Formation of benzo[b]fluorenes and the benzo[a]fluorene core of the fluostatins by cyclization of diaryldiynones.

Article abstract of DOI:10.1021/ol0067336

[figure: see text] Thermal cyclization of 1-[2-(trimethylsilylethynyl)phenyl]-3-arylpropinones was expected to give benzo[b]fluorenones. However, benzo[a]-fluorenones were also formed as a result of a new rearrangement. These tetracycles possess the core structure of the fluostatins and isoprekinamycin.

Full text of DOI:10.1021/ol0067336

ORGANIC
LETTERS
2001
Vol. 3, No. 2
153-155
Formation of Benzo[b]fluorenes and the
Benzo[a]fluorene Core of the Fluostatins
by Cyclization of Diaryldiynones
Carmen Atienza, Cristina Mateo, OÄ scar de Frutos, and Antonio M. Echavarren*
Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid, Cantoblanco,
28049 Madrid, Spain
anton.echaVarren@uam.es
Received October 13, 2000
ABSTRACT
Thermal cyclization of 1-[2-(trimethylsilylethynyl)phenyl]-3-arylpropinones was expected to give benzo[b]fluorenones. However, benzo[a]-
fluorenones were also formed as a result of a new rearrangement. These tetracycles possess the core structure of the fluostatins and
isoprekinamycin.
Kinafluorenone (1)1 and stealthin A (2)2 are representative
benzo[b]fluorene natural products structurally related to the
kinamycins,3 a group of naturally occurring quinones that
display a variety of interesting antibiotic activities.4
arylalkyne-allenes developed by Schmittel.6,7 Since the
thermal reaction of enynes with alkynes also leads to
(4) For recent synthetic work, see: (a) Koyama, H.; Kamikawa, T. J.
Chem. Soc., Perkin Trans. 1 1998, 203. (b) Mohri, S.; Stefinovic, M.;
Scieckus, V. J. Org. Chem. 1996, 61, 5722. (c) Koyama, H.; Kamikawa,
T. Tetrahedron Lett. 1997, 38, 3973 and references therein. (d) Kumamoto,
T.; Tabe; Yamaguchi, K.; Ishikawa, T. Tetrahedron Lett. 2000, 41, 5693.
(e) Frutos, OÄ .; Atienza, C.; Echavarren, A. M. Eur. J. Org. Chem. 2000, in
press, and references therein.
(5) de Frutos, OÄ .; Echavarren, A. M. Tetrahedron Lett. 1997, 38, 7941.
(6) (a) Schmittel, M.; Strittmatter, M.; Kiau, S. Tetrahedron Lett. 1995,
36, 4975. (b) Schmittel, M.; Strittmatter, M.; Vollmann, K.; Kiau, S.
Tetrahedron Lett. 1996, 37, 999. (c) Schmittel, M.; Kiau, S.; Siebert, M.;
Strittmatter, M. Tetrahedron Lett. 1996, 37, 7691. (d) Schmittel, M.;
Strittmatter, M.; Kiau, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 1843. (e)
Schmittel, M.; Keller, M.; Kiau, S.; Strittmatter, M. Chem. Eur. J. 1997, 3,
807. (f) Schmittel, M.; Maywald, M.; Strittmatter, M. Synlett 1997, 165.
(g) Schmittel, M.; Strittmatter, M.; Kiau, S. Angew. Chem., Int. Ed. Engl.
1997, 35, 1843. (h) Engels, B.; Lennartz, C.; Hanrath, M.; Schmittel, M.;
Strittmatter, M. Angew. Chem., Int. Ed. 1998, 110, 2067. (i) Schmittel, M.;
Strittmatter, M. Tetrahedron 1998, 54, 13751. (j) Schmittel, M.; Rodr´ıguez,
D.; Steffen, J.-P. Angew. Chem., Int. Ed. 2000, 39, 2152.
Recently, we reported a concise approach for construction
of the tetracyclic nucleus of the benzo[b]fluorene antibiotics5
based on application of the [4 + 2] cycloaddition of
(1) (a) Cone, M. C.; Melville, C. R.; Gore, M. P.; Gould, S. J. J. Org.
Chem. 1993, 58, 1058. (b) Carney, J. R.; Hong, S.-T.; Gould, S. J.
Tetrahedron Lett. 1997, 38, 3139.
(2) Shin-ya, K.; Furihata, K.; Teshima, Y.; Hayakawa, Y.; Seto, H.
Tetrahedron Lett. 1992, 33, 7025.
(7) (a) Dopico, P. G.; Finn, M. G., Tetrahedron 1999, 55, 29. (b) Alajar´ın,
M.; Molina, P.; Vidal, A. J. Nat. Prod. 1997, 60, 747. (c) Wang, K. K.;
Zhang, H.-R.; Petersen, J. L. J. Org. Chem. 1999, 64, 1650. (d) Zhang,
H.-R.; Wang, K. K. J. Org. Chem. 1999, 64, 7996.
(3) Gould, S. J. Chem. ReV. 1997, 97, 2499.
10.1021/ol0067336 CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/19/2000

