Au- and Pt-catalyzed cycloisomerizations of 1,5-enynes to cyclohexadienes with a broad alkyne scope

Article abstract of DOI:10.1021/ja063384n

We describe the development of gold- and platinum-catalyzed cycloisomerizations of 1,5-enynes. This catalytic process displays a wide alkyne scope and furnishes a range of highly functionalized 1,4- and 1,3-cyclohexadienes. In the case of 1-siloxy-1-yne-5-enes, the reactions are efficiently catalyzed by AuCl (1 mol %) at ambient temperature to afford siloxy cyclohexadienes or the corresponding 1,2- and 1,3-cyclohexenones upon subsequent protodesilylation. We propose that the reaction proceeds via a novel mechanism involving a series of 1,2-alkyl shifts. Elucidation of this unusual reaction mechanism enabled us, in turn, to significantly expand the scope of the cycloisomerization by incorporation of a quaternary center at the C(3) position of the enyne. Indeed, we established that PtCl₂ (5 mol %) efficiently catalyzed the cycloisomerizations of 1,5-enynes containing terminal, internal, and arene-conjugated alkynes. Since a variety of 1,5-enynes are readily accessible, the cycloisomerization provides a rapid approach to a wide range of highy substituted cyclohexadienes for many subsequent synthetic applications.

Full text of DOI:10.1021/ja063384n

Published on Web 07/07/2006
Au- and Pt-Catalyzed Cycloisomerizations of 1,5-Enynes to
Cyclohexadienes with a Broad Alkyne Scope
Jianwei Sun, Matthew P. Conley, Liming Zhang, and Sergey A. Kozmin*
Contribution from the UniVersity of Chicago, Department of Chemistry,
5735 South Ellis AVenue, Chicago, Illinois 60637
Received May 19, 2006; E-mail: skozmin@uchicago.edu
Abstract: We describe the development of gold- and platinum-catalyzed cycloisomerizations of 1,5-enynes.
This catalytic process displays a wide alkyne scope and furnishes a range of highly functionalized 1,4- and
1,3-cyclohexadienes. In the case of 1-siloxy-1-yne-5-enes, the reactions are efficiently catalyzed by AuCl
(1 mol %) at ambient temperature to afford siloxy cyclohexadienes or the corresponding 1,2- and 1,3-
cyclohexenones upon subsequent protodesilylation. We propose that the reaction proceeds via a novel
mechanism involving a series of 1,2-alkyl shifts. Elucidation of this unusual reaction mechanism enabled
us, in turn, to significantly expand the scope of the cycloisomerization by incorporation of a quaternary
center at the C(3) position of the enyne. Indeed, we established that PtCl2 (5 mol %) efficiently catalyzed
the cycloisomerizations of 1,5-enynes containing terminal, internal, and arene-conjugated alkynes. Since
a variety of 1,5-enynes are readily accessible, the cycloisomerization provides a rapid approach to a wide
range of highy substituted cyclohexadienes for many subsequent synthetic applications.
Introduction
ization provides a rapid approach to a wide range of highly
substituted cyclohexadienes for many subsequent synthetic
Transition-metal-catalyzed cycloisomerization of 1,6-enynes
represents an efficient strategy for the assembly of a variety of
five-membered and six-membered alkenes and dienes.1 The
corresponding metal-catalyzed cycloisomerizations of 1,5-
enynes have been developed to a much less significant extent.
Indeed, the only known mode of reactivity of 1,5-enynes entails
the formation of [3.1.0] bicyclohexenes.2,3 While important from
a conceptual viewpoint, the synthetic utility of this process is
limited to producing cyclopropane-fused bicyclic alkenes.
Herein, we describe the development of gold- and platinum-
catalyzed cycloisomerizations of 1,5-enynes to furnish a range
of 1,4- and 1,3-cyclohexadienes. This process was enabled by
our recent discovery of the gold-catalyzed skeletal rearrangement
of 1-siloxy-5-en-1-ynes,4 which was determined to proceed via
a remarkable mechanism involving a series of 1,2-alkyl shifts.
