Synthesis of the benzo[b]fluorene core of the kinamycins by arylalkyne-allene and arylalkyne-alkyne cycloadditions

Article abstract of DOI:10.1002/ejoc.200500926

Arylalkyne-allene and arylalkyne-alkyne cycloadditions yields benzo[a]fluorenones, which are related to the tetracyclic core of the kinamycins. In the arylalkyne-alkyne cycloadditions, we found a rearrangement that produces benzo-[a]fluorenones, in addition to the expected benzo[b]fluorenones. This rearrangement could be suppressed in the presence of phenol, which allowed the synthesis of 4,9-dimeth-oxy-2-methyl-11H-benzo[b] fluoren-11-one in excellent yield. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500926

FULL PAPER
DOI: 10.1002/ejoc.200500926
Synthesis of the Benzo[b]fluorene Core of the Kinamycins by Arylalkyne–
Allene and Arylalkyne–Alkyne Cycloadditions
Esther González-Cantalapiedra,[a] Óscar de Frutos,[a] Carmen Atienza,[a] Cristina Mateo,[a]
and Antonio M. Echavarren*[a,b]
Keywords: Quinones / Cycloadditions / Alkynes / Allenes / Natural products
Arylalkyne–allene and arylalkyne–alkyne cycloadditions
yields benzo[a]fluorenones, which are related to the tetracyc-
lic core of the kinamycins. In the arylalkyne–alkyne cycload-
ditions, we found a rearrangement that produces benzo-
[a]fluorenones, in addition to the expected benzo[b]fluor-
enones. This rearrangement could be suppressed in the pres-
ence of phenol, which allowed the synthesis of 4,9-dimeth-
oxy-2-methyl-11H-benzo[b]fluoren-11-one
in
excellent
yield.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
sis of compound 3.[14] A similar approach for the synthesis
of the kinafluorene skeleton has been published.[15] Gould[5]
and Kamikawa[16] completed the synthesis of the stealthins.
A formal synthesis of the stealthins was also reported by
Snieckus.[17] Other work, directed towards the synthesis of
the more simple members of this family, have been re-
ported.[18–21] However, thus far, only one approach for the
synthesis of the more functionalized kinamycins (1) has
been reported.[22]
We approached the synthesis of the benzo[b]fluorene
core of the kinamycins by the arylalkyne–allene cycload-
dition,[23] which was inspired by the [4+2] cycloaddition of
arylalkyne–allenes developed by Schmittel.[24,25] As the
thermal reaction of enynes with alkynes also leads to annu-
lation,[26] we decided to explore in parallel this approach,
which is based on the arylalkyne–alkyne cycloaddition.[27]
Saá and co-workers have extensively studied similar arylal-
kyne–alkyne cycloadditions.[28,29] In this paper, we report
full details of our work, directed towards the synthesis of
kinamycins based on the intramolecular reaction of arylal-
kynes with allenes or alkynes.
Introduction
The kinamycins (1) are antibiotics originally isolated
from Streptomyces murayamaensis by Omura in 1970 (Fig-
ure 1).[1] Although the kinamycins were characterized as N-
cyanobenzo[b]carbazoles, they were later redefined as di-
azoparaquinones,[2] following our synthesis of 2, with the
structure originally assigned to prekinamycin.[3,4] Prekina-
mycin was shown to be diazobenzo[b]fluorene quinone
3.[5,6] Kinafluorenone (4)[7] and stealthin A (5),[8] are other
representative benzo[b]fluorene natural products structur-
ally related to the kinamycins. Interestingly, isoprekinamy-
cin, originally assigned as a diazobenzo[b]fluorene,[1] was
also reassigned to the diazobenzo[a]fluorene derivative 6.[5]
The fluostatins A (7) and B (8) are also naturally occurring
benzo[a]fluorenes.[9]
In addition to having antibacterial properties, some of
the kinamycins show antitumor activity, which has been at-
tributed to the loss of dinitrogen from the diazo group to
generate a radical intermediate that induces DNA cleav-
age.[10,11] This loss of dinitrogen is probably initiated by a
one-electron addition to the p-quinone.[12] Lomaiviticins A
(9) and B (10) are particularly interesting dimeric com-
pounds, as they show very potent antitumor activity, in ad-
dition to antibacterial activity against Staphylococcus au-
reus.[13]
Results and Discussion
Cycloaddition Arylalkyne/Allene
The novel structures and antitumor activities of the kina-
mycins have stimulated the interest for the development of
their total synthesis. Hauser completed an efficient synthe-
We decided to access to target 3 through the retrosyn-
thetic plan outlined in Scheme 1. Thus, compound 3 could
be available from compound 11 by the benzylic oxidation
and oxidation of the B ring to the p-quinone. Intermediate
11 could be assembled by the arylalkyne/allene intramol-
ecular cycloaddition of 12. The allene moiety of 12 could
be introduced by a [2,3]-sigmatropic rearrangement of the
propargyl alcohol 13, which could be constructed by the
[a] Departamento de Química Orgánica, Universidad Autónoma
of Madrid,
Cantoblanco, 28049 Madrid, Spain
[b] Institute of Chemical Research of Catalonia (ICIQ),
Av. Països Catalans 16, 43007 Tarragona, Spain
Fax: +34-977-920-225
E-mail: aechavarren@iciq.es
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Synthesis of the Benzo[b]fluorene Core of the Kinamycins
FULL PAPER
Figure 1. Kinamycins and related naturally occurring compounds.
addition of the lithium acetylide of 14 to the benzaldehyde after being heated in toluene under reflux in the presence
15. of HOAc.
The benzaldehyde 15 was prepared in two steps from 16 Thionyl chloride has been reported to promote reaction
(Scheme 2). Thus, o-lithiation of 16 with lithium N,N,NЈ- cascades similar to those required for the synthesis of 3
trimethylethylenediamide and nBuLi,[30] followed by trap- (Scheme 1).[32] In the event, when the propargyl alcohol 13
ping of the lithium derivative with 1,2-diiodoethane[31] was treated with thionyl chloride in the presence of pyridine
yields compound 17 in 55% yield. Sonogashira coupling of in anhydrous Et2O, the initially formed chlorosulfite un-
the aryl iodide 17 with (trimethylsilyl)acetylene gave 15 in dergoes a SNiЈ reaction to form the chlorinated allene 19
54% yield. Addition of the lithium acetylide of 14 to the (Scheme 3). Indeed, the allene 19 and the cyclized product
aldehyde 15 provided the alcohol 13 in 80% yield. The pro- 20 were detected in the 1H NMR of the crude reaction
pargyl alcohol 13 led only to the acetate 18 in 75% yield mixture. When this mixture was heated in toluene under
Scheme 1.
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E. González-Cantalapiedra, Ó. de Frutos, C. Atienza, C. Mateo, A. M. Echavarren
FULL PAPER
Scheme 2.
Scheme 3.
reflux, the desilylated tetracyclic chloride 21 was obtained temperature, but it undergoes smooth cycloaddition–aro-
as the only compound, albeit the isolated yield was low matization after being heated in toluene in the presence of
(24%).
an excess of 1,4-cyclohexadiene to give the benzo[b]fluorene
We also obtained a very similar result in the cyclization 26 as the major compound in 58% yield. The tetracyclic
of a simple model system (Scheme 4). Thus, reaction be- compound 26 possesses the skeleton of the kinamicins. 1,4-
tween the known compound 22[33] and lithium phenylace- Cyclohexadiene was added to facilitate aromatization of the
tylide gave the alcohol 23 in 80% yield. Reaction of 23 with initially formed tetracyclic intermediate. However, some-
thionyl chloride and pyridine, followed by heating of the what surprisingly, in the absence of the 1,4-cyclohexadiene,
crude mixture in xylene under reflux furnished the desi- compound 25 was recovered unchanged after being heated
lylated 24 in 29%.
in toluene for 5 days. Reaction of 13 with phenylsulfenyl
Because of the low yields achieved in the cyclizations of chloride and NEt3 failed to give the corresponding allenyl
13 and 23 initiated by reaction with thionyl chloride, we sulfoxide.
decided to try the preparation of different allenes by the
Unfortunately, oxidation of the B ring of 21 (see
[2,3]-sigmatropic rearrangement of the appropriate O-deriv- Scheme 3) or 26 with a variety of reagents [Pb(OAc)4, CrO3,
atized alcohols. Thus, reaction of 13 with Ph2PCl and NEt3 CAN] led to the oxidation of the A and/or D rings. Simi-
in THF led to clean formation of the allene 25 by phos- larly, attempted substitution of the TMS of 26 by a trifluo-
phorylation of the alcohol, followed by [2,3]-sigmatropic re- roacetoxy group with Pb(OCOCF3)4 in CF3COOH[35] led
arrangement (Scheme 5).[34] The allene 25 is stable at room only to desilylation.
Scheme 4.
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Synthesis of the Benzo[b]fluorene Core of the Kinamycins
FULL PAPER
Scheme 5.
Cycloaddition Arylalkyne/Alkyne
In addition to the expected benzo[b]fluorenones 38 and
39, the benzo[a]fluorenones 40 were obtained from the
ynones 33, 35–37, although the former were isolated as the
major products (Table 1). Interestingly, in the cyclization of
34, with an o-methoxy substituent, the benzo[a]fluorenone
40b was isolated as the major product under method A
(Table 1, Entries 4 and 6). The desilylated tetracycle 39a,
with the regiochemistry of naturally occurring benzo[b]fluo-
renones, was obtained in 25% yield following conditions B
(Table 1, Entry 5). Treatment of the ynones 33–37 with
Lewis acids such as ZnCl2 or Y(OTf)3 eed only to un-
changed starting materials.
The remarkable formation of benzo[a]fluorenones in the
cyclization of the ynones 33–37 unveils a new rearrange-
ment. A similar rearrangement was subsequently discovered
by Saá and co-workers.[28c] A rationale for this transforma-
tion was proposed by this group on the basis of the electro-
cyclization of the initial product, a strained allene 41 to give
42a,[29] which is in equilibrium with 42b. Intermediate 42b
then undergoes electrocyclization to form 43 (Scheme 8).
An alternative mechanistic suggestion advanced in our pre-
An alternative approach for the synthesis of 3 and related
compounds, is outlined in Scheme 6. In this case, the inter-
mediate 27 has the correct oxidation state at the C ring.
The key cycloadditions were expected to take place from
ynones of type 28.
The model substrates 33–37 were readily assembled in
two steps by the reaction of the benzaldehyde 22[33] with
the corresponding lithium arylacetylides, followed by oxi-
dation of the alcohols 23–32 with BaMnO4 (Scheme 7).
The cyclizations of 33–37 were best carried out by heat-
ing 0.06–0.2  solutions in 1,2-dichlorobenzene under re-
flux (180 °C) (method A). Alternatively, the reactions could
also be carried out in the solid state as a dispersion in celite
(method B), or in toluene in a sealed tube (method C). Un-
der these conditions, benzylated derivatives were obtained
as byproducts as a result of hydrogen abstraction from tolu-
ene followed by radical coupling. Following method C γ-
terpinene was added as a high-boiling 1,4-cyclohexadiene
to facilitate hydrogen migration in the final aromatization
step.
Scheme 6.
Scheme 7.
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E. González-Cantalapiedra, Ó. de Frutos, C. Atienza, C. Mateo, A. M. Echavarren
FULL PAPER
Table 1. Thermal cyclization of arylynones 33–37.
