. Kelty, N. Brown and M. Reed, Photochem.
Photobiol., 2001, 74, 656.
4
5
M. Kar and A. Basak, Chem. Rev., 2007, 107, 2861.
F. S. Fouad, C. F. Crasto, Y. Lin and G. B. Jones, Tetrahedron
Lett., 2004, 45, 7753; D. Falcone, J. Li, A. Kale and G. B. Jones,
Bioorg. Med. Chem. Lett., 2008, 18, 934; J. Kagan, X. Wang,
X. Chen, K. Y. Lau, I. V. Batac, R. W. Tuveson and J. B. Hudson,
J. Photochem. Photobiol., B, 1993, 21, 135; N. J. Turro,
A. Evenzahav and K. C. Nicolaou, Tetrahedron Lett., 1994, 35,
8089; T. Kaneko, M. Takahashi and M. Hirama, Angew. Chem.,
Int. Ed., 1999, 38, 1267; I. I. G. Plourde, II, A. El-Shafey,
F. S. Fouad, A. S. Purohit and G. B. Jones, Bioorg. Med. Chem.
Lett., 2002, 12, 2985; J. D. Spence, A. E. Hargrove,
H. L. Crampton and D. W. Thomas, Tetrahedron Lett., 2007,
48, 725.
An initial evaluation of the nuclease activity of the photo-
generated enyne–allene 2 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
agarose gel electrophoresis.w To produce reactive enyne–allene
6
7
R. L. Funk, E. R. R. Young, R. M. Williams, M. F. Flanagan and
T. L. Cecil, J. Am. Chem. Soc., 1996, 118, 3291; Z. Zhao,
J. G. Peacock, D. A. Gubler and M. A. Peterson, Tetrahedron
Lett., 2005, 46, 1373; N. Choy, B. Blanco, J. Wen, A. Krishan and
K. C. Russell, Org. Lett., 2000, 2, 3761.
2
in the presence of DNA, a solution of cyclopropenone 1 in
water–DMSO (4 : 1) mixtures was added to a solution of
jX174 supercoiled circular DNA in TE buffer and irradiated
G. Bucher, A. A. Mahajan and M. Schmittel, J. Org. Chem., 2008,
for 10 min using 350 nm lamps (6 Â 4W). The concentration of
7
3, 8815; M. Schmittel, A. A. Mahajan and G. Bucher, J. Am.
Chem. Soc., 2005, 127, 5324.
8 T. Shiraki and Y. Sugiura, Biochemistry, 1990, 29, 9795.
I. V. Alabugin and M. Manoharan, J. Phys. Chem. A, 2003, 107,
363; I. V. Alabugin, M. Manoharan and S. V. Kovalenko, Org.
À1
DNA was kept at 10 ng mL in all experiments, while
the initial concentration of cyclopropenone 1 varied from
9
0
to 5 mM. The duration of irradiation was sufficient to
3
achieve at least 95% conversion of 1, as was determined by
HPLC. The irradiated and control solutions were incubated
for 16 h at 25 1C in the dark and analyzed by gel electro-
phoresis. At concentrations above 0.1 mM, photo-generated
enyne–allene 2 was found to induce ca. 15% single-strand
cleavage of jX174 DNA (RF II), but no observable
double-strand cleavage (RF III). A further increase in the
concentration of precursor 1 results in the reduced photo-
nuclease efficiency due to aggregation of the substrate.
Incubation of the DNA with cyclopropenone precursor 1 in
the dark does not induce any detectable DNA cleavage. The
relatively low nuclease efficiency of 2 can be explained either
by predominant polar cycloaromatization pathway or by the
low affinity of 1 to a dDNA molecule. In order to address the
latter problem, we are currently working on the design and
synthesis of cyclopropenone 1 analogs containing a dDNA
minor-groove binding moiety.
Lett., 2002, 4, 1119; A. E. Clark, E. R. Davidson and J. M. Zaleski,
J. Am. Chem. Soc., 2001, 123, 2650.
10 P. J. Benites, R. C. Holmberg, D. S. Rawat, B. J. Kraft, L. J. Klein,
D. G. Peters, H. H. Thorp and J. M. Zaleski, J. Am. Chem. Soc.,
2003, 125, 6434; S. Bhattacharyya, M. Pink, M. H. Baik and
J. M. Zaleski, Angew. Chem., Int. Ed., 2005, 44, 592.
11 (a) A. Polukhtine, G. Karpov and V. V. Popik, Curr. Top. Med.
