Synthesis and reactivity of cinnoline-fused cyclic enediyne

Article abstract of DOI:10.1021/jo201148h

A short and efficient synthesis of cinnoline-fused cyclic enediyne is reported. Richter cyclization of o-(1,3-butadiynyl)phenyltriazene produced 3-alkynyl-4-bromocinnoline. The Sonogashira coupling of the latter with 5-hexyn-1-ol was employed for the intr

Full text of DOI:10.1021/jo201148h

NOTE
pubs.acs.org/joc
Synthesis and Reactivity of Cinnoline-Fused Cyclic Enediyne
Olga V. Vinogradova,† Irina A. Balova,*,‡ and Vladimir V. Popik*,†
†Department of Chemistry, University of Georgia, Athens, Georgia 30602, United States
‡Department of Chemistry, St. Petersburg State University, 198504 St. Petersburg, Russian Federation
S Supporting Information
b
ABSTRACT:
A short and efficient synthesis of cinnoline-fused cyclic enediyne is reported. Richter cyclization of o-(1,3-butadiynyl)phenyltriazene
produced 3-alkynyl-4-bromocinnoline. The Sonogashira coupling of the latter with 5-hexyn-1-ol was employed for the introduction
of a second acetylenic moiety. The crucial cyclization step was achieved under NozakiÀHiyamaÀKishi conditions. Cinnoline-fused
10-membered ring enediyne is more reactive than corresponding carbocyclic analog and produces good yield of the Bergman
cyclization product upon mild heating. This enediyne induces single-strand dDNA scissions upon incubation at 40 °C.
atural antibiotics belonging to the enediyne family are
among themostpotentantineoplasticagentseverdiscovered.1
enhanced dDNA affinity via intercalation mechanism.16,17 Final-
ly, cinnoline-based compounds structurally similar to the com-
pound 10 (vide infra) have been recently shown to inhibit
topoisomerase I activity, even in multidrug resistant cancer cells.18
This feature can be employed for the development of antibiotics
with dual antineoplastic activity mode. Initial enediyne cycloar-
omatization produces p-benzyne diradical, which abstract hydro-
gen from DNA inducing strand scission. The TOPO I inhibition
by the stable product of the first step further increases the
cytotoxic effect of the drug. Here, we report an efficient synthesis
of a model cinnoline-fused 10-membered enediyne system, as
well as preliminary studies of its cycloaromatization and nuclease
activity.
The first step of the target cinnolinoenediyne 8 synthesis
employs recently developed method for the preparation of
3-alkynyl-4-halocinnolines (Scheme 1).19 Reaction of diethyl-
amine with o-iodobenzenediazonium chloride, produced in situ
by diazotization of o-iodoaniline, gave triazene 1 in 94% yield.
Sonogashira cross-coupling20 of the latter with mono TMS-
potected buta-1,3-diyne led to o-(trimethylsilylbuta-1,3-diynyl)-
phenyltriazene 2 in an excellent yield. HBr-induced cleavage of 2,
followed by Richter-type cyclization of the resulting arenediazo-
nium salt, produced 4-bromo-3-(trimethylsilylethynyl)cinnoline
(3, Scheme 1). The bromine atom in 3 was replaced with
5-hexyn-1-ol under Sonogashira conditions to introduce the second
acetylenic moiety. To synthesize the cyclic analogue of the cyn-
nolinoenediyne 4, we decided to employ NozakiÀHiyamaÀ
Kishi reaction,21 adapted to iodoacetylenes by Crevisy and
N
The cytotoxicity of these natural products is attributed to the
ability of the (Z)-3-ene-1,5-diyne fragment to undergo Bergman
cyclization2 and produce DNA-damaging p-benzyne diradical.1
The development of methods to control cycloaromatization
reactions and direct powerful DNA-cleaving activity of enediyne
antibiotics toward cancerous cells represents an important goal in
current medicinal chemistry.3 In addition, enediyne cycloaroma-
tization is used in the development of selective nucleases,4 enzyme
inhibitors,5 high-performance linear aromatic polymers,6 and
polymer initiators7 and in the synthesis of polyaromatic com-
pounds.8 Natural enediynes are too scarce for practical use; there-
fore, there is a significant interest in developing efficient syntheses
of simpler enediyne compounds. High temperatures required to
induce cyclization of acyclic enediynes make them unsuitable for
a majority of applications, especially in biology and biochemistry.