Entry
Ynone
Method[a]
Time [h]
Products (%)[b]
Ratio 38+39/40
1
2
3
4
5
6
7
8
9
33
33
33
34
34
34
35
36
37
A
B
C
A
B
C
A
A
A
96
14
79
48
24
16
216
48
48
38a (25), 39a (18), 40a (8)
38a (20), 39a (32), 40a (24)
38a (11), 39a (37), 40a (18)
38b (17)[c], 40b (63)
5.3:1
2.2:1
2.7:1
1.3.7
1:1
1:3.3
1.5:1
4.9:1
3.4:1
39b (25), 40b (25)
38b (9)[d], 40b (30),
38c (13), 39c (45), 40c (38)
38d (30), 39d (9), 40d (8)
38e (41), 39e (7), 40e (14)
[a] A = 1,2-dichlorobenzene under reflux (180 °C); B = celite, 180 °C; C = toluene, γ-terpinene, 180 °C, sealed tube. [b] Isolated yields.
[c] Based on 71% conversion. [d] Based on 79% conversion.
liminary communication[27] via intermediates of type 44 intermediates of type 41 (Scheme 8) is faster than their
seems less likely according to the calculations.[29,36]
equilibration via 42a–b.
Oxidation of the B ring in the tetracyclic 46 was tried
under a variety of conditions without success. When the
reaction was carried out in a mixture of CH3CN and
CH2Cl2 at room temperature for 30 min with H5IO6 and
CrO3 as catalyst, the oxidation on the A ring occurred selec-
tively and leads to the quinone 47 as an orange solid in
45% yield (Scheme 9).
The lithiation of 46 at C-10 assisted by the OMe and
carbonyl group using LDA, followed by borylation with
B(OMe)3, and reaction with H2O2 was also attempted. Un-
fortunately, after treatment of 46 with LDA, only starting
material was recovered.
As all attempts to oxidize the B ring failed, we thought
to replace the TMS group by another substituent that could
be later transformed into a phenol, thus facilitating the oxi-
dation at the B ring. Thus, we decided to introduce a hy-
droxyisopropyl group (Me2COH), which could be con-
verted into a phenol group by the benzylic hydroperoxide
rearrangement.[37,38] The preparation of the required sub-
strate began with the reaction between the aldehyde 17 and
the lithium acetylide of 14 to give the alcohol 48 in 99%
yield (Scheme 10). Sonogashira reaction of 48 with 2-meth-
ylbut-3-yn-2-ol afforded 49 (85% yield), which was oxidized
with BaMnO4 to give 50. Protection of the tertiary alcohol
as a TROC carbonate proceeded only in poor yield to give
51.
Scheme 8.
The ynone 45, with the substitution at the aryl rings re-
Several attempts to cyclize the ketone 50 were carried out
quired for the synthesis of 3, was synthesized in 99% yield under different reaction conditions, where in most cases
from the alcohol 13 by oxidation with BaMnO4 (Scheme 9). very complex mixtures were obtained. On the other hand,
After some optimization, we found that when the cycliza- heating of compound 50 in toluene with Sc(OTf)3 led to the
tion of 45 was carried out by heating in 1,2-dichlorobenzene 9H-fluoren-9-one 52 in 25% yield (Scheme 11). Cyclization
under reflux in the presence of phenol (10 equiv.), the desi- of the TROC derivative 51 in 1,2-dichlorobenzene in the
lylated tetracycle 46 was obtained in 91% yield. It is inter- presence of phenol gave also 52 in 59% yield. The cycliza-
esting to remark that in the presence of phenol no benzo[a]- tion of 51 actually proceeded more efficiently in the absence
fluorenone is observed, which suggest that protonation of of phenol, leading to 52 in 73% yield.
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Synthesis of the Benzo[b]fluorene Core of the Kinamycins
FULL PAPER
Scheme 9.
Scheme 10.
membered ring allene 54, which finally gives the 9H-flu-
oren-9-one 52 by a formal 1,5-hydrogen migration.
The elimination of acetone from 50 would afford 55,
which could then be functionalized at the terminal alkyne
group with a OTIPS group, whose hydrolysis would allow
the direct introduction of the desired phenol at the B ring.
However, upon treatment of 50 with NaOH in refluxing
toluene for 2 h, a mixture of the alkyne 14 (42%) and the
phthalide 56 (25%)[39] was obtained (Scheme 13). Presum-
ably, under the basic conditions, a fragmentation of 55 oc-
curs via the tetrahedral intermediate 57 which yields 14 and
the carboxylate 58, that cyclizes to give the phthalide 56.
The terminal alkyne 59 was obtained by the deprotection
of 13 with KF/MeOH[40] at room temperature in 99% yield
(Scheme 14). Oxidation of the alcohol was then carried out
with BaMnO4 in CH2Cl2 at room temperature to give the
Scheme 11.
A probable mechanism for the formation of 52 is shown ketone 60 in 97% yield. The oxidation of the terminal al-
in Scheme 12. Accordingly, the dehydration of 50 could kyne of 60 with lithium tert-butylperoxide[41] followed by
form the 1,3-enyne 53, which would form the strained six- the treatment with triisopropylsilyl trifluoromethanesulfon-
Scheme 12.
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E. González-Cantalapiedra, Ó. de Frutos, C. Atienza, C. Mateo, A. M. Echavarren
FULL PAPER
Scheme 13.
Scheme 14.
ate[42] led in all cases to mixtures of products. The depro-
tonation of alkyne with tBuLi or nBuLi, followed by oxi-
dation with tBuOOLi, and treatment with TfOTIPS also
failed to provide the desired OTIPS derivative.
TLC aluminum sheets coated with 0.2 mm GF254 silica gel. All
reactions were carried out under Ar. Solvents were purified and
dried by standard methods. Chromatographic purifications were
carried out with flash-grade silica gel. TIPS = triisopropylsilyl,
TROC = trichloroethoxycarbonyl.
1-Ethynyl-2-methoxybenzene (14): This acetylene is commercially
available (Aldrich). Alternatively, the acetylene 14 was prepared in
two steps: (i) To a mixture of 2-iodoanisole (3.600 g, 2.0 mL,
15.38 mmol), [Pd(PPh3)4] (440 mg, 0.40 mmol) and CuI (292 mg,
1.54 mmol) in piperidine (50 mL) was added (trimethylsilyl)acety-
lene (1.580 g, 2.28 mL, 16.15 mmol), and the mixture was stirred
at 23 °C for 24 h. The mixture was portioned between Et2O and a
saturated aqueous NH4Cl (pH 8 with NH4OH) solution, the or-
ganic extract was washed with a 3.5% aqueous HCl solution, fol-
lowed by a saturated aqueous NaCl solution, dried (MgSO4) and
the solvents evaporated. The residue was chromatographed (hex-
ane/EtOAc, 100:1 ) to give [2-(methoxyphenyl)ethynyl]trimethylsil-
ane (3.070 g, 98%) as a colorless oil. Rf = 0.37 (hexane/EtOAc,
Summary
Arylalkyne––allene and arylalkyne–alkyne cycload-
ditions produce the ready assemblage of the tetracyclic core
of the kinamycins. However, all attempts to selectively oxid-
ize the B ring of the resulting aromatized cycloadducts to a
quinone to provide the desired compounds failed. We found
a rearrangement in the arylalkyne–alkyne cycloadditions
that gives rise to benzo[a]fluorenones, in addition to the
expected benzo[b]fluorenones. This rearrangement could be
suppressed in the presence of phenol, which allowed to syn-
thesize of 4,9-dimethoxy-2-methyl-11H-benzo[b]fluoren-11-
one (46) in excellent yield. Oxidation of 46, with the substi-
tution pattern of prekinamycin (3) and related natural
products, led to 4-methoxy-2-methyl-6H-benzo[b]fluorene-
6,9,11-trione (47) in moderate yield. On the other hand,
5-methoxy-1-(2-methoxyphenyl)-3,7-dimethyl-9H-fluoren-
9-one (52) was obtained as a result of a 1,3-enyne/alkyne
cycloaddition. Work on alternative strategies for the synthe-
sis of members of this family of natural occurring quinon-
oid compounds are currently underway in our group.
1
100:1 ). H NMR (300 MHz, CDCl3): δ = 0.29 (s, 9 H), 3.86 (s, 3
H), 6.85 (d, J = 7.5 Hz, 1 H), 6.89 (td, J = 7.6, 1.0 Hz, 1 H), 7.27
(ddd, J = 7.4, 4.9, 1.7 Hz, 1 H), 7.45 (dd, J = 7.5, 1.7 Hz, 1 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = –0.3 (3 C), 55.6, 98.2, 101.2,
110.5, 112.2, 120.2, 129.9, 134.0, 160.2 ppm. (ii) A mixture of
[(methoxyphenyl)ethynyl]trimethylsilane (3.070 g, 15.02 mmol),
K2CO3 (207 mg, 1.50 mmol) in MeOH (20 mL) was stirred at 23 °C
for 20 h. The mixture was portioned between Et2O and a saturated
aqueous NaCl solution, dried (MgSO4) and the solvents evapo-
rated. The residue was chromatographed (hexane/EtOAc, 125:1) to
give 14 (1.804 g, 83%) as a yellow oil. Rf = 0.40 (hexane/EtOAc,
1
125:1). H NMR (200 MHz, CDCl3): δ = 3.34 (s, 1 H), 3.84 (s, 3
H), 6.84 (dd, J = 8.4, 0.8 Hz, 1 H), 6.89 (ddd, J = 7.6, 7.4, 1.1 Hz,
1 H), 7.28 (ddd, J = 8.4, 7.6, 1.8 Hz, 1 H), 7.46 (dd, J = 7.5, 1.7 Hz,
1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 55.4, 79.9, 81.03,
110.3, 110.9, 120.1, 130.0, 133.8, 160.3 ppm.
Experimental Section
General Remarks: The NMR spectra were carried out at 23 °C,
unless otherwise stated. Only the most significant MS fragmenta-
tions are given. The FAB-MS spectra were obtained by using m-
nitrobenzyl alcohol as the matrix. Rf values were determined on
2-Iodo-3-methoxy-5-methylbenzaldehyde (17): To a solution of
N,N,NЈ-trimethylethylenediamine (747 mg, 0.95 mL, 7.34 mmol) in
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Synthesis of the Benzo[b]fluorene Core of the Kinamycins
THF (15 mL) at –20 °C, was added nBuLi (3.1 mL, 2.24  in hex- orated. The residue was chromatographed (hexane/EtOAc, 6:1) to
FULL PAPER
anes 7.00 mmol). After 5 min aldehyde 16 (1.000 g, 6.67 mmol) was
added in THF (15 mL). After 10 min, nBuLi (8.9 mL, 2.24  in
hexane, 20.00 mmol) was added and the mixture was stirred at
–20 °C for 10 h. After being cooled to –78 °C, 1,2-diiodoethane
(4.700 g, 16.68 mmol) in THF (20 mL) was added and the resulting
mixture was warmed to 23 °C for 12 h. After being partitioned be-
tween Et2O and a saturated aqueous NaCl solution, the organic
extract was dried (MgSO4) and the solvents evaporated. The resi-
due was chromatographed (hexane/EtOAc, 10:1) to give 17
(1.007 g, 55%) as a white solid. M.p. 74–75 °C. Rf = 0.39 (hexane/
give 18 as a yellow solid (28 mg, 75%). M.p. 91–92 °C. Rf = 0.21
(hexane/EtOAc, 6:1). H NMR (CDCl3, 300 MHz): δ = 0.20 (s, 9
1
H), 2.10 (s, 3 H), 2.41 (s, 3 H), 3.88 (s, 3 H), 3.89 (s, 3 H), 6.71 (s,
1 H), 6.87 (d, J = 8.3 Hz, 1 H), 6.90 (td, J = 7.5, 1.0 Hz, 1 H), 7.00
(s, 1 H), 7.30 (dd, J = 7.5, 1.8 Hz, 1 H), 7.45–7.48 (m, 2 H) ppm.
