Synthetic studies of kinamycin antibiotics: Stereoselective synthesis of the highly oxygenated D-ring and construction of the ABD-ring system of kinamycins

Article abstract of DOI:10.1002/ejoc.201300858

A concise and stereoselective synthesis of the highly oxygenated D-ring of the kinamycin family of antitumor antibiotics was achieved from commercially available 3-methyl-2-cyclohexen-1-one. The key steps included a regioselective isomerization of a cis-epoxy alcohol, a regioselective reductive ring opening of a benzylidene ketal, and a stereoselective α-hydroxy-directed ketone reduction. The Ullmann coupling between a bromonaphthaldehyde AB-ring fragment and an α-iodocyclohexenone, which is a versatile D-ring precursor, effected the construction of the functionalized ABD-ring system that may provide access to kinamycin F and its structural analogues. A concise and stereoselective synthesis of the highly oxygenated D-ring of the kinamycins was achieved from commercially available 3-methyl-2-cyclohexenone. Also, a metal-catalyzed coupling reaction between an AB-ring fragment and a D-ring precursor enabled the construction of the functionalized ABD-ring system that may provide entry to synthesis of the kinamycins.

Full text of DOI:10.1002/ejoc.201300858

FULL PAPER
DOI: 10.1002/ejoc.201300858
Synthetic Studies of Kinamycin Antibiotics: Stereoselective Synthesis of the
Highly Oxygenated D-Ring and Construction of the ABD-Ring System of
Kinamycins
Maria-Dimitra Ouzouni[a] and Demosthenes Fokas*[a]
Keywords: Natural products / Antibiotics / Synthetic methods / Cross-coupling / Regioselectivity / Diastereoselectivity
A concise and stereoselective synthesis of the highly oxygen-
ated D-ring of the kinamycin family of antitumor antibiotics
was achieved from commercially available 3-methyl-2-cy-
clohexen-1-one. The key steps included a regioselective
isomerization of a cis-epoxy alcohol, a regioselective re-
ductive ring opening of a benzylidene ketal, and a stereose-
lective α-hydroxy-directed ketone reduction. The Ullmann
coupling between a bromonaphthaldehyde AB-ring frag-
ment and an α-iodocyclohexenone, which is a versatile D-
ring precursor, effected the construction of the functionalized
ABD-ring system that may provide access to kinamycin F
and its structural analogues.
Introduction
kinamycin F, which is detected as a metabolite in the culture
The kinamycins are a family of structurally unique natu- broths of Streptomyces murayamaensis,[3] may be generated
ral products that contain a highly oxygenated cyclohexene in cells by esterase activity on the O-acetylated forms of
ring and an unusual diazobenzo[b]fluorene moiety (see Fig- kinamycin. It may also represent the active metabolite that
ure 1).[1] Four kinamycin antibiotics, namely, A–D, were is responsible for the observed inhibition of cancer cell
isolated in 1970 from the culture broth of Streptomyces mu- growth.[4,5] The potential of the kinamycins as new antican-
rayamaensis and display a strong inhibition of Gram-posi- cer agents was realized only recently with the isolation of
tive bacteria.[2] Kinamycin C exhibits cell growth inhibitory lomaiviticin A, a potent antitumor antibiotic that contains
effects in the 60-cancer cell line panel of the National Can- unique dimeric diazobenzofluorene glycoside structures.[6]
cer Institute (NCI). It was proposed that fully deacetylated The biological activity of the kinamycins and lomaiviticin
Figure 1. The family of diazobenzo[b]fluorene antitumor antibiotics.
is thought to arise from the reductive cleavage[6,7] of DNA
in which the diazonapthoquinone function is involved.[8]
[a] Laboratory of Medicinal Chemistry, Department of Materials
Science and Engineering, University of Ioannina,
These molecules have become attractive synthetic targets,
Ioannina 45110, Greece
and several total syntheses of the kinamycins[9] as well as
E-mail: dfokas@cc.uoi.gr
Homepage: http://www.materials.uoi.gr
the synthesis of the dimeric unit of the lomaiviticin agly-
Supporting information for this article is available on the
con[10] have been reported.
WWW under http://dx.doi.org/10.1002/ejoc.201300858.
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M.-D. Ouzouni, D. Fokas
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In the search of a convergent entry to kinamycin F and clohexenone 11, which is a highly oxygenated D-ring pre-
its structural analogs, we surmised that access was possible cursor that has in place the latent C-2, C-3, and C-4 kina-
from α-naphthylcyclohexenone 22, which is the product of a mycin chiral centers,[11] could result from cyclohexenediol
metal-catalyzed coupling between α-iodocyclohexenone 11 4, which is the product of a regioselective isomerization of
and bromonaphthaldehyde 21 (see Scheme 1). AB-ring frag- epoxy alcohol 3. Entry to 3 could, in turn, be achieved from
ment 21 could be prepared from naphthoquinone 18. Cy- commercially available 3-methyl-2-cyclohexenone (1).
Scheme 1. Proposed strategy for the synthesis of kinamycin F.
Scheme 2. Stereoselective synthesis of the highly oxygenated D-ring cyclohexenone 11 (PPTS = pyridinium p-toluenesulfonate, NMO =
N-methylmorpholine N-oxide, DMSO = dimethyl sulfoxide).
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Synthetic Studies of Kinamycin Antibiotics
Furthermore, the stereoselective reduction of cyclohex- kinetic and thermodynamic formation of complex 5A over
enone 11 to the corresponding cyclohexenol with the de- 5B, in which aluminum complexation occurs at the more
sired trans stereochemistry between the C-1 and C-2 chiral sterically hindered ketal O-2 atom, electronic factors should
centers would establish the D-ring of the kinamycins. be considered as well. For example, the presence of nonpo-
Herein, we wish to report the results of our studies per- lar hexane in the solvent system may increase the Lewis
taining to the regio- and stereoselective synthesis of the acid character of the aluminum and, thus, enhance its com-
highly oxygenated D-ring[12] of the kinamycins. Our investi- plexation with the more nucleophilic ketal O-1 atom and
gation involves the preparation of cyclohexenone 11 (see lead to the predominant formation of complex 5A. On the
Scheme 2) and cyclohexene 15 (see Scheme 4) as well as the contrary, the use of the more polar CH2Cl2 as the sole reac-
assembly of the kinamycin ABD-ring intermediate 22 (see tion solvent most likely enables the equal coordination of
Scheme 6).
DIBALH at both ketal oxygens to give aluminum com-
plexes 5A and 5B and result in a 1:1 mixture of 6a and 6b,
respectively (see Scheme 3).
