Gold-catalyzed synthesis of polycyclic enones from carbon tethered 1,3-enynyl carbonyls via tandem heteroenyne metathesis and Nazarov reaction

Article abstract of DOI:10.1021/ol801265s

(Chemical Equation Presented) An efficient and general Au(III)-catalyzed tandem reaction, heteroenyne metathesis and Nazarov cyclization, of 1,3-enynyl ketones to produce fused tri- and tetracyclic enones has been developed. The products were formed with

Full text of DOI:10.1021/ol801265s

ORGANIC
LETTERS
2008
Vol. 10, No. 14
3137-3139
Gold-Catalyzed Synthesis of Polycyclic
Enones from Carbon Tethered
1,3-Enynyl Carbonyls via Tandem
Heteroenyne Metathesis and Nazarov
Reaction
Tienan Jin* and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku UniVersity,
Sendai 980-8578, Japan
tjin@mail.tains.tohoku.ac.jp; yoshi@mail.tains.tohoku.ac.jp
Received June 4, 2008
ABSTRACT
An efficient and general Au(III)-catalyzed tandem reaction, heteroenyne metathesis and Nazarov cyclization, of 1,3-enynyl ketones to produce
fused tri- and tetracyclic enones has been developed. The products were formed with excellent regioselectivity of the double bond position
and with very high diastereoselectivities. In this reaction, the Au(III) catalyst exhibits dual roles for activating both alkynes and carbonyls.
Lewis acid- and transition-metal-catalyzed transformations
have been demonstrated to be powerful tools for synthetic
organic chemistry.1 Generally, the ordinary Lewis acids, such
as BF3, AlCl3, etc., are known to activate carbonyl and imine
groups by formation of a σ-complex by which the attack of
nucleophiles is facilitated (Scheme 1).1a,b,e On the other hand,
with C-C multiple bonds, which makes feasible the nu-
cleophilic attack to an electron-deficient carbon to give an
organometallic intermediate having a C-Nu bond (Scheme
1).1c–e It is thought that proper choice of a Lewis acid which
may exhibit dual roles makes it possible to activate both C-C
multiple bonds and CdX (X ) O, N,...) unsaturated bonds
in a single transformation.2
We recently reported that cationic Au(III) catalyst brought
about the intramolecular heteroenyne metathesis cyclization
of the carbon-tethered alkynyl ketones 1, leading to the
formation of highly substituted cyclic enones 3 via the
π-complex between Au catalyst and alkyne (Scheme 2).3 We
envisioned that when R′ was an alkenyl group the 1,3-enynyl
Scheme 1
.
Principal Role of a Lewis Acid and Transition Metal
Catalysta
(1) For reviews, see: (a) Lewis Acids in Organic Synthesis; Yamamoto,
H., Ed.; Wiley-VCH: Weinheim, 2000; Vols. 1-2. (b) Lewis Acid Reagents;
Yamamoto, H., Ed.; Oxford University Press: New York, 1999. (c)
Transition Matal Reagents and Catalysts: InnoVations in Organic Synthesis;
Wiley: New York, 2000. (d) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180.
(e) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817.
aNu ) Nucleophiles.
(2) (a) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am.
Chem. Soc. 2002, 124, 764. (b) Nakamura, I.; Bajracharya, G. B.;
Mizushima, Y.; Yamamoto, Y. Angew. Chem., Int. Ed. 2002, 41, 4328. (c)
Kamijo, S.; Yamamoto, Y. J. Org. Chem. 2003, 68, 4764.
one of the representative roles of transition metal catalysts,
such as AuCl, PtCl2, etc., is the formation of a π-complex
10.1021/ol801265s CCC: $40.75
Published on Web 06/24/2008
2008 American Chemical Society