13C NMR (CDCl3, 75 MHz, DEPT): δ = –0.10 (3 CH3), 20.85
(CH3), 22.16 (CH3), 55.69 (CH3), 55.99 (CH3), 64.70 (CH), 83.59
(C), 89.17 (C), 97.66 (C), 104.10 (C), 109.17 (C), 110.57 (CH),
111.49 (C), 111.97 (CH), 120.28 (CH), 121.48 (CH), 130.15 (CH),
133.88 (CH), 140.03 (C), 140.15 (C), 160.45 (C), 160.53 (C), 169.37
EtOAc, 9:1). IR (KBr): ν = 2956, 2929, 2846, 2739, 1687, 1580, (C) ppm. EI-MS: m/z (%) = 420 (3) [M+], 377 (100). EI-HRMS:
˜
1
1384, 1083, 513 cm–1. H NMR (200 MHz, CDCl3): δ = 2.38 (s, 3
H), 3.93 (s, 3 H), 6.87 (br. s, 1 H), 7.32 (br. s, 1 H), 10.16 (s, 1 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 21.1, 56.7, 117.2, 122.1,
122.9, 136.2, 140.0, 158.1, 196.6 ppm. EI-MS: m/z (%) = 276 (100)
[M+], 232 (6), 147 (14), 118 (13), 90 (29). C9H9IO2 (275.96): calcd.
C 39.14, H 3.29; found C 38.83, H 3.44.
m/z for C25H28O3Si (404.18): calcd. 420.1756; found 420.1730.
10-Chloro-4,9-dimethoxy-2-methyl-11H-benzo[b]fluorene (21): To a
mixture of 13 (100 mg, 0.18 mmol) in anhydrous Et2O (6 mL) at
0 °C was added a mixture of thionyl chloride (0.01 mL, 0.20 mmol)
and pyridine (0.03 mL, 0.39 mmol) in anhydrous Et2O (4 mL).
Then, the reaction mixture was warmed to room temperature. After
16 h water was added, and the mixture was extracted with Et2O.
The combined organic extracts were washed with a saturated NaCl
3-Methoxy-5-methyl-2-[(trimethylsilyl)ethynyl]benzaldehyde (15): A
mixture of 17 (970 mg, 3.52 mmol), (trimethylsilyl)acetylene
(518 mg, 0.75 mL, 5.28 mmol), Pd(OAc)2 (40 mg, 0.18 mmol) and solution, and water, dried (Na2SO4), and evaporated to give a yel-
PPh3 (92 mg, 0.36 mmol) in NEt3 (10 mL) was heated at 80 °C for
20 h. After being cooled to room temperature, the mixture was por-
tioned between EtOAc and a saturated aqueous NaCl solution, the
organic extract was dried (MgSO4) and the solvents evaporated.
The residue was chromatographed (hexane/EtOAc, 12:1) to give 15
(710 mg, 82%) as a white solid. M.p. 83–84 °C: Rf = 0.38 (hexane/
low oil. This crude oil was heated in toluene (3 mL) under reflux.
After 16 h the mixture was cooled to room temperature and con-
centrated. The mixture was chromatographed (hexane/CH2Cl2,
10:1) to give 21 as a yellow solid (16 mg, 24%), along with traces
of the 5-TMS compound as shown in the MS. M.p. 169–170 °C.
1
Rf = 0.24 (hexane/CH2Cl2, 10:1). H NMR (CDCl3, 300 MHz): δ
EtOAc, 9:1). IR (KBr): ν = 2957, 2839, 2741, 1690, 1584, 1450,
= 2.46 (s, 3 H), 3.99 (s, 3 H), 4.04 (s, 2 H), 4.05 (s, 3 H), 6.73 (s, 1
˜
1083, 855 cm–1. 1H NMR (200 MHz, CDCl3): δ = 0.23 (s, 9 H), H), 6.90 (dd, J = 6.7, 0.9 Hz, 1 H), 7.01 (s, 1 H), 7.37 (t, J = 7.9 Hz,
2.31 (s, 3 H), 3.83 (s, 3 H), 6.83 (br. s, 1 H), 7.23 (br. s, 1 H), 10.46
1 H), 7.54 (dd, J = 7.5, 0.8 Hz, 1 H), 8.32 (s, 1 H) ppm. 13C NMR
(s, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = –0.2 (3 C), 21.6, (CDCl3, 75 MHz, DEPT): δ = 22.04 (CH3), 38.04 (CH2), 55.32
56.0, 96.2, 105.8, 113.2, 116.5, 119.0, 137.0, 140.1, 160.7, 191.1
ppm. EI-MS: m/z (%) = 246 (28) [M+], 231 (100), 216 (14), 188
(18), 173 (25). C14H18O2Si (246.11): calcd. C 68.25, H 7.36; found
C 67.89, H 7.45.
(CH3), 56.17 (CH3), 106.95 (CH), 109.88 (CH), 118.08 (CH),
120.37 (CH), 120.98 (C), 122.03 (CH), 124.74 (C), 125.65 (CH),
126.30 (C), 137.56 (C), 139.50 (C), 139.58 (C), 140.74 (C), 145.33
(C), 156.32 (C), 156.47 (C) ppm. EI-MS: m/z (%) = 396 (3) [M+
+ TMS], 324 (100) [M+], 289 (55) [M+ – Cl]. EI-HRMS: m/z for
C23H25ClO2Si: calcd. 396.1312; found 396.1316; calcd. for
C20H17ClO2: 324.0917, found 324.0913.
1-{3-Methoxy-5-methyl-2-[(trimethylsilyl)ethynyl]phenyl}-3-(2-meth-
oxyphenyl)prop-2-yn-1-ol (13): To a solution of 14 (174 mg,
1.32 mmol) in THF (4 mL) at 0 °C was slowly added nBuLi
(0.55 mL, 2.38  in hexanes, 1.32 mmol). After 10 min, the alde-
hyde 15 (324 mg, 1.32 mmol) in THF (4 mL) at 0 °C was added.
Then the mixture was warmed to 23 °C and stirred at this tempera-
ture for 5 h. The mixture was portioned between EtOAc and a satu-
rated aqueous NaCl solution, the organic extract was dried
(Na2SO4) and the solvents evaporated. The residue was chromato-
graphed (hexane/EtOAc, 4:1) to give 13 (412 mg, 83%) as a yellow-
3-Phenyl-1-{2-[(trimethylsilyl)ethynyl]phenyl}prop-2-yn-1-ol (23): To
a solution of phenylacetylene (630 mg, 3.12 mmol) in THF (20 mL)
at 0 °C was added nBuLi (1.25 mL, 2.5  solution in hexanes,
3.12 mmol). After 30 min, 2-[2-(trimethylsilyl)ethynyl]benzaldehyde
(22)[33] (318 mg, 3.12 mmol) in THF (20 mL) was added, and the
mixture was stirred for 5 h at 23 °C. The mixture was diluted with
EtOAc, washed with a saturated NaCl solution, and dried
(Na2SO4). The solvent was evaporated, and the residue was chro-
matographed (hexane/EtOAc, 10:1) to give 23 as a yellow oil
(757 mg, 80%). Rf = 0.32 (hexane/EtOAc, 10:1). 1H NMR (CDCl3,
300 MHz): δ = 0.30 (s, 9 H), 3.11 (br. s, 1 H), 6.08 (d, J = 5.5 Hz,
1 H), 7.26–7.34 (m, 4 H), 7.38 (td, J = 7.7, 1.4 Hz, 1 H), 7.47–7.54
(m, 3 H), 7.74 (dd, J = 7.9, 1.0 Hz, 1 H) ppm. 13C NMR (CDCl3,
75 MHz, DEPT): δ = –0.13 (3 CH3), 63.74 (CH), 86.43 (C), 88.14
(C), 100.71 (C), 102.35 (C), 121.16 (CH), 122.55 (CH), 126.68
ish-white solid. M.p. 114–115 °C. Rf = 0.22 (hexane/EtOAc, 5:1).
1
IR (KBr): ν = 3514, 2962, 2833, 2152, 1606, 1495, 1298 cm–1. H
˜
NMR (200 MHz, CDCl3): δ = 0.29 (s, 9 H), 2.38 (s, 3 H), 3.21 (d,
J = 5.7 Hz, 1 H), 3.87 (s, 6 H), 6.08 (d, J = 5.7 Hz, 1 H), 6.66 (br.
s, 1 H), 6.85–6.92 (m, 2 H), 7.27–7.31 (m, 2 H), 7.45 (dd, J = 4.5,
1.7 Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = –0.1 (3 C),
22.0, 55.6, 55.9, 63.8, 82.7, 92.1, 98.8, 104.2, 107.5, 110.5, 111.3,
111.7, 120.0, 120.2, 129.8, 133.7, 140.4, 144.6, 160.1, 160.5 ppm.
EI-MS: m/z (%) = 378 (9) [M+], 363 (100), 305 (19), 231 (45). (CH), 128.12 (CH), 128.23 (CH), 128.49 (CH), 129.14 (CH), 131.77
C23H26O3Si (378.17): calcd. C 72.98, H 6.92; found C 72.98, H
6.86.
(3 CH), 132.78 (CH), 142.87 (C) ppm. EI-MS: m/z (%) = 304 (3)
[M+], 288 (13), 213 (34). EI-HRMS: m/z for C20H20OSi: calcd.
304.1283; found 304.1288. C20H20OSi (304.13): calcd. C 78.90, H
6.62; found C 78.52, H 7.04.
1-{3-Methoxy-5-methyl-2-[2-(trimethylsilyl)ethynyl]phenyl}-3-(2-meth-
oxyphenyl)prop-2-ynyl Acetate (18): To a mixture of 13 (50 mg,
0.09 mmol) in toluene (2 mL) was added HOAc (0.2 mL), and the
reaction was heated under reflux for 16 h. The mixture was cooled
to room temperature and was portioned between CH2Cl2 and
water, the organic extract was dried (MgSO4) and the solvents evap-
10-Chloro-11H-benzo[b]fluorene (24): To a mixture of 23 (100 mg,
0.33 mmol) in anhydrous Et2O (10 mL) at 0 °C was added a mix-
ture of thionyl chloride (0.03 mL, 0.36 mmol), and pyridine
(0.06 mL, 0.73 mmol) in anhydrous Et2O (5 mL). Then, the reac-
Eur. J. Org. Chem. 2006, 1430–1443
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1437

E. González-Cantalapiedra, Ó. de Frutos, C. Atienza, C. Mateo, A. M. Echavarren
FULL PAPER
tion mixture was warmed to room temperature. After 16 h water
was added, and the mixture was extracted with Et2O. The com-
bined organic extracts were washed with a saturated NaCl solution,
and water, dried (Na2SO4), and evaporated to give a yellow oil.
This crude oil was heated in xylene (5 mL) under reflux for 16 h.