Results and Discussion
Hydroxylation of the mixture of cyclohexenols 6a and 6b
The synthesis commenced with the Luche reduction of with catalytic OsO4 occurred from the opposite face of the
cyclohexenone 1 to cyclohexenol 2,[13] which was directly allylic oxygen[19] to produce triols 7a and 7b, which estab-
epoxidized with meta-chloroperoxybenzoic acid (m-CPBA) lished the stereochemistry at the C-2, C-3, and C-4 chiral
to generate epoxy alcohol 3[14] (see Scheme 2). Compound centers. The separation of the resulting mixture by flash
3 underwent a Ti(OiPr)4 mediated regioselective isomeriza- chromatography enabled the isolation of the desired triol 7a
tion to produce cis-diol 4 in 64% yield.[15] The protection in 76% yield. Protection of the cis-diol moiety in 7a as an
of 4 with p-methoxybenzaldehyde dimethyl acetal afforded acetonide gave alcohol 8 in 91% yield, which underwent
benzylidene ketal 5 (PMP = p-methoxyphenyl) in 94% yield a Swern[20] oxidation to generate ketone 9 in 84% yield.
as a mixture of diastereomers. The reductive ring opening Treatment of 9 with trimethylsilyl trifluoromethanesulfon-
of ketal 5 with diisobutylaluminum hydride (DIBALH)[16] ate (TMSOTf) and NEt3 resulted in the intermediate tri-
in a mixture of CH2Cl2/hexane (1:10) at –78 °C proceeded methylsilyl enol ether, which underwent a Saegusa–Ito[21]
from the less-hindered site and gave an inseparable mixture oxidation of afford enone 10 in 77% yield. The clean forma-
of alcohols 6a and 6b in 72% yield, in which the desired tion of the desired trimethylsilyl enol ether of ketone 9 was
regioisomer 6a (PMB = p-methoxybenzyl) was the major also observed upon treatment of the ketone with lithium
product (6a/6b = 5:1).[17] However, alcohols 6a and 6b were hexamethyldisilazide (LHMDS) in tetrahydrofuran (THF)
obtained as a 1:1 mixture when CH2Cl2 was utilized as the followed by the addition of TMSCl. Finally, iodination[22]
sole reaction solvent.
of 10 by treatment with iodine and pyridine under Baylis–
The regioselective reductive ring opening of ketal 5 to Hillman conditions,[23] produced the desired α-iodocy-
give 6a in CH2Cl2/hexane (1:10) may presumably involve clohexenone 11 in 87% yield (see Scheme 2).
the association of DIBALH at the less sterically hindered
Attempts to stereoselectively reduce iodoenone 11 with
site of the ketal, that is, the O-1 atom could form aluminum lithium aluminum hydride (LAH) to the corresponding D-
complex 5A, which could then undergo a hydride transfer ring cyclohexenol were not fruitful, and cis-alcohol 12 (J1,2
through a four-centered transition state or an oxocarb- = 4.4 Hz in CDCl3) was formed as the sole product (see
enium ion.[18] Apart from steric factors that may favor the Scheme 4). In the hope to achieve the desired stereochemis-
Scheme 3. Likely mechanism for the observed regioselectivity in the reductive ring opening of ketal 5.
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Scheme 4. Entry to the D-ring of kinamycins through an α-hydroxy-directed ketone reduction [DMAP = 4-(N,N-dimethylamino)pyridine].
try through an α-hydroxy-directed ketone reduction, enone pare a similar substrate (see Scheme 5). The allylation of 17
11 was converted into hydroxyketone 13 upon treatment with vinyl acetic acid in the presence of silver nitrate and
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). ammonium persulfate[28] afforded naphthalenedione 18,[9b]
However, the reduction of 13 with a series of reducing which was converted into substrate 19 upon treatment with
agents such as NaBH4/CeCl3·7H2O or DIBALH, resulted PMB-Cl and freshly prepared Ag2O. The reduction of quin-
in cis-diol 14 (J1,2 = 4.0 Hz in CDCl3). On the contrary, one 19 with Na2S2O4 gave the intermediate hydroquinone,
compound 13 underwent a facile α-hydroxy-directed ketone which was successfully methylated with MeI and K2CO3 to
[24]
reduction with Me4NBH(OAc)3
to yield trans-diol 15 provide bromonaphthalene derivative 20. Attempts to iso-
(J1,2 = 8.1 Hz in CDCl3). The conversion of 15 into diacet- merize the allyl group in 20 by treatment with tBuOK in
ate 16 clearly confirmed the desired trans stereochemistry THF as the solvent by employing existing literature proto-
(J1,2 = 9.0 Hz in CDCl3). The observed coupling constants cols, described for the syntheses of similar systems,[9b,28b,28c]
are consistent with the half-chair being the predominant were not fruitful, and starting material was recovered. How-
conformation in which the C-1 and C-2 hydroxy or acetoxy ever, dropwise addition of a solution of 20 in DMSO to a
groups are in pseudoequatorial orientations and are com- solution of tBuOK in THF effected the successful isomer-
parable to the J1,2 values reported for kinamycins A, C, D, ization of 20 to provide an internal olefin, which underwent
E, and J.[25] Nuclear Overhauser effect spectroscopy (1H-1H a Lemieux–Johnson oxidation to afford aldehyde 21.
NOESY) of diacetate 16 revealed contacts between H-1 and
Initial attempts to construct adduct 22 by applying
the C-3 methyl, H-4 and the C-3 methyl, and between H- Ullmann conditions as described in the literature[9b,26] for
2 and the α-methyl of the acetonide, which confirmed the the coupling of similar substrates were not very successful.
assigned structure of D-ring cyclohexene 16.
