Mimicking polyolefin carbocyclization reactions: Gold-Catalyzed intramolecular phenoxycyclization of 1,5-enynes

Article abstract of DOI:10.1021/ol900864n

PPh₃AuNTf₂ promotes highly efficient intramolecular phenoxycyclization reactions on 1,5-enynes under mild conditions. The original tricyclic and functionalized heterocycles were isolated In good to excellent yields. The 6-eneto cycli

Full text of DOI:10.1021/ol900864n

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2888-2891
Mimicking Polyolefin Carbocyclization
Reactions: Gold-Catalyzed
Intramolecular Phenoxycyclization of
1,5-Enynes
Patrick Yves Toullec, Thomas Blarre, and Ve´ronique Michelet*
Laboratoire Charles Friedel, UMR 7223, Ecole Nationale Supe´rieure de Chimie de
Paris, 11, rue P. et M. Curie, 75231 Paris Cedex 05, France
Veronique-michelet@enscp.fr
Received April 20, 2009
ABSTRACT
PPh3AuNTf2 promotes highly efficient intramolecular phenoxycyclization reactions on 1,5-enynes under mild conditions. The original tricyclic and
functionalized heterocycles were isolated in good to excellent yields. The 6-endo cyclization process is predominant and operates via a biomimetic
cascade cation-olefin process. The efficiency of this system was further demonstrated in the cycloisomerization reaction of a 1,5,9-dienyne.
Since the introduction of the Stork-Eschenmoser postulate1
more than 50 years ago, polyolefin carbocyclizations have been
a field of constant interplay between biologists and chemists.2
From a synthetic point of view, the involved enzyme-like
domino processes3 have attracted a lot of attention due to the
ability of these transformations to allow the construction of
polycyclic functionalized structures in a highly selective manner
mainly featuring the 6-endo mode of cyclization. Synthetic
strategies involving chiral iodonium ion-4 and Lewis acid-
mediated5 polyprenoid cyclizations have appeared as an alterna-
tive due to the analogy of their reactivity with one of the protons
toward alkenes. Among them, the development of the first
enantioselective Bro¨nsted-Lewis acid catalyst by Yamamoto
et al. represents a major advance in the field.6 Cationic
carbophilic late transition metal complexes, such as Pt or Hg,7
(1) (a) Stork, G.; Burgstahler, A. W. J. Am. Chem. Soc. 1955, 77, 5068.
(b) Eschenmoser, A.; Ruzicka, L.; Jeger, O.; Arigoni, D. HelV. Chim. Acta
1955, 38, 1890. (c) Eschenmoser, A.; Arigoni, D. HelV. Chim. Acta 2005,
88, 3011.
(4) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900.
(5) Cyclizations promoted by SnCl4: (a) van Tamelen, E. E.; Seiler,
M. P.; Wierenga, W. J. Am. Chem. Soc. 1972, 94, 8229. (b) Johnson, W. S.;
Bunes, L. A. J. Am. Chem. Soc. 1976, 98, 5597. (c) van Tamelen, E. E.;
Hwu, J. R. J. Am. Chem. Soc. 1983, 105, 2490. Epoxide activation with Al
catalysts: (d) Corey, E. J.; Wood, H. B. J. Am. Chem. Soc. 1996, 118, 11982.
Nazarov cyclization: (e) Bender, J. A.; Blize, A. E.; Browder, C. C.; Giese,
S.; West, F. G. J. Org. Chem. 1998, 63, 2430. (f) Bender, J. A.; Arif, A. M.;
West, F. G. J. Am. Chem. Soc. 1999, 121, 7443.
(2) (a) Wendt, K. U.; Schulz, G. E.; Corey, E. J.; Liu, D. R. Angew.
Chem., Int. Ed. 2000, 39, 2812. (b) de la Torre, M. C.; Sierra, M. A. Angew.
Chem., Int. Ed. 2004, 43, 160. (c) Roder, R. A.; Johnston, J. N. Chem.
ReV. 2005, 105, 4730.
(3) For representative examples, see: (a) Mamane, V.; Hannen, P.;
Fu¨rstner, A. Chem.sEur. J. 2004, 10, 4556. (b) Nevado, C.; Echavarren,
A. M. Chem.sEur. J. 2005, 11, 3155. (c) Chatani, N.; Inoue, H.; Ikeda,
T.; Murai, S. J. Org. Chem. 2000, 65, 4913. (d) Hashmi, A. S. K.; Salathe´,
R.; Frost, T. M.; Schwarz, L.; Choi, J.-H. Appl. Catal. A: Gen. 2005, 291,
238.
(6) (a) Ishihara, K.; Nakamura, S.; Yamamoto, H. J. Am. Chem. Soc.
1999, 121, 4906. (b) Nakamura, S.; Ishihara, K.; Yamamoto, H. J. Am.
Chem. Soc. 2000, 122, 8131. (c) Ishihara, K.; Ishibashi, H.; Yamamoto, H.
J. Am. Chem. Soc. 2002, 124, 3647. (d) Ishibashi, H.; Ishihara, K.;
Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 11122.
10.1021/ol900864n CCC: $40.75
Published on Web 05/29/2009
 2009 American Chemical Society