The mixture was cooled to room temperature, and evaporated and
the residue was chromatographed (hexane) to give 24 as a white
solid (24 mg, 29%). M.p. 106–107 °C. Rf = 0.55 (hexane). 1H NMR
solution of 2-ethynylanisole (14) (129 mg, 0.98 mmol) in THF
(4 mL) at 0 °C. After stirring for 30 min, a solution of 22 (200 mg,
0.98 mmol) in THF (4 mL) was added. The reaction mixture was
stirred at 23 °C for 5 h, diluted with EtOAc and washed with satu-
rated aqueous NaCl solution. The organic layer was dried
(Na2SO4), the solvent was evaporated, and the residue was chro-
matographed (hexane/EtOAc, 30:1) to give 29 as a yellow oil
(235 mg, 71%). 1H NMR (CDCl3, 300 MHz): δ = 0.27 (s, 9 H),
(CDCl3, 300 MHz): δ = 4.13 (s, 2 H), 7.36–7.46 (m, 2 H), 7.51– 3.30 (br. s, 1 H, OH), 3.81 (s, 3 H), 6.15 (s, 1 H), 6.83 (d, J =
7.62 (m, 3 H), 7.90–7.97 (m, 2 H), 8.12 (s, 1 H), 8.31 (dd, J = 8.9,
8.5 Hz, 1 H), 6.88 (td, J = 8.5, 0.8 Hz, 1 H), 7.29–7.22 (m, 2 H),
7.34 (td, J = 7.3, 1.2 Hz, 1 H), 7.42 (dd, J = 7.3, 1.6 Hz, 1 H), 7.49
1.2 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz, DEPT): δ = 36.83
(CH2), 116.87 (CH), 120.80 (CH), 123.82 (CH), 125.31 (CH), (dd, J = 7.7, 1.6 Hz, 1 H), 7.84 (dd, J = 8.1, 1.2 Hz, 1 H) ppm. 13
C
126.09 (CH), 126.33 (CH), 127.12 (CH), 127.59 (C), 127.99 (CH),
NMR (CDCl3, 75 MHz; DEPT): δ = –0.27 (3 CH3), 55.55 (CH3),
128.44 (CH), 130.03 (C), 134.37 (C), 139.28 (C), 140.59 (C), 140.73 63.50 (CH), 82.72 (C), 92.23 (C), 100.12 (C), 102.32 (C), 110.49
(C), 142.97 (C) ppm. EI-MS: m/z (%) = 250 (11) [M+], 215 (100).
EI-HRMS: m/z for C17H11Cl: calcd. 250.0549; found 250.0553.
(C), 111.61 (C), 120.20 (CH), 121.20 (CH), 126.81 (CH), 127.87
(CH), 128.93 (CH), 129.82 (CH), 132.44 (CH), 133.56 (CH), 142.87
(C), 159.97 (C) ppm.
Diphenyl[3-(5-methyl-3-methoxy-2-trimethylsilylethynylphenyl)-1-
(2-methoxyphenyl)-1,2-propadienyl]oxophosphorane (25): To a solu-
tion of 13 in THF (10 mL) at –78 °C was added NEt3 (184 mg,
3-o-Tolyl-1-{2-[(trimethylsilyl)ethynyl]phenyl}prop-2-yn-1-ol (30):
nBuLi (0.61 mL 2.5  in hexanes) was slowly added to a solution
0.25 mL, 1.82 mmol) and Ph2PCl (387 mg, 0.32 mL, 1.75 mmol). of 2-ethynyltoluene (178 mg, 1.53 mmol) in THF (5 mL) at 0 °C.
The mixture was warmed to –40 °C for 30 min, and the resulting
solution was stirred for 90 min at this temperature. The mixture
was portioned between EtOAc and a saturated NaCl solution, the
organic extract was dried (Na2SO4) and the solvents evaporated.
The residue was chromatographed (hexane/EtOAc, 1:1) to give 25
(731 mg, 93%) as a vitreous yellow solid. Rf = 0.21 (hexane/EtOAc,
After stirring for 30 min, a solution of 22 (310 mg, 1.53 mmol) in
THF (5 mL) was added. The reaction mixture was stirred at 23 °C
for 16 h, diluted with EtOAc and washed with saturated aqueous
NaCl solution. The organic layer was dried (Na2SO4), the solvent
was evaporated, and the residue was chromatographed (hexane/
1
EtOAc, 7:1) to give 30 as a yellow oil (373.5 mg, 77%). H NMR
(CDCl3, 300 MHz): δ = 0.37 (s, 9 H), 2.51 (s, 3 H), 3.40 (br. s, 1
1:1). IR (neat, cm–1): ν = 3056, 2919, 2222, 2144, 1931, 1567, 1470,
˜
1
1074, 872. H NMR (300 MHz, CDCl3): δ = 0.25 (s, 9 H), 2.31 (s, H, OH), 6.22 (s, 1 H), 7.26–7.23 (m, 1 H), 7.25–7.30(m, 2 H), 7.33
3 H), 3.61 (s, 3 H), 3.80 (s, 3 H), 6.48 (br. s, 1 H), 6.74 [d, J (1H- (td, J = 7.7, 1.6 Hz, 1 H), 7.43 (td, J = 7.7, 1.6 Hz, 1 H), 7.52 (br.
31P) = 11 Hz, 1 H], 6.83 (br. s, 1 H), 6.89 (td, J = 7.6, 1.0 Hz, 1
d, J = 7.3 Hz, 1 H), 7.59 (dd, J = 7.3, 1.2 Hz, 1 H), 7.83 (dd, J =
H), 7.20 (td, J = 7.7, 1.7 Hz, 1 H), 7.25–7.49 (m, 7 H), 7.64 (dt, J 7.7, 1.2 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz; DEPT): δ =
= 7.6, 1.4 Hz, 1 H), 7.74–7.86 (m, 4 H) ppm. 13C NMR (75 MHz, –0.28 (3 CH3), 20.55 (CH3), 63.52 (CH), 85.14 (C), 92.12 (C),
CDCl3): δ = –0.04 (3 C), 21.95, 55.19, 55.78, 94.01, 94.20, 98.98,
100.37 (C), 102.37 (C), 120.89 (C), 122.18 (C), 125.31 (CH), 126.39
99.62, 100.93, 103.27, 107.87, 109.96, 111.13, 119.86, 120.78, (CH), 127.84 (CH), 128.32 (CH), 128.96 (CH), 129.21 (CH), 131.94
127.80 [d, J (13C-31P) = 6.3 Hz], 127.97 [d, J (13C-31P) = 6.3 Hz], (CH), 132.61 (CH), 140.14 (C), 143.04 (C) ppm. C21H22OSi
130.63, 129.23, 131.58–131.38 (m, 2 C), 132.01 [d, J (13C-31P) = (318.14): calcd. C 79.20, H 6.96; found C 78.78, H 7.39.
6.3 Hz], 133.40 [d, J (13C-31P) = 6.3 Hz], 135.68 [d, J (13C-31P) =
3-m-Tolyl-1-{2-[(trimethylsilyl)ethynyl]phenyl}prop-2-yn-1-ol (31):
8.4 Hz], 139.05, 156.70, 156.76, 160.38, 214.27 ppm. EI-MS: m/z =
nBuLi (0.5 mL 2.5  in hexanes) was slowly added to a solution of
3-ethynyltoluene (188 mg, 1.61 mmol) in THF (5 mL) at 0 °C. After
stirring for 30 min, a solution of 22 (325 mg, 1.53 mmol) in THF
562 (100) [M+], 531 (46), 490 (57), 361 (70). C35H35O3PSi (562.21):
calcd. C 74.71, H 6.27; found C 74.33, H 6.34.
Diphenyl[10-(4,9-dimethoxy-2-methyl-5-(trimethylsilyl)-11H-benzo- (5 mL) was added. The reaction mixture was stirred at 23 °C for
[b]fluorenyl)]oxophosphorane (26): A solution of 25 (180 mg,
0.32 mmol) and 1,4-cyclohexadiene (0.45 mL, 4.8 mmol) in toluene
(9 mL) was heated at 110 °C for 48 h. The solvent was evaporated
and the residue was chromatographed (hexane/EtOAc, 1:1) to give
16 h, diluted with EtOAc and washed with saturated aqueous NaCl
solution. The organic layer was dried (Na2SO4), the solvent was
evaporated, and the residue was chromatographed (hexane/EtOAc,
7:1) to give 31 as a yellow oil (249 mg, 49%). 1H NMR (CDCl3,
26 (105 mg, 58%) as a pale red solid. M.p. 111–112 °C. Rf = 0.20 300 MHz): δ = 0.32 (s, 9 H), 2.32 (s, 3 H), 3.21 (s, 1 H, OH), 6.09
(hexane/EtOAc, 1:1). IR (KBr): ν = 3055, 2934, 1608, 1555, 1458,
(s, 1 H), 7.14 (br. d, J = 7.3 Hz, 1 H), 7.21 (br. t, J = 7.6 Hz, 1 H),
7.27–7.31 (m, 3 H), 7.39 (br. d, J = 7.3 Hz, 1 H), 7.53 (br. d, J =
7.3 Hz, 1 H), 7.76 (br. d, J = 7.3 Hz, 1 H) ppm. 13C NMR (CDCl3,
75 MHz; DEPT): δ = –0.23 (3 CH3), 21.03 (CH3), 63.58 (CH),
86.45 (C), 87.79 (C), 100.51 (C), 102.32 (C), 121.04 (C), 122.26 (C),
126.11 (CH), 127.95 (CH), 128.01 (CH), 128.70 (CH), 129.01 (CH),
˜
1263, 1088. 1H NMR (300 MHz, CDCl3): δ = 0.44 (s, 9 H), 2.40
(s, 3 H), 2.82 (s, 3 H), 3.90 (s, 3 H), 4.40–4.20 (m, 2 H), 6.40 (d, J
= 7.7 Hz, 1 H), 6.61 (br. s, 1 H), 6.88 (br. s, 1 H), 7.33 (t, J =
8.1 Hz, 1 H), 7.31–7.44 (m, 6 H), 7.62–7.74 (m, 4 H), 7.83 (dd, J
= 8.0, 1.4 Hz, 1 H) PPM. 13C NMR (75 MHz, CDCl3): δ = 2.30
(3 C), 21.90, 38.97, 52.57, 54.38, 104.56, 109.27, 117.72, 118.18, 129.24 (CH), 132.25 (CH), 132.64 (CH), 137.74 (C), 142.90 (C)
119.55, 121.51, 123.62 [d, J (13C-31P) = 6.0 Hz], 124.52, 127.70,
127.94, 128.10, 130.44, 138.06, 139.90 [d, J (13C-31P) = 6.4 Hz],
140.13, 147.06, 147.17, 151.36 [d, J (13C-31P) = 6.2 Hz], 153.91,
154.56 ppm (4 signals were missing due to poor relaxation or over-
lapping). EI-MS m/z (%) = 562 (100) [M+], 490 (16), 439 (8), 361
(6). EI-HRMS: m/z for C35H35O3PSi: calcd. 562.2093; found:
562.2083.
ppm. C21H22OSi (318.14): calcd. C 79.20, H 6.96; found C 78.63,
H 7.41.
3-p-Tolyl-1-{2-[(trimethylsilyl)ethynyl]phenyl}prop-2-yn-1-ol (32):
nBuLi (0.54 mL 2.5  in hexanes) was slowly added to a solution
of 4-ethynyltoluene (157 mg, 1.35 mmol) in THF (10 mL) at 0 °C.
