Gold-catalyzed synthesis of carbon-bridged medium-sized rings

Article abstract of DOI:10.1021/ol901722q

Bicyclo[m.n.1]alkenone frameworks possessing quaternary carbon centers adjacent to a bridged ketone are frequently found in bioactive natural products. Although several methods have been developed to construct such frameworks, most of them are specific to a particular scaffold. Herein, we report a mild and highly efficient method to generate carbon-bridged frameworks of various sizes using phosphlno gold(I) catalysts.

Full text of DOI:10.1021/ol901722q

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4236-4238
Gold-Catalyzed Synthesis of
Carbon-Bridged Medium-Sized Rings
Francis Barabe´, Genevie`ve Be´tournay, Gabriel Bellavance, and Louis Barriault*
Center for Catalysis Research and InnoVation, UniVersity of Ottawa, Department of
Chemistry, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
lbarriau@uottawa.ca
Received July 27, 2009
ABSTRACT
Bicyclo[m.n.1]alkenone frameworks possessing quaternary carbon centers adjacent to a bridged ketone are frequently found in bioactive natural
products. Although several methods have been developed to construct such frameworks, most of them are specific to a particular scaffold. Herein,
we report a mild and highly efficient method to generate carbon-bridged frameworks of various sizes using phosphino gold(I) catalysts.
Highly oxygenated and densely substituted bicyclo[m.n.1]-
alkanone cores are commonly found in nature as structural
frameworks of bioactive natural products.1 Most of these
compounds bear quaternary carbon centers adjacent to the
bridged ketone. These comprise enaimeone A (1),2 hyperforin
(2)3 (isolated from Hyperycum perforatum, known as St. John’s
wort), and penostastin (3)4 (Figure 1).
Owing to the promising biological properties and chal-
Figure 1. Structure of enaimeone (1), hyperforin (2), and penostatin
lenging structures of these molecules, considerable research
efforts have been devoted to develop efficient methods to
construct carbon bridged-medium sized rings.5 However,
most of them are specific for a particular framework.
F (3).
efficient strategy to generate fused-carbocyclic rings.6,7
However, reports of their use in the synthesis of bicyclo-
[m.n.1]alkenone rings are rare and substrate specific.8 Taking
advantage of the affinity of phosphino gold(I) salts for triple
bonds,9 we envisioned a Au(I)-catalyzed 6-endo-dig cycliza-
tion of cyclic silyl enol ether 4 to synthesize bicyclic
bridgehead ketone 7 (Scheme 1). A cursory inspection of
To address this issue, transition-metal-promoted cycliza-
tions of enol ethers with alkynes represent an attractive and
(1) Ciochina, R.; Grossman, R. B. Chem. ReV. 2006, 106, 3963.
(2) Winkelmann, K.; Heilmann, J.; Zerbe, O.; Rali, T.; Sticher, O. HelV.
Chim. Acta 2001, 84, 3380.
(3) (a) For isolation of hyperforin, see: Gurevich, A. I.; Dobrynin, V. N.;
Kolosov, M. N.; Popravko, S. A.; Riabova, I. D. Antibiotiki 1971, 16, 510.
(b) Bystrov, N. S.; Chernov, B. K.; Dobrynin, V. N.; Kolosov, M. N.
Tetrahedron Lett. 1975, 2791. (c) For synthetic studies, see: Mehta, G.;
Bera, M. K. Tetrahedron Lett. 2009, 50, 3519. (d) Mehta, G.; Bera, M. K.
Tetrahedron Lett. 2008, 49, 1417. (e) Shimizu, Y.; Kuramochi, A.; Usuda,
H.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2007, 48, 4173. (f) Nicolaou,
K. C.; Carenzi, G. E. A.; Jeso, V. Angew. Chem., Int. Ed. 2005, 44, 3895.
(4) (a) For isolation of penostatin F, see: Numata, A.; Iwamoto, C.;
Minoura, K.; Hagishita, S.; Nomoto, K. J. Chem. Soc., Perkin Trans. 1
1998, 449. For synthetic studies, see: (b) Barriault, L.; Ang, P. A. J.;
Lavigne, R. M. A. Org. Lett. 2004, 6, 1317.
(5) (a) For a review on the synthesis of bicyclo[3.3.1]nonanes, see:
Butkus, E. Synlett 2001, 1827. (b) For a review on the synthesis of the
bicyclo[4.3.1]decenone skeleton of phomoidrides, see: Spiegel, D. A.;
Njardason, J. T.; McDonald, I. M.; Wood, J. L. Chem. ReV. 2003, 103,
2691. (c) For a review on the synthesis of the bicyclo[5.3.1]undecene
framework of Taxol, see: Boa, A. N.; Jenkins, P. R.; Lawrence, N. J.
Contemp. Org. Synth. 1994, 1, 47. (d) Sheehan, S. M.; Lalic, G.; Chen,
J. S.; Shair, M. D. Angew. Chem., Int. Ed. 2000, 39, 2714. (e) Lavigne,
R. M. A.; Riou, M.; Girardin, M.; Morency, L.; Barriault, L. Org. Lett.
2005, 7, 5921
.
10.1021/ol901722q CCC: $40.75
Published on Web 08/24/2009
 2009 American Chemical Society

