The skeletal rearrangement of gold- and platinum-catalyzed cycloisomerization of cis-4,6-dien-1-yn-3-ols: Pinacol rearrangement and formation of bicyclo[4.1.0]heptenone and reorganized styrene derivatives

Article abstract of DOI:10.1021/ja076175r

With gold and platinum catalysts, cis-4,6-dien-1-yn-3-ols undergo cycloisomerizations that enable structural reorganization of cyclized products chemoselectively. The AuCl₃-catalyzed cyclizations of 6-substituted cis-4,6-dien-1-yn-3-ols proceeded via a 6-exo-dig pathway to give allyl cations, which subsequently undergo a pinacol rearrangement to produce reorganized cyclopentenyl aldehyde products. Using chiral alcohol substrates, such cyclizations proceed with reasonable chirality transfer. In the PtCl ₂-catalyzed cyclization of 7,7-disubstituted cis-4,6-dien-1-yn-3-ols, we obtained exclusively either bicyclo-[4.1.0]heptenones or reorganized styrene products with varied substrate structures. On the basis of the chemoselectivity/structure relationship, we propose that bicyclo[4.1.0]heptenone products result from 6-endo-dig cyclization, whereas reorganized styrene products are derived from the 5-exo-dig pathway. This proposed mechanism is supported by theoretic calculations.

Full text of DOI:10.1021/ja076175r

Published on Web 11/20/2007
The Skeletal Rearrangement of Gold- and Platinum-Catalyzed
Cycloisomerization of cis-4,6-Dien-1-yn-3-ols: Pinacol
Rearrangement and Formation of Bicyclo[4.1.0]heptenone and
Reorganized Styrene Derivatives
Jhih-Meng Tang,† Sabyasachi Bhunia,† Shariar Md. Abu Sohel,† Ming-Yuan Lin,†
Hsin-Yi Liao,‡ Swarup Datta,† Arindam Das,† and Rai-Shung Liu*,†
Contribution from Department of Chemistry, National Tsing-Hua UniVersity,
Hsinchu, Taiwan, ROC, and Department of Science Education, National Taipei UniVersity
of Education, Taipei, Taiwan, ROC
Received August 16, 2007; E-mail: rsliu@mx.nthu.edu.tw
Abstract: With gold and platinum catalysts, cis-4,6-dien-1-yn-3-ols undergo cycloisomerizations that enable
structural reorganization of cyclized products chemoselectively. The AuCl3-catalyzed cyclizations of
6-substituted cis-4,6-dien-1-yn-3-ols proceeded via a 6-exo-dig pathway to give allyl cations, which
subsequently undergo a pinacol rearrangement to produce reorganized cyclopentenyl aldehyde products.
Using chiral alcohol substrates, such cyclizations proceed with reasonable chirality transfer. In the PtCl2-
catalyzed cyclization of 7,7-disubstituted cis-4,6-dien-1-yn-3-ols, we obtained exclusively either bicyclo-
[4.1.0]heptenones or reorganized styrene products with varied substrate structures. On the basis of the
chemoselectivity/structure relationship, we propose that bicyclo[4.1.0]heptenone products result from 6-endo-
dig cyclization, whereas reorganized styrene products are derived from the 5-exo-dig pathway. This proposed
mechanism is supported by theoretic calculations.
1. Introduction
manifested by their applications to short synthesis of natural
compounds.5 Catalytic cycloisomerization of enynes often occurs
with a skeletal rearrangement because a nonclassical carbocation
participates as a reaction intermediate;6,7 in such cases, the
control of chemoselectivity becomes an important issue. Al-
though the allyl cation is a synthetically useful intermediate
because of both its thermodynamic stability and high electro-
philicity,8,9 this cationic species has been seldom employed in
the cycloisomerization of enynes.10,11 We seek to explore the
cycloisomerization of enynes via allyl cations, which not only
Platinum- and gold-catalyzed cycloisomerization of acyclic
1,6- and 1,7-enynes1-4 provides one-pot synthesis of complex
carbocyclic molecules, which are not readily available from
conventional syntheses. The values of such reactions are
† National Tsing-Hua University.
‡ National Taipei University of Education.
(1) For recent reviews for gold and platinum catalysis, see: (a) Fu¨rstner, A.;
Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410. (b) Gorin, D. J.;
Toste, F. D. Nature 2007, 446, 395. (c) Jimenez-Nunez, E.; Echavarren,
A. M. Chem. Commun. 2007, 333. (d) Zhang, L.; Sun, J.; Kozmin, S. A.
AdV. Synth. Catal. 2006, 348, 2271. (e) Hashmi, A. S. H. Angew. Chem.,
Int. Ed. 2005, 44, 6990.