Elucidation of this novel reaction mechanism enabled us, in turn,
to significantly extend the scope of the initial cycloisomerization
precursors, which now includes 1,5-enynes containing terminal,
internal, arene-conjugated, and electron-rich alkynes. Since a
variety of 1,5-enynes are readily accessible, the cycloisomer-
applications.
Results and Discussion
In the course of our investigation of basic reactivity of siloxy
alkynes,5 we have established that HNTf2 was capable of
efficient activation of an electron-rich alkyne moiety toward
subsequent intramolecular additions of arenes and alkenes to
provide efficient access to substituted tetralone and cyclohex-
enone derivatives.5d While the reaction of siloxy alkynes with
arenes proceeded using a catalytic amount of the Brønsted acid
promoter, the corresponding enyne cyclizations required the use
of a stoichiometric amount of HNTf2. In search of a catalytic
enyne cyclization protocol, we examined the effect of a series
of transition metal salts on cyclization of siloxy enyne 1 (Table
1). We envisioned that subjection of enyne 1 to an appropriate
catalyst capable of chemoselective electrophilic activation of
the alkyne moiety should induce the desired 6-endo-cyclization,
followed by protodemetalation to give the expected 1-siloxy-
1,3-cyclohexadiene. Our selection of metal salts was based on
the known alkynophilicity of platinum(II),6 silver(I),7 and gold-
(I)8 compounds. While AgNTf2 proved to be an excellent
catalyst in other reactions involving siloxy alkynes, subjection
of enyne 1 to various amounts of either AgNTf2 or AgOTf
resulted in formation of multiple reaction products (Table 1,
entries 1 and 2). However, treatment of siloxy enyne 1 with 5
mol % AuCl gave a new product that was subsequently
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ReV. 2002, 102, 813. (b) Trost, B. M.; Krische, M. J. Synlett 1998, 1. (c)
Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Chem. ReV. 1996,
96, 635. (d) Driver, S. T.; Geissert, A. J. Chem. ReV. 2004, 104, 1317. (e)
Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. Chem.sEur. J. 2003, 9,
2627. (f) Me´ndez, M.; Mamane, V.; Fu¨rstner, A. Chemtracts 2003, 16,
397.
(2) (a) Mamane, V.; Gress, T.; Krause, H.; Fu¨rstner, A. J. Am. Chem. Soc.
2004, 126, 8654. (b) Harrak, Y.; Blaszykowski, C.; Bernard, M.; Cariou,
K.; Mainetti, E.; Mouries, V.; Dhimane, A. L.; Fensterbank, L.; Malacria,
M. J. Am. Chem. Soc. 2004, 126, 8656. (c) Luzung, M. R.; Markham, J.
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(5) (a) Schramm, M. P.; Reddy, D. S.; Kozmin, S. A. Angew. Chem., Int. Ed.
2001, 40, 4274. (b) Sweis, R. F.; Schramm, M. P.; Kozmin, S. A. J. Am.
Chem. Soc. 2004, 126, 7442. (c) Reddy, D. S.; Kozmin, S. A. J. Org. Chem.
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126, 10204. (e) Sun, J.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 13512.
(3) Nieto-Oberhuber, C.; Mun˜oz, M. P.; Bun˜uel, E.; Nevado, C.; Ca´rdenas,
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J. AM. CHEM. SOC. 2006, 128, 9705-9710
9705

A R T I C L E S
Sun et al.