Iodoenone 11 and bromonaphthaldehyde 21 were dissolved
Iodocyclohexenes 15 and 16 are ideal candidates to par- in DMSO followed by the addition of the metal catalysts
ticipate in a Suzuki or Stille reaction with an appropriate and heating at 65 °C to afford low yields (ca. 20–30%) of
AB-ring fragment to assemble the ABD-ring system of the the desired compound 22 as well as other dimerization by-
kinamycins. However, their precursor α-iodocyclohexenone products. However, after careful experimentation, iodo-
11 appeared to be an attractive candidate for an Ullmann[26] enone 11 and bromonaphthaldehyde 21 underwent a facile
reaction with bromonaphthaldehyde 21. This direct cou- Ullmann coupling reaction to form the latent C-11a–C-11b
pling would obviate the preparation of the boronated and kinamycin bond and generate α-naphthylcyclohexenone 22
stannylated AB-ring fragments.
in 62% yield (see Scheme 6). Indeed, the dropwise addition
The synthesis of compound 21 commenced from readily of a solution of 21 to a mixture of iodoenone 11, Pd2(dba)3,
available bromojuglone 17[27] by employing a modified ver- copper, and CuI in DMSO followed by heating the reaction
sion of the protocol that was used by Nicolaou[9b] to pre- mixture at 65 °C for 2 h was required to minimize the di-
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Synthetic Studies of Kinamycin Antibiotics
Scheme 5. Synthesis of the AB-ring fragment 21 (DMF = N,N-dimethylformamide).
merization of bromonaphthaldehyde 21 and enone 11 and vanced tetracyclic intermediate that could be converted into
ensure the formation of the product.[29] Compound 22 in- kinamycin F through a series of known transformations
corporates the ABD-ring system of the kinamycins and (see Scheme 7).
contains the appropriate functionality to enable the C-ring
closure by a C-4a–C-5 bond connection. For example, the
cyanation of the aldehyde group in 22 should render the
corresponding cyanohydrin silyl ether 23 an appropriate
Conclusions
In summary, this study established an efficient method
for the regio- and stereoselective synthesis of the highly oxy-
genated D-ring of the kinamycins by employing cyclohex-
enone 11 and cyclohexene 15, which were prepared from
commercially available cyclohexenone 1 in 10 and 12 steps,
respectively. This study also achieved the construction of α-
naphthylcyclohexenone 22, a highly functionalized interme-
diate that could provide access to the tetracyclic ring system
of the kinamycins. Furthermore, the chemistry that was de-
veloped here may be amenable to asymmetric synthesis
given that access to optically active material can be
achieved by either the enzymatic resolution[30] of racemic
allylic alcohol 2 or the chiral reduction[31] of cyclohexenone
1. Studies toward the conversion of 22 into benzofluor-
enone 24 and kinamycin F are currently in progress.
substrate for an intramolecular cyanohydrin anion alkyl-
ation to synthesize benzofluorenone 24, which is an ad-
Scheme 6. Construction of the kinamycin ABD-ring system
through an Ullmann-type coupling reaction.
Experimental Section
General Methods: All commercially available chemicals were used
without further purification. All reactions were performed under
argon with dry solvents under anhydrous conditions, unless other-
wise noted. Tetrahydrofuran, diethyl ether (Et2O), dichloromethane
(CH2Cl2), acetonitrile (CH3CN), dimethylformamide, and dimethyl
sulfoxide were purchased in anhydrous form and used without fur-
ther purification. Air- and moisture-sensitive liquids were transfer-
red with a syringe. Organic solutions were concentrated by rotary
evaporation at 40 °C. Flash column chromatography was per-
formed with silica gel 60 (230–400 mesh) as described by Still et
al.[32] Thin layer chromatography was performed with precoated
silica gel 60 F254 plates, and the eluent is reported in parenthesis.
TLC plates were visualized by exposure to ultraviolet light (UV)
and/or submersion into aqueous potassium permanganate solution
(KMnO4/H2SO4) followed by heating. Infrared spectra were re-
1
corded with a Shimadzu 8400S FTIR spectrometer. The H NMR
spectroscopic data were recorded with a 250 or 400 MHz Bruker
Scheme 7. Proposed strategy for the conversion of 22 to kinamy-
cin F (CAN = cerium ammonium nitrate).
Avance FT-NMR spectrometer. The 13C NMR spectroscopic data
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M.-D. Ouzouni, D. Fokas
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were recorded at 62.9 MHz. Distortionless enhancement by polar-
ization transfer spectra [DEPT (135)] were recorded at 62.9 MHz.
The 13C NMR and the DEPT (135) data are combined and repre-
sented in the order of chemical shift, carbon type obtained from
DEPT (135) experiments. The 1H-1H NOESY spectroscopic data
were recorded with a 500 MHz Bruker Avance FT-NMR spectrom-
eter. Chemical shifts are reported in ppm relative to the solvent
signal. Multiplicity is indicated by s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet), br. (broad), dd (doublet of doublets),
and ddd (doublet of doublets of doublets). ESI (electrospray ion-
ization) mass spectra were recorded with an Agilent 1100 Series
LC/MSD instrument. High resolution mass spectra were obtained
under electrospray ionization conditions with a Thermo Scientific
LC–MS/linear trap quadrupole (LTQ)-Orbitrap mass spectrometer.
(10 mL) and methanol (10 mL). The resulting mixture was stirred
vigorously at room temperature and then filtered through a Celite
pad. The filtrate was concentrated under reduced pressure, and the
resulting oil was dissolved in EtOAc (80 mL). The resulting solu-
tion was then washed with water (70 mL). The aqueous phase was
extracted with EtOAc (4ϫ 60 mL), and the combined organic lay-
ers were washed with brine (70 mL), dried with Na2SO4, filtered,
and concentrated under reduced pressure to give the crude product.
Purification by flash chromatography on silica gel (EtOAc/hexane,
1:6) afforded an inseparable mixture of regioisomeric alcohols 6a
and 6b (6a/6b, 5:1; 2.32 g, 72%) as a colorless oil; Rf = 0.38 (hex-
ane/EtOAc, 4:1; UV, KMnO4). Data for alcohol 6a: 1H NMR
(250 MHz, CDCl3): δ = 7.30 (d, J = 8.5 Hz, 2 H), 6.89 (d, J =
8.6 Hz, 2 H), 5.55 (s, 1 H), 4.65 (ABq, J = 11.2 Hz, 2 H), 3.93 (br.
s, 1 H), 3.81 (s, 4 H), 2.34 (br. s, 1 H), 2.16 (br. s, 1 H), 2.04–1.83
Diol 4: A solution of epoxy alcohol 3 (5.4 g, 42.0 mmol) in CH2Cl2
(90 mL) was treated with Ti(OiPr)4 (22.5 mL, 75.6 mmol), and the
reaction mixture was stirred at room temperature overnight. The
solvent was evaporated under reduced pressure, and the resulting
residue was dissolved in Et2O (80 mL) followed by the addition of
water (50 mL). A white precipitate was formed, which was treated
in an ice bath with concentrated HCl dropwise until it gradually
dissolved, resulting in two clear phases. The ether phase was sepa-
rated, and the remaining aqueous phase was extracted with EtOAc
(3ϫ 60 mL). The combined organic phases were washed with brine
(60 mL), dried with Na2SO4, filtered, and concentrated under re-
duced pressure to give the crude product. Purification by flash
chromatography on silica gel (EtOAc/hexane, from 1:4 to 1:2) af-
forded diol 4 (3.44 g, 64%) as a pale yellow oil; Rf = 0.28 (hexane/
(m, 1 H), 1.73 (s, 3 H), 1.68–1.59 (m, 2 H) ppm. IR (film): ν
=
˜
max
3421, 3036, 2999, 2934, 2914, 2876, 2842, 1639, 1612, 1585,
1514 cm–1. HRMS (ESI-LTQ): calcd. for C15H20O3Na [M + Na]+
271.1305; found 271.1303.