(4) For cycloisomerization of enynes by other metals, see selected examples:
(a) Trost, B. M.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 1993, 32, 1085.
(b) Goeke, A.; Sawamura, M.; Kuwano, R.; Ito, Y. Angew. Chem., Int.
Ed. 1996, 35, 662. (c) Wender, P. A.; Sperandio, D. J. Org. Chem. 1998,
63, 4164. (d) Chatani, N.; Kataoka, K.; Murai, S.; Furukawa, N.; Seki, Y.
J. Am. Chem. Soc. 1998, 120, 9104. (e) Trost, B. M.; Toste, F. D. J. Am.
Chem. Soc. 2000, 122, 714. (f) Se´meril, D.; Cle´ran, M.; Bruneau. C.;
Dixneuf, P. H. AdV. Synth. Catal. 2001, 343, 184. (g) Chatani, N.; Inoue,
H.; Kotsuma, T.; Murai, S. J. Am. Chem. Soc. 2002, 124, 10294.
(5) For applications to the syntheses of natural products, see: (a) Fu¨rstner,
A.; Szillat, H.; Gabor, B.; Mynott, R. J. Am. Chem. Soc. 1998, 120, 8305.
(b) Trost, B. M.; Doherty, G. A. J. Am. Chem. Soc. 2000, 122, 3801. (c)
Mamane, V.; Gress, T.; Krause. H.; Fu¨rstner. A. J. Am. Chem. Soc. 2004,
126, 8654. (d) Harrak, Y.; Blaszykowski, C.; Bernard, M.; Cariou, K.;
Mainetti, E.; Mourie`s, V.; Dhimane, A.-L.; Fensterbank, L.; Malacria. M.
J. Am. Chem. Soc. 2004, 126, 8656. (e) Fu¨rstner, A.; Kennedy, J. W. J.
Chem. Eur. J. 2006, 12, 7398.
(6) (a) Ma, S.-M.; Yu, S.; Gu, Z. Angew. Chem., Int. Ed. 2006, 45, 200. (b)
Bruneau, C. Angew. Chem., Int. Ed. 2005, 44, 2328. (c) Aubert, C.; Buisine,
O.; Malacria, M. Chem. ReV. 2002, 102, 813. (d) Mendez, M.; Mamane,
V.; Fu¨rstner, A. Chemtracts: Org. Chem. 2003, 16, 397. (e) Diver, S. T.;
Giessert, A. J. Chem. ReV. 2004, 104, 1317.
(7) Madhushaw, R.; Lo, C.-Y.; Hwang, C.-W.; Su, M.-D.; Shen, H.-C.; Pal,
S.; Shaikh, I. R.; Liu, R.-S. J. Am. Chem. Soc. 2004, 126, 15560.
(8) (a) Olah, G. A.; Liang, G.; Mo, Y. K. J. Am. Chem. Soc. 1972, 98, 7333.
(b) Olah, G. A.; Mayr, H. J. Am. Chem. Soc. 1976, 94, 3544.
(2) For gold-catalyzed cycloisomerizations of enynes, see selected examples:
(a) Nieto-Oberhuber, C.; Munoz, P. M.; Bunuel, E.; Nevado, C.; Cardenas,
D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 2402. (b) Luzung,
M. R.; Markham, J. P.; Toste. F. D. J. Am. Chem. Soc. 2004, 126, 10858.
(c) Horino, Y.; Luzung, M. R.; Toste, F. D. J. Am. Chem. Soc. 2006, 128,
11364. (d) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2004, 126, 11806.
(e) Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804. (f) Sun, J.; Conley, M.
P.; Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2006, 128, 9705. (g) Buzas,
A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128, 12614. (h) Kirsch, S. F.;
Binder, J. T.; Crone, B.; Duschek, A.; Haug, T. T.; Lie´bert, C.; Menz, H.
Angew. Chem., Int. Ed. 2007, 46, 2310.
(3) For PtCl2-catalyzed cycloisomerization of enynes, see selected examples:
(a) Chatani, N.; Furukawa, N.; Sakurai, H.; Murai, S. Organometallics 1996,
15, 901. (b) Trost, B. M.; Doherty, G. A. J. Am. Chem. Soc. 2000, 122,
3801. (c) Fu¨rstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000,
122, 6785. (d) Me´ndez, M.; Munoz, M. P.; Nevado, C.; Cardenas, D. J.;
Echavarren, A. M. J. Am. Chem. Soc. 2001, 123, 10511. (e) Mamane, V.;
Gress, T.; Krause. H.; Fu¨rstner. A. J. Am. Chem. Soc. 2004, 126, 8654. (f)
Harrak, Y.; Blaszykowski, C.; Bernard, M.; Cariou, K.; Mainetti, E.;
Mourie`s, V.; Dhimane, A.-L.; Fensterbank, L.; Malacria. M. J. Am. Chem.