Among cyclic enediynes, 11- or larger ring systems possess reac-
tivity similar to that of the acyclic analogus,9 while nine-mem-
bered ring enediynes are virtually unknown because of fast spon-
taneous cyclization.10,11 The rate of the Bergman cyclization of
10-membered ring enediyne compounds strongly depends on
both the ring strain of enediyne-containing cycle12 and the
electronic properties of substituents.13,14 While fusion with het-
erocycles provides an alternative strategy for the control of elec-
tronic properties of the enediyne system, only few examples of
heterocycle-fused enediynes are known.15 Nitrogen heterocycles,
such as cinnoline discussed in this report, can be protonated, thus
broadening the range of the electronic density modulation of
the enediyne π-system. In addition, conjugation with cinnolines
provides enediyne-based nucleases with an additional benefit:
Received: June 3, 2011
Published: June 30, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo201148h J. Org. Chem. 2011, 76, 6937–6941
|

The Journal of Organic Chemistry
NOTE
Scheme 1. Synthesis of Cinnolinoenediyne 8
Scheme 2. Thermally Induced Bergman Cyclization of Enediyne 8
Beau22 (Scheme 1). Iodoacetylene component for this reaction
was prepared by removing trimethylsyl protecting group in 4 and
subsequent treating of the resulting terminal acetylene 5 with
NIS in the presence of AgNO3.23 The hydroxyl group of in 6 was
oxidized by PCC to corresponding aldehyde 7 in 52% yield.24
The crucial cyclization of iodoacetylene 7, conducted under
conventional NozakiÀHiyamaÀKishi cross-coupling conditions
in THF, initially failed to produce the target compound. Accord-
ing to DIP-MS analysis, the insoluble precipitate formed in this
reaction contained some of the cyclized product but all our iso-
lation attempts yielded only small amounts of 8. Since cinnolines
are known to from complexes with various transition metals,25
we suspected that insoluble product was a complex of cinnoline
moiety in 8 and Ni or Cr. To alleviate this problem, we have
performed NozakiÀHiyamaÀKishi coupling in DMF. The con-
sumption of starting material was somewhat slower in this
medium, but we were able to isolate the target enediyne 8 in
40% yield. In addition, using DMF as a reaction medium allowed for
the 10-fold increase in concentration of the precursor 7 without
significant formation of the dimer. We have also tried to conduct the
reaction in DMSO but obtained only trace amounts the product.
Upon heating to 75 °C in 2-propanol, enediyne 8 undergoes
smooth Bergman cycloaromatization producing, upon double
hydrogen abstraction from the solvent, a single product, benzo-
[c]cinnoline derivative 10, which was isolated in 60% yield
(Scheme 2).
Figure 1. HPLC traces of the cycloaromatization reaction of 1 mM
solutions of enediynes 8 (filled squares) and 11 (empty circles) in
2-propanol at 75 °C. Growth of the concentration of corresponding
cyclized products (10, filled circles, and 1,2,3,4-tetrahydro-1-anthrace-
nol, empty squares) is also shown. The lines were drawn using
parameters obtained by least-squares fitting of the data to a single
exponential equation.