also promote stoichiometrically, and very recently, catalytically8
in the case of platinum, the polyenes’ cyclization. From the
organometallic perspective, we postulated that the replacement
of the terminal alkene moiety by an alkyne function would
release a highly reactive vinyl-metal intermediate prone to
protodemetalation.9 Whereas several reports have been devoted
to the late transition carbophilic Lewis acid catalyzed cycloi-
somerization of 1,6-enynes,9,10 few reports deal with 1,5-
enynes.11,12 The Kozmin group reported the formation of
bicyclic ethers upon cycloisomerization of 1,5-enynes pos-
sessing an internal hydroxyle or amine function (Scheme
1).11c They reported a strong influence of the stereochemistry
chemists in line with the discovery of promising biological
properties.16 In this paper, we describe a highly efficient gold-
catalyzed 6-endo-dig intramolecular phenoxycyclization of
1,5-enynes and 1,5,9-dienynes.
As a model reaction, we prepared 1,5-enyne 1a (see the
Supporting Information) and attempted its cyclization in the
presence of various Bronsted or Lewis acid catalysts (Table
1). The use of hydrochloric acid as the electrophilic alkyne
Table 1. [M]-Catalyzed Cycloisomerization of 1,5-Enyne 1a
Scheme 1. Au-Catalyzed Cycloisomerization of 1,5-Enynes
entry
catalyst (%)
conditions
yielda (%)
1
2
HCl (50)
toluene/diethyl ether (4/1)
PdCl2 (5)
toluene, 80 °C, 16 h
PdCl2 (5), PPh3 (10),
AgSbF6 (12.5)
PtCl2 (5)
3
4
5
6
7
8
9
dioxane, 60 °C, 16 h
toluene, 80 °C, 16 h
b
PPh3AuCl (1), AgSbF6 (1) diethyl ether, 20 °C, 16 h
78
95
95
95
30c
PPh3AuNTf2 (1)
PPh3AuNTf2 (1)
PPh3AuNTf2 (1)
AuCl3 (10)
diethyl ether, 20 °C, 1 h
toluene, rt, 1 h
CH2Cl2, rt, 1 h
CH3CN, rt
of the alkene on the regioselectivity of the cyclization event:
whereas Z alkenes lead to the obtention of products resulting
from a 6-endo cyclization, E alkenes produces bicyclic
5-endo compounds. As part of our ongoing program devoted
to the development of atom-economical metal-catalyzed
cycloisomerization reactions13 and considering the biological
and medicinal importance of the hexahydroxanthene core,14
we engaged in the application of the tandem nucleophilic
addition/cycloisomerization reaction to the synthesis involv-
ing 1,5-enynes and oxygen nucleophiles. The tricyclic
arrangement is indeed present in a family of hydroquinone-
containing sesquiterpenes containing more than a hundred
isolated natural products of marine origin.15 These natural
products along with synthetic analogues featuring the same
structural architecture have attracted attention from synthetic
a Isolated yield. b Presence of 2a and 3a detected. c 35% conversion.
activator did not lead to any conversion of the starting material
(Table 1, entry 1). Palladium-based systems, in the presence or
the absence of silver salts (Table 1, entries 2 and 3), did not
engender any reactivity neither. The use of PtCl2 led to the
formation of a complex mixture of products including tetrahy-
droxanthene 2a corresponding to the hydroxycyclization product
and the chromane 3a, resulting from the hydroalkoxylation of
the alkene double bond.17 (Table 1, entry 4). In the presence
of cationic Au(I) complexes,18 the clean formation of the
bicyclic ether 2a in 78% yield was this time observed under
very mild conditions (Table 1, entry 5). The use of 1 mol %
(7) For an Hg study, see: (a) Nishizawa, M.; Takenaka, H.; Hayashi,
Y. J. Org. Chem. 1986, 51, 806. For Pt studies, see: (b) Koh, J. H.; Gagne´,
M. R. Angew. Chem., Int. Ed. 2004, 43, 3459. (c) Feducia, J. A.; Gagne´,
M. R. J. Am. Chem. Soc. 2008, 130, 592.
(8) Mullen, C. A.; Gagne´, M. R. J. Am. Chem. Soc. 2007, 129, 11880.
(9) (a) Chianese, A. R.; Lee, S. J.; Gagne´, M. R. Angew. Chem., Int.
Ed. 2007, 46, 4042. (b) Fu¨rstner, A.; Davies, P. W. Angew. Chem., Int. Ed.
2007, 46, 3410. (c) Nevado, C.; Echavarren, A. M. Synthesis 2005, 167.
(10) For selected reviews on metal-catalyzed cycloisomerizations, see:
(a) Trost, B. M.; Krische, M. J. Synlett 1998, 1. (b) Buisine, O.; Aubert,
C.; Malacria, M. Chem. ReV. 2002, 102, 813. (c) Lloyd-Jones, G. C. Org.
Biomol. Chem. 2003, 1, 215. (d) Fairlamb, I. J. S. Angew. Chem., Int. Ed.
2004, 43, 1048. (e) Zhang, L.; Sun, J.; Kozmin, S. A. AdV. Synth. Catal.
2006, 348, 2271. (f) Reference 9. (g) Michelet, V.; Toullec, P. Y.; Genet,
J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268. (h) Gimenez-Nunez, E.;
(13) (a) Chao, C.-M.; Vitale, M.; Toullec, P. Y.; Geneˆt, J.-P.; Michelet,
V. Chem.sEur. J. 2009, 15, 1319. (b) Leseurre, L.; Chao, C.-M.; Seki, T.;
Genin, E.; Toullec, P. Y.; Geneˆt, J.-P.; Michelet, V. Tetrahedron 2009, 65,
1911. (c) Chao, C.-M.; Genin, E.; Toullec, P. Y.; Geneˆt, J.-P.; Michelet,
V. J. Organomet. Chem. 2009, 694, 538. (d) Toullec, P. Y.; Chao, C.-M.;
Chen, Q.; Geneˆt, J.-P.; Michelet, V. AdV. Synth. Catal. 2008, 250, 2401.
(e) Neatu, F.; Li, Z.; Richards, R.; Toullec, P. Y.; Geneˆt, J.-P.; Dumbuya,
K.; Gottfried, J. M.; Steinru¨ck, H.-P.; Paˆrvulescu, V. I.; Michelet, V.
Chem.sEur. J. 2008, 14, 9412. (f) Toullec, P. Y.; Genin, E.; Antoniotti,
S.; Geneˆt, J.-P.; Michelet, V. Synlett 2008, 707. (g) Leseurre, L.; Toullec,
P. Y.; Geneˆt, J.-P.; Michelet, V. Org. Lett. 2007, 9, 4049. (h) Genin, E.;
Leseurre, L.; Toullec, P. Y.; Genet, J.-P.; Michelet, V. Synlett 2007, 1780.
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J.-P.; Michelet, V. ARKIVOC 2007, V, 67. (j) Toullec, P. Y.; Genin, E.;
Leseurre, L.; Geneˆt, J.-P.; Michelet, V. Angew. Chem., Int. Ed. 2006, 45,
7427. (k) Genin, E.; Toullec, P. Y.; Antoniotti, S.; Brancour, C.; Geneˆt,
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.
(11) For Hg-catalyzed carbocyclization (three examples), see: (a)
Imagawa, H.; Iyenaga, T.; Nishizawa, M. Synlett 2005, 703. (b) Imagawa,
H.; Iyenaga, T.; Nishizawa, M. Org. Lett. 2005, 7, 451. For Au-catalyzed
alkoxy and aminocyclization, see: (c) Zhang, L.; Kozmin, S. A. J. Am.
Chem. Soc. 2005, 127, 6962. (d) Buzas, A. K.; Istrate, F. M.; Gagosz, F.
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.
(12) During the preparation of this manuscript, the Gagne´ group reported
the platinum-catalyzed phenoxycyclization of 1,5-enynes using 20 mol %
of a dicationic pincer-ligated platinum complex (two examples); see: Nelsen,
D. L.; Gagne´, M. R. Organometallics 2009, 28, 950
.
Org. Lett., Vol. 11, No. 13, 2009
2889