Soc. 2004, 126, 8656. (g) Blaszykowski, C.; Harrak, Y.; Goncalves, M.-
H.; Cloarec, J.-M.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M. Org.
Lett. 2004, 6, 3771. (h) Soriano, E.; Marco-Contelles, J. J. Org. Chem.
2005, 70, 9345. (i) Harrison, T. J.; Patrick, B. O.; Dake, G. R. Org. Lett.
2007, 9, 367.
9
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J. AM. CHEM. SOC. 2007, 129, 15677-15683
15677

A R T I C L E S
Tang et al.
Table 2. Gold-Catalyzed Cyclization of cis-4,6-Dien-1-yn-3-ols
Table 1. Catalytic Transformation of Enyne 1 into Aldehyde 2
over Various Catalysts
a [substrate] ) 0.5 M, 25 °C. b Yields are reported after separation from
a silica column. c Starting alcohol 1 was completely consumed for all entries.
Scheme 1
control the chemoselectivity but also provide unprecedented
reaction routes. Here, we provide a full account11 of gold- and
platinum-catalyzed cycloisomerizations of cis-4,6-dien-1-yn-3-
ols in various modes, which effect a skeletal rearrangement of
cyclized products highly chemoselectively.
2. Results and Discussion
2.1. Cyclization of 6-Substituted cis-4,6-Dien-1-yn-3-ols.
We first examined the cycloisomerization of cis-4,6-dien-1-yn-
3-ol (1) with various acid catalysts, as this species is designed
to generate an allyl cation. Table 1 shows the results on
screening of various π-acid catalysts; the best result was
obtained with AuCl3 (3 mol %) in dry CH2Cl2 (25 °C, 10 min),
which gave structurally reorganized aldehyde 2 in 74% yield.
Here, the reaction periods refer to the complete consumption
of starting alcohol 1. Among other π-acid activators, AuPPh3-
OTf, AuPPh3SbF6, AgSbF6, PtCl2/CO, PtCl2, and AuCl showed
moderate activity to produce desired aldehyde 2 in 38-59%
yields, whereas AgOTf, AuClPPh3, and TfOH are virtually
inactive toward cyclization in CH2Cl2 at 25 °C. The structural
24a were produced efficiently using AuCl3 catalyst (3-10 mol
%) in dry CH2Cl2 at 25 °C. Entries 1-4 show the suitability of
this cyclization for dienynols 3-6 bearing a terminal alkyne,
which gave desired aldehydes 14a-17a in 67-98% yields. The
value of this cyclization is further shown by its applicability to
internal alkyne substrates 7-13 containing methyl, n-propyl,
n-butyl, phenyl, and trimethylsilyl substituents; the desired
aldehydes 18a-24a were produced efficiently with this
gold catalyst, whereas byproducts 19b, 20b, 21c, and 24c were
obtained in small proportions (<11%). Only one stereoisomer
was obtained for cyclized products 18a-24a, of which the
alkenyl R2 substituents lie away from the aldehyde according
to X-ray data of compound 24a.12 Cyclopentadienyl alkynes
19b and 20b resulted from an acid-catalyzed Nazarov cycliza-
tion,13 whereas cyclohexadienyl aldehydes 21c and 24c
appear to arise from 7-endo-dig cyclization/pinacol rearrange-
ment.14,15
1
assignment of aldehyde 2 relies on its H NOE effect;12 this
proposed structure is confirmed by an X-ray diffraction study12
of its related aldehyde 24a (see Table 2).
To examine the generality of this cycloisomerization, we
prepared various cis-4,6-dien-1-yn-3-ols, 3-13; the results are
depicted in Table 2. In all cases, the resulting aldehydes 14a-
(9) (a) Trost, B. M.; Verhoeven, T. R. In ComprehensiVe Organometallic
Chemistry; Wilkinson, G., Ed.; Pergamon Press: Oxford, 1982; Vol. 8,
Chapter 57. (b) Godleski, S. A. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon Press: Oxford
1991; Vol. 4, Chapter 3.3.
