Diversity in gold- and silver-catalyzed cycloisomerization of epoxide-alkyne functionalities

Article abstract of DOI:10.1021/ol802047g

(Chemical Equation Presented) We report Au(I)- and Ag(I)-catalyzed cycloisomerizations of epoxide-alkyne functionalities in both aromatic and nonaromatic systems, leading to diversified carbocyclic and heterocyclic frameworks with high chemoselectivities. The use of such cycloisomerizations is reflected by a facile access to the cores of natural pallidol and gibberic acid.

Full text of DOI:10.1021/ol802047g

ORGANIC
LETTERS
2008
Vol. 10, No. 21
5059-5062
Diversity in Gold- and Silver-Catalyzed
Cycloisomerization of Epoxide-Alkyne
Functionalities
Guan-You Lin, Chia-Wen Li, Siao-Hua Hung, and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua UniVersity, Hsinchu, Taiwan (ROC)
rsliu@mx.nthu.edu.tw
Received September 2, 2008
ABSTRACT
We report Au(I)- and Ag(I)-catalyzed cycloisomerizations of epoxide-alkyne functionalities in both aromatic and nonaromatic systems, leading
to diversified carbocyclic and heterocyclic frameworks with high chemoselectivities. The use of such cycloisomerizations is reflected by a
facile access to the cores of natural pallidol and gibberic acid.
One important advent in modern catalysis is the generation
of reactive metal carbenoids and nonclassical carbocations
in the cycloisomerzation of enynes catalyzed by electrophilic
metals.1,2 The use of this method is manifested by the
diversity of carbo- and heterocyclic products as substrate
structures and catalysts are modified.1,2 Although there is
growing interest on metal-mediated coupling reactions of
epoxides with alkynes,3 no precedent is reported for genera-
tion of metal carbenoids from such functionalities.4,5 Herein,
we report new Au(I)- and Ag(I)-catalyzed cycloisomeriza-
tions of epoxide-alkyne functionalities to give diversified
carbocyclic and heterocyclic compounds selectively; Au(I)
generates carbenoid species, whereas Ag(I) gives carbocation
intermediates. The significance of this new catalysis is its
easy construction of the central skeletons of naturally
occurring pallidol,6a gibberic acid,6b and flavothebaone.6c
Table 1 shows the results for disubstituted epoxide 1a (E/Z
) 1.1)7 using cationic Ag(I) and Au(I) catalysts after we
(3) (a) McDonald, F. E.; Schultz, C. C. J. Am. Chem. Soc. 1994, 116,
9363. (b) Marson, C. M.; Khan, A.; McGregor, J. Tetrahedron Lett. 1995,
36, 7154. (c) Gansauer, A.; Pierobon, M.; Bluhm, H. Angew. Chem., Int.
Ed. 1998, 37, 101. (d) Gansauer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem.
Soc. 1998, 120, 12849. (e) Molinaro, C.; Jamison, T. F. J. Am. Chem. Soc.
2003, 125, 8076. (f) Madhushaw, R. J.; Lin, M.-Y.; Sohel, S. M. A.; Liu,
R.-S. J. Am. Chem. Soc. 2004, 126, 6895. (g) Hashmi, A. S. K.; Sinba, P.
AdV. Synth. Catal. 2004, 346, 432. (h) Dai, L.-Z.; Qi, M.-J.; Shi, Y.-L.;
Liu, X.-G.; Shi, M. Org. Lett. 2007, 9, 3191. (i) Shu, X.-Z.; Liu, X.-Y.;
Xiao, H.-Q.; Ji, K.-G.; Guo, L.-N.; Qi, C.-Z.; Lian, A.-M. AdV. Synth. Catal.
2007, 349, 2493. (j) Cordonnier, M.-C.; Blanc, A.; Pale, P. Org. Lett. 2008,
10, 1569.
(1) (a) Echavarren, A. M.; Nevado, C. Chem. Soc. ReV. 2004, 33, 431.