Table 1. Optimization of Cycloisomerization
Scheme 1
entry
cataylst
solvent
temp,
°
C
yield,a
%
1
2
3
4
5
6
7
AgNTf2 (10 mol %)
AgOTf (10 mol %)
AuCl (5 mol %)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
20
20
20
20
20
20
80
<5b
<5b
93
AuCl (1 mol %)
93
PPh3AuCl (5 mol %)
PPh3AuCl/AgBF4 (5 mol %)
PtCl2 (10 mol %)
<5c
88
66
a Refers to isolated yields of spectroscopically pure products that were
full characterized by NMR, IR, and MS. b Complex mixture of products
was observed. c No reaction was observed.
identified as siloxy cyclohexadiene 2 (entry 3). Structural
assignment of 2 was based on a series of NMR studies, including
COSY, NOESY, HMQC, and HMBC experiments, which
unambiguously established the structure of cyclohexadiene 2,
corresponding to a formal and highly unusual migration of a
siloxy substituent from the C(1) to the C(6) position. Subsequent
experimentation established that the catalytic loading of AuCl
can be decreased to 1 mol % with the reaction being complete
within 20 min at room temperature, highlighting the remarkable
catalytic efficiency of this process. Addition of triphenylphos-
phine resulted in inhibition of catalytic activity presumably due
to the competitive binding of the phosphine ligand to Au(I).
The catalytic efficiency, however, can be recovered using Au-
(PPh3)Cl in the presence of AgBF4, presumably due to the
generation of a cationic gold complex. Among several other
metal salts examined, we found that the cycloisomerization can
also be catalyzed by PtCl2 (10 mol %) at 80 °C in benzene to
give cyclohexadiene 2 in 66% yield (entry 7). These studies
revealed that AuCl proved to be the most effective catalyst for
the cycloisomerization of siloxy enyne 1.
allyl bromide 4,9 followed by desilylation, afforded terminal
alkyne 5. Generation of lithium acetylide, followed by oxidation
with t-BuOOLi and silylation using TIPSOTf, furnished the
required siloxy alkyne 6 in quantitative yield.10 Subjection of
siloxy enyne 3 to AuCl (1 mol %) at 20 °C in CH2Cl2 afforded
the expected siloxy diene 7 in 50% yield (Scheme 1). The
5-trimethylsilylmethyl group was retained in the cyclization
product 4 despite the labile nature of this material. Subsequent
treatment of siloxy diene 7 with aq. HCl in MeCN afforded
1,3-cyclohexenone 8 in 77% yield. This experiment demon-
strated chemoselective protodesilylation of the silyl enol ether
fragment in the presence of the allyl silane moiety, providing
efficient synthetic access to a nonconjugated cyclohexenone.
We next examined the outcome of the cycloisimerization upon
introduction of the aryl moieties into the cyclization substrates
(Scheme 2). To this end, we prepared 3-phenyl and 5-phenyl
Scheme 2
Our investigation of the scope of the Au-catalyzed skeletal
reorganization of siloxy enynes began with the preparation of
enyne 6 (Scheme 1). Propargylic alkylation of alkyne 3 with
(6) (a) Blum, J.; Beer-Kraft, H.; Badrieh, Y. J. Org. Chem. 1995, 60, 5567.
(b) Chatani, N.; Furukawa, N.; Sakurai, H.; Murai, S. Organometallics 1996,
15, 901. (c) Chatani, N.; Kataoka, K.; Murai, S.; Furukawa, N.; Seki, Y. J.
Am. Chem. Soc. 1998, 120, 9104. (d) Fu¨rstner, A.; Szillat, H.; Gabor, B.;
Mynott, R. J. Am. Chem. Soc. 1998, 120, 8305. (e) Fu¨rtsner, A.; Szillat,
H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122, 6785. (f) Trost, B. M.; Doherty,
G. A. J. Am. Chem. Soc. 2000, 122, 3801. (g) Fu¨rstner, A.; Szillat, H.;
Stelzer, F. J. Am. Chem. Soc. 2001, 123, 11863. (h) Me´ndez, M.; Mun˜oz,
M. P.; Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc.
2001, 123, 10511. (i) Mainetti, E.; Mouries, V.; Fensterbank, L.; Malacria,
M.; Marco-Contelles, J. Angew. Chem., Int. Ed. 2002, 41, 2132. (j) Martin-
Matute, B.; Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. J. Am. Chem.
Soc. 2003, 125, 5757. (k) Cadran, N.; Cariou, K.; Herve, G.; Aubert, C.;
Fensterbank, L.; Malacria, M.; Marco-Contelles, J. J. Am. Chem. Soc. 2004,
126, 3408.