annulation,8 we decided to explore the cyclization of 1-[2-
(trimethylsilylethynyl)phenyl]-3-arylpropinones (I) (Scheme
derived from 5a-d13 followed by oxidation of the alcohols
6a-d with BaMnO4 (Scheme 2).
1).
Scheme 2
Scheme 1
The cyclizations of 3a-c were best carried out by heating
0.06-0.2 M solutions in 1,2-dichlorobenzene under refluxing
conditions (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).14 We first studied the cyclization of 3a with an o-methoxy
substituent, which surprisingly led to the formation of benzo-
[a]fluorenones 7a-e and of benzo[a]fluorenone 7a as the
major product under method A (Table 1, entries 1 and 3).15
Desilylated tetracycle 9a, with the regiochemistry of naturally
occurring benzo[b]fluorenones, was obtained in 25% yield
under conditions B (entry 2). Mixtures of benzo[a]- and
benzo[b]fluorenones were also obtained from ynones 3b-
d, although in these cases the later were the major products
(entries 4-9).16
The reaction was expected to proceed through diradical
II and strained cyclic allene III as intermediates to give
benzo[b]fluorenones IV.7-10 The alternative thermal cycliza-
tion of 1-[(2-phenylethynyl)phenyl]propynones (V) has been
recently shown to proceed through diradical VI and allene
VII to give benzo[b]fluorenes VIII (X ) H, Ph, SiMe3).9a,11
Ynones 3a-d were readily synthesized in two steps by
reaction of benzaldehyde 412 with the lithium acetylides
(8) (a) Danheiser, R. L.; Gould, A. E.; Ferna´ndez de la Pradilla, R.;
Helgason, A. L. J. Org. Chem. 1994, 59, 5514. (b) Burrell, R. C.; Daoust,
K. J.; Bradley, A. Z.; DiRico, K. J.; Johnson, R. P. J. Am. Chem. Soc.
1996, 118, 4218. (c) Wills, M. S. B.; Danheiser, R. L: J. Am. Chem. Soc.
1998, 120, 9378. (d) Gonza´lez, J. J.; Francesch, A.; Ca´rdenas, D. J.;
Echavarren, A. M. J. Org. Chem. 1998, 63, 2854.
(9) (a) Rodr´ıguez, D.; Navarro, A.; Castedo, L.; Dom´ınguez, D.; Saa´,
C. Org. Lett. 2000, 2, 1497. See also: (b) Rodr´ıguez, D.; Castedo, L.;
Dom´ınguez, D.; Saa´, C. Tetrahedron Lett. 1999, 40, 7701. (c) Schmittel,
M.; Strittmatter, M.; Schenk, W. A.; Hagel, M. Z. Naturforsch. 1998, 53b,
1015.
(10) For related cyclization of diynes, see: (a) Bradley, A. Z.; Johnson,
R. P. J. Am. Chem. Soc. 1997, 119, 9917. (b) Miyawaki, K.; Suzuki, R.;
Kawano, T.; Ueda, I. Tetrahedron Lett. 1997, 38, 3943. (c) Miyawaki, K.;
Kawano, T.; Ueda, I. Tetrahedron Lett. 1998, 39, 6923. (d) Ueda, I.; Sakurai,
Y.; Kawano, T.; Wada, Y.; Futai, M. Tetrahedron Lett. 1999, 40, 319.
(11) However, extension of this approach for the synthesis of benzo[b]-
fluorenones with the required OR substituent on the A ring based on this
approach would presumably give rise to mixtures of regioisomers.
(12) Suufert, J.; Abraham, E.; Raeppel, S.; Bru¨ckner, R. Liebigs Ann.
1996, 447.
(13) Arylacetylenes 5a-e were prepared by the palladium-catalyzed
Sonogashira coupling of the corresponding aryl iodides or bromides with
trimethylsilylacetylene followed by desilylation.
(14) (a) γ-Terpinene was added, as a high boiling 1,4-cyclohexadiene,
to facilitate hydrogen migration (step III f IV, Scheme 1). (b) Benzylated
derivatives were obtained as byproducts under these conditions as a result
hydrogen abstraction from toluene followed by radical coupling.
(15) Benzo[a]fluorenones 7 show downfield signals in the 1H NMR
spectra at 9.06-8.84 and 8.39-7.95 (s) corresponding to H-1 and H-5,
respectively. The carbonyl signal of 7 appears at δ 196.1-196.7 in the 13
C
NMR spectra, while benzo[b]fluorenones 8 and 9 show this resonance at δ
193.8-193.1. The structures of 7a, 7e, 8e, and 9e were confirmed by 1H-
1H (COSY or NOESY) and 1H-13C (HMBC and HMQC) correlations. 9b
1
showed H and 13C NMR data identical with those described.9a
154
Org. Lett., Vol. 3, No. 2, 2001