As shown in Scheme 1, this AuCl3 catalysis is extendible to
acyclic dienynols 25 and 26 which provided aldehydes 27 and
(10) For use of allylic cations for metal-catalyzed cycloisomerization of enynes,
see: (a) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,
5802. (b) Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442. (c)
Wang, S.; Zhang, L. J. Am. Chem. Soc. 2006, 128, 14274. (d) Faza, O. N.;
Lopez, C. S.; Alvarez, R.; de Lera, A. R. J. Am. Chem. Soc. 2006, 128,
2434.
(13) Selected examples: (a) Nazarov, I. N.; Torgov, I. B.; Terekhova, L. N.
IzV. Akad. Nauk SSSR Otd. Khim. Nauk 1942, 200. (b) Janka, M.; He, W.;
Haedicke, I. E.; Fronczek, F. R.; Frontier, A. J.; Eisenberg, R. J. Am. Chem.
Soc. 2006, 128, 5312. (c) Malona, J. A.; Colbourne, J. M.; Frontier, A. J.
Org. Lett. 2006, 8, 5661. (d) Lee, J. H.; Toste, F. D. Angew. Chem., Int.
Ed. 2007, 46, 912 and ref 10b.
(14) The asymmetric syntheses in pinacol rearrangements deal exclusively with
diastereomeric courses rather than the enantiospecificity in this study; see
selected examples: (a) Overman, L. E.; Pennington, L. D. J. Org. Chem.
2003, 68, 7143 (review). (b) Trost, B. M.; Brandi, A. J. Am. Chem. Soc.
(11) Preliminary results of this work on the formations of reorganized styrene
products, see: Lin, M.-Y.; Das, A.; Liu, R.-S. J. Am. Chem. Soc. 2006,
128, 9340.
(12) The 1H NOE spectroscopy of key compounds and the X-ray crystallographic
data of compound 26a are provided in Supporting Information.
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Skeletal Rearrangement of Cyclized Products
A R T I C L E S
has a large allyl strain18 between the equatorial methoxymethyl
ether and the bulky AuCl3 fragment. The stereochemistry of
Scheme 2
-
this 1,2-alkyl migration (pinacol rearrangement) is proposed to
proceed via addition of a new carbon-carbon bond to the si-
face of the carbocation center of species B′′ to retain the chirality
of the molecule.14 Here, additional water is required to
decompose the methoxymethyloxonium fragment in species C.
An alternative mechanism (path b) involves formation of a
cyclopropane ring via a through-space bond formation as shown
by species D,15 which ultimately produces aldehyde (-)-20a
with the same configuration and the observed alkene geometry.
We have calculated the relative energies of the two conform-
ers B′ and B′′ using the B3LYP/LAN2DZ method.19 As we
expected, state B′′ has 5.97 kcal/mol lower energy than state
B′ because of a large 1,3-allyl strain in the latter.
2.2. Cyclization of 7,7-Disubstituted cis-4,6-Dien-1-yn-3-
ols. To generate tertiary cations, we prepared three cis-4,6-dien-
1-yn-3-ols 33-35, used for either 5-exo-dig or 6-endo-dig enyne
cyclization, as depicted in eq 1
28 in 71% and 76% yields, respectively, but the analogous
reaction is inapplicable to dienynol 29 bearing a cyclopentane,
which underwent aromatization in dry CH2Cl2 to give phenol
product 30 (20%) through a separate pathway16 (Scheme 2).
We performed 13C-labeling experiments to elucidate the
mechanism of this structural reorganization. Gold catalysis of
alcohol 13C-1 bearing 10% 13C-content at the CH(OH) carbon
gave aldehyde 13C-2 with the 13C-content located at its aldehyde
carbon. We prepared also chiral (R)-alcohols 9-mom (77% ee)
and 31 (87% ee)17 bearing a methoxymethyl ether group; their
cyclized aldehydes (-)-20a (73% ee) and (-)-32 (68% ee) were
obtained with only a small loss of enantiomeric purity. These
observations indicate an atypical chirality transfer for this gold
catalysis, which is astonishing because the adjacent chiral
alcohol is normally ineffective to transfer the chirality in the
related pinacol rearrangement.14,15
. For such substrates, we observed substrate-dependent
chemoselectivity and obtained skeletally rearranged cyclized
products 36a,b, 37, and 38, as shown in Table 3. Treatment of
alcohol 33 with PtCl2 (5 mol %) in hot toluene (90 °C, 1 h)
produced bicyclo[4.1.0]heptenone 36a and cycloheptadienone
36b in 3% and 83% yields, respectively. The presence of CO
Scheme 3 shows a plausible mechanism to rationalize the
gold-catalyzed skeletal rearrangement of species (-)-9-mom;
this cycloisomerization involves atypical chirality transfer in
pinacol-type rearrangement.14-15 We envisage that the cycliza-
tion is initiated on the 6-exo-dig cyclization of Au-π-alkyne
species A to form a stable allyl cation B. To rationalize the
observed chirality transfer, we propose an equilibrium between
conformational isomers B′ and B′′ of the allyl cation B, which
generate an enantiomeric pair of product 20a, as depicted in
path a. The occurrence of chirality transfer arises from the
disparate rates of the 1,2-alkyl migration of the two conformers.