(7) (a) Ferrara, J. D.; Djebli, A.; Tessier-Youngs, C.; Youngs, W. J. J. Am.
Chem. Soc. 1988, 110, 647. (b) Clark, T. B.; Woerpel, K. A. J. Am. Chem.
Soc. 2004, 126, 9522 and references therein.
substituted enynes 9 and 11 using a similar alkylation/oxidation
tactic as that described above. Subjection of siloxy enyne 9 to
the standard cycloisomerization protocol afforded the expected
siloxy cyclohexadiene 11 in 73% yield, demonstrating that aryl
substitution at the C(3) position was well tolerated. Treatment
of enyne 11 with AuCl resulted, however, in the formation of
(8) (a) Hashmi, A. S. K., Frost, T. M.; Bats, J. W. J. Am. Chem. Soc. 2000
122, 11553. (b) Hashmi, A. S. K., Schwartz, L.; Choi, J.-H.; Frost, T. M.
Angew. Chem., Int. Ed. 2000, 39, 2285. (c) Mizushima, E.; Sato, K.;
Hayashi, T.; Tanaka, M. Angew. Chem., Int. Ed. 2002, 41, 23. (d) Asao,
N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am. Chem.
Soc. 2002, 124, 12650. (e) Reetz, M. T.; Sommer, K. Eur. J. Org. Chem.
2003, 3485. (f) He, C.; Shi, Z. J. Org. Chem. 2004, 69, 3669. (g) Kennedy-
Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526.
(h) Yao, X.; Li, C. J. Am. Chem. Soc. 2004, 126, 6884. (i) Asao, N.; Aikawa,
H.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 7458. (j) Yao, T.; Zhang,
X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164. (k) Sherry, B. D.;
Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978. (l) Zhang, L.; Kozmin,
S. A. J. Am. Chem. Soc. 2005, 127, 6962.
(9) ComprehensiVe Carbanion Chemistry; Buncel, E., Durst, T., Eds.; Elsevi-
er: Amsterdam, 1984; Vol. B, pp 107-145.
(10) Julia, M.; Saint-Jalmes, V. P.; Verpeaux, J.-N. Synlett 1993, 3, 233.
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Cycloisomerizations of 1,5-Enynes to Cyclohexadienes
A R T I C L E S
two reactions products, which were identified as the expected
1,4-diene 12 and a conjugated 1,3-diene 13 produced in a 4:1
ratio.
A similar outcome was observed in cycloisomerizations of
enynes 14 and 17 (Scheme 3). Subjection of enyne 14 to the
alkyl shift to give oxocarbenium ion F. Another 1,2-alkyl shift,
followed by fragmentation of the zwitterionic intermediate G,
affords six-membered gold carbene H. Depending on the nature
of the R1 and R2 substituents of the enyne, gold carbene H can
participate in two alternative elimination pathways to afford
isomeric 1,3- and 1,4-cyclohexadienes (I and J) with a
concomitant regeneration of AuCl.
Scheme 3
To further probe the effect of 1-siloxy substitution, we
subjected enyne 20 (Scheme 5) to the standard cyclization
Scheme 5
protocol. The reaction produced [3.1.0] bicyclohexene 21 as a
single product. Similar observations have been reported by
Echavarren,3 Fu¨rstner,2a Malacria,2b and Toste.2c These results
further highlight the crucial role of a siloxy alkyne moiety on
the outcome of the enyne cycloisomerization, presumably due
to the stabilization of cationic intermediate E.
standard cyclization protocol afforded cyclohexadienes 15 and
16 in a 6:1 ratio (82% combined yield). Cycloisomerization of
enyne 17 containing a trisubstituted alkene moiety produced
dienes 18 and 19 in a 3:1 ratio in quantitative yield. It is
noteworthy that skeletal reorganization of enyne 17 resulted in
the switching of the C(6)-methyl and the C(1)-siloxy groups,
corresponding to the formal metathesis of the alkene and alkyne
fragments. Apart from expanding the scope of this novel
cycloisomerization reaction, these experiments provided further
insight that enabled us to provide a mechanistic rationale of
the experimental observations.