After stirring for 30 min, a solution of 22 (273 mg, 1.31 mmol) in
THF (10 mL) was added. The reaction mixture was stirred at 23 °C
for 16 h, diluted with EtOAc and washed with saturated aqueous
NaCl solution. The organic layer was dried (Na2SO4), the solvent
3-(2-Methoxyphenyl)-1-{2-[(trimethylsilyl)ethynyl]phenyl}prop-2-yn-
1-ol (29): nBuLi (0.39 mL 2.5  in hexanes) was slowly added to a
1438
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1430–1443

Synthesis of the Benzo[b]fluorene Core of the Kinamycins
was evaporated, and the residue was chromatographed (hexane/ (C), 119.89 (C), 122.49 (C), 128.12 (CH), 128.41 (CH), 130.21
FULL PAPER
EtOAc, 7:1) to give 32 as a yellow oil (230 mg, 54%). 1H NMR
(CDCl3, 200 MHz): δ = 0.28 (s, 9 H), 2.35 (s, 3 H), 2.91 (d, J =
5.4 Hz, 1 H, OH), 6.05 (d, J = 5.4 Hz, 1 H), 7.12 (br. d, J = 7.5 Hz,
1 H), 7.25–7.43 (m, 5 H), 7.52 (br. d, J = 7.5 Hz, 1 H), 7.74 (br. d,
J = 7.5 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz; DEPT): δ =
–0.28 (3 CH3), 21.21 (CH3), 63.41 (CH), 86.25 (C), 87.44 (C),
100.35 (C), 102.33 (C), 119.31 (C), 120.89 (C), 126.41 (CH), 127.77
(CH), 128.73 (CH), 128.89 (CH), 131.43 (CH), 132.45 (CH), 138.26
(C), 142.88 (C) ppm. C21H22OSi (318.14): calcd. C 79.20, H 6.96;
found C 78.69, H 7.13.
(CH), 131.05 (CH), 131.61 (CH), 132.11 (CH), 133.50 (CH), 134.87
(CH), 138.27 (C), 138.86 (C), 177.37 (C) ppm. EI-MS: m/z (%) =
316 (33) [M+], 301 (100), 242 (19).
3-p-Tolyl-1-{2-[(trimethylsilyl)ethynyl]phenyl}prop-2-yn-1-one (37):
BaMnO4 (369 mg, 1.44 mmol) was added to a solution of 32
(230 mg, 0.72 mmol) in CH2Cl2 (20 mL) at 23 °C. The reaction
mixture was stirred for 3 days, filtered through celite and the sol-
vents evaporated. The residue was chromatographed (hexane/
EtOAc, 9:1) to give 37 as a yellow oil (206 mg, 90%). 1H NMR
(CDCl3, 300 MHz): δ = 0.21 (s, 9 H), 2.39 (3 H), 7.20 (br. d, J =
3-Phenyl-1-{2-[(trimethylsilyl)ethynyl]phenyl}prop-2-yn-1-one (33): 8.0 Hz, 2 H), 7.43 (td, J = 7.6, 1.5 Hz, 1 H), 7.49 (td, J = 7.4,
BaMnO4 (343 mg, 1.34 mmol) was added to a solution of 23
(203 mg, 0.67 mmol) in CH2Cl2 (20 mL) at 23 °C. The reaction
mixture was stirred for 3 days, filtered through celite and the sol-
vents evaporated. The residue was chromatographed (hexane/
EtOAc, 9:1) to give 33 as a yellow oil (184 mg, 91%). 1H NMR
1.6 Hz, 1 H), 7.54 (br. d, J = 8.2 Hz, 2 H), 7.61(dd, J = 7.7, 1.6 Hz,
1 H), 8.09 (dd, J = 7.4, 1.3 Hz, 1 H) ppm. 13C NMR (CDCl3,
75 MHz; DEPT): δ = –0.27 (3 CH3), 21.74 (CH3), 87.89 (C), 94.02
(C), 101.25 (C), 102.90 (C), 117.10 (C), 122.55 (C), 128.16 (CH),
129.39 (CH), 131.12 (CH), 132.11 (CH), 133.20 (CH), 134.94 (CH),
(CDCl3, 300 MHz): δ = 0.21 (s, 9 H), 7.36–7.55 (m, 5 H), 7.59– 139.07 (C), 141.48 (C), 177.61 (C) ppm. C21H20OSi (316.13): calcd.
7.72 (m, 3 H), 8.10 (dd, J = 7.9, 1.9 Hz, 1 H) ppm. 13C NMR
(CDCl3, 75 MHz; DEPT): δ = –0.26 (3 CH3), 87.97 (C), 93.30 (C),
101.36 (C), 102.90 (C), 120.18 (C), 122.60 (C), 128.24 (CH), 128.61
(CH), 130.77 (CH), 131.19 (CH), 132.27 (CH), 133.14 (CH), 134.99
(CH), 138.88 (CH), 177.48 (C) ppm. C20H18OSi (302.11): calcd. C
79.43, H 6.00; found C 79.15, H 6.12.
C 79.70, H 6.37; found C 79.38, H 6.16.
Thermal Cyclization of Diaryldiynones in 1,2-Dichlorobenzene. Ge-
neral Procedure: A solution of 33–37 in 1,2-dichlorobenzene (0.2 
for 33, 0.06–0-09  for 34–37) was heated under reflux for the
stated time (Table 1). The solvent was evaporated, and the residue
was chromatographed (gravity column, hexane/EtOAc, 30:1).
3-(2-Methoxyphenyl)-1-{2-[(trimethylsilyl)ethynyl]phenyl}prop-2-yn-
1-one (34): BaMnO4 (1.501 g, 5.86 mmol) was added to a solution
of 29 (980 mg, 2.93 mmol) in CH2Cl2 (20 mL) at 23 °C. The reac-
tion mixture was stirred for 3 days, filtered through celite and the
solvents evaporated. The residue was chromatographed (hexane/
2-Methoxy-6-(trimethylsilyl)benzo[a]fluorene-11-one (40b): 1H
NMR (C6D6, 500 MHz): δ = 0.29 (s, 9 H), 3.52 (s, 3 H), 6.81 (t, J
= 7.6 Hz, 9-H or 8-H), 7.00 (td, J = 7.6, 1.2 Hz, 8-H or 9-H), 7.09
(dd, J = 9.0, 2.6 Hz, 3-H), 7.33 (d, J = 9.0 Hz, 4-H), 7.63 (d, J =
5.9 Hz, 10-H or 7-H), 7.64 (d, J = 5.9 Hz, 7-H or 10-H), 7.95 (s,
5-H), 8.84 (d, J = 2.5 Hz, 1-H) ppm. 13C NMR (CDCl3, 75 MHz;
DEPT): δ = 0.29 (3 CH3), 55.54 (CH3), 101.61 (CH, C-1), 116.87
(C), 119.96 (CH), 123.62 (CH), 125.81 (C), 128.63 (CH), 129.20
(C), 129.31 (CH), 130.10 (CH), 132.08 (C), 133.60 (CH), 135.22
(C), 142.70 (CH, C-5), 144.95 (C), 151.40 (C), 161.21 (C), 196.24
(C) ppm. EI-MS: m/z (%) = 332 (98) [M+], 317 (100), 289 (47). The
structure was supported by COSY experiment (C6D6, 500 MHz),
HMQC and HMBC experiments.
1
EtOAc, 8:1) to give 34 as a yellow solid (774 mg, 79%). H NMR
(CDCl3, 300 MHz): δ = 0.22 (s, 9 H), 3.93 (s, 3 H), 6.91–6.99 (m,
2 H), 7.39–7.51 (m, 3 H), 7.56–7.62 (m, 2 H), 8.29–8.33 (m, 1 H)
ppm. 13C NMR (CDCl3, 75 MHz): δ = –0.25 (3 CH3), 55.83 (CH3),
90.30 (C), 92.00 (C), 100.90 (C), 103.22 (C), 92.00 (C), 109.55 (C),
110.83 (CH), 120.59 (CH), 122.57 (C), 128.04 (CH), 132.05 (CH),
132.47 (CH), 134.98 (CH), 138.89 (C), 161.76 (C), 177.21 (C) ppm.
3-o-Tolyl-1-{2-[(trimethylsilyl)ethynyl]phenyl}prop-2-yn-1-one (35):
BaMnO4 (395 mg, 1.54 mmol) was added to a solution of 30
(245 mg, 0.77 mmol) in CH2Cl2 (15 mL) at 23 °C. The reaction
mixture was stirred for 17 h, filtered through celite and the solvents
evaporated. The residue was chromatographed (hexane/EtOAc,
6-(Trimethylsilyl)benzo[a]fluorene-11-one (40a): 1H NMR (CDCl3,
300 MHz): δ = 0.55 (s, 9 H), 7.26 (td, J = 7.4, 0.9 Hz, 1 H), 7.40–
7.47 (m, 2 H), 7.51–7.62 (m, 1 H), 7.62–7.65 (m, 1 H), 7.67 (d, J
= 7.6 Hz, 1 H), 7.77 (br. d, J = 8.2 Hz, 1 H), 8.16 (s, 1 H), 9.06
(dd, J = 8.5, 1.1 Hz, 1 H) ppm. 13C NMR (CDCl3, 125 MHz): δ =
0.66, 123.97, 124.05, 124.62, 126.98, 127.34, 128.85, 129.10, 130.27,
130.68, 132.62, 133.72, 134.11, 135.41, 143.50, 145.47, 151.30,
196.52 ppm. EI-MS: m/z (%) = 302 (100) [M+], 287 (96), 259 (56).
1
10:1) to give 35 as a yellow oil (228 mg, 93%). H NMR (CDCl3,
300 MHz): δ = 0.22 (s, 9 H), 2.51 (s, 3 H), 7.17 (br. t, J = 8 Hz, 1
H), 7.22 (br. d, J = 8 Hz, 1 H), 7.31 (td, J = 7.7, 1.2 Hz, 1 H), 7.41
(td, J = 7.3, 1.2 Hz, 1 H), 7.47 (td, J = 7.7, 1.6 Hz, 1 H), 7.58 (dd,
J = 6.5, 1.0 Hz, 1 H), 7.59 (dd, J = 7.3, 2.0 Hz, 1 H), 8.11 (dd, J
= 7.7, 1.6 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz; DEPT): δ
= –0.42 (3 CH3), 20.55 (CH3), 91.59 (C), 92.20 (C), 101.12 (C),
102.91 (C), 119.78 (C), 122.35 (C), 125.70 (CH), 128.04 (CH),
129.63 (CH), 130.66 (CH), 130.97 (CH), 132.03 (CH), 133.50 (CH),
134.84 (CH), 138.86 (C), 142.04 (C), 177.18 (C) ppm. EI-MS: m/z
(%) = 316 (33) [M+], 301 (100).
2-Methyl-6-(trimethylsilyl)benzo[a]fluorene-11-one (40c): 1H NMR
(CDCl3, 500 MHz): δ = 0.57 (s, 9 H), 2.56 (s, 3 H), 7.25–7.28 (m,
2 H), 7.45 (td, J = 7.6, 1.1 Hz, 1 H), 7.64–7.69 (m, 3 H), 8.12 (s, 1
H), 8.87 (d, J = 0.6, 1 H) ppm. 13C NMR (CDCl3, 125 MHz;
DEPT): δ = 0.71 (3 CH3), 22.64 (CH3), 123.49 (CH), 123.90 (CH),
123.93 (CH), 126.75 (C), 128.69 (CH), 128.99 (CH), 129.30 (CH),
130.96 (C), 131.36 (C), 132.20 (C), 134.02 (CH), 135.49 (C), 140.70
(C), 143.26 (CH), 145.51 (C), 151.40 (C), 196.60 (C) ppm. EI-MS:
m/z (%) = 316 (100) [M+], 302 (99), 243 (11).