evolve to give allene XI. The transformation of X to XI is
somewhat reminiscent of that proposed in the benzene ring
contraction rearrangement, which occurs in skeletal reorga-
nizations of polycyclic aromatic hydrocarbons under pyroly-
sis.18 Alternatively, IX might suffer ring opening to form
cyclodeca-1,3,5,7-tetraen-9-yne intermediate XII, which
could electrocyclize to give XI.19
The unexpected formation of benzo[a]fluorenones 7 in the
thermal cyclizations of ynones 3 suggests a simple approach
for the synthesis of fluostatins A (10) and B (11).20 In
particular, 10, a selective inhibitor of the enzyme dipeptidyl
peptidase III,19a shows a core structure that is related to that
of 7d. Interestingly, isoprekinamycin, a metabolite isolated
from Streptomyces murayaensis several years ago, which was
originally named prekinamycin,3 has been very recently
demonstrated to be diazobenzo[a]fluorenone 12.21
Table 1. Thermal Cyclization of Arylynones 3
time
products
(%)b
ratio
entry ynone methoda (h)
7:(8 + 9)
1
2
3
4
5
6
7
8
9
3a
3a
3a
3b
3b
3b
3c
3d
3e
A
B
C
A
B
C
A
A
A
48 7a (63), 8a (17)c
24 7a (25), 9a (25)
16 7a (30), 8a (9)d
96 7b (8), 8b (25), 9b (18)
14 7b (24), 8b (20), 9b (32)
79 7b (18), 8b (11), 9b (37)
216 7c (38), 8c (13), 9c (45)
48 7d (8), 8d (30), 9d (9)
48 7e (14), 8e (41), 9e (7)
3.7:1
1:1
3.3:1
1:5.3
1:2.2
1:2.7
1:1.5
1:4.9
1:3.4
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.
Addition of an alcohol was expected to trap intermediates
of type III, leading to benzo[b]fluorenones IV (Scheme 1).9a
However, no effect on the product selectivity was observed
upon addition of ethylenglycol, a high boiling proton donor,
to the reaction mixtures. On the other hand, treatment of
ynones 3 with Lewis acids such as ZnCl2 or Y(OTf)3 led
only to unchanged starting materials.
The remarkable formation of benzo[a]fluorenones in the
cyclization of ynones 3 unveils a new rearrangement. A
rationale for this transformation is presented in Scheme 3.
The approach described in this paper allows for the
synthesis of benzo[a]- and benzo[b]fluorenones22 from
readily available starting materials. Efforts at controlling the
selectivity in the thermal closure of more substituted ynones
of type 3 for the synthesis of kinafluorenone (1), fluostatin
A (10), and isoprekinamycin (12) are in progress.
Scheme 3
Acknowledgment. We are grateful to the DGES (project
PB97-0002-C2-01) for support of this research and to the
MEC for predoctoral fellowships to OÄ . de F. and a contract
to C.M. We also thank Prof. C. Saa´ for helpful discussions.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0067336
(17) The most stable structure for these intermediates has been shown
to be the singlet rather than the triplet (biradical).9a
(18) (a) Preda, D. V.; Scott, L. T. Org. Lett. 2000, 2, 1489. (b) Scott, L.
T. Pure Appl. Chem. 1996, 68, 291. (c) Scott, L. T.; Hashemi, M. M.;
Schultz, T. H.; Wallace, M. B. J. Am. Chem. Soc. 1991, 113, 9692. (d) See
also ref 8c.
(19) We thank a reviewer for suggesting this fascinating pathway.
(20) (a) Akiyama, T.; Harada, S.; Kojima, F.; Takahashi, Y.; Imada, C.;
Okami, Y.; Muraoka, Y.; Aoyagi, T.; Takeuchi, T. J. Antibiot. 1998, 51,
553. (b) Akiyama, T.; Nakamura, K. T.; Takahashi, Y.; Naganawa, H.;
Muraoka, Y.; Aoyagi, T.; Takeuchi, T. J. Antibiot. 1998, 51, 586.
(21) Proteau, P. J.; Li, Y.; Chen, J.; Williamson, R. T.; Gould, S. J.;
Laufer, R. S.; Dmitrienko, G. I. J. Am. Chem. Soc. 2000, 122, 8325.
(22) The synthesis of substituted benzo[a]- and benzo[b]fluorenones could
be of interest in the analysis of organic pollutants. For the occurrence of
these derivatives in urban aerosols, see, e.g.: Allen, J. O.; Dookeran, N.
M.; Taghizadeh, K.; Lafleur, A. L.; Smith, K. A.; Sarofim, A. F. EnViron.
Sci. Technol. 1997, 31, 2064.
Ring closure of a diradical of type II (Scheme 1) would give
intermediate IX,17 which would yield benzo[b]fluorenones
8a-d by a formal [1,5]-hydrogen migration.5,6,9 Strained
allene IX could also rearrange to a carbene X, which may
(16) Chromatography (gravity column, 30:1 hexane/EtOAc) allowed for
the separation of the benzo[a]- and benzo[b]fluorenones.
Org. Lett., Vol. 3, No. 2, 2001
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