Formation of nonconjugated and conjugated cyclohexadienes
can be explained using mechanistic analysis presented in Scheme
4. The process begins by activation of siloxy alkyne B with
π-acidic AuCl toward the intramolecular attack by the proximate
alkene (structure C), resulting in the cyclization to give
cyclopropyl gold carbene E. Formation of similar metal carbene
intermediates has been proposed in the Pt- and Au-catalyzed
cycloisomerizations of 1,5- and 1,6-enynes en route to [3,1,0]
and [4,1,0] bicycloalkenes.2,3 However, instead of the previously
observed hydride migration and elimination pathway, the
intermediate gold carbene E undergoes a highly unusual 1,2-
The mechanistic analysis presented in Scheme 4 suggested
to us that the introduction of a quaternary center at the C(3)
position of the cycloisomerization substrate (Table 2) should
favor exclusively the reaction pathway leading to the conjugated
diene product (G f I, Scheme 4) due to the absence of the
C(3) hydrogen required for the formation of 1,4-diene. However,
the caveat was that the introduction of the quaternary center in
the direct proximity to the siloxy alkyne moiety could inhibit
the coordination of the AuCl with the alkyne required for
initiation of the catalytic cycle. To our delight, subjection of
enynes 22 to the general cycloisomerization conditions afforded
exclusively a conjugated diene 23 in 88% yield (entry 1, Table
2). Similarly, treatment of phenyl-substituted enyne 24 with
AuCl afforded the expected product 25 in 89% yield (entry 2).
Finally, cycloisomerization of dienyne 26 proceeded with
complete chemoselectivity for the disubstituted alkene to afford
27 as a single reaction product in 84% yield (entry 3). Additional
studies revealed that while both di- and trisubstituted alkenes
efficiently participated in the cycloisomerization process, ter-
Scheme 4
9
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A R T I C L E S
Sun et al.
Table 2. Au-Catalyzed Cycloisomerization of Siloxy Enynes
Scheme 7
a Refers to isolated yields of spectroscopically pure products that were
full characterized by NMR, IR, and MS.
minal monosubstituted alkenes proved to be unreactive under
the current catalytic protocol.
2-Siloxy-1,3-cyclohexadienes produced by the gold-catalyzed
cycloisomerizations can be efficiently converted to 1,2-cyclo-
hexenones, highlighting the general synthetic utility of this
process. A representative example is depicted in Scheme 6.
Scheme 6
scope of the cycloisomerization process. It was our expectation
that the presence of the quaternary center at the C(3) should
disfavor path A due to the lower migratory aptitude of the C(3)
alkyl substituents. The reaction would then proceed via path B
leading to [2.1.1] bicyclic intermediate O, followed by another
1,2-alkyl shift, fragmentation, and elimination to give cyclo-
hexadiene S.
To test this mechanism-based hypothesis, we examined
cycloisomerization of enyne 29 containing a phenyl-substituted
alkyne (Table 3). Subjection of enyne 29 to AuCl indeed
Treatment of siloxy diene 23 with aqueous HCl in MeCN at
ambient temperature afforded cyclohexenone 28 in 91% yield.