Chem., 2008, 8, 460; (b) D. R. Pandithavidana, A. Poloukhtine and
V. V. Popik, J. Am. Chem. Soc., 2009, 131, 351; (c) G. Karpov,
A. Kuzmin and V. V. Popik, J. Am. Chem. Soc., 2008, 130, 11771.
1
2 K. K. Wang, Chem. Rev., 1996, 96, 207.
13 I. H. Goldberg, Acc. Chem. Res., 1991, 24, 191.
4 T. Bekele, S. R. Brunette and M. A. Lipton, J. Org. Chem., 2003,
8, 8471; K. Toshima, K. Ohta, T. Kano, T. Nakamura,
1
6
M. Nakata, M. Kinoshita and S. Matsumura, Bioorg. Med. Chem.,
1996, 4, 105.
15 J. Ciabattoni and E. C. Nathan, J. Am. Chem. Soc., 1969, 91, 4766;
E. V. Dehmlow, R. Neuhaus and H. G. Schell, Chem. Ber., 1988,
1
7
21, 569; A. Poloukhtine and V. V. Popik, J. Org. Chem., 2003, 68,
833.
16 Z.-L. Cheng and Q.-Y. Chen, Chin. J. Chem., 2006, 24, 1219;
Z.-L. Cheng and Q.-Y. Chen, J. Fluorine Chem., 2005, 126, 39;
W. Xu and Q.-Y. Chen, J. Org. Chem., 2002, 67, 9421.
In summary, we have demonstrated that reactive cyclic
enyne–allenes can be photochemically generated from
thermally stable precursors with good quantum and chemical
yields. The reactivity of benzannulated ten-membered ring
enyne–allene 2 depends on the media. In solvents of low
polarity products of the cycloaromatization reaction are
consistent with the intermediate formation of a diradical
species. In 2-propanol, on the other hand, the reactions
apparently proceed via a polar mechanism.
1
7 K. T. Potts and J. S. Baum, Chem. Rev., 1974, 74, 189; B. Halton
and M. G. Banwell, in The Chemistry of Cyclopropyl Group,
ed. Z. Rappoport, Wiley, New York, 1987, 1300.
18 M. Isaka, S. Ejiri and E. Nakamura, Tetrahedron, 1992, 48, 2045.
´
19 C. Crevisy and J.-M. Beau, Tetrahedron Lett., 1991, 32, 3171.
20 D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155.
21 K. Takai, M. Tagashira, T. Kudora, K. Oshima, K. Utimoto and
H. Nozaki, J. Am. Chem. Soc., 1986, 108, 6048; T. D. Aicher and
Y. Kishi, Tetrahedron Lett., 1987, 28, 3463; T. Brandstetter
and M. E. Maier, Tetrahedron, 1994, 50, 1435; C. W. Harwig,
S. Py and A. G. Fallis, J. Org. Chem., 1997, 62, 7902.
2
2 A. G. Myers, B. Zheng and M. Movassaghi, J. Org. Chem., 1997,
2, 7507; A. G. Myers and B. Zheng, J. Am. Chem. Soc., 1996, 118,
4492.
Notes and references
6
1
G. B. Jones and F. S. Fouad, Curr. Pharm. Des., 2002, 8, 2415;
D. B. Borders and T. W. Doyle, Enediyne Antibiotics as
Antitumor Agents, Marcel Dekker, New York, 1995;
G. M. Cragg, D. G. Kingston and D. J. Newman, Anticancer
agents from Natural Products, Taylor & Francis Group, Boca
Raton, FL, 2005; A. L. Smith and K. C. Nicolaou, J. Med. Chem.,
23 M. C. Pacheco and V. Gouverneur, Org. Lett., 2005, 7, 1267.
24 A. G. Myers, E. Y. Kuo and N. S. Finnney, J. Am. Chem. Soc.,
1989, 111, 8057; R. Nagata, H. Yamanaka, E. Okazaki and
I. Saito, Tetrahedron Lett., 1989, 30, 4995; A. G. Myers,
P. S. Dragovich and E. Y. Kuo, J. Am. Chem. Soc., 1992, 114,
9369.
25 (a) C. J. Cramer, B. L. Kormos, M. Seierstad, E. C. Sherer and
P. Winget, Org. Lett., 2001, 3, 1881; (b) M. E. Cremeens,
T. S. Hughes and B. K. Carpenter, J. Am. Chem. Soc., 2005,
127, 6652.
1996, 39, 2103.
U. Galm, M. H. Hager, S. G. VanLanen, J. Ju, J. S. Thorson and
2
B. Shen, Chem. Rev., 2005, 105, 739; B. Shen and K. Nonaka, Curr.
Med. Chem., 2003, 10, 2317; M. Gredicak and I. Jeric, Acta
ˇ ´
Pharm., 2007, 57, 133.
This journal is ꢀc The Royal Society of Chemistry 2009
Chem. Commun., 2009, 5707–5709 | 5709