To evaluate the influence of cinnoline heterocycle on the
reactivity of 10-membered ring enediyne, we have compared the
rate of the Bergman cyclization of 8 with that of 3,4-benzocyclo-
deca-1,5-diyne (11, Figure 1). The accurate rate measurements of
the cyclization reactions of 8 and 11 at 75 °C in 2-propanol were
conducted by following the decay of starting material and forma-
The rates of the Bergman cyclization of cinnolinoenediyne 8
determined from the decay of the starting material (kdecay = (4.15
( 0.19) Â 10À5 sÀ1) and the formation of the product (kform
=
(4.13 ( 0.19) Â 10À5 sÀ1) are in excellent agreement. Enediyne
8 is four times more reactive than benzo-fused analogue 11
(kdecay = (9.14 ( 0.28) Â 10À6 sÀ1 and kform = (1.01 ( 0.07) Â
tion of the products using HPLC. The reaction follows the first-
10À5 À1). In fact, proper assessment of the cinnoline rate en-
s
order equation well as shown on the insert in Figure 1.
hancement effect comes from the comparison of the reactivity
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The Journal of Organic Chemistry
NOTE
3,3-Diethyl-1-(2-iodophenyl)triazene (1).26 o-Iodoaniline
(25.402 g, 115.99 mmol) was added to a solution of concentrated
HCl (29 mL) in water (50 mL), stirred vigorously for 10 min, and cooled
to À2 °C, and a solution of NaNO2 (8.625 g, 125.0 mmol) in water
(20 mL) was slowly added. The reaction mixture was stirred at ca. À5 °C
for 20 min, and then diethylamine (14.0 mL, 135.6 mmol) was added
dropwise. The reaction mixture was brought to rt, stirred for 30 min, and
neutralized by addition of aqueous NaOH solution (2 M, 110 mL). A
dark oily product was extracted with ether (3 Â 100 mL). Combined
ethereal solutions were washed with brine (100 mL), dried with anhy-
drous magnesium sulfate, and evaporated under reduced pressure. Crude
product was purified by flash chromatography (hexanes, Rf = 0.05) to
afford pure 1 (33.011 g, 108.95 mmol, 94%) as a yellow oil. 1H NMR
(300 MHz): 1.31 (t, J = 7.2 Hz, 6H), 3.79 (q, J = 7.2 Hz, 4H), 6.79À6.85
(m, 1H), 7.23À7.29 (m, 1H), 7.33À7.36 (dd, J1 = 8.1 Hz, J2 = 1.5 Hz,
1H), 7.82À7.85 (dd, J1 = 8.1 Hz, J2 = 1.2 Hz, 1H). 1C NMR (75 MHz):
10.98 (broad s), 14.51 (broad s), 42.01 (broad s), 53.40 (broad s), 96.54,
117.50, 126.45, 128.59, 139.00, 150.39. FW calcd for C10H14IN3: 303.
MS found: 303 (15) [M+], 231 (45), 203 (100), 184 (3), 118 (1), 104
(3), 91 (10), 76 (61), 72 (29), 62 (10), 56 (17), 50 (25).
3,3-Diethyl-1-(2-[(4-trimethylsilyl)buta-1,3-diynyl]phe-
nyl)triazene (2). A degassed solution of triazene 1 (0.033 mol, 10 g),
Pd(PPh3)4 (3.6 mmol, 4.2 g), PPh3 (3.6 mmol, 944 mg), 1-(trimeth-
ylsilyl)buta-1,3-diyne (0.072 mol, 8.8 g), and CuI (7.2 mmol, 1.4 g) in
Et3N (170 mL) was stirred at 45 °C overnight. The reaction mixture was
diluted with hexanes, passed through a short layer of silica gel (5% of
EtOAc in hexanes), and concentrated in vacuum. The residue was
purified by chromatography (hexanes/Et3N/EtOAc 100:1:0 f 100:2:0
f 100:2:1) to give 9.1 g (93%) of 2 as yellow oil. 1H NMR (400 MHz):
0.22 (s, 9H), 1.31 (s, 6H), 3,79 (q, 4H, J = 7.2 Hz), 7.03 (dt, 1H, J3 = 7.2
Hz, J4 = 1.2 Hz), 7.27 (dt, 1H, J3 = 7.2 Hz, J4 = 1.6 Hz), 7.37 (dd, 1H, J3 =
8.0 Hz, J4 = 0.8 Hz), 7.47 (dd, 1H, J3 = 7.6 Hz, J4 = 1.6 Hz). 13C NMR
(100 MHz): À0.1, 76.0, 77.9, 88.7, 90.3, 116.1, 117.4, 124.7, 129.1,
134.0, 154.6. EIMS m/z: 268 (M+ À Et, 29), 197 (M+ ÀN3Et2, 76), 167
(M+ À N3Et2 À 2CH3, 100). HRMS: calcd for C17H23N3Si [M + H+]
298.1734, found 298.1731.