Our studies established that the presence of a siloxy alkyne
moiety in the enyne cycloisomerization precursor was respon-
sible for the novel skeletal reorganization to furnish 1,4- or 1,3-
cyclohexadienes. In the absence of the siloxy alkyne, the
cyclization afforded exclusively the [3.1.0] bicyclohexene. The
two alternative mechanistic pathways are depicted in Scheme
7. The initial step is the formation of a cyclopropyl metal
carbene L, which can undergo two alternative transformations
depending on the substitution at the C(1) and the C(3) position
of enyne. Indeed, the presence of a siloxy group at the alkyne
terminus (R4 ) OTIPS) strongly favors mechanistic path B due
to efficient stabilization of cationic intermediate O. In the
absence of such stabilization and the presence of a â-hydrogen
(R3 ) H) the reaction follows path A leading to formation of
[3.1.0] bicyclohexene N via an alternative 1,2-shift, followed
by demetalation. This mechanistic analysis suggested to us that
removal of the labile hydrogen at the C(3) of the enyne by
incorporation of the quaternary center (R2, R3 ) Alkyl) may
favor the formation of cyclohexene S even in the absence of
the siloxy group at the alkyne terminus. This intriguing
possibility would result in significant expansion of the alkyne
Table 3. Optimization of Pt-Catalyzed 1,5-Enyne
Cycloisomerization
entry
cataylst
solvent
temp,
°C
yield,a
%
1
2
3
4
5
6
7
8
AuCl (5 mol %)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene/MeCN
20
20
20
20
80
20
80
80
16
22
AuCl3 (5 mol %)
PPh3AuCl (5 mol %)
PPh3AuSBF4 5(mol %)
AgNTf2 (5 mol %)
PtCl2 (15 mol %)
PtCl2 (15 mol %)
PtCl2 (5 mol %)
<5
<5
<5
<5
62
66
a Refers to isolated yields of spectroscopically pure products that were
full characterized by NMR, IR, and MS.
produced the desired cyclohexadiene 30 albeit in a disappoint-
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Cycloisomerizations of 1,5-Enynes to Cyclohexadienes
A R T I C L E S
Table 4. Pt-Catalyzed Cycloisomerization of 1,5-Enynes
Au, Scheme 7) leading to a competition between the two
possible reaction pathways A and B. Indeed, Toste reported the
Au(I)-catalyzed formation of [3.1.0] bicyclohexene-type prod-
ucts as a result of the C(3)-alkyl group migration,2c correspond-
ing to reaction pathway A in Scheme 7. We decided to examine
the use of Pt(II)-based catalysts to promote the desired
transformation, since platinum carbene L (M ) Pt, Scheme 7)
would be expected to exhibit lower reactivity and could
potentially lead to a higher selectivity for the desired path B.
While PtCl2 (15 mol %) proved to be unreactive at ambient
temperature (entry 6), the reaction proceeded at 80 °C in toluene
to give cyclohexadiene 30 in 62% yield, a much higher
efficiency compared to that when using gold complexes. Aiming
at further reduction in the catalyst loading and improvement of
the reaction efficiency, we examined a range of additives and
found that the use of toluene containing a stoichiometric amount
of MeCN gave the best results. Cyclohexadiene 30 was produced
in 66% isolated yield using 5 mol % of PtCl2. Overall, these
studies revealed that Pt-based catalysis proved to be more
effective than Au-based systems for cycloisomerization of
1-phenyl-substituted enyne 29.
Investigation of the scope of Pt-catalyzed 1,5-enyne cyclo-
isomerization revealed that a range of substituted and terminal
alkynes can efficiently participate in this process (Table 4),
significantly expanding a range of cyclohexadienes that can be
assembled by the cycloisomerization process. Subjection of the
benzyl ether containing 1-phenyl enyne 31 to the cycloisomer-
ization protocol afforded the expected diene 32 in 63% yield
(entry 1). Furthermore, the use of either 1-alkyl-substituted or
terminal alkynes 33 and 35 resulted in efficient skeletal
reorganizations into the reaction products 34 and 36, obtained
in 81% and 73% yield, respectively (entries 2 and 3). The results
presented in entries 4 and 5 indicated that aryl substitution at
the C(5) position of the enyne was well tolerated. Removal of
the siloxy group at the C(3) position did not have any effect on
the efficiency of the cycloisomerization. Indeed, subjection of
alkynes 41, 43, and 45 to standard catalytic protocol afforded
the corresponding cyclohexadienes 42, 44, and 46 in 72-82%
yield (entries 6, 7, and 8). Furthermore, the process enabled
rapid construction of spirocyclic dienes 48, 50, and 52 (entries
9, 10, and 11) from the corresponding cyclohexane-containing
enynes. While cycloisomerizations were successful using a range
of enynes containing disubstituted alkenes, at present, trisub-
stituted and terminal olefins did not afford the cycloisomeriza-
tion products with high efficiency.