(b) Zhang, L.; Sun, J.; Kozmin, S. A. AdV. Synth. Catal. 2006, 348, 2271.
(c) Jime´nez-Nu´n˜ez, E.; Echavarren, A. M. Chem. Commun. 2007, 333. (d)
Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395. (e) Hashmi, A. S. K.
Chem. ReV. 2007, 107, 3180. (f) Lipschutz, B. H.; Yamamoto, Y. Chem.
(4) For generation of R-carbonyl gold carbenoids from Ph2SO, see: (a)
Shapiro, N. D.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 4160. (b) Witham,
C. A.; Mauleo´n, P.; Shapiro, N. D.; Sherry, B. D.; Toste, F. D. J. Am.
Chem. Soc. 2007, 129, 5838. (c) Li, G.; Zhang, L. Angew. Chem., Int. Ed.
2007, 46, 5156.
ReV. 2008, 108, 2793
.
(5) For generation of R-carbonyl gold carbenoids from nitrone, see:
Yeom, H.-S.; Lee, J.-E.; Shin, S. Angew. Chem., Int. Ed. 2008, 47, 7040.
(6) (a) Snyder, S. A.; Zografos, A. L.; Lin, Y. Angew. Chem., Int. Ed.
2007, 46, 8186. (b) Hanson, J. R.; Ling, Y.-Z. J. Chem. Soc., Perkin Trans.
1 1984, n/a, 173. (c) Bentley, K. W.; Selby, I. A.; Young, C. A. J. Chem.
Soc., Perkin Trans. 1 1974, n/a, 682.
(2) (a) Martin-Matute, B.; Nevado, C.; Ca´rdenas, D. J.; Echavarren,
A. M. J. Am. Chem. Soc. 2003, 125, 5757. (b) Fu¨rstner, A.; Davies, P. W.;
Gress, T. J. Am. Chem. Soc. 2005, 127, 8244. (c) Johansson, M.; Gorin,
D. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002. (d)
Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 6962. (e) Jime´nez-
Nu´n˜ez, E.; Echavarren, A. M. Chem. Commun. 2007, n/a, 333. (f) Marion,
(7) The E/Z ratios of starting epoxides 1a-j, 4e,g, and 8b,g are provided
in the Supporting Information.
N.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750
.
10.1021/ol802047g CCC: $40.75
Published on Web 10/15/2008
2008 American Chemical Society

Table 1. Catalyst Screening for Substituted Epoxides 1a and 4a
Table 2. Catalytic Cycloisomerization of Epoxide-Alkyne
PPh3AuCl
mol %
AgX,
mol % (X) (h)
time
product
ketonesc
(yield, %)
entry substratea
(yield, %)b
entry
epoxidesa,b
1
2
3
4
5
6
7
1a
1a
1a
3a
4a
4a
3b
5 (SbF6)
5 (SbF6)
2 (SbF6)
2 (SbF6) 24
2 (SbF6) 24
6
1
6
3a (90)
1
2
3
4
5
6
7
8
R1 ) Me, R2 ) Ph (1b)
R1 ) CH2Ph, R2 ) Ph (1c)
2b (73)
2c (46)
2d (80)
2e (74)
2f (60)
2g (76)
2h (70)
2i (81)
6b (89)
6c (81)
6d (81)
6e (78)
6f (71)
5
5
5
5
2a (35), 3a (35)
2a (78), 3a (1)
3a (95)
R1 ) nPr, R2 ) 4-MeOC6H4 (1d)
R1 ) nPr, R2 ) 4-FC6H4 (1e)
R1 ) nPr, R2 ) 2-thienyl (1f)
R1 ) nPr, R2 ) nPr (1 g)
4a (57), 5a (41)
2 (SbF6)
2 (SbF6) 24
0.5 6a (86)
3b (94)
R1 ) nPr, R2 ) Me (1 h)
a [Epoxides] ) 0.1 M in dry CH2Cl2. b Yields were reported after elution
R1 ) nPr, R2 ) NMeTs (1i)
R3 ) R4 ) Me, Ar ) 4-MeOC6H4 (4b)
R3 ) R4 ) Me, Ar ) 4-FC6H4 (4c)
R3 ) R4 ) Me, Ar ) 2-thienyl (4d)
R3 ) Me, R4 ) Ph, Ar ) Ph (4e)
R3, R4 ) -(CH2)4-, Ar ) Ph (4f)
from a silica column.