Triol 7a: To a solution of alcohols 6a and 6b (1.31 g, 5.3 mmol) in
acetone/H2O (6:1, 40 mL) were added N-methylmorpholine-N-ox-
ide (931 mg, 7.94 mmol) and 4% aqueous OsO4 (1.65 mL,
0.2 mmol). The reaction mixture was stirred at room temperature
for 18 h and then concentrated to a reduced volume (10 mL), which
was diluted with water (15 mL). The resulting solution was then
extracted with EtOAc (4ϫ 40 mL). The combined organic layers
were washed with brine, dried with Na2SO4, filtered, and concen-
trated under reduced pressure to give the crude product. Purifica-
tion by flash chromatography on silica gel (EtOAc/hexane, 3:1) af-
forded the desired triol 7a (1.14 g, 76%) as a white solid; Rf = 0.23
1
EtOAc, 1:1; KMnO4). H NMR (250 MHz, CDCl3): δ = 5.56 (m,
1 H), 3.93 (d, J = 3.6 Hz, 1 H), 3.76 (m, 1 H), 2.20–1.95 (br. s, 4 H),
1.81 (d, J = 1.7 Hz, 3 H), 1.70 (m, 2 H) ppm. 13C NMR (62.9 MHz,
CDCl3): δ = 133.7 (C), 125.7 (CH), 70.3 (CH), 69.8 (CH), 25.6
1
(hexane/EtOAc, 1:3; UV, KMnO4). H NMR (250 MHz, CDCl3):
δ = 7.28 (d, J = 8.9 Hz, 2 H), 6.90 (d, J = 8.6 Hz, 2 H), 4.62 (ABq,
J = 11.3 Hz, 2 H), 4.12 (m, 1 H), 3.81 (s, 3 H), 3.72 (m, 1 H), 3.58
(d, J = 3.3 Hz, 1 H), 2.13–1.99 (br. s, 3 H), 1.87–1.76 (m, 2 H),
1.74–1.58 (m, 2 H), 1.36 (s, 3 H) ppm. 13C NMR (62.9 MHz,
CDCl3): δ = 159.5 (C), 130.5 (C), 129.4 (CH), 114.1 (CH), 82.7
(CH), 74.8 (C), 73.5 (CH), 73.4 (CH2), 67.6 (CH), 55.4 (CH3), 25.4
(CH ), 24.0 (CH ), 20.9 (CH ) ppm. IR (film): ν = 3369, 3032,
˜
max
2
2
3
2937, 2914, 2881, 2839, 1647, 1444 cm–1. HRMS (ESI-LTQ): calcd.
for C7H12O2Na [M + Na]+ 151.0730; found 151.0721.
Ketal 5: To a solution of diol 4 (467 mg, 3.64 mmol) in CH2Cl2
(15 mL) were added 4-methoxybenzaldehyde dimethyl acetal
(1.2 mL, 7.2 mmol) and pyridinium p-toluenesulfonate (92 mg,
0.37 mmol). The reaction mixture was stirred at room temperature
for 1 h and then diluted with water (10 mL). The resulting solution
was extracted with CH2Cl2 (3ϫ 20 mL). The combined organic
layers were dried with Na2SO4, filtered, and concentrated under
reduced pressure to give the crude product. Purification by flash
chromatography on silica gel (EtOAc/hexane, 1:4) afforded ketal 5
(833 mg, 94%) as a colorless oil; Rf = 0.58 (hexane/EtOAc, 4:1;
UV, KMnO4). 1H NMR (250 MHz, CD3OD, mixture of dia-
stereomers): δ = 7.39 (d, J = 8.7 Hz, 2 H), 6.93 (d, J = 8.8 Hz, 2
H), 5.82 (s, 0.3 H), 5.79 (s, 0.7 H), 4.59–4.31 (m, 2 H), 3.81 (s, 3
H), 2.31–1.85 (m, 4 H), 1.80 (s, 3 H) ppm. 13C NMR (62.9 MHz,
CD3OD, mixture of diastereomers): δ = 162.0 (C), 161.9 (C), 133.1
(C), 132.3 (C), 132.0 (C), 131.5 (C), 129.6 (CH), 129.1 (CH), 128.4
(CH), 126.7 (CH), 114.6 (CH), 104.8 (CH), 104.7 (CH), 103.4
(CH), 77.3 (CH), 77.0 (CH), 76.0 (CH), 75.5 (CH), 55.7 (CH3),
53.1 (CH3), 26.9 (CH2), 26.4 (CH2), 22.0 (CH2), 21.4 (CH2), 20.7
(CH ), 25.1 (CH ), 23.1 (CH ) ppm. IR (film): ν = 3412, 2951,
˜
max
2
2
3
2932, 2870, 1643, 1614, 1587, 1514 cm–1. HRMS (ESI-LTQ): calcd.
for C15H22O5Na [M + Na]+ 305.1359; found 305.1359.