4-Bromo-2-(trimethylsilylethynyl)cinnoline (3). Concen-
trated hydrobromic acid (0.15 mol, 13 mL) was added to a solution of
the triazene 2 (0.025 mol, 7.4 g) in acetone (100 mL) at 0 °C and the
mixture stirred for 10 min. The cooling bath was removed, the reaction
mixture was stirred for 1.5 h at rt and was quenched with brine, and
aqueous layer was extracted with ethyl acetate (30 Â 3 mL). The
combined organic layers were dried over MgSO4, solvent was evapo-
rated in vacuum, and the residue was purified by column chromatogra-
phy (EtOAc (1 f 25%) in hexanes) to give 5.8 g (76%) of 3 as colorless
crystals. Mp: 62À63 °C. 1H NMR (400 MHz): 0.36 (s, 9H), 7.85À7.92
(m, 2H), 8.19 (dd, 1H, J3 = 7.2 Hz, J4 = 2.0 Hz), 8.57 (dd, 1H, J3 = 7.6
Hz, J4 = 2.0 Hz). 13C NMR (100 MHz): À0.2, 98.8, 105.3, 123.3, 124.1,
130.4, 131.7, 132.7, 137.0, 140.1, 149.0. EIMS: m/z 306 (M+2, 62), 304
(M+, 66), 291 (M+2 À CH3, 14), 289 (M+ À CH3), 263 (M+2 À N2, 29),
261 (M+ À N2, 23), 225 (M+ À Br, 78), 197 (M+ À Br-N2, 100), 182
(M+ À Br-N2-CH3, 9), 167 (31), 152 (16). HRMS: calcd for C13H13-
BrN2Si [M + H+] 305.0110, 307.0089, found 305.0103, 307.0083.
6-[3-(Trimethylsilylethynyl)cinnolin-4-yl]hex-5-yn-1-ol (4). A
degassed solution of cinnoline 3 (19 mmol, 5.8 g), hex-5-yn-1-ol (23
mmol, 2.54 mL), CuI (2.2 mmol, 417 mg), and Pd(PPh3)4 (1.1 mmol,
1.27 g) in Et3N (50 mL) was stirred at 50 °C for 17 h., diluted with
hexane (100 mL), and filtered through a short layer of silica gel (30%
hexane in EtOAc). The resulting solution was concentrated in vacuo,
and the residue was purified by chromatography (EtOAc in hexanes
(5 f 75%)) to give 4.8 g (79%) of 4 as yellow oil. 1H NMR (400 MHz):
0.34 (s, 9H), 1.52 (bs, 1H), 1.85À1.88 (m, 4H), 2.73 (t, 2H, J = 6.4 Hz),
3.77 (t, 2H, J = 6.4 Hz), 7.75À7.84 (m, 2H), 8.14 (d, 1H, J = 8.0 Hz),
8.51 (d, 1H, J = 8.0 Hz). 13C NMR (100 MHz): 0.1, 20.2, 25.0, 32.1,
Figure 2. Cleavage of jX174 plasmid DNA by enediyne 8: lane 1, DNA
alone incubated for 24 h at 40 °C; lanes 2À4, DNA incubated with 8
(200 μM, 2 mM, and 4 mM).
of 8 with naphthalene-fused 10-membered ring enediynes, which
are stable below 100 °C.13b In other words, the electron-poor
cinnoline moiety significantly enhances the rate of enediyne
cycloaromatization.
Evaluation of enediyne 8 nuclease activity was carried out
using supercoiled plasmid DNA cleavage assay.24 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 of jX174 plasmid DNA in
aqueous TE buffer (pH = 7.6) were incubated in the presence of
various concentration of enediyne 8 for 24 h at 40 °C. Agarose gel
electrophoresis results are shown in Figure 2.