3-m-Tolyl-1-{2-[(trimethylsilyl)ethynyl]phenyl}prop-2-yn-1-one (36):
BaMnO4 (356 mg, 1.38 mmol) was added to a solution of 31
(221 mg, 0.69 mmol) in CH2Cl2 (15 mL) at 23 °C. The reaction
mixture was stirred for 17 h, filtered through celite and the solvents
evaporated. The residue was chromatographed (hexane/EtOAc,
10:1) to give 36 as a yellow solid (182 mg, 83%). 1H NMR (CDCl3,
3-Methyl-6-(trimethylsilyl)benzo[a]fluorene-11-one (40d): 1H NMR
(CDCl3, 500 MHz): δ = 0.56 (s, 9 H), 2.51 (s, 3 H), 7.27 (t, J =
7.4 Hz, 1 H), 7.43–7.46 (m, 2 H), 7.57 (s, 1 H), 7.64 (d, J = 7.2 Hz,
300 MHz): δ = 0.22 (s, 9 H), 2.34 (s, 3 H), 7.25–7.30 (m, 2 H), 1 H), 7.66 (d, J = 7.6 Hz, 1 H), 8.10 (s, 1 H), 8.96 (d, J = 8.6 Hz,
7.40–7.50 (m, 4 H), 7.61 (dd, J = 6.9, 1.6 Hz, 1 H), 8.10 (dd, J =
1 H) ppm. 13C NMR (CDCl3, 125 MHz; DEPT): δ = 0.67 (3 CH3),
22.12 (CH3), 113.02 (C), 123.81 (CH), 123.99 (CH), 124.37 (CH),
7.7, 1.6 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz; DEPT): δ =
–0.36 (3 CH3), 21.03 (CH3), 87.68 (C), 93.59 (C), 101.21 (C), 102.85 127.35 (C), 127.76 (CH), 128.88 (CH), 132.53 (C), 132.63 (CH),
Eur. J. Org. Chem. 2006, 1430–1443
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1439

E. González-Cantalapiedra, Ó. de Frutos, C. Atienza, C. Mateo, A. M. Echavarren
FULL PAPER
134.03 (C), 134.10 (CH), 135.40 (C), 136.75 (C), 142.77 (CH), 1.1 Hz, 1 H), 7.70–7.73 (m, 2 H), 7.83 (s, 1 H), 8.67 (s, 1 H) ppm.
145.67 (C), 150.41 (C), 196.67 (C) ppm. EI-MS: m/z = 316 (100) EI-MS: m/z (%) = 260 (100) [M+], 217 (75), 189 (28).
[M+], 301 (82), 229 (10).
Benzo[b]fluorene-11-one (39a):[28b,43] 1H NMR (CDCl3, 500 MHz):
δ = 7.35 (dt, J = 7.4, 0.9 Hz, 1 H), 7.47 (td, J = 8.1, 1.2 Hz, 1 H),
4-Methyl-6-(trimethylsilyl)benzo[a]fluorene-11-one (40e): 1H NMR
7.55 (td, J = 8.1, 1.3 Hz, 1 H), 7.56 (td, J = 7.4, 1.1 Hz, 1 H), 7.72
(dt, J = 7.5, 0.8 Hz, 1 H), 7.75 (dt, J = 8.2, 0.7 Hz, 1 H), 7.83 (dd,
J = 8.1, 0.6 Hz, 1 H), 7.87 (s, 1 H), 7.89 (dt, J = 8.1, 0.6 Hz, 1 H),
8.17 (s, 1 H) ppm. 13C NMR (CDCl3, 125 MHz; DEPT): δ = 119.48
(CH), 121.41 (CH), 124.90 (CH), 126.13 (CH), 127.36 (CH), 129.19
(CH), 129.42 (CH), 129.61 (CH), 131.24 (CH), 133.24 (C), 134.08
(C), 135.43 (CH), 136.62 (C), 137.36 (C), 138.84 (C), 145.28 (C),
193.53 (C) ppm. EI-MS: m/z (%) = 230 (100) [M+], 202 (22).
9-Methylbenzo[b]fluorene-11-one (39c): 1H NMR (CDCl3,
500 MHz): δ = 2.74 (s, 3 H), 7.33 (d, J = 7.0 Hz, 1 H), 7.37 (td, J
= 7.5, 0.8 Hz, 1 H), 7.46 (d, J = 7.8 Hz, 1 H), 7.58 (td, J = 7.4,
1.0 Hz, 1 H), 7.70 (d, J = 8.1 Hz, 1 H), 7.74 (d, J = 7.6 Hz, 1 H),
7.79 (d, J = 7.4 Hz, 1 H), 7.89 (s, 1 H), 8.40 (s, 1 H) ppm. 13C
NMR (CDCl3, 125 MHz; DEPT): δ = 30.11 (CH3), 120.11 (CH),
121.40 (CH), 122.53 (CH), 124.89 (CH), 127.61 (CH), 128.36 (CH),
129.21 (CH), 129.54 (CH), 132.93 (CH), 133.23 (C), 135.39 (CH),
136.68 (C), 137.67 (C), 138.12 (C), 138.51 (C), 145.27 (C), 193.82
(C) ppm. EI-MS: m/z (%) = 244 (100) [M+], 215 (43).
8-Methylbenzo[b]fluorene-11-one (39d): 1H NMR (CDCl3,
500 MHz): δ = 2.50 (s, 3 H), 7.33 (td, J = 7.5, 0.9 Hz, 1 H), 7.38
(dd, J = 8.4, 1.4 Hz, 1 H), 7.55 (td, J = 7.5, 1.1 Hz, 1 H), 7.66 (br.
s, 1 H), 7.69 (dd, J = 7.5, 0.7 Hz, 1 H), 8.09 (s, 1 H), 7.82 (s, 1 H),
7.74 (dd, J = 7.5, 0.7 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H) ppm. 13C
NMR (CDCl3, 125 MHz; DEPT): δ = 21.95 (CH3), 119.30 (CH),
121.25 (CH), 124.85 (CH), 125.60 (CH), 128.97 (CH), 129.36 (CH),
130.46 (CH), 131.59 (CH), 133.29 (C), 134.27 (C), 135.39 (CH),
135.48 (C), 136.55 (C), 137.32 (CH), 138.06 (C), 145.46 (C), 193.74
(C) ppm. EI-MS: m/z (%) = 244 (100) [M+], 215 (41).
7-Methylbenzo[b]fluorene-11-one (39e): 1H NMR (CDCl3,
500 MHz): δ = 2.52 (s, 3 H), 7.30 (dd, J = 8.3, 1.6 Hz, 8-H), 7.34
(td, J = 7.4, 1.0 Hz, 3-H), 7.55 (td, J = 7.5, 1.2 Hz, 2-H), 7.61 (s,
6-H), 7.71 (dt, J = 7.5, 0.9 Hz, 1-H), 7.75 (dt, J = 7.4, 0.8 Hz, 9-
H), 7.78 (s, 5-H), 7.79 (d, J = 8.1 Hz, 4-H), 8.13 (s, 10-H) ppm.
13C NMR (CDCl3, 75 MHz; DEPT): δ = 21.84 (CH3), 118.47
(CH), 120.90 (CH), 124.35 (CH), 125.52 (CH), 128.12 (CH), 129.00
(CH), 130.57 (CH), 131.74 (C), 132.08 (C), 134.87 (CH), 136.26
(C), 137.18 (C), 138.55 (C), 139.33 (C), 144.85 (C), 193.15 (C) ppm;
Long range 1H-13C correlations were observed between the car-
bonyl carbon (δ = 193.15) and 10-H (s, 8.13) and 1-H (dt, 7.71).
The 1H NMR assignment was based on NOESY experiment
(300 MHz, CDCl3) and HMBC experiments (CDCl3, 75 MHz). EI-
MS: m/z (%) = 244 (100) [M+], 215 (43).
(CDCl3, 300 MHz): δ = 0.56 (s, 9 H), 2.69 (s, 3 H), 7.29–7.24 (m,
3-H and 9-H), 7.43 (td, J = 7.6, 1.3 Hz, 8-H), 7.48 (dd, J = 8.5,
6.9 Hz, 2-H), 7.63 (dt, J = 7.1, 0.6 Hz, 10-H), 7.67 (d, J = 7.6 Hz, 7-
H), 8.39 (s, 5-H), 8.96 (d, J = 8.4 Hz, 1-H) ppm. 13C NMR (CDCl3,
75 MHz; DEPT): δ = 0.17 (3 CH3), 19.41 (CH3), 122.40 (CH),
123.43 (CH), 123.54 (CH), 127.11 (C), 127.34 (CH), 128.59 (CH),
129.65 (CH), 130.54 (C), 131.61 (C), 132.33 (C), 133.61 (CH),
134.76 (C), 135.00 (C), 138.91 (CH), 144.85 (C), 150.32 (C), 196.08
(C) ppm. EI-MS: m/z (%) = 316 (100) [M+], 301 (82), 273 (45).
The structure was supported by a NOESY experiment (500 MHz,
CDCl3).
9-Methoxy-5-(trimethylsilyl)benzo[b]fluorene-11-one (38b): 1H
NMR (CDCl3, 500 MHz): δ = 0.60 (s, 9 H), 4.00 (s, 3 H), 6.81 (d,
J = 7.7 Hz, 1 H), 7.34 (t J = 7.5 Hz, 1 H), 7.43 (d, J = 7.8 Hz, 1
H), 7.52 (td, J = 7.5, 1.3 Hz, 1 H), 7.68 (d, J = 8.6 Hz, 1 H), 7.76
(d, J = 7.0 Hz, 1 H), 7.78 (d, J = 8.0 Hz, 1 H), 8.70 (s, 1 H) ppm.
13C NMR (CDCl3, 75 MHz; DEPT): δ = 3.17 (3 CH3), 55.66
(CH3), 104.90 (CH), 121.20 (C), (one carbon signal was not ob-
served), 122.29 (CH), 124.03 (CH), 124.51 (C), 126.45 (CH), 128.12
(CH), 128.73 (CH), 132.21 (C), 133.56 (CH), 136.77 (C), 142.67
(C), 146.57 (C), 147.57 (C), 157.85 (C), 193.20 (C) ppm. EI-MS:
m/z (%) = 322 (100) [M+], 317 (82), 273 (21).
9-Methyl-5-(trimethylsilyl)benzo[b]fluorene-11-one (38c): 1H NMR
(CDCl3, 500 MHz): δ = 0.63 (s, 9 H), 2.75 (s, 3 H), 7.31 (d, J =
7.0 Hz, 1 H), 7.37 (td, J = 7.3, 0.8 Hz, 1 H), 7.42 (dd, J = 8.3,
7.0 Hz, 1 H), 7.56 (td, J = 7.8, 1.3 Hz, 1 H), 7.79 (d, J = 7.8 Hz, 1
H), 7.82 (d, J = 7.3 Hz, 1 H), 8.00 (d, J = 8.3 Hz, 1 H), 8.43 (d, J
= 0.8 Hz, 1 H) ppm. EI-MS: m/z (%) = 316 (89) [M+], 301 (100),
273 (38).
8-Methyl-5-(trimethylsilyl)benzo[b]fluorene-11-one (38d): 1H NMR
(CDCl3, 500 MHz): δ = 0.61 (s, 9 H), 2.72 (s, 3 H), 7.32 (td, J =
7.4, 0.8 Hz, 1 H), 7.35 (dd, J = 8.4, 1.4 Hz, 1 H), 7.52 (td, J = 7.5,
1.1 Hz, 1 H), 7.63 (br. s, 1 H), 7.76 (d, J = 8.4 Hz, 1 H), 7.77 (d, J
= 8.6 Hz, 1 H), 8.02 (d, J = 8.6 Hz, 1 H), 8.09 (s, 1 H) ppm. 13C
NMR (CDCl3, 125 MHz; DEPT): δ = 3.62 (3 CH3), 21.60 (CH3),
124.54 (CH), 126.60 (CH), 126.81 (CH), 129.01 (CH), 130.14 (CH),
130.39 (CH), 130.80 (CH), 133.36 (C), 133.54 (C), 134.25 (CH),
134.89 (C), 136.57 (CH), 137.03 (C), 140.17 (C), 146.59 (C), 147.32
(C), 193.82 (C) ppm. EI-MS: m/z (%) = 316 (98) [M+], 301 (100),
273 (52).