Alcohol 8: A solution of triol 7a (847 mg, 3.0 mmol) in CH2Cl2
(35 mL) was treated with 2,2-dimethoxypropane (737 μL,
6.0 mmol) and a catalytic amount of pyridinium p-toluenesulfonate
(37 mg, 0.15 mmol). The reaction mixture was stirred at room tem-
perature for 7 h and then quenched with water (10 mL). The re-
sulting solution was extracted with CH2Cl2 (3ϫ 30 mL). The com-
bined organic layers were washed with brine (20 mL), dried with
Na2SO4, filtered, and concentrated under reduced pressure to give
the crude product. Purification by flash chromatography on silica
gel (EtOAc/hexane, 1:6) afforded alcohol 8 (880 mg, 91%) as a pale
1
yellow oil; Rf = 0.28 (hexane/EtOAc, 4:1; UV, KMnO4). H NMR
(250 MHz, CDCl3): δ = 7.30 (d, J = 8.6 Hz, 2 H), 6.88 (d, J =
8.6 Hz, 2 H), 4.78 (d, J = 11.6 Hz, 1 H), 4.58 (d, J = 11.6 Hz, 1
H), 4.04 (q, J = 3.0 Hz, 1 H), 3.99 (t, J = 2.8 Hz, 1 H), 3.81 (s, 3
H), 3.52 (d, J = 3.1 Hz, 1 H), 2.15–1.95 (m, 2 H), 1.90–1.80 (m, 1
H), 1.79–1.70 (m, 2 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.38 (s, 3
H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 159.4 (C), 130.8 (C),
129.5 (CH), 113.9 (CH), 107.5 (C), 82.8 (C), 81.7 (CH), 80.5 (CH),
72.2 (CH2), 68.5 (CH), 55.4 (CH3), 28.4 (CH3), 27.4 (CH3), 24.5
(CH ), 20.3 (CH ) ppm. IR (film): ν = 3005, 2934, 2918, 2839,
˜
max
3
3
1643, 1614, 1589, 1516 cm–1. HRMS (ESI-LTQ): calcd. for
C15H18O3Na [M + Na]+ 269.1148; found 269.1148.
Cyclohexenols 6a and 6b: A solution of ketal 5 (3.22 g, 13.0 mmol)
in CH2Cl2/hexane (1:10, 90 mL) at –78 °C was treated dropwise
with diisobutylaluminium hydride (1.0 m in hexanes, 78 mL,
78.0 mmol). The reaction mixture was gradually warmed to 0 °C
over a period of 2 h and then carefully quenched with acetone
(CH ), 20.5 (CH ), 20.0 (CH ) ppm. IR (film): ν = 3418, 2935,
˜
max
2
3
2
1639 cm–1. HRMS (ESI-LTQ): calcd. for C18H26O5Na [M + Na]+
345.1672; found 345.1665.
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Synthetic Studies of Kinamycin Antibiotics
Ketone 9: A solution of oxalyl chloride (1.1 mL, 9.9 mmol) in
CH2Cl2 (20 mL) at –78 °C under argon was treated dropwise with
iodocyclohexenone 11 (170 mg, 87%) as a colorless oil; Rf = 0.40
(hexane/EtOAc, 4:1; UV, KMnO4). H NMR (250 MHz, CDCl3):
1
DMSO (1.4 mL, 19.8 mmol) and then with alcohol 8 (800 mg, δ = 7.46 (d, J = 4.6 Hz, 1 H), 7.28 (d, J = 8.6 Hz, 2 H), 6.87 (d, J
2.48 mmol) as a solution (15 mL) in CH2Cl2/DMSO (3:1). After
stirring at –78 °C for 15 min, the reaction mixture was treated with
Et3N (6.2 mL, 44.6 mmol) and gradually warmed to 0 °C over a
period of 2 h. It was then quenched with water (20 mL), and the
resulting solution was extracted with CH2Cl2 (3ϫ 50 mL). The
combined organic layers were washed with brine (20 mL), dried
with Na2SO4, filtered, and concentrated under reduced pressure to
give the crude product. Purification by flash chromatography on
silica gel (EtOAc/hexane, 1:8) afforded ketone 9 (670 mg, 84%) as
a colorless oil; Rf = 0.33 (hexane/EtOAc, 4:1; UV, KMnO4). 1H
NMR (250 MHz, CDCl3): δ = 7.26 (d, J = 8.6 Hz, 2 H), 6.86 (d,
J = 8.6 Hz, 2 H), 4.62 (d, J = 11.8 Hz, 1 H), 4.42 (d, J = 11.8 Hz,
1 H), 4.09 (t, J = 3.0 Hz, 1 H), 3.80 (s, 3 H), 3.76 (s, 1 H), 2.63–
2.47 (m, 1 H), 2.36–2.16 (m, 3 H), 1.37 (s, 3 H), 1.33 (s, 3 H), 1.30
(s, 3 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 208.8 (C), 159.6
(C), 129.8 (CH), 129.5 (C), 113.9 (CH), 108.7 (C), 85.6 (C), 84.5
(CH), 79.0 (CH), 72.3 (CH2), 55.4 (CH3), 33.1 (CH2), 27.5 (CH3),
= 8.7 Hz, 2 H), 4.75 (d, J = 11.7 Hz, 1 H), 4.51 (d, J = 11.7 Hz, 1
H) 4.37 (d, J = 4.6 Hz, 1 H), 4.17 (s, 1 H), 3.79 (s, 3 H), 1.42 (s, 3
H), 1.37 (s, 3 H), 1.26 (s, 3 H) ppm. 13C NMR (62.9 MHz, CDCl3):
δ = 191.4 (C), 159.7 (C), 149.5 (CH), 130.2 (CH), 129.0 (C), 114.0
(CH), 111.4 (C), 105.0 (C), 83.5 (C), 81.0 (CH), 79.6 (CH), 73.0
(CH2), 55.4 (CH3), 28.0 (CH3), 27.9 (CH3), 20.2 (CH3) ppm. IR
(film): ν
= 3038, 2986, 2934, 2868, 2835, 1711, 1612, 1585,
˜
max
1514 cm–1. HRMS (ESI-LTQ): calcd. for C18H20IO5 [M – H]+
443.0361; found 443.0364.
Hydroxy Ketone 13: A biphasic solution of iodocyclohexenone 11
(25 mg, 0.056 mmol) in CH2Cl2/H2O (10:1, 3 mL) was treated with
DDQ (19 mg, 0.08 mmol). The reaction mixture was stirred at
room temperature for 18 h and then diluted with water (10 mL).
The resulting solution was then extracted with CH2Cl2 (3ϫ
10 mL). The combined organic layers were washed with aqueous
NaHCO3 (10 mL) and brine (10 mL), dried with Na2SO4, filtered,
and concentrated under reduced pressure to give the crude product.
Purification by flash chromatography on silica gel (EtOAc/hexane,
1:8) afforded hydroxyketone 13 (13 mg, 72%) as a pale yellow oil;
Rf = 0.20 (hexane/EtOAc, 4:1; UV, KMnO4). 1H NMR (250 MHz,
CDCl3): δ = 7.61 (d, J = 5.2 Hz, 1 H), 4.66 (s, 1 H), 4.41 (d, J =
5.2 Hz, 1 H), 3.26 (br. s, 1 H), 1.58 (s, 3 H), 1.45 (s, 3 H), 1.26 (s,
3 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 193.6 (C), 148.8
(CH), 111.8 (C), 103.1 (C), 83.8 (C), 79.8 (CH), 77.4 (CH), 28.2
26.6 (CH ), 23.3 (CH ), 20.8 (CH ) ppm. IR (film): ν = 2984,
˜
max
3
2
3
2934, 2880, 2837, 1724, 1637, 1612, 1585, 1514 cm–1. HRMS (ESI-
LTQ): calcd. for C18H24O5Na [M
343.1516.