Cinnolinoenediyne 8 induces substantial single strand clea-
vage of jX174 DNA (RF II), while linearized form (RF III) was
not observed under experimental conditions. Integration of
fluorescence of bands on the gel shown in Figure 2, allowed us
to evaluate the relative abundance of the native and circular forms
of jX174 DNA. Thus, incubation of the latter with the 200 μM
of enediyne 8 produces 8% of single strand cleavage (corrected
for blank experiment). At 2 and 4 mM concentrations of 8, DNA-
cleavage efficiency grows to 43 and 50% correspondingly (lanes 3
and 4, Figure 2). While efficient DNA scission requires relatively
high concentrations of 8, one should take into account that
overall conversion of enediyne 8 during incubation time is about
3%. Our group has previously synthesized analogues of benzo-
cyclodecadiyne 11, which undergo fast spontaneous cyclization
under ambient conditions.26 We expect that similar structural
features incorporated in the structure 8, will turn it into an
efficient nuclease. We also explore structural modification that
would allow enhance topoisomerase I binding affinity of the
cyclization product 10.
’ EXPERIMENTAL SECTION
General Methods. All organic solvents were dried and freshly dis-
tilled before use. Flash chromatography was performed using 40À63 μm
silica gel. All NMR spectra were recorded in CDCl3 and referenced
to TMS unless otherwise noted. Melting points are uncorrected. Tetra-
hydrofuran was distilled from sodium/benzophenone ketyl; ether and
hexanes were distilled from sodium. Other reagents were obtained from
commercial sources and used as received unless otherwise noted.
Materials. 1,4-Bis(trimethylsilyl)buta-1,3-diyne, 1-(trimethylsilyl)-
buta-1,3-diyne, and 4,5-benzocyclodeca-2,6-diyne-1-ol (11) were pre-
pared according to the literature procedurs.24
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NOTE
62.4, 74.5, 101.2, 102.4, 107.9, 122.4, 125.2, 125.3, 130.4, 131.2, 132.0
142.0, 147.8. EIMS m/z 322 (M+, 64), 307 (M+ À CH3, 58), 291 (M+ À
CH2OH, 32), 277 (M+ À 3CH3, 100), 233 (34), 190 (21). HRMS: calcd
for C19H22N2OSi [M + H+] 323.1580, found 323.1570.
calcd for C16H12N2O [M + H+] 249.1028, found 249.1034. UV (i-
PrOH, 25 °C, c = 1.82 Â 10À5 M): λ = 263 (ε = 55000), λ = 308 (ε =
5600), λ = 321 (ε = 5900), λ = 351 (ε = 5200).
8,9,10,11-Tetrahydrodibenzo[c,g]cinnolin-8-ol (10). A so-
lution of enediyne 8 (0.06 mmol, 15 mg) in 5 mL of 2-propanol was
incubated at 75 °C for 24 h. The solvent was evaporated under reduced
pressure, and the residue was purified by flash chromatography (EtOAc/
hexanes/CH2Cl2 1:1:1) to give 9 mg (60%) of 10 as white solid. Mp:
6-(3-Ethynylcinnoline-4-yl)hex-5-yn-1-ol (5). K2CO3 (15.4
mmol, 2.13 g) was added to a solution of cinnoline 4 (14 mmol, 4.51 g)
in 120 mL MeOH, and reaction mixture was stirred at for 2 h at rt. EtOAc
(150 mL) and brine (200 mL) were added to the reaction mixture.