Scheme 8
a Refers to isolated yields of spectroscopically pure products that were
full characterized by NMR, IR, and MS.
ingly low yield accompanied by several other products (entry
1). The use of AuCl3, as well as a range of other gold-based
and silver-based compounds, proved inefficient at catalyzing
the reaction (entries 2-5). These results could be explained by
a highly reactive nature of electrophilic gold carbene L (M )
9
J. AM. CHEM. SOC. VOL. 128, NO. 30, 2006 9709

A R T I C L E S
Scheme 9
Sun et al.
substitution of a complex cyclohexadiene product by the
construction of the corresponding acyclic 1,5-enyne precursor.
To probe the utility of the cycloisomerization process for the
assembly of fused bicyclic systems incorporating multiple
stereogenic centers, enoate 57 was subjected to conjugate
addition and alkylation, which delivered ester 58 as a single
detectable diastereomer (Scheme 9). Conversion of ester 58 to
enyne 59 was based on a four-step sequence entailing a DIBAL
reduction, Swern oxidation, alkyne formation, and Sonogashira
cross-coupling. Subjection of 1,5-enyne 59 to the standard
cyclosiomerization conditions (5 mol % of PtCl2, toluene-
acetonitrile, 80 °C) afforded [4.3.0] bicyclononadiene 60 in 80%
yield. It is noteworthy that the compatibility of a range of
hydroxyl and carbonyl protecting groups with the PtCl2-based
cycloisomerization protocol, as well as the ability to readily
assemble spirocyclic and fused bicyclic dienes, indicates a
significant potential of this reaction for subsequent applications
in the area of complex molecule synthesis.
Conclusion
In closing, we have described how the initial discovery and
elucidation of the reaction mechanism of the Au-catalyzed
cycloisomerization of 1-siloxy-5-en-1-ynes had resulted in the
development of the corresponding Pt-catalyzed process that
enabled significant expansion of the substrate scope. Indeed, a
wide range of 1,5-enynes containing terminal, internal, arene-
conjugated, and electron-rich alkynes participate in the cyclo-
isomerization under mild conditions and with high efficiency.
These unique catalytic transformations proceed via an unusual
mechanism involving a series of 1,2-alkyl shifts resulting in a
rapid assembly of a variety of densely functionalized cyclo-
hexadienes as well as the corresponding cyclohexenones.
To probe the effect of increased steric congestion in the tether
between the alkene and alkyne units of the cyclization substrate,
we assembled enyne 55 (Scheme 8) by treatment of lithium
enolate of ester 53 with dichloroacetylene in THF-HMPA using
the protocol developed by Kende.11 To our delight, this
transformation afforded ester 54 with good diastereoselectivity.
Reduction of chloroalkyne 54 with Cu powder and AcOH,
conversion of the resulting ester to the corresponding alcohol
with LiAlH4, installation of the TBS group, and alkylation of
the terminal alkyne with hexyl iodide afforded enyne 55.
Subjection of 55 to the general cyclization protocol afforded
the expected cyclohexadiene 56 in 78% yield as a single
diastereomer. The structure of 56 was unambiguously estab-
lished by a combination of the COSY and NOESY experiments,
validating the initial diastereochemical prediction of the outcome
of the alkylation of ester 53. This example provides another
demonstration of the synthetic potential of the enyne cyclo-
isomerization process to enable effective control of the final
Acknowledgment. This work was supported by the NSF
CAREER (CHE-0447751). S.A.K. thanks the Dreyfus Founda-
tion, the Alfred P. Sloan Foundation, Amgen, and GlaxoSmith-
Kline for additional financial support.
Supporting Information Available: Full characterization of
new compounds and experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) Kende, A. S.; Fludzinski, P.; Hill, J. H. J. Am. Chem. Soc. 1984, 106,
3551.
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