Synthesis of fused carbocycles via a selective 6-endo dig gold(I)-catalyzed carbocyclization

Article abstract of DOI:10.1021/ol202314q

A gold-catalyzed synthesis of fused carbocycles via a regioselective 6-endo dig process is reported. The selectivity can be modulated by the steric and electronic properties of gold(I) complexes. The ligands can influence the pathway selectivity for the f

Full text of DOI:10.1021/ol202314q

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5580–5583
Synthesis of Fused Carbocycles via a
Selective 6-Endo Dig Gold(I)-Catalyzed
Carbocyclization
†
Francis Barabe, Patrick Levesque, Ilia Korobkov, and Louis Barriault*
ꢀ
Centre for Catalysis Research and Innovation, Department of Chemistry, 10 Marie
Curie, University of Ottawa, Ottawa, Canada, K1N 6N5
lbarriau@uottawa.ca
Received August 25, 2011
ABSTRACT
A gold-catalyzed synthesis of fused carbocycles via a regioselective 6-endo dig process is reported. The selectivity can be modulated by the steric
and electronic properties of gold(I) complexes. The ligands can influence the pathway selectivity for the first bond formation rather than through a
common intermediate generated after an initial bond formation. This gold(I)-catalyzed transformation provides access to synthetically useful
carbocyclic motifs that are found in numerous diterpenoid natural products.
The development of methods that efficiently generate
bicyclo[4.3.0]nonanes and bicyclo[4.4.0]decanes posses-
sing quaternary centers at the ring junction constitute a
significant challenge in organic synthesis. These structural
motifs are embedded in several medicinally important
molecules such as diterpenes and steroids. To assemble
these scaffolds, one can envisage cyclizations of cyclic
enol ethers with alkynes promoted by transition metal
catalysts.1 The high affinity of Au(I/III) salts to alkynes
and allenes in the presence of many other functional
groups combinedwithits abilitytostabilize cationic charge
provides tremendous opportunities for the discovery of
novel and useful reactions.2 Although Au(I)-catalyzed
5-exo, 5-endo, and 6-exo dig cyclizations have been exten-
sively studied by Toste and others,3 the Au(I)-catalyzed
6-endo dig process (1f2) to generate fused carbocycles has
proven to be more challenging (Scheme 1).1f,4 In fact, Lee
reported that phosphino Au(I)-catalyzedreactions of cyclic
enol ethers 1 (n = 0, 1) with homopropargylic alkynes
exclusively gave the 5-exo dig product 3 regardless of the
substituents R1 on the triple bond.3e
† To whom X-ray inquiries should be addressed.
Recently, it has been shown that divergent reactivity
and stereoselectivity in gold-catalyzed reactions can be
achieved by variation of the ancillary ligands.5,6 From this
perspective, we envisaged the possibility that both 5-exo
(1) For selected examples, see: (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,
H.; Kusama, K. 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.;Eur. J. 2003,
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M. H.; Reif, M. S.; Kirsch, F. Org. Lett. 2005, 7, 3925. (c) Staben, S. T.;
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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. (f) Binder, J. T.; Crone,
B.; Haug, T. T.; Menz, H.; Kirsch, S. F. Org. Lett. 2008, 10, 1025.
(4) (a) Kozak, J. A.; Patrick, B. O.; Dake, G. R. J. Org. Chem. 2010,
75, 8585. (b) Minnihan, E. C.; Colletti, S. L.; Toste, F. D.; Shen, H. C.
J. Org. Chem. 2007, 72, 6287.
(2) For recent reviews, see: (a) Toste, F. D.; Gorin, D. J. Nature 2007,
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446, 395. (b) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Commun.
€
2007, 333. (c) Furtsner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007,
46, 3410. (d) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180. (e) Gorin,
D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev. 2008, 108, 3351. (f) Li, Z.;
Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239. (g) Arcadi, A. Chem.
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r
10.1021/ol202314q
Published on Web 09/15/2011
2011 American Chemical Society