dramatically improved the chemoselectivity (30:1) and the
conversion (76%) (run 2). On the other hand, the replacement
Scheme 1. Proposed Mechanism for the Au(I)-Catalyzed Cyclization
-
of the counterion by SbF6 and OTf- proved to be de-
trimental to the selectivity despite a slight improvement of
the conversion (runs 3 and 4). Surprisingly, the air stable
Echavarren catalyst 13,11 gave mainly the hydration product
10a in dichloroethane (run 5). In contrast, high chemose-
lectivity was achieved when toluene was used as solvent (run
7). Additional experimentation demonstrated that 2 mol %
of 13 in acetone was optimal for this process (run 8).12
Having established the reaction conditions, the scope of this
Au(I)-catalyzed 6-endo-dig cyclization was then examined
(Table 2).13 Enol ethers 4b, 4c,and 4d were readily converted
to ketones 7b, 7c, and 7d in 85, 80, and 98% yields,
respectively. Thus, the frameworks of the three natural products
depicted in Figure 1 are rapidly and efficiently synthesized using
this new approach. The method tolerates substitution, as
evidenced by the cyclization of substrates 4e-h, which give
the desired ketones 7e-h exclusively and in high yields. It
worth noting is that bicyclo[3.3.1]nonenones 7g and 7h bear
the two bridgehead quaternary carbon centers present in 2 and
related natural polycyclic polyprenylated acetylphloroglucin
compounds.
Next, we looked at the Au(I)-catalyzed carbocyclization
of substrates possessing a tetrasubstituted enol ether and an
internal alkyne. Compounds 4i-l were treated under the
standard conditions to provide the corresponding bicyclo-
[3.3.1]nonenones 7i-l in 78-92% yield. These results con-
firmed that alkyl and/or aryl substitutions at R1 and R2 in 4 do
not impair the regio- and chemoselectivity of the reaction.
In the context of its application to the total synthesis of
natural polycyclic polyprenylated acetylphloroglucins, we
further probed the scope of this transformation.
the mechanism reveals that the Au(I)-catalyzed cyclization
can proceed via three distinct pathways. In path A, a 6-endo-
dig cyclization of 4 gives intermediate 6 which after
protonation leads to the desired product 7. Conversely, Au(I)
complex 5 can undergo competitive 5-exo-dig cyclization
to afford intermediate 8 (path B) and 11 (path C) which upon
protonation and hydrolysis provide the hydration product 10
and the bicyclic ketone 12, respectively.
Keeping this in mind, we examined various cationic
phosphinogold(I) complexes. Treatment of silyl enol ether
4a10 with 5 mol % of Ph3PAuCl/AgBF4 in DCM at room
temperature gave the bridged ketone 7a as the major product
in low conversion (30%) (Table 1, run 1). The minor product
(6) (a) Drouin, J.; Boaventura, M. A.; Conia, J. M. J. Am. Chem. Soc.
1985, 107, 1726. (b) Drouin, J.; Boaventura, M. A. Tetrahedron Lett. 1987,
28, 3923. (c) Huang, H.; Forsyth, C. J. J. Org. Chem. 1995, 60, 2773. (d)
Iwasawa, N.; Maeyama, K.; Kusama, H. Org. Lett. 2001, 3, 3871. (e)
Iwasawa, N.; Miura, T.; Kiyota, K.; Kusama, H.; Lee, K.; Lee., P. H. Org.
Lett. 2002, 4, 4463. (f) Nevado, C.; Cardenas, D. J.; Echavarren, A. M.
Chem.sEur. J. 2003, 9, 2627. (g) Corkey, B. K.; Toste, F. D. J. Am. Chem.
Soc. 2007, 129, 2764.
Table 1. Optimization
(7) For Au(I)-catalyzed cyclization, see: (a) Dankwardt, J. K. Tetrahe-
dron Lett. 2001, 42, 5809. (b) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org.
Lett. 2005, 7, 3925. (c) Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.;
Corkey, B. K.; LaLonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006,
45, 5991. (d) Linghu, X.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem.,
Int. Ed. 2007, 46, 7671. (e) Lee, K.; Lee, P. H. AdV. Synth. Catal. 2007,
349, 2092.
(8) For terminal alkynes, 10 mol % W(CO)5(THF) is required, see: (a)
Iwasawa, N.; Maeyama, K. J. Am. Chem. Soc. 1998, 120, 1928. For
substituted alkynes, a stoichiometric amount of W(CO)5(THF) is required,
see: (b) Iwasawa, N.; Miura, T. J. Am. Chem. Soc. 2002, 124, 518. (c) For
EtAlCl2-mediated cyclization, see: Imamura, K.; Yoshikawa, E.; Gevorgyan,
V.; Yamamoto, Y. Tetrahedron Lett. 1999, 40, 4081.
(9) Recent reviews on gold catalysis: (a) Muzart, J. Tetrahedron 2008,
64, 5815. (b) Fu¨rstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46,
3410. (c) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180. (d) Jimenez-
Nu´nez, E.; Echavarren, A. M. Chem. Commun. 2007, 333. (e) Gorin, D. J.;
Toste, F. D. Nature 2007, 446, 395.
(10) The preparation of silyl enol ethers 4a-l is described in the
Supporting Information.
a
Determined by H NMR. b 2 mol % of catalyst was used. c Isolated
1
yield ) 90%.
(11) Nieto-Oberhuber, C.; Lopez, S.; Echavarren, A. M. J. Am. Chem.
Soc. 2005, 127, 6178.
(12) All reaction vessels were treated in a KOH/i-PrOH bath prior to
use.
ketone 10a results from a cyclization via path B. The
replacement of triphenylphosphine by triethylphosphine
(13) In all runs, no products from path B or C were observed by 1H
NMR of the crude reaction mixture.
Org. Lett., Vol. 11, No. 18, 2009
4237