catalyst of the cationic gold complex (PPh3)AuNTf2,19 allowed
full conversion within 1 h at room temperature (Table 1, entry
6), the desired tricyclic product being isolated in 95% yield.
The reaction can be conducted in a variety of solvents including
diethyl ether, toluene, or CH2Cl2 (Table 1, entries 6-8). As a
comparison with the Kozmin group’s results (Scheme 1),11c
the reaction was conducted in acetonitrile in the presence of
AuCl3 (Table 1, entry 9). A low conversion was observed, and
2a was isolated in 30% yield.
within 15 min to 1 h in the presence of 1 mol % of
PPh3AuNTf2. The substitution of the phenol ring does not
Scheme 2
.
Au-Catalyzed Cycloisomerization of (E)- or
(Z)-1,5-Enynes
The 6-endo mode of cyclization has been proven on the
basis of 2D NMR experiments conducted on compound 2c
(Table 2). These optimum conditions were applied to a
variety of 1,5-enynes and dienynes substrates (Table 2 and
Scheme 2). All of the reactions tested went to completion
Table 2. 1,5-Enyne and 1,5,9-Dienyne Cyclizations Catalyzed
by PPh3AuNTf2
affect the yield of the transformation as both electron-
donating (Table 2, entries 3 and 5-8) or electron-withdraw-
ing groups (Table 2, entries 2 and 4) are well tolerated. The
corresponding tricyclic derivatives 2b-i were isolated in
76-96% yield. The cyclization takes place with the same
order of reactivity when the phenol ring is substituted with
a methyl group at the 2 position or at the 4 position (Table
2, entries 3, 5). The substitution on the alkyne can be either
a methyl (Table 2, entries 1-6), a hydrogen (Table 2, entry
7), or an aromatic ring (Table 2, entry 8). It is remarkable
to notice that the 6-endo cyclization of the 1,5-enyne
fragment occurs irrelevantly of the substitution of the alkyne
moiety (Table 2, entries 6-8).
The 6-endo mode of cyclization being observed for all enynes
possessing an (E)-alkene (1a-i), we decided to investigate the
reactivity of substrates (E)-1j and (Z)-1j possessing respectively
a (E)- or (Z)-alkenyl side chain (Scheme 2). As expected the
hexahydroxanthene (trans)-2j was obtained in 83% isolated
yield. We were pleased to see that the (cis)-2j derivative
possessing a cis ring junction was obtained as a single regio-
and diastereoisomer in 90% yield.
Mechanistically, a reasonable initial η2 coordination of
cationic gold(I) fragment on the alkyne function would then
trigger a double-cyclization process. The 6-endo cyclization
process is in complete accordance with a Stork-Eschenmoser-
type carbocationic cyclization and in complete coherence with
Fu¨rstner’s group20 results on the carboxycyclization of 1,6-
a Isolated yields. Small amounts (0-10%) of a minor isomer, presumably
resulting from the 5-endo cyclization, were obtained as byproduct.
2890
Org. Lett., Vol. 11, No. 13, 2009