+
Na]+ 343.1516; found
Cyclohexenone 10: A solution of ketone 9 (200 mg, 0.62 mmol) in
CH2Cl2 (15 mL) was treated with Et3N (522 μL, 3.7 mmol) and
TMSOTf (340 μL, 1.9 mmol). The reaction mixture was stirred at
room temperature for 1 h and then diluted with water (10 mL). The
resulting solution was then extracted with CH2Cl2 (3ϫ 20 mL).
The combined organic layers were washed with brine (20 mL),
dried with Na2SO4, filtered, and concentrated under reduced pres-
sure to give the crude trimethylsilyl enol ether. The resulting enol
ether was dissolved in DMSO (2 mL), and the solution was treated
with Pd(OAc)2 (14 mg, 0.06 mmol). The reaction mixture was de-
gassed under vacuum and stirred at room temperature for 48 h un-
der oxygen (balloon). It was then quenched with water (10 mL),
and the solution was extracted with EtOAc (3ϫ 10 mL). The com-
bined organic layers were washed with brine (20 mL), dried with
Na2SO4, filtered, and concentrated under reduced pressure to give
the crude product. Purification by flash chromatography on silica
gel (EtOAc/hexane, 1:6) afforded cyclohexenone 10 (147 mg, 77%)
as a colorless oil; Rf = 0.23 (hexane/EtOAc, 4:1; UV, KMnO4). 1H
NMR (250 MHz, CDCl3): δ = 7.31 (d, J = 8.6 Hz, 2 H), 6.86 (d,
J = 8.6 Hz, 2 H), 6.76 (dd, J = 10.2, 4.4 Hz, 1 H), 6.12 (d, J =
10.2 Hz, 1 H), 4.83 (d, J = 11.9 Hz, 1 H), 4.63 (d, J = 11.9 Hz, 1
H), 4.45 (d, J = 4.5 Hz, 1 H), 4.16 (s, 1 H), 3.79 (s, 3 H), 1.42 (s,
3 H), 1.35 (s, 3 H), 1.29 (s, 3 H) ppm. 13C NMR (62.9 MHz,
CDCl3): δ = 197.4 (C), 159.6 (C), 140.1 (CH), 130.7 (CH), 130.1
(CH), 129.6 (C), 113.9 (CH), 110.8 (C), 83.7 (C), 82.2 (CH), 78.0
(CH), 73.0 (CH2), 55.4 (CH3), 28.0 (CH3), 27.6 (CH3), 19.6
(CH ), 27.3 (CH ), 18.0 (CH ) ppm. IR (film): ν = 3582, 1703,
˜
max
3
3
3
1601, 1551 cm–1. HRMS (ESI-LTQ): calcd. for C10H13IO4Na [M
+ Na]+ 346.9751; found 346.9746.
Cyclohexene-trans-diol 15: A solution of hydroxyketone 13 (18 mg,
0.055 mmol) and Me4NBH(OAc)3 (71 mg, 0.27 mmol) in CH3CN
(2 mL) at –20 °C was treated with acetic acid (500 μL). The reac-
tion mixture was gradually warmed and stirred at room tempera-
ture overnight. It was then quenched with aqueous NaHCO3
(5 mL), and the resulting mixture was extracted with CH2Cl2 (3ϫ
15 mL). The combined organic layers were washed with brine
(10 mL), dried with Na2SO4, filtered, and concentrated under re-
duced pressure to give the crude product. Purification by flash
chromatography on silica gel (EtOAc/hexane, 1:3) afforded diol 15
(13 mg, 72%) as a colorless oil; Rf = 0.18 (hexane/EtOAc, 2:1; UV,
KMnO4). 1H NMR (250 MHz, CDCl3): δ = 6.56 (dd, J = 4.7,
1.2 Hz, 1 H), 4.14 (d, J = 4.6 Hz, 1 H), 3.93 (d, J = 8.2 Hz, 1 H),
3.87 (d, J = 8.1 Hz, 1 H), 2.71 (br. s, 2 H), 1.49 (s, 3 H), 1.41 (s, 3
H), 1.32 (s, 3 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 133.9
(CH), 110.8 (C), 109.2 (C), 81.4 (C), 80.0 (CH), 75.7 (CH), 74.7
(CH), 28.7 (CH ), 27.3 (CH ), 18.0 (CH ) ppm. IR (film): ν =
˜
max
3
3
3
3418, 2933, 1643, 1637, 1439, 1379 cm–1. HRMS (ESI-LTQ): calcd.
for C10H15IO4Na [M + Na]+ 348.9907; found 348.9903.
Diacetate 16: A solution of diol 15 (8 mg, 0.025 mmol), NiPr2Et
(9 μL, 0.05 mmol), acetic anhydride (12 μL, 0.125 mmol), and a
catalytic amount of DMAP in CH2Cl2 (1 mL) was stirred at room
temperature overnight. The reaction mixture was diluted with water
(3 mL) and a few drops of HCl (1 n solution), and the resulting
solution was then extracted with CH2Cl2 (3ϫ 10 mL). The com-
bined organic layers were washed with brine (10 mL), dried with
Na2SO4, filtered, and concentrated under reduced pressure to give
the crude product. Purification by flash chromatography on silica
gel (EtOAc/hexane, 1:6) afforded diacetate 16 (8.2 mg, 80%) as a
colorless oil; Rf = 0.33 (hexane/EtOAc, 4:1; UV, KMnO4). 1H
NMR (250 MHz, CDCl3): δ = 6.67 (dd, J = 5.3, 1.8 Hz, 1 H), 5.48
(ddd, J = 9.0, 1.8, 0.8 Hz, 1 H), 5.42 (d, J = 9.0 Hz, 1 H), 4.12 (dd,
(CH ) ppm. IR (film): ν
= 3047, 2986, 2935, 2868, 2837, 1703,
˜
3
max
1637, 1612, 1593, 1514 cm–1. HRMS (ESI-LTQ): calcd. for
C18H22O5Na [M + Na]+ 341.1359; found 341.1361.