Scheme 2
.
Dual Roles of Au(III) Catalyst for the Tandem
Cyclization of 1,3-Enynyl Carbonyls
Table 1. Au-Catalyzed Tandem Cyclization of Various
1,3-Enynyl Carbonylsa
carbonyls 1 would produce the divinyl ketones through a
π-complex, which may undergo the sequential Nazarov
reaction via σ-complex, affording the fused polycyclic enones
2 containing a cylopentenone ring.
The Nazarov reaction, which is one of the most powerful
methods for the construction of cyclopentenones, proceeds
mostly by the use of a stoichiometric amount (or even more)
of acid promoters, and a catalytic Nazarov reaction is very
rare, especially for constructing tri- and tetracyclic car-
bocycles with various ring sizes,4a–c,5 although the catalytic
process is well-known for synthesizing simple cyclopenten-
ones.4 The earliest methods always required one or more
equivalents of strong acids (polyphosphoric acid/100 °C),
and the structural limitation of divinyl ketone starting
materials or their precursors diminished the synthetic utility
of the reaction.6 More recently, two attractive strategies for
the construction of polycyclic rings were reported: Den-
mark’s silicon-directed Nazarov cyclization and West’s
interrupted Nazarov cyclization with alkenes and arenes were
promoted by a stoichiometric amount of Lewis acids.7
Herein, we report an efficient and general synthetic method
for various fused tri- and tetracyclic enones via the cationic
Au(III)-catalyzed tandem heteroenyne metathesis and Naz-
arov cyclization (eq 1). The products were formed in good
to high yields with excellent regioselectivity of the double
bond position and with very high diastereoselectivities.
a Reaction conditions: 2 mol % of AuCl3 and 6 mol % of AgSbF6, 1
(0.5 mmol), toluene (0.2 M), 100 °C. b Isolated yield. c 50 °C. d 5 mol %
of AuCl3 and 15 mol % of AgSbF6 were used at 100 °C.
80% yield (Table 1, entry 1).8 We then examined the scope of
the polycycle synthesis. The enynyl ketone 1bbearing a steri-
cally bulky tert-butyl on the 4-position of the cyclohexene ring
was subjected to the reaction condition affording a 6:1 mixture
of diastereomers 2b with the cis-anti isomer as a major
The reaction of 1a using 2 mol % of AuCl3 and 6 mol % of
AgSbF6 was performed at 50 °C for 1 h, giving the desired
[6,5,6] linear tricycle 2a having a cyclopentenone skeleton in
(6) (a) Braude, E. A.; Coles, J. A. J. Chem. Soc. 1952, 1430. (b) Braude,
E. A.; Forbes, W. F. J. Chem. Soc. 1953, 2208. (c) Eaton, P. E.; Giordano,
C.; Schloemer, G.; Vogel, U. J. Org. Chem. 1976, 41, 2238. (d) Harding,
K. E.; Clement, K. S. J. Org. Chem. 1984, 49, 3870. (e) Mehta, G.;
Krishnamurthy, N. J. Chem. Soc., Chem. Commun. 1986, 1319.
(7) (a) Denmark, S. E.; Wallace, M. A.; Walker, C. B. J. Org. Chem.
1990, 55, 5543. (b) Denmark, S. E.; Klix, R. C. Tetrahedron 1988, 44,
4043. (c) Bender, J. A.; Arif, A. M.; West, F. G. J. Am. Chem. Soc. 1999,
121, 7443. (d) Browder, C. C.; Marmsater, F. P.; West, F. G. Org. Lett.
2001, 3, 3033.
(3) Jin, T.; Yamamoto, Y. Org. Lett. 2007, 9, 5259.
(4) For recent reviews, see: (a) Tius, M. A. Eur. J. Org. Chem. 2005,
2193. (b) Pellissier, H. Tetrahedron 2005, 61, 6479. (c) Frontier, A. J.;
Collison, C. Tetrahedron 2005, 61, 7577. For an efficient Au-catalyzed
synthesis of cyclopentenones via tandem Nazarov reaction, see: (d) Zhang,
L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442.
(8) The reaction of 1a in the presence of a protic acid, such as HSbF6
or TfOH, gave a complex mixture of products, indicating that the use of
AuCl3/AgSbF6 catalyst is essential for the present tandem reaction.
(5) (a) Mehta, G.; Srikrishna, A. Chem. ReV. 1997, 97, 671. (b) Liang,
G.; Xu, Y.; Seiple, I. B.; Trauner, D. J. Am. Chem. Soc. 2006, 128, 11022
.
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Org. Lett., Vol. 10, No. 14, 2008