9
10
11
12
13
found poor activity for commonly used catalysts (5 mol %)
including PtCl2, PtCl2/CO, AuClPPh3, AuCl, AuCl3, and
AgOTf in CH2Cl2 (23 °C, 24-48 h).8 AgSbF6 was active in
the rearrangement of epoxide 1a to ketone 3a in a 90% yield
(entry 1). The use of PPh3AuCl/AgSbF6, each at 5 mol %
loading, led to 3-1H-indenyl ketones 2a (35%) and side
product 3a (35%, entries 2). The yield of desired ketone 2a
was improved up to 78% with PPh3AuCl/AgSbF6 (5/2 mol
%, entry 3). Ketone 3a was not the intermediate for 3-1H-
indenyl ketone 2a because it was recovered exclusively with
this modified catalyst in CH2Cl2 (23 °C, 24 h, entry 4). The
same reaction on trisubstituted epoxide 4a gave diketone 5a
(41%) in addition to unreacted 4a (57%); nevertheless, we
improved the yield of 3-1H-indenyl ketone 6a up to 86%
with AgSbF6 catalyst (2 mol %). Herein, formation of 6a
from epoxide 4a does not involve ketone 3b as a reaction
intermediate according to the control experiment depicted
in entry 7.
Table 2 summarizes the results for various di- and
trisubstitutedepoxides1b-iand4b-f,catalyzedbyPPh3AuCl/
AgSbF6 (5/2 mol %) and AgSbF6 (2 mol %), respectively.
This catalysis is applicable to epoxides 1b-c bearing various
R1 substituents (R1 ) Me and CH2Ph), giving cyclized
ketones 2b,c in 73% and 46% yields, respectively (entries 1
and 2). For epoxides 1d-i comprising various alkynyl R2
substituents (R2 ) 4-MeOC6H4, 4-FC6H4, 2-thienyl, 1-propyl,
methyl, and NMeTs), the suitability of this catalysis is
reflected by good yields (60-80%) of resulting cyclized
ketones 2d-i. A 1,2-methyl migration is extendible to
epoxides 4b-d bearing various arylalkynyl susbtituents (Ar
) 4-MeOC6H4, 4-FC6H4, and 2-thienyl, entries 9-11), giving
the resulting ketones 6b-d in 81-89% yields. Treatment
of epoxide 4e with AgSbF6 (5%) in CH2Cl2 (23 °C, 10 min)
provided cyclized ketones 6e in 78% yield, of which the
a [Epoxides] ) 0.1 M, 23 °C, CH2Cl2. b The E/Z ratios of the epoxides
are provided in the Supporting Information. c Yields were reported after
elution from a silica column.
phenyl group was 1,2-shifted to the neighboring indenyl
C(1)-carbon (entries 12). The same silver-catalyzed cycloi-
somerization of epoxides 4f provided desired ketone 6f (72%)
with a ring expansion.
The generation of diketone 5a from epoxide 4a (Table 1,
entry 5) is likely formed from water oxidation of R-carbonyl
Au(I)-benzylidene B.9 To verify this intermediacy, as
depicted in Scheme 1, epoxide 1b was treated with PPh3AuCl/
AgSbF6 (5/2 mol %) and Ph2SO4b (4 equiv) in CH2Cl2 (23
°C, 48 h), giving a 68% yield of diketone 5b. Treatment of
epoxide 4a with styrene or ethoxyethene (10 equiv) with the
same Au(I)/Ag(I) catalyst delivered cyclopropane and acetal
Scheme 1
(8) Screening of catalyst activity over commonly used catalysts is
provided in Table S1, Supporting Information.