Iodocyclohexenone 11: A solution of cyclohexenone 10 (140 mg,
0.44 mmol) in CH2Cl2 (2 mL) and pyridine (4 mL) was treated with
I2 (335 mg, 1.32 mmol). After stirring at room temperature for
18 h, the reaction mixture was quenched with water (4 mL) and
aqueous Na2S2O3 (3 mL), and the resulting mixture was then ex-
tracted with EtOAc (3ϫ 20 mL). The combined organic layers were
washed with brine (7 mL), dried with Na2SO4, and concentrated
under reduced pressure to give the crude product. Purification by
flash chromatography on silica gel (EtOAc/hexane, 1:6) afforded
Eur. J. Org. Chem. 2013, 6181–6189
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6187

M.-D. Ouzouni, D. Fokas
FULL PAPER
J = 5.3, 0.8 Hz, 1 H), 2.13 (s, 3 H), 2.08 (s, 3 H), 1.51 (s, 3 H), 1.38
action mixture was diluted with water (4 mL), and the resulting
(s, 6 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 169.9 (C), 169.8 solution was extracted with EtOAc (3ϫ 10 mL). The combined
(C), 135.4 (CH), 111.2 (C), 103.2 (C), 80.1 (CH), 79.9 (C), 73.5 organic layers were washed with brine (10 mL), dried with Na2SO4,
(CH), 73.2 (CH), 28.0 (CH3), 27.2 (CH3), 21.1 (CH3), 21.0 (CH3), filtered, and concentrated under reduced pressure to give the crude
18.1 (CH ) ppm. IR (film): ν
= 2982, 2935, 2866, 1755, 1634, isomerized bromonaphthalene, which was used directly without any
˜
3
max
1454, 1435, 1377, 1232, 1215 cm–1. HRMS (ESI-LTQ): calcd. for
C14H19IO6Na [M + Na]+ 433.0119; found 433.0123.
further purification. A solution of the resulting bromonaphthalene
in THF/H2O (2:1, 3 mL) was treated with 4% aqueous OsO4
(0.16 m solution, 6 μL, 0.001 mmol) and NaIO4 (49 mg,
0.23 mmol). The reaction mixture was stirred at room temperature
overnight and then diluted with water (4 mL). The resulting solu-
tion was then extracted with EtOAc (3ϫ 15 mL). The combined
organic layers were washed with brine, dried with Na2SO4, filtered,
and concentrated under reduced pressure to give the crude product.
Purification by flash chromatography on silica gel (EtOAc/hexane,
1:8) afforded bromonaphthaldehyde 21 (26 mg, 64%) as a pale yel-
Benzyloxynaphthoquinone 19: To a solution of hydroxynaphtho-
quinone 18 (258 mg, 0.88 mmol) in CH2Cl2 (12 mL) were added p-
methoxybenzyl chloride (239 μL, 1.76 mmol) and freshly prepared
Ag2O[33] (204 mg, 0.88 mmol). After stirring at room temperature
overnight, the reaction mixture was filtered through a Celite pad,
and the resulting filtrate was concentrated under reduced pressure
to give the crude product. Purification by flash chromatography on
silica gel (EtOAc/hexane, 1:5) afforded naphthoquinone 19
(233 mg, 64%) as a yellow oil; Rf = 0.35 (hexane/EtOAc, 4:1; UV).
1H NMR (250 MHz, CDCl3): δ = 7.81 (d, J = 7.5 Hz, 1 H), 7.60
(t, J = 8.3, 7.8 Hz, 1 H), 7.46 (d, J = 8.5 Hz, 2 H), 7.33 (d, J =
8.5 Hz, 1 H), 6.94 (d, J = 8.5 Hz, 2 H), 5.87 (m, 1 H), 5.26 (dd, J
= 14.5, 1.5 Hz, 1 H), 5.23 (s, 2 H), 5.13 (dd, J = 10.0, 1.5 Hz, 1
H), 3.82 (s, 3 H), 3.62 (d, J = 6.5 Hz, 2 H) ppm. 13C NMR
(62.9 MHz, CDCl3): δ = 180.1 (C), 178.3 (C), 159.6 (C), 159.2 (C),
150.8 (C), 136.8 (C), 134.8 (CH), 133.5 (C), 132.0 (CH), 130.2 (C),
128.6 (CH), 128.0 (C), 120.7 (CH), 120.3 (CH), 118.2 (CH2), 114.3
1
low oil; Rf = 0.33 (hexane/EtOAc, 4:1; UV). H NMR (250 MHz,
CDCl3): δ = 10.5 (s, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.58 (t, J =
8.1 Hz, 1 H), 7.46 (d, J = 8.6 Hz, 2 H), 7.07 (d, J = 7.8 Hz, 1 H),
6.96 (d, J = 8.6 Hz, 2 H), 5.16 (s, 2 H), 3.96 (s, 3 H), 3.84 (s, 3 H),
3.28 (s, 3 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 190.9 (CH),
159.8 (C), 159.1 (C), 157.1 (C), 150.6 (C), 134.1 (C), 130.5 (CH),
129.6 (CH), 128.4 (C), 125.2 (C), 120.3 (C), 115.5 (CH), 114.2
(CH), 111.4 (C), 109.2 (CH), 71.5 (CH2), 65.5 (CH3), 61.4 (CH3),
55.5 (CH ) ppm. IR (film): ν
= 3005, 2934, 2839, 1691, 1645,
˜
3
max
1612, 1551, 1514, 1441, 1366, 1250, 1047 cm–1. HRMS (ESI-LTQ):
calcd. for C21H1979/81BrO5Na [M + Na]+ 453.0308/455.0288; found
453.0302/455.0279.
(CH), 71.1 (CH ), 55.4 (CH ), 35.8 (CH ) ppm. IR (film): ν =
˜
max
2
3
2
1672, 1607, 1585, 1550, 1514 cm–1. HRMS (ESI-LTQ): calcd. for
C21H1779/81BrO4Na [M + Na]+ 435.0202/437.0182; found 435.0207/
437.0187.