diastereomer (entry 2). The enynyl ketone with dihydronaph-
thalene 1c afforded the tetracycle 2c in a good yield, although
a higher temperature was needed (entry 3). The enynyl ketones
with various sizes of cyclic alkenes were tested. For example,
the reaction with the enynyl ketones having cyclopentene and
cycloheptene moieties gave the corresponding linear tricycles
2d and 2e in 70% and 72% yield, respectively (entries 4 and
5), while the enynyl ketone 1f bearing a cyclooctene moiety
afforded 52% of the corresponding tricycle 2f along with 33%
of an isomer 2f′, in which the double bond was away from the
ring-fused position. Perhaps the double bond migration took
place to avoid ring strain (entry 6). In addition to the cyclic
enynes, the reaction proceeded smoothly with the acyclic enynyl
ketone 1g, leading to the bicyclic cyclopentenone 2g in 50%
yield (entry 7). Furthermore, the cis-anti tetracyclic enones, 2h,
2i, and 2j, were readily produced diastereoselectively from the
Au-catalyzed tandem reaction of the corresponding cyclic
enynes containing cyclic ketones, although a higher catalytic
loading was necessary when R1 was an ethoxycarbonyl group
(entries 8, 9, and 10). The benzene tethered cyclic enynyl ketone
1k underwent the tandem cyclization readily to give the
corresponding tetracycle 2k in 40% yield (entry 11).
Table 2. Au-Catalyzed Tandem Heteroenyne Metathesis and
Aromatic Nazarov Reactiona
a Reaction conditions: 2 mol % of AuCl3 and 6 mol % of AgSbF6, 1
(0.5 mmol), toluene (0.2 M), 100 °C, 4 h. b Isolated yield.
reaction of the alkynyl ketone 1l substituted with a strong
electron-donating 1,3-dioxoyl group on the aromatic ring
produced the linear tetracyclic fluorenone derivative 2l in
66% yield (Table 2, entry 1). Interestingly, the 1- and
2-naphthyl-substituted alkynyl ketones, 1m and 1n, were
converted to the corresponding tetracyclic benzofluorenone
derivatives 2m and 2n in 92% and 96% yields, respectively,
and 2n was obtained as a single regioisomer (entries 2 and
3).
The structure of 2k was unambiguously determined by
X-ray crystallography (Figure 1) which indicated that the
ring-fusion stereochemistry of the ethyl and the proton groups
was cis, and those of other products were assigned by
analogy.9
In conclusion, we have developed an efficient method for
constructing various fused tri- and tetracyclic enones via the
Au-catalyzed tandem heteroenyne metathesis and Nazarov
reaction. The Au(III) catalyst exhibits dual roles for activating
both alkynes and carbonyls, and it should be noted that a
catalytic Nazarov reaction proceeds very smoothly in this
system.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL801265S
Figure 1. ORTEP drawings of 2k.
(9) CCDC-685029 contains the supplementary crystallographic data for
2k. The detailed data can be obtained free of charge from The Cambridge
Crystallographic Data Centre at www.ccdc.cam.ac.uk/data_request/cif. The
stereochemistry of products, 2b, 2f′, 2h, 2i, and 2j, was confirmed by
measurement of various 1D, 2D, and NOE spectra. See Supporting
Information for details.
Next, we investigated the Au-catalyzed tandem reaction
with the aryl-substituted alkynes instead of enynes. The
Org. Lett., Vol. 10, No. 14, 2008
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