7-Methyl-5-(trimethylsilyl)benzo[b]fluorene-11-one (38e): 1H NMR
(CDCl3, 500 MHz): δ = 0.64 (s, 9 H), 2.55 (s, 3 H), 7.30 (dd, J =
8.2, 1.5 Hz, 8-H), 7.36 (td, J = 7.5, 0.8 Hz, 2-H), 7.55 (td, J = 7.5,
1.3 Hz, 3-H), 7.78–7.81 (m, 1-H, 4-H, 9-H), 7.93 (br. d, J = 0.8 Hz,
6-H), 8.15 (s, 10-H) ppm. 13C NMR (CDCl3, 75 MHz; DEPT): δ
= 3.36 (3 CH3), 22.08 (CH3), 123.99 (CH), 126.39 (CH), 128.20
(CH), 128.65 (CH), 129.57 (CH), 130.66 (C), 130.88 (CH), 132.33
(C), 133.64 (CH), 133.84 (C), 136.68 (C), 137.91 (CH), 141.78 (C),
146.69 (C), 147.08 (C), 193.15 (C) (one carbon signal was not ob-
served); Long range 1H-13C correlations were observed between the
carbonyl carbon (δ = 193.15) and 10-H (s, 8.15 ppm) and 1-H (m,
1-{3-Methoxy-5-methyl-2-[2-(trimethylsilyl)ethynyl]phenyl}-3-(2-
methoxyphenyl)prop-2-yn-1-one (45): A mixture of 13 (218 mg,
0.58 mmol), and BaMnO4 (444 mg, 1.73 mmol) in CH2Cl2 (15 mL)
was stirred at 23 °C for 16 h. The mixture was filtered through ce-
lite, and washed with CH2Cl2. The solvent was evaporated, and the
residue was chromatographed (hexane/EtOAc, 5:1) to give 45 as a
yellow solid (216 mg, 99%). M.p. 118–119 °C. Rf = 0.24 (hexane/
1
EtOAc, 5:1). H NMR (CDCl3, 300 MHz): δ = 0.28 (s, 9 H), 2.47
(s, 3 H), 3.92 (s, 3 H), 3.95 (s, 3 H), 6.92 (s, 1 H), 6.94 (d, J =
8.1 Hz, 1 H), 6.98 (t, J = 7.5 Hz, 1 H), 7.45 (td, J = 8.2, 1.6 Hz, 1
H), 7.60 (dd, J = 7.7, 1.6 Hz, 1 H), 7.72 (s, 1 H) ppm. 13C NMR
(CDCl3, 75 MHz, DEPT): δ = –0.12 (3 CH3), 21.85 (CH3), 55.73
(CH3), 56.31 (CH3), 89.84 (C), 92.34 (C), 92.34 (C), 98.63 (C),
105.03 (C), 108.71 (C), 109.56 (C), 110.77 (CH), 115.66 (CH),
120.52 (CH), 124.71 (CH), 132.39 (CH), 134.99 (CH), 139.32 (C),
1
7.81–7.78). The H NMR assignment was based on a NOESY ex-
periment (500 MHz, CDCl3). EI-MS: m/z (%) = 316 (91) [M+], 301
(100), 273 (41).
9-Methoxybenzo[b]fluorene-11-one (39b): 1H NMR (CDCl3,
300 MHz): δ = 4.01 (s, 3 H), 6.83 (dd, J = 7.6, 1.0 Hz, 1 H), 7.35
(td, J = 7.5, 1.0 Hz, 1 H), 7.39–7.50 (m, 2 H), 7.56 (td, J = 7.5, 140.56 (C), 161.42 (C), 161.70 (C), 177.50 (C) ppm.
1440 Eur. J. Org. Chem. 2006, 1430–1443
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of the Benzo[b]fluorene Core of the Kinamycins
FULL PAPER
4,9-Dimethoxy-2-methyl-11H-benzo[b]fluoren-11-one (46): A mix-
ture of 45 (271 mg, 0.72 mmol), and phenol (678 mg, 7.20 mmol)
in 1,2-dichlorobenzene (10 mL) was heated under reflux for 72 h.
The mixture was cooled to room temperature and the solvent was
evaporated. The residue was chromatographed (hexane/EtOAc, 5:1)
residue was chromatographed (hexane/EtOAc, 3:2) to give 49 as a
yellow solid (554 mg, 85%): m.p. 143–144 °C; Rf = 0.1 (hexane/
EtOAc, 3:2). H NMR (CDCl3, 300 MHz): δ = 1.68 (s, 6 H), 2.39
(s, 3 H), 3.48 (br. s, 1 H), 3.63 (d, J = 4.9 Hz, 1 H), 3.88 (s, 3 H),
3.90 (s, 3 H), 6.06 (d, J = 4.9 Hz, 1 H), 6.67 (s, 1 H), 6.89 (d, J =
1
to give 46 as a yellow solid (200 mg, 91%). M.p. 201–202 °C. Rf = 8.3 Hz, 1 H), 6.91 (t, J = 7.5 Hz, 1 H), 7.29 (s, 1 H), 7.30 (td, J =
1
0.28 (hexane/EtOAc, 5:1). H NMR (CDCl3, 300 MHz): δ = 2.41
(s, 3 H), 3.99 (s, 3 H), 4.03 (s, 3 H), 6.79 (d, J = 7.3 Hz, 1 H), 6.88
8.9, 1.8 Hz, 1 H), 7.43 (dd, J = 7.5, 1.6 Hz, 1 H) ppm. 13C NMR
(CDCl3, 75 MHz, DEPT): δ = 22.02 (CH3), 31.23 (CH3), 31.34
(s, 1 H), 7.19 (s, 1 H), 7.38 (J = 7.3 Hz, 1 H), 7.43 (t, J = 7.3 Hz, (CH3), 55.72 (CH3), 55.94 (CH3), 63.60 (CH), 65.62 (C), 75.90 (C),
1 H), 8.02 (s, 1 H), 8.58 (s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz, 82.37 (C), 92.66 (C), 103.58 (C), 107.55 (C), 110.66 (CH), 111.43
DEPT): δ = 21.78 (CH3), 55.55 (2 CH3), 115.14 (CH), 117.02 (CH), (C), 111.83 (C), 119.92 (CH), 120.42 (CH), 129.84 (CH), 133.67
117.97 (CH), 120.12 (CH), 121.09 (CH), 121.93 (CH), 129.24 (CH), (CH), 139.89 (C), 143.84 (C), 160.00 (C), 160.06 (C) ppm. ESI-
138.10 (C), 138.19 (C), 138.41 (C), 141.04 (C), 155.96 (C), 157.80 TOF: m/z (%) = 387 [M+ + Na]. ESI-TOF-HRMS: m/z for
(C), 193.64 (C) ppm (three signals were not observed due to over-
lapping). EI-MS: m/z (%) = 304 (100) [M+], 289 (7), 261 (25). EI-
HRMS: m/z for C20H16O3: calcd. 304.1099; found 304.1102.
C23H24NaO4: calcd. 387.1572; found 387.1566.
1-[2-(3-Hydroxy-3-methylbut-1-ynyl)-3-methoxy-5-methylphenyl]-3-
(2-methoxyphenyl)prop-2-yn-1-one (50): A mixture of 49 (554 mg,
1.52 mmol) and BaMnO4 (1.000 g, 3.0 mmol) in CH2Cl2 (20 mL)
was stirred at 23 °C for 16 h. The mixture was filtered through
celite, and washed with CH2Cl2. The solvent was evaporated, and
the residue was chromatographed (hexane/EtOAc, 3:2) to give 50
as a yellow solid (467 mg, 85%): m.p. 91–92 °C; Rf = 0.26 (hexane/
4-Methoxy-2-methyl-6H-benzo[b]fluorene-6,9,11-trione (47): H5IO6
(28 mg, 0.12 mmol) was dissolved in CH3CN (1 mL) with vigorous
stirring, and then CrO3 (0.29 mg, 0.003 mmol) was added to the
solution. The resulted solution was cooled to 0 °C. Compound 46
(9 mg, 0.03 mmol) was dissolved in CH3CN (1 mL), and CH2Cl2
(2 mL) was added to the above solution. Immediately, the solution
was orange, and a white precipitate formed. After 30 min stirring
at 23 °C, the mixture was filtered, and the solvent was evaporated.
The residue was chromatographed (hexane/EtOAc, 5:1) to give 47
as an orange solid (4 mg, 45%). M.p. 206–208 °C. Rf = 0.21 (hex-
1
EtOAc, 3:2). H NMR (CDCl3, 300 MHz): δ = 1.67 (s, 6 H), 3.50
(s, 3 H), 3.94 (s, 3 H), 3.99 (s, 3 H), 6.95 (s, 1 H), 6.98 (d, J =
7.5 Hz, 1 H), 7.02 (td, J = 7.5, 1.6 Hz, 1 H), 7.48 (td, J = 7.5,
1.6 Hz, 1 H), 7.63 (dd, J = 7.5, 1.6 Hz, 1 H), 7.79 (s, 1 H) ppm.
13C NMR (CDCl3, 75 MHz, DEPT): δ = 21.89 (CH3), 31.39 (2
CH3), 55.89 (CH3), 56.36 (CH3), 65.95 (C), 89.84 (C), 92.45 (C),
103.64 (C), 109.66 (C), 109.67 (CH), 110.93 (CH), 115.84 (CH),
1
ane/EtOAc, 5:1). H NMR (CDCl3, 300 MHz): δ = 2.44 (s, 3 H),
4.06 (s, 3 H), 6.70 (s, 1 H), 7.02 (s, 2 H), 7.21 (s, 1 H), 8.30 (s, 1
H), 8.42 (s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz, DEPT): δ = 120.73 (CH), 125.12 (CH), 132.47 (CH), 135.05 (CH), 139.04 (C),
22.02 (CH3), 55.81 (CH3), 117.94 (CH), 118.96 (CH), 121.08 (CH),
160.75 (C), 161.70 (C) ppm (three signals were not observed due
121.90 (CH), 127.15 (C), 131.86 (C), 136.18 (C), 136.75 (C), 137.23 to overlapping). EI-MS: m/z (%) = 362 (6) [M+], 303 (20) [M+
–
(C), 138.41 (CH), 138.94 (CH), 143.70 (C), 148.40 (C), 156.31 (C),
183.99 (CO), 184.98 (CO), 192.32 (CO) ppm. EI-MS: m/z (%) =
304 (100) [M+], 261 (12), 222 (9). EI-HRMS: m/z for C19H12O4:
calcd. 304.0736; found 304.0746.
C3H7O]. EI-HRMS: m/z for C23H22O4: calcd. 362.1518; found
362.1522.
2,2,2-Trichloroethyl 4-{2-Methoxy-6-[3-(2-methoxyphenyl)pro-
pioloyl]-4-methylphenyl}-2-methylbut-3-yn-2-yl Carbonate (51): A
mixture of 50 (50 mg, 0.14 mmol), 2,2,2-trichloroethyl chloro-
formate (31 mg, 0.15 mmol), DMAP (10 mg, 0.07 mmol) in pyri-
dine (2 mL) was stirred at 23 °C for 16 h. The mixture was diluted
with CH2Cl2, and washed with HCl (10%). The aqueous layer was
extracted with Et2O, dried (Na2SO4), and the solvents evaporated.