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Org. Lett., Vol. 10, No. 21, 2008

products 7a and 7b in 78-81% yields. With additional
trapping experiments,10 we confirmed the intermediacy of
gold-carbenoids B, but we could not identify Ag(I)--
carbenoid species because the production of cyclized ketone
6a from epoxide 2a was unaffected by these reagents. The
1,2-phenyl shift in the Ag(I)-catalyzed transformation of
epoxide 4e into cyclized ketone 6e (Table 2, entry 12) is
unusual as we observed different 1,2-migration patterns for
Ag(I)-catalyzed rearrangement of the model molecule 4g,
which gave ketone 3c and 3d in a 89% combined yields (3c/
3d ) 6.4) via expected tertiary cationic intermediate.
Table 3. Cycloisomerization of Nonaromatic Epoxides to
Polycyclic 2H-Pyrans
Accordingly, we envisage that PPh3Au+ initially com-
plexes the internal alkyne of species 1a to induce a 7-endo-
cyclization to yield seven-membered oxacyclic species A,
of which the gold-enol moiety promotes cleavage of the
ether ring to form Au(I)-carbene B (Scheme 2). This carbene
Scheme 2
species is also represented by its pentadienyl cationic
resonance B′ to induce an electrocyclization cyclization11
to generate 1-indanyl cation C. A subsequent 1,2-hydride
shift12 of this intermediate gave 2-indanyl cation C that
formed desired 3-1H-indenyl ketone 2a after elimination of
PPh3Au+. In the case of trisubstituted epoxide 4a, PPh3Au+
species generates the corresponding intermediate B′′ with
its methyl and PhCO groups at the inner positions to inhibit
the cyclization. For silver catalysis, prior rearrangemnt of
epoxide to ketone, followed by ketone-alkyne metathesis,13
i.e., 6a f 3b f 6a, is unlikely to occur under reaction
a [Epoxides] ) 0.1 M, 23 °C, CH2Cl2. b The E/Z ratios of the epoxides
are provided in the Supporting Information. c Yields were reported after
elution from a silica column.
conditions (see Table 1, entry 7, and Scheme 1), and we
propose that the mechanism likely involves a 1,2-phenyl shift
of intermediate A′ to give oxonium species E, which
ultimately gave desired ketone 6e through a rearrangement
of oxetane intermediate F.
The diversity of this epoxide-alkyne cycloisomerization
is also reflected by formation of complex 2H-pyran com-
pounds 9a-f from nonaromatic epoxides 8a-f catalyzed by
PPh3AuCl/AgSbF6 (5/5 mol %) in CH2Cl2 at 23 °C. Herein,
the key intermediate H is formed by a 6-exo-dig attack of
the epoxide at the alkyne of π-intermediate G, and its
structure is best represented by its gold-carbenoid resonance
form H′, which triggers a Nazarov-type cyclization11 to give
the observed products.
(9) Taduri, B. P.; Sohel, S. M. A.; Cheng, H.-M.; Liu, R.-S. Chem.
Commun. 2007, 2530.
(10) Additional trapping experiments to verify gold-carbenoids B and
H′ are depicted in Scheme S1, Supporting Information.
(11) (a) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577. (b)
Song, D.; Rostami, A.; West, F. G. J. Am. Chem. Soc. 2007, 129, 12019.
(12) We prepared deuterium labeled d1-1a, and its cycloisomerization
provided highly deuterated ketone d1-2a (97%), clearly indicative of 1,2-
hydride shift. NMR spectra data of d1-1a and d1-2a are provided in the
Supporting Information.