Layers were separated, and aqueous layer was extracted with ethyl
acetate (3 Â 30 mL). Combined organic layers were washed with brine,
dried over MgSO4, and solvent removed in vacuum. The residue was
purified by column chromatography (hexanes/EtOAc 6:1 f hexanes/
EtOAc/MeOH 1:1:0.01) to give 3.4 g (96%) of enediyne 6 as colorless
crystals. Mp: 59À62 °C. 1H NMR (400 MHz): 1.73 (bs, 1H),
1.85À1.88 (m, 4H), 2.74 (t, J = 6.4 Hz, 2H), 3.64 (s, 1H), 3.77 (t,
J = 5.6 Hz), 7.77À7.87 (m, 2H), 8.16 (d, J = 8.4 Hz, 1H), 8.52 (d, J = 8.4
Hz, 1H). 13C NMR (100 MHz): 20.2, 24.9, 32.0, 62.4, 74.4, 80.6, 83.7,
108.3, 123.0, 125.2 130.4, 131.4, 132.2, 141.3, 148.0. EIMS m/z: 250
(M+, 100), 222 (M+ À N2, 64), 163 (M+ À N2-CH2CH2CH2OH, 92).
HRMS: calcd for C16H15N2O [M + H+] 251.1184, found 251.1177.
6-(3-Iodoethynylcinnoline-4-yl)hex-5-yn-1-ol (6). Enediyne
5 (13 mmol, 3.25 g) and AgNO3 (1.5 mmol, 255 mg) were added to a
solution of NIS (15 mmol, 3.37 g) in 40 mL of acetone and reaction
mixture was stirred for 1.5 h at r.t. Acetone was evaporated in vacuum
and the residue was purified by chromatography (hexanes/EtOAc 2:1 f
1:2) to yield 3.2 g (65%) of 6 as colorless crystals. Mp > 97 °C dec); 1H
NMR (400 MHz, DMSO-d6): 1.68À1.75 (m, 4H), 2.75 (t, J = 6.0 Hz,
2H), 3.52 (td, J = 5.6, 5.2 Hz, 2H), 4.50 (q, J = 5.2 Hz, 1 H), 7.95À8.02
(m, 2H), 8.14 (dd, J3 = 5.2 Hz, J4 = 1.6 Hz, 1H), 8.49 (dd, J3 = 5.2 Hz, J4 =
1.6 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): 19.3, 24.6, 28.3, 31.6,
60.2, 73.6, 90.0, 109.1, 122.0, 124.3, 124.7, 129.7, 132.1, 133.0, 141.4,
147.0. EIMS m/z: 376 (M+, 100), 249 (M+ À I, 41), 221 (M+ À I-N2,
71). HRMS: calcd for C16H13IN2O [M + H+] 377.0151, found
377.0140.
1
196À198 °C. H NMR (400 MHz): 1.94À2.09 (m, 3H), 2.15À2.23
(m, 2H), 3.04À3.24 (m, 2H), 5.14 (dd, J = 5.2 Hz, J = 10.4 Hz, 1H),
7.88À7.90 (m, 2H), 8.27 (s, 1H), 8.52À8.54 (m, 1H), 8.70À8.74
(m, 1H), 8.33 (s, 1H). 13C NMR (100 MHz,): 19.1, 30.2, 32.2, 68.5,
120.2, 120.7, 120.9, 121.5, 129.2, 130.5, 131.4, 131.5, 141.8, 142.2, 144.7,
145.3. EIMS m/z: 250 (M+, 100), 232 (M+ À H2O, 25), 222 (M+ À N2,
25), 203 (16), 194 (16), 178 (11), 165 (38), 152 (9), 101 (18). HRMS:
calcd for C16H14N2O [M + H+] 251.1184, found 251.1182. UV
(i-PrOH, 25 °C, c = 6 Â 10À5): λ = 260 (ε = 16000).
DNA Cleavage Experiments. Solutions of enediyne 8 in DMSO
(15 μL) (0 mM, 0.54 mM, 5.4 mM, 10.8 mM) were added to 25 μL
of aqueous solution of jX174 plasmid DNA (10 ng/μL, in TE buffer
[pH = 7.6]). The solutions were incubated for 24 h in 40 °C. Incubated
samples were mixed with a glycerol-based loading buffer (7 μL) con-
taining xylene cyanol loading dye and loaded onto a 1% agarose gel
containing 0.5 μg/mL of ethidium bromide. Gel was developed at 80 V
(400 mA) for 2 h and photographed on the UV transilluminator. The
relative intensities of fluorescent bands on the developed gel were cal-
culated using Alpha Ease FC software package by Alpha Innotech, Inc.