Table 1. Screening Conditions
Scheme 1. Gold-Catalyzed Cyclization of Silylenol Ether 1
dig and 6-endo dig products could be obtained selectively
from the same starting material by modulating the steric
and electronic properties of the gold(I) catalyst. Herein, we
report a gold-catalyzed synthesis of fused carbocycles via a
regioselective 6-endo dig process.7
We started our investigation by examining the cycliza-
tion using various phosphino gold(I) salts (Table 1).
Treatment of 4 with Ph3PAuSbF6 in DCM gave the hydro-
lysis product 7 as the major product (entry 1). Although
the replacement of the counterion SbF6 by BF4 consider-
ably reduced the hydrolysis product formation (entry 2),
no significant increases of the 6-endo dig product 6 ratio
were noticed using either Et3PAuCl or (4-CF3C6H4P)3-
AuCl (entries 3 and 4) in DCM. Conversely, the cyclization
using [L1AuNCMe]SbF6 (2 mol %) in acetone gave
5 and 6 in a ratio of 64:36 in 86% yield (entry 5).8 On the
basis of these results, we hypothesized that an increase of
steric interactions between R1 and the Au(I) complex by
having bulkier ligands on the metal could disfavor the
5-exo dig cyclization (1f3). The replacement of JohnPhos
(L1) by XPhos (L2)8 and Me4XPhos (L3) resulted in an
inversion of selectivity favoring the 6-endo dig product 6
(entries 6 and 7). Interestingly, the use of other Buchwald
ligands such as L4, L5, and L7 did not improve the endo
selectivity or the yield (entries 8, 9, and 11).9 The cycliza-
tion using RuPhos (L6)10 and DavePhos (L8) favored the
5-exo dig product 5 in a ratio of 71:29 and 62:38 respec-
tively (entries 10 and 12).
Having found that Au(I)-catalyzed carbocyclization
using XPhos (L2) and Me4XPhos (L3) favors the 6-endo
dig cyclization process, we evaluated the scope of the
reaction using various internal alkynes (Table 2). Cycliza-
tion of cyclic tetrasubstituted enol ethers 8aÀc gave the
bicyclic products 9aÀc possessing an angular methyl in a
ratio of 6-endo/5-exo ranging from 71:29 to 97:3 in
83À91% yields (entries 1À3). Six-membered ring trisub-
stituted enol ether 8d gave the 6-endo dig product 9d in
a ratio of 77:23 in 54% yield whereas the conversion
a Determined by 1H NMR of the crude reaction mixture. b Combined
isolated yields. c Reactions run in DCM.
of phenyl acetylene 8e exclusively afforded the 6-endo dig
cyclized compound 9e in 60% yield (entries 4 and 5).
Similarly, conversion of electronic rich alkynes 8f and 8g
provided the desired bicycle[4.4.0]decenones 9f and 9g in
72% and 78% yields respectively, as the sole isomer
(entries 6 and 7). However, erosion of the endo regioselec-
tivity was observed with electron-deficient alkynes such as
8hÀj (entries 8À10). To apply this method in the context of
diterpene synthesis, it would be practical for the Au(I)-
cyclization to be tolerant toward vinyl groups. To this end,
Au(I)-catalyzed cyclization of enynes was examined
(entries 11À15). Enynes 8k and 8l were converted to the
desired dienes 9k and 9l as the sole isomer (>95:5) in 60
and 48%yieldsrespectively(entries 11and12). Cyclization
of enynes 8m and 8o gave the corresponding 6-endo dig
products 9m and 9o as the major isomers in good overall
yields (entries 13 and 14). Carbocyclization of 8p using
[L3AuNCMe]SbF6 afforded diene 9p in 84% yield (endo/
exo = 87:13) (entry 15). These results are strikingly
different from those previously reported (cf. Scheme 1),
in particular, entries 4 and 5.
ꢀ
ꢀ
(5) (a) Mauleon, P.; Zeldin, R. M.; Gonzalez, A. Z.; Toste, F. D. J.
Am. Chem. Soc. 2009, 131, 6348. (b) Benitez, D.; Shapiro, N. D.; Tkatchouk,
E.; Wang, Y.; Goddard, W. A.; Toste, F. D. Nat. Chem. 2009, 1, 482.
€
(6) Alcarazo, M.; Stork, T.; Anoop, A.; Thiel, W.; Furstner, A.
Angew. Chem., Int. Ed. 2010, 49, 2542.
(7) For synthesis of bridgehead ketone via 6-endo dig cyclization, see:
ꢀ
ꢀ
Barabe, F.; Betournay, G.; Bellavance, G.; Barriault, L. Org. Lett. 2009,
10, 4236.
(8) Nieto-Oberhuber, C.; Lopez, S.; Echavarren, A. M. J. Am. Chem.
Soc. 2005, 127, 6178.
(9) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
(10) Gao, H.; Wu, X.; Zhang, J. Chem. Commun. 2010, 46, 8764.
At first glance, one can hypothesize that steric interac-
tionsbetweenthe biarylphosphine ligandandthe substrate
are at the origin of the difference in selectivities. Indeed, the
Org. Lett., Vol. 13, No. 20, 2011
5581