α-Naphthylcyclohexenone 22: A solution of iodocyclohexenone 11
(14 mg, 0.032 mmol) in DMSO (500 μL) at room temperature was
treated with CuI (2.3 mg, 0.012 mmol), Pd2(dba)3 (2.8 mg,
0.003 mmol), and Cu (20 mg, 0.31 mmol) followed by the dropwise
Bromonaphthalene 20: To
a solution of naphthoquinone 19
(122 mg, 0.29 mmol) in EtOAc (3 mL) and Et2O (8 mL) was added
Na2S2O4 (308 mg, 1.77 mmol) in water (10 mL). After stirring at
room temperature for 30 min, the biphasic reaction mixture was
extracted with EtOAc (3ϫ 20 mL). The combined organic layers
were washed with brine (15 mL), dried with Na2SO4, filtered, and
concentrated under reduced pressure to give the crude hydroquin-
one as a yellow oil. A solution of the resulting hydroquinone in
DMF (4 mL) was treated with K2CO3 (269 mg, 1.95 mmol) fol-
lowed by the addition of MeI (110 μL, 1.77 mmol). The reaction
mixture was stirred at room temperature overnight and then diluted
with water (10 mL). The resulting solution was then extracted with
EtOAc (3ϫ 15 mL). The combined organic layers were washed
with brine (15 mL), dried with Na2SO4, filtered, and concentrated
under reduced pressure to give the crude product. Purification by
flash chromatography on silica gel (EtOAc/hexane, 1:20) afforded
bromonaphthalene 20 (64 mg, 50%) as a yellow oil; Rf = 0.60 (hex-
addition of
a solution of bromonaphthaldehyde 21 (20 mg,
0.046 mmol) in DMSO (500 μL). The reaction mixture was heated
at 65 °C for 2 h and then filtered through a Celite pad. The re-
sulting filtrate was diluted with EtOAc (10 mL), and the resulting
solution was washed with water (10 mL). The organic phase was
separated, and the aqueous phase was extracted with EtOAc (3ϫ
10 mL). The combined organic layers were washed with brine
(10 mL), dried with Na2SO4, filtered, and concentrated under re-
duced pressure to give the crude product. Purification by flash
chromatography on silica gel (EtOAc/hexane, from 1:10 to 1:2) af-
forded compound 22 (13 mg, 62%) as a yellow oil; Rf = 0.28 (hex-
1
ane/EtOAc, 2:1; UV). H NMR (400 MHz, CDCl3): δ = 10.47 (s,
1 H), 7.78 (d, J = 8.2 Hz, 1 H), 7.60 (t, J = 8.1, 8.2 Hz, 1 H), 7.53
(d, J = 8.6 Hz, 2 H), 7.48 (d, J = 8.6 Hz, 2 H), 7.09 (d, J = 7.8 Hz,
1 H), 6.97 (d, J = 8.6 Hz, 2 H), 6.89 (d, J = 8.6 Hz, 2 H), 6.56 (d,
J = 4.7 Hz, 1 H), 5.19 (s, 2 H), 5.05 (s, 1 H), 4.92 (d, J = 11.8 Hz,
1 H), 4.63 (d, J = 4.9 Hz, 1 H), 4.62 (d, J = 11.8 Hz, 1 H), 3.85 (s,
3 H), 3.80 (s, 6 H), 3.67 (s, 3 H), 1.44 (s, 3 H), 1.43 (s, 3 H), 1.26
(s, 3 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 198.0 (C), 190.8
(CH), 161.5 (C), 159.8 (C), 159.4 (C), 156.9 (C), 151.7 (C), 138.9
(C), 135.0 (C), 133.4 (CH), 130.7 (CH), 130.6 (CH), 130.5 (C),
129.6 (CH), 128.4 (C), 124.3 (C), 123.2 (C), 120.9 (C), 115.9 (CH),
114.2 (CH), 113.8 (CH), 110.5 (C), 109.6 (CH), 83.1 (CH), 78.8
(CH), 78.1 (C), 72.7 (CH2), 71.5 (CH2), 66.0 (CH3), 62.0 (CH3),
55.5 (CH3), 27.7 (CH3), 27.1 (CH3), 19.1 (CH3) ppm. IR (film):
1
ane/EtOAc, 4:1; UV). H NMR (250 MHz, CDCl3): δ = 7.73 (d, J
= 8.3 Hz, 1 H), 7.47 (d, J = 8.5 Hz, 2 H), 7.39 (t, J = 8.1 Hz, 1 H),
6.99 (d, J = 7.8 Hz, 1 H), 6.95 (d, J = 8.5 Hz, 2 H), 6.06 (m, 1 H),
5.13 (s, 2 H), 5.11 (dd, J = 11.0, 1.0 Hz, 1 H), 5.02 (dd, J = 17.0,
1.3 Hz, 1 H), 3.95 (s, 3 H), 3.84 (s, 3 H), 3.79 (d, J = 5.7 Hz, 2 H),
3.66 (s, 3 H) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 159.6 (C),
155.5 (C), 151.6 (C), 149.8 (C), 136.5 (CH), 130.7 (C), 129.9 (C),
129.6 (CH), 129.1 (C), 126.8 (CH), 120.7 (C), 117.7 (C), 115.8
(CH2), 115.5 (CH), 114.1 (CH), 109.0 (CH), 71.6 (CH2), 63.3
(CH ), 61.3 (CH ), 55.4 (CH ), 34.5 (CH ) ppm. IR (film): ν =
˜
max
3
3
3
2
3011, 2961, 2930, 1637, 1560, 1515 cm–1. HRMS (ESI-LTQ): calcd.
for C23H2479/81BrO4 [M + H]+ 443.0852/445.0832; found 443.0863/
445.0845.
ν
= 2993, 2934, 2839, 1709, 1674, 1610, 1570, 1551, 1514 cm–1.
˜
max
HRMS (ESI-LTQ): calcd. for C39H40O10Na [M + Na]+ 691.2514;
found 691.2513.
Bromonaphthaldehyde 21: A solution of tBuOK (1.0 m in THF,
190 μL, 0.19 mmol) in THF (500 μL) at 0 °C was treated dropwise
Supporting Information (see footnote on the first page of this arti-
1
with
a
solution (2 mL) of bromonaphthalene 20 (42 mg, cle): H and 13C NMR spectra for all new compounds (4–11, 13,
0.095 mmol) in THF/DMSO (1:8). After stirring for 2 min, the re-
15, 16, and 19–22) and NOESY spectrum for 16.
6188
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6181–6189

Synthetic Studies of Kinamycin Antibiotics
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Acknowledgments
This research was supported by the 7th European Community
Framework Programme with a Marie Curie International Reinte-
gration Grant (MC-IRG-200176). The authors wish to thank Pro-
fessors G. Varvounis, M. Siskos, A. Zarkadis, and I. Hatzidakis in
the Department of Chemistry at the University of Ioannina for
providing adequate lab space at the early stages of the project. The
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NMR experiments and Drs. P. Stathopoulos and A. Karkabounas
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Received: June 12, 2013
Published Online: August 6, 2013
Eur. J. Org. Chem. 2013, 6181–6189
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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