Halogenated alkynes 4m and 4n were subjected to the
optimized reaction conditions (Table 3). Much to our
Table 2. Gold(I)-Catalyzed 6-Endo Cyclization
Table 3. Au(I)-Catalyzed Cyclized of Halogenated Alkynes
entry
substrate
solvent
ratio 7:12a
yield (%)
1
2
3
4
5
6
7
8
9
a
4m
4n
4m
4n
4m
4n
4m
4n
4o
1
acetone
acetone
benzene
benzene
MeOH
MeOH
CHCl3
1.2:1
2.1:1
2.6:1
2.9:1
1:2.3
1:1.2
10.3:1
12.5:1
>95:5
88
91
83
88
73
68
92
85
93
CHCl3
acetone
Determined by H NMR.
surprise, mixtures of 6-endo 7m,n and 5-exo 12m,n (cy-
clization via path C) were obtained (entries 1 and 2). To
improve the reaction selectivity, other solvents were investi-
gated. It was found that the cyclization in benzene gave also a
mixture of 7m,n and 12m,n (ratio ≈ 3:1) (entries 3 and 4),
whereas in MeOH, the formation of the 5-exo products 12m,n
were slightly favored (entries 5 and 6). The best results were
obtained in chloroform (entries 7 and 9) to give mainly the
desired bicyclo[3.3.1]nonenone 7m and 7n in 92% and 85%
yield, respectively. Interestingly, Au(I)-catalyzed cyclization of
bromoalkyne 4o afforded the corresponding bicyclic-bridged
ketone 7o in 93% yield as the sole isomer (entry 9).
In summary, we have developed a mild and efficient
method to generate bicyclo[m.3.1]alkenones using phosphino
gold(I) catalysts. The attractive feature of this method resides
in ability to construct carbon bridged-medium rings of
various sizes as well as the installment of quaternary carbon
centers adjacent to the bridgehead ketone. Applications of
this method to the synthesis of hyperforin (2) and related
compounds are underway and will be reported in due course.
Acknowledgment. We thank the Natural Science and
Engineering Research Council of Canada (NSERC), Merck
Research Laboratories, Merck Frosst Canada, Boehringer In-
gelheim (Laval), Canada Foundation for Innovation, Ontario
Innovation Trust, and the University of Ottawa for generous
funding. F.B. thanks NSERC (CGS-M). We thank Prof. Mick
Sherburn (Australian National University) for helpful discussions
and Dr. Tara Krell (University of Ottawa) for X-ray analysis.
Supporting Information Available: Experimental details
and analytical data for all new compounds and ORTEP view
of 7k. This material is available free of charge via the Internet
at http://pubs.acs.org.
a Reaction performed in acetonitrile.
OL901722Q
4238
Org. Lett., Vol. 11, No. 18, 2009