Table 2. Intramolecular Cyclization of Cyclic Enol Ether with
Internal Alkynes
Figure 1. Crystallographic data of L3AuCl.
one might assume that bulkiness of the Buchwald ligand
could deform the PÀAuÀC angle at the transition state
which would result in a reduction of the Au-dπfC-pπ
overlap (Scheme 2).12 As a consequence, this would imply
a cationic type mechanism where a partial positive charge
at C1 is formed at the transition state.
Scheme 2. Proposed Mechanism
On the basis that a neighboring electron-rich substituent
R2 can stabilize the partial charge, one can rationalize that
the relative energy of TS-1 leading to 12 should be lower
than that of TS-2 thus favoring the formation of endo dig
product 9. By contrast, electron-withdrawing groups
should disfavor TS-1 and an erosion of the regioselectivity
should be observed. The ratio observed for the Au(I)-
catalyzed cyclizations of electron-rich and -poor aryl
alkynes 8fÀj are in agreement with the proposed mechan-
ism (Table 2, entries 6À10).
The cyclization of terminal or internal alkynes on a
linear template 14aÀc provided the desired 6-endo dig
cyclized products 15aÀc in very good to excellent yields
as the sole regioisomer (eq 1).4b The reaction conditions
prove to be mild as no conjugated enones resulting from a
double bond migration were observed.
a Determined by 1H NMR of the crude reaction mixture. b Com-
bined isolated yields. c Reaction run in DCM at À10 ꢀC. d 5 mol %
[L2AuNCMe]SbF6 was used. e Reaction performed in MeOH.
increase of the ligand size favors the formation of the
6-endo dig product. However, the electronic factors could
not be ignored. Crystallographic data of L3AuCl revealed
that —PÀAuÀCl = 169ꢀ (Figure 1).11 On this basis,
In another experiment, we investigated the effect of
σ-donating ligands on the reaction regioselectivity. To
(11) See Supporting Information for details.
5582
Org. Lett., Vol. 13, No. 20, 2011

our surprise, cyclization of enol ether 4 using [IPrAuNCMe]-
SbF6 (L9)13 gave only the 5-exo dig ketone 5 in 91% yield
as the sole isomer (Scheme 3).14 Similarly, carbocyclization
of tetrasubstituted enol ethers 8a and 8c predominantly
afforded the 5-exo dig products 10a and 10c in ratios of
92:8 (94%) and 86:14 (86%) respectively. Aryl alkynes 8h,
8i and enyne 8p were converted to the corresponding 5-exo
products 10h, 10i and 10o in good yields. These results are
in sharp contrast with those depicted in Tables 1 and 2
where the cyclization of the same enol ethers using Me4X-
Phos (L3) provided the 6-endo dig products. This reveals
that divergent regioselectivities can be obtained by mod-
ulating the bulkiness and electronic properties of the
ancillary ligand. In the case of the cyclization with
[IPrAuNCMe]SbF6 (L9), it seems that the electronic den-
sity and steric environment of the alkyne are less contributing
to the regioselectivity of the reaction. One could attribute this
to the ligand size and the σ-donation properties of L9.
In summary, we have demonstrated that the gold(I)-
catalyzed 6-endo dig pathway is accessible and not limited
to substrates possessing steric or electronic biases. The
ancillary ligand can affect the pathway selectivity for the
first bond formation rather than through a common inter-
mediate generated after an initial bond formation. Further-
more, this type of reaction provides an access to synthetically
useful motifs that are found in numerous natural products.
DFT calculations to gain further insight into the observed
selectivity as well as the design and application of new
catalysts to the synthesis of diterpenes are currently under-
way, and the results will be reported in due course.
Scheme 3. 5-Exo Dig Cyclization of Cyclic Enol Ethersa
a Reaction performed in MeOH.
Acknowledgment. We thank the Natural Science and
Engineering Research Council of Canada (NSERC),
Merck Research Laboratories, Merck-Frosst Canada,
Boehringer Ingelheim (Laval), PREA, Canada Founda-
tion for Innovation, Ontario Innovation Trust, and the
University of Ottawa for generous funding. F.B. thanks
the NSERC for postgraduate scholarship (CGS-D1).
(12) Benitez, D.; Tkatchouk, E.; Gonzalez, A. Z.; Goddard, W. A.;
Toste, F. D. Org. Lett. 2009, 11, 4798.
Supporting Information Available. Full characteriza-
tion, experimental details and 1H and 13C NMR spectra
for all new compounds, and crystallographic data (CIF)
for 5, 6, and L3AuCl can be found in the Supporting
Information. This material is available free of charge via
the Internet at http://pubs.acs.org.
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(13) de Fremont, P.; Scott, N. M.; Stevens, E. D.; Nolan, S. P.
Organometallics 2005, 24, 2411.
(14) For a review on coinage metalÀNHC complexes, see: (a) Lin,
J. C. Y.; Huang, R. T. W.; Lee, C. S.; Bhattacharyya, A.; Hwang, W. S.;
Lin, I. J. B. Chem. Rev. 2009, 109, 3561. (b) Gonzalez, S. D.; Marion, N.;
Nolan, S. P. Chem. Rev. 2009, 109, 3612. (c) Nolan, S. P. Acc. Chem. Res.
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