enynes. As depicted in Scheme 2, the cis or trans relationship
of the corresponding hexahydroxanthene results from a chairlike
cyclization process.
To further probe the gold-catalyzed biomimetic cascade
cation-olefin cyclization, the reactivity of dienyne 4 was also
attempted: we were pleased to find that the expected cyclization
smoothly occurred leading to the tetracyclic derivative 5
featuring the trans-trans arrangement21 in 50% yield (Scheme
3). Although tricycles 2a-j have been obtained in high yields
enynes under mild conditions. The original tricyclic and
functionalized heterocycles were isolated in good to excellent
yields. We have showed that the 6-endo cyclization process
is predominant and operates via a biomimetic cascade cation-
olefin process. The efficiency of this system was further
demonstrated in the cycloisomerization reaction of 1,5,9-
dienyne. This process paves the way for further applications
in enantioselective tandem nucleophile addition/cycloisomer-
ization reactions. Current efforts are focused on expanding
the scope of this methodology to other classes of nucleo-
philes.
Scheme 3. Au-Catalyzed Cycloisomerization of 1,5,9-Dienyne 4
Acknowledgment. This work was supported by the Centre
National de la Recherche Scientifique (CNRS) and the
Ministe`re de l’Education et de la Recherche for financial
support. We are grateful to the National Research Agency
(ANR-JCJC06 145296) for a grant. We thank Dr. M.-N.
Rager (Ecole Nationale Supe´rieure de Chimie de Paris, Paris,
France) for 2D and NOESY experiments on compounds 2c
and 5.
Supporting Information Available: Experimental pro-
cedure, full analyses of 1a-j, 2a-j, 4, and 5, and 2D and
NOESY experimental analysis of 2c and 5. This material is
available free of charge via the Internet at http://pubs.acs.org.
with a high degree of diastereoselectivity (>20/1), the low yield
observed for the formation of 5 may be rationalized as an
evidence of an alternative mechanism involving stepwise
cation-olefin cyclization.7c,12
OL900864N
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In summary, we have showed that PPh3AuNTf2 efficiently
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experiments. All attempts to isolate byproducts were unsuccessful.
Org. Lett., Vol. 11, No. 13, 2009
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