’ ASSOCIATED CONTENT
S
Supporting Information. Preparation of known synthetic
b
intermediates and NMR spectra of the newly synthesized com-
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
6-(3-Iodoethynylcinnoline-4-yl)hex-5-ynal (7). PCC (12 mmol,
2.59 g) was added to a solution of alcohol 6 (8 mmol, 3.00 g) in 300 mL of
CH2Cl2, and the reaction mixture was stirred for 2 h at rt. The resulting
solution was passed through a short layer of silica gel (20 f 50% EtOAc in
hexanes) and solvent removed under reduced pressure. The crude product
was purified by column chromatography (EtOAc/hexanes 1:5 f EtOAc/
hexanes/CH2Cl2 1:1:2) to give 1.6 g (52%) of 7 as colorless crystals. Mp >
111 °C dec. 1H NMR (400 MHz): 2.07 (quint, J = 6.8 Hz, 2H), 2.77 (t, J =
6.8 Hz, 2H), 2.84 (td, J = 7.2, 0.8 Hz, 2H), 7.77À7.86 (m, 2H), 8.11 (dd, J3
= 8.0 Hz, J4 = 0.8 Hz, 1H), 8.51 (dd, J3 = 8.0 Hz, J4 = 0.8 Hz, 1H), 9.92 (s,
1H). 13C NMR (100 MHz): 17.2, 19.6, 20.8, 42.7, 75.0, 91.7, 106.8, 122.9,
125.0, 125.1, 130.4, 131.5, 132.3, 142.1, 147.8, 201.5. EIMS: m/z 374 (M+,
68), 346 (M+ À N2, 11), 247 (M+ À I, 32), 219 (M+ À I-N2, 100). HRMS:
calcd for C16H11IN2O [M + H+] 374.9994, found 375.0002.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: irinabalova@pobox.spbu.ru; vpopik@uga.edu.
’ ACKNOWLEDGMENT
We are grateful to the Georgia Cancer Coalition for support of
this project. I.A.B. acknowledges Saint-Petersburg State Univer-
sity (research grant 12.38.14.2011).
’ REFERENCES
Cinnolino[5,4-c]cyclodeca-4-ene-2,6-diyn-1-ol (8). A solu-
tion of aldehyde 7 (0.4 mmol, 150 mg) in 5 mL of DMF was added
dropwise over 2 min to a suspension of CrCl2 (1.6 mmol, 197 mg) and
NiCl2 (0.04 mmol, 5 mg) in 40 mL of dry degassed DMF under argon
and stirred vigorously overnight at rt. Et2O (50 mL) and brine (50 mL)
were added to the reaction mixture, the layers were separated, and the
aqueous layer was extracted with ether. Combined organic layers were
dried over MgSO4 and concentrated in vacuum. The residue was
purified by column chromatography (EtOAc/hexanes/CH2Cl2 1:1:0.1
f 3:1:0.1) to produce 40 mg (40%) of the target enediyne 8 as colorless
solid. Mp: 72À74 °C. 1H NMR (400 MHz): 1.91À1.99 m (1H),
2.20À2.38 (m, 3H), 2.60À2.75 (m, 2H), 4.81 (dd, J = 8.2 Hz, J = 2.8 Hz,
1H), 7.76À7.87 (m, 2H), 8.05 (dd, J3 = 7.2 Hz, J4 = 0.8 Hz), 8.50 (d, J =
8.0 Hz). 13C NMR (100 MHz): 22.0, 23.3, 37.3, 62.8, 78.4, 82.8, 103.0,
112.0, 123.8, 125.1, 126.9, 130.1, 131.3, 131.8, 145.6, 148.3. EIMS m/z:
248 (M+, 16), 230 (M+ À H2O, 91), 202 (M+ À H2O-N2, 100). HRMS:
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