Table 3 shows the applicability of this cycloisomerization
to trisubstituted epoxides 8a-f with varied epoxide R2 and
aryl groups; the products yields were generally high (>71%)
except for fluorophenyl derivative 9f (49% yield). The
carbenoid character of species H′ was verified by a trapping
experiment with Ph2SO oxidation.4b,10
(13) (a) Rhee, J. U.; Krische, M. J. Org. Lett. 2005, 7, 2493. (b) Jin, T.;
Yamamoto, Y. Org. Lett. 2007, 9, 5259. (c) Jin, T.; Yamamoto, Y. Org.
Lett. 2008, 10, 3137.
Org. Lett., Vol. 10, No. 21, 2008
5061

Scheme 3
Scheme 4
Scheme 3 provides additional diversified cycloisomeriza-
tion of epoxide 8g, which was initiated by an epoxy
rearrangement. Treatment of epoxide 8g with AgSbF6 (5 mol
%) and PPh3AuCl/AgSbF6 (5/2%) in CH2Cl2 (23 °C) for a
brief time (1.0 and 0.5 h), respectively, gave aldehyde 10a
in 95% yield. A subsequent oxo-alkyne metathesis13,14 of
compounds 10a with PPh3AuCl/AgSbF6 (5/5 mol %) fur-
nished distinct 3-1H-indenyl ketone 10b efficiently.
Scheme 4 shows the value of these new cyclizations for a
rapid construction of the central cores of natural pallidol and
gibberic acid, as represented by ketones 11 and 4j, respec-
tively. Treatment of epoxide 1j with PPh3AuCl(5%)/
AgSbF6(2%) provided desired ketone 2j (71%), which
underwent BF3-catalyzed Nazarov cyclization to give tetra-
cyclic ketone 11 (61%). Treatment of epoxide 4h with AgBF4
(5%) led to ring expansion to give tricyclic ketone 4i (57%),
which was treated by PtO2/H2 in CH3OH (23 °C, 4 h) to
give ketone 4j having the stereochemistry matching the core
of gibberic acid; the structure of 4j was determined by H
NOE spectra.
In summary, we report gold-catalyzed cycloisomerizations
of epoxide-alkyne functionalities in both aromatic and
nonaromatic systems, leading to 3-1H-indenyl ketones and
polycyclic 2H-pyrans, respectively. Gold-catalyzed cycloi-
somerization is proposed to involve generation of gold-
carbenoid intermediates, which are identified by a series of
trapping experiments.10 Although AgSbF6 is very efficient
for cycloisomerization of aromatic trisubstituted epoxides,
the cyclization pathway is distinct from those of gold catalyst.
For epoxides of special types such as species 8g, Au(I) gave
distinct 3-1H-indenyl ketones, reflecting the effects of
epoxide substituents. The diversity of such cycloisomeriza-
tions enables one-pot construction of various carbocyclic and
heterocyclic frameworks, including the cores of pallidol6a
and gibberic acid.6b
1
Acknowledgment. We thank the National Science Coun-
(14) Krische and co-workers reported13a AgSbF6-catalyzed aldehyde/
alkyne metathesis at elevated temperatures (50-80 °C) rather than ambient
conditions (23 °C).
(15) During preparation of this manuscript, Hashmi reported gold-
catalyzed cycloisomerization of aromatic 1,2-disubsituted epoxides using
different gold catalysts, which overlaps with the initial portion of this work.
We note that the gold-carbenoid intermediate was not identified therein.
See: Hashmi, A. S. K.; Buhrle, M.; Salathe, R.; Bats, J. W. AdV. Synth.
Catal. 2008, 350, 2059 (published online August 19, 2008)
cil, Taiwan, for supporting this work.
Supporting Information Available: NMR spectra and
spectral data of new compounds 1a-j, 2a-j, 3a-d, 4a-j,
5a,b, 6a-f, 7a,b, 8a-h, 9a-f, 10a,b, and 11. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL802047G
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Org. Lett., Vol. 10, No. 21, 2008