The residue was chromatographed (hexane/EtOAc, 5:1) to give 51
as a yellow solid (26 mg, 36%). M.p. 101–102 °C. Rf = 0.18 (hex-
1-(2-Iodo-3-methoxy-5-methylphenyl)-3-(2-methoxyphenyl)prop-2-
yn-1-ol (48): To a solution of 1-ethynyl-2-methoxybenzene (14)
(200 mg, 1.51 mmol) in THF (10 mL) at 0 °C was added nBuLi
(0.58 mL, 2.5  solution in hexanes, 1.51 mmol). After 30 min, 17
(417 mg, 1.51 mmol) in THF (10 mL) was added, and the mixture
was stirred at 23 °C for 5 h. The mixture was diluted with EtOAc,
washed with a saturated NaCl solution, and dried (Na2SO4). The
solvent was evaporated, and the residue was chromatographed
(hexane/EtOAc, 5:1) to give 48 as a yellow solid (610 mg, 99%).
1
ane/EtOAc, 5:1). H NMR (CDCl3, 300 MHz): δ = 1.87 (s, 6 H),
2.45 (s, 3 H), 3.87 (s, 3 H), 3.94 (s, 3 H), 4.78 (s, 2 H), 6.89 (s, 1
H), 6.92–6.99 (m, 2 H), 7.43 (td, J = 7.7, 1.8 Hz, 1 H), 7.58 (dd, J
= 7.7, 2.0 Hz, 1 H), 7.76 (s, 1 H) ppm. 13C NMR (CDCl3, 75 MHz,
DEPT): δ = 21.89 (CH3), 28.69 (2 CH3), 55.83 (CH3), 56.47 (CH3),
76.39 (CH2), 79.76 (C), 89.63 (C), 92.27 (C), 98.08 (C), 108.28 (C),
1
M.p. 72–73 °C. Rf = 0.14 (hexane/EtOAc, 5:1). H NMR (CDCl3,
300 MHz): δ = 2.42 (s, 3 H), 2.89 (br. s, 1 H), 3.91 (s, 3 H), 3.92
(s, 3 H), 6.06 (s, 1 H), 6.67 (s, 1 H), 6.91 (d, J = 8.1 Hz, 1 H), 6.94
(td, J = 7.5, 1.1 Hz, 1 H), 7.34 (td, J = 7.5, 1.6 Hz, 1 H), 7.44 (s,
1 H), 7.48 (dd, J = 7.5, 1.6 Hz, 1 H) ppm. 13C NMR (CDCl3, 109.69 (C), 110.89 (CH), 116.10 (CH), 120.66 (CH), 122.06 (C),
75 MHz, DEPT): δ = 21.42 (CH3), 55.72 (CH3), 56.57 (CH3), 69.29 124.91 (C), 125.26 (CH), 132.39 (CH), 135.05 (CH), 139.40 (C),
(CH), 83.16 (C), 86.87 (C), 92.33 (C), 110.69 (CH), 111.71 (C),
140.07 (C), 151.66 (C), 161.18 (C), 161.78 (C), 177.24 (C) ppm. EI-
112.03 (CH), 120.36 (CH), 121.81 (CH), 129.98 (CH), 133.62 (CH), MS: m/z (%) = 422 (8) [M+ – CCl3], 344 (57) [M+ – OTROC], 313
139.79 (C), 143.92 (C), 157.98 (C), 160.24 (C) ppm. EI-MS: m/z
(%) = 408 (77) [M+], 281 (52) [M+ – I]. EI-HRMS: m/z for
C18H17IO3: calcd. 408.0222; found 408.0228.
(100).
5-Methoxy-1-(2-methoxyphenyl)-3,7-dimethyl-9H-fluoren-9-one
(52). Method A: A mixture of 50 (25 mg, 0.07 mmol), and Sc(OTf)3
(34 mg, 0.07 mmol) in toluene (2 mL) was heated under reflux
4-{2-[1-Hydroxy-3-(2-methoxyphenyl)prop-2-ynyl]-6-methoxy-4-
methylphenyl}-2-methylbut-3-yn-2-ol (49): A mixture of 48 (731 mg, for 16 h. The mixture was cooled to room temperature, partitioned
1.79 mmol), 2-methyl-3-butyn-2-ol (158 mg, 1.88 mmol), [Pd(PPh3)4] between H2O, and CH2Cl2, washed with saturated NaCl solution,
(207 mg, 0.18 mmol), and CuI (26 mg, 0.18 mmol) in piperidine and dried (Na2SO4). The residue was cromatographed (hexane/
(10 mL) was stirred at 23 °C for 16 h. The mixture was diluted with
Et2O, and washed with saturated NaHCO3 solution, HCl 10%, and
H2O, and dried (Na2SO4). The solvent was evaporated, and the
EtOAc, 5:1 ) to give 52 as a yellow solid (6 mg, 25%). Method B:
Compound 51 (12 mg, 0.02 mmol) in 1,2-dichlorobenzene (1.5 mL)
was heated under reflux for 72 h. The mixture was cooled to room
Eur. J. Org. Chem. 2006, 1430–1443
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1441

E. González-Cantalapiedra, Ó. de Frutos, C. Atienza, C. Mateo, A. M. Echavarren
FULL PAPER
temperature, and the solvent was evaporated. The residue was chro-
1 H), 7.59 (dd, J = 7.6, 1.6 Hz, 1 H), 7.76 (d, J = 0.6 Hz, 1 H)
ppm. 13C NMR (CDCl3, 75 MHz, DEPT): δ = 21.91 (CH3), 55.80
(CH3), 56.34 (CH3), 77.16 (C), 86.63 (CH), 90.21 (C), 92.33 (C),
matographed (hexane/EtOAc, 5:1) to give 50 as a yellow solid
1
(5 mg, 73%). M.p. 197–198 °C. Rf = 0.36 (hexane/EtOAc, 5:1). H
NMR (CDCl3, 300 MHz): δ = 2.35 (s, 6 H), 2.42 (s, 3 H), 3.73 (s, 109.55 (C), 110.79 (CH), 115.61 (CH), 120.61 (CH), 124.96 (CH),
3 H), 3.98 (s, 3 H), 6.83 (s, 1 H), 6.89 (d, J = 0.7 Hz, 1 H), 6.96–
7.04 (m, 3 H), 7.22 (dd, J = 7.5, 1.7 Hz, 1 H), 7.37 (dd, J = 7.5,
1.8 Hz, 1 H), 7.61 (d, J = 0.7 Hz, 1 H) ppm. 13C NMR (CDCl3,
75 MHz, DEPT): δ = 21.67 (CH3), 22.05 (CH3), 55.50 (2 CH3),
110.57 (CH), 116.79 (CH), 117.68 (CH), 120.22 (CH), 123.84 (CH),
127.60 (C), 129.21 (CH), 130.11 (CH), 130.71 (CH), 136.69 (C),
137.22 (C), 140.62 (C), 144.65 (C), 144.86 (C), 155.07 (C), 157.03
(C), 220.00 (C) ppm (two signals were not observed due to overlap-
ping). EI-MS m/z (%) 344 [M+, 64], 313 (100). EI-HRMS: m/z for
C23H20O3: calcd. 344.1412; found 344.1425. The structure was con-
firmed by COSY, NOESY, HMQC, and HMBC experiments.
132.45 (CH), 135.02 (CH), 139.75 (C), 140.70 (C), 161.78 (C),
177.34 (C) ppm (two signals were not observed due to overlapping).
EI-MS: m/z (%) = 304 (23) [M+], 289 (100). EI-HRMS: m/z for
C20H16O3: 304.1099; found 304.1095.
Acknowledgments
We thank the MEC (project CTQ2004-02869 and predoctoral fel-
lowship to Ó. F.), the CAM (postdoctoral contract to C. M. and
predoctoral fellowship to E. G.-C.) and the ICIQ foundation for
support. We also acknowledge Dr. Diego J. Cárdenas for calcula-
tions on the rearrangement of Scheme 8 carried out with a simple
model.
1-Ethynyl-2-methoxybenzene (14) and 4-Methoxy-6-methyl-3-meth-
ylidenephthalide (55): To a solution of 51 (64 mg, 0.18 mmol) in
toluene (3 mL) was added NaOH (21 mg, 0.53 mmol), and the mix-
ture was heated under reflux for 2 h. The mixture was cooled to
room temperature, diluted with CH2Cl2, washed with a saturated
NaCl solution, and dried (MgSO4). The solvent was evaporated to
give a mixture of 14 and 55. The products could be separated by
flash column chromatography (hexane/EtOAc, 10:1). 14: Yellow oil
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1
(9.6 mg, 42%): Rf = 0.5 (hexane/EtOAc, 10:1). H NMR (CDCl3,
300 MHz): δ = 3.31 (s, 1 H), 3.89 (s, 3 H), 6.88 (d, J = 8.4 Hz, 1
H), 6.91 (t, J = 7.5 Hz, 1 H), 7.32 (td, J = 8.2, 1.5 Hz, 1 H), 7.46
(dd, J = 9.1, 1.5 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz,
DEPT): δ = 55.75 (CH3), 80.05 (C), 81.07 (CH), 110.57 (CH),
111.13 (C), 120.39 (CH), 130.23 (CH), 134.11 (CH), 160.54 (C)
ppm. 56: White solid (8.4 mg, 25%). Rf = 0.21 (hexane/EtOAc,
10:1). 1H NMR (CDCl3, 300 MHz): δ = 2.48 (s, 3 H), 3.98 (s, 3
H), 5.24 (d, J = 2.0 Hz, 1 H), 5.41 (d, J = 1.8 Hz, 1 H), 6.97 (s, 1
H), 7.29 (s, 1 H) ppm. EI-MS: m/z (%) = 190 (100) [M+], 119 (82).
EI-HRMS m/z found for C11H10O3: calcd. 190.0629, found
190.0626.
1-(2-Ethynyl-3-methoxy-5-methylphenyl)-3-(2-methoxyphenyl)prop-
2-yn-1-ol (59): A mixture of 13 (152 mg, 0.40 mmol), and KF
(84 mg, 1.45 mmol) in MeOH (5 mL) was stirred at 23 °C for 16 h.
The mixture was diluted with CH2Cl2, washed with H2O, and dried
(MgSO4). The solvent was evaporated, and the residue was croma-
tographed (hexane/EtOAc, 5:1) to give 59 as a yellow solid (125 mg,
99 %). M.p. 78–80 °C. Rf = 0.1 (hexane/EtOAc, 5:1). 1H NMR
(CDCl3, 300 MHz): δ = 2.40 (s, 3 H), 2.84 (d, J = 5.5 Hz, 1 H),
3.61 (s, 1 H), 3.88 (s, 3 H), 3.90 (s, 3 H), 6.10 (d, J = 4.7 Hz, 1 H),
6.70 (s, 1 H), 6.87 (d, J = 8.3 Hz, 1 H), 6.89 (td, J = 7.5, 1.0 Hz, 1
H), 7.27–7.31 (m, 1 H), 7.32 (s, 1 H), 7.44 (dd, J = 7.5, 1.6 Hz, 1
H) ppm. 13C NMR (CDCl3, 75 MHz, DEPT): δ = 22.11 (CH3),
55.70 (CH3), 56.01 (CH3), 63.57 (CH), 77.60 (C), 82.89 (C), 86.20
(CH), 92.12 (C), 110.60 (CH), 111.39 (CH), 120.15 (CH), 120.32
(CH), 129.93 (CH), 133.73 (CH), 140.79 (C), 144.54 (C), 160.22
(C), 161.01 (C) ppm (two signals were not observed due to overlap-
ping). EI-MS: m/z (%) = 306 (61) [M+], 289 (23). EI-HRMS:
m/z for C20H18O3: 306.1256; found 306.1259.
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1442
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 1430–1443

Synthesis of the Benzo[b]fluorene Core of the Kinamycins
FULL PAPER
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Received: November 26, 2005
Published Online: January 12, 2006
Eur. J. Org. Chem. 2006, 1430–1443
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