Species B′′ is obviously more stable than B′ because the latter
20
(1 atm) increased the electrophilicity of PtCl2 such that the
cyclization proceeded under mild conditions, giving bicyclic
ketone 36a with yield up to 79% (entry 2). Transformation of
species 36a into cycloheptadienone 36b is presumably catalyzed
by acid with a mechanism proposed in eq 2. AuCl and AuCl3
gave a messy mixture of products in CH2Cl2 (20 °C, 10-30
min), from which bicyclic ketone 36a was obtained in small
yields (<24%). Notably, AuPPh3SbF6 led to rapid decomposi-
tion of initial substrate 33 despite its high electrophilicity (entry
5). The cycloisomerization of alcohol substrate 34 bearing a
cyclohexyl group proceeded efficiently using several π-acids
including PtCl2, PtCl2/CO, AuCl, AuCl3, and Zn(OTf)2, giving
styrene derivative 37 with yields exceeding 71% (entries 6-10).
1984, 106, 5041. (c) Hanaki, N.; Link, J. T.; MacMillan, D. W. C.;
Overman, L. E.; Trankle, W. G.; Wurster, J. A. Org. Lett. 2000, 2, 223.
(d) Youn, J.-H.; Lee, J.; Cha, J. K. Org. Lett. 2001, 3, 2935. (e) Nicolaou,
K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45,
7134.
1
(15) For metal-catalyzed cycloisomerization of enynes involving pinacol rear-
rangement, see: (a) Kirsch, S. F.; Binder, J. T.; Crone, B.; Duschek, A.;
Haug, T. T.; Lie´bert, C.; Menz, H. Angew. Chem., Int. Ed. 2007, 46, 2310.
(b) Huang, X.; Zhang, L. J. Am. Chem. Soc. 2007, 129, 6398.
(16) The following scheme depicts the mechanism for aromatization of alcohol
substrate 29 to compound 30; here, we did not obtain aldehyde product
via pinacol rearrangement because of its highly strained [3.3.0]-octene
framework.
Its H NMR spectroscopy revealed an isopropylidene shift. In
such reactions, MS 4 Å was present for AuCl, AuCl3, and Zn-
(18) (a) Hoffman, R. W. Chem. ReV. 1989, 1841. (b) Broeker, J. L.; Hoffman,
R. W.; Houk, K. N. J. Am. Chem. Soc. 1991, 113, 5006. (c) Allinger, N.
L.; Hirsh, J. A.; Miller, M. A.; Tyminski, I. J. J. Am. Chem. Soc. 1968, 90,
5773.
(19) The procedure for theoretic calculation is provided in Supporting Informa-
tion.
(20) For PtCl2/CO catalytic system, see: (a) Fu¨rstner, A.; Davies, P. W.; Gress,
T. J. Am. Chem. Soc. 2005, 127, 8244. (b) Fu¨rstner, A.; Davies, P. W. J.
Am. Chem. Soc. 2005, 127, 15024. (c) Fu¨rstner, A.; A¨ıssa, C. J. Am. Chem.
Soc. 2006, 128, 6306. (d) Chang, H.-K.; Datta, S.; Das, A.; Odedra, A.;
Liu, R.-S. Angew. Chem., Int. Ed. 2007, 46, 4744. (e) Taduri, B. P.; Ran,
Y.-F.; Huang, C.-W.; Liu, R.-S. Org. Lett. 2006, 8, 883.
(17) The synthesis of chiral species including (-)-9-mom and (-)-31 are
provided in Supporting Information.
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A R T I C L E S
Scheme 3
Tang et al.
Table 3. Cyclization Chemoselectivities Using Various π-Acid
Catalysts
Table 4. PtCl2-Catalyzed Synthesis of Bicyclo[4.1.0]heptenones
via Cyclization of Alcohols Bearing a Bridging Cyclopentane Ring
a [substrate] ) 0.8 M, 50 °C, 5 mol % PtCl2, 1 atm CO, toluene, 0.5 h.
a 5 mol % for PtCl2, AuCl, AuCl3, AuClPPh3/AgSbF6 and 10 mol % for
Zn(OTf)2, [substrate] ) 0.80-1.0 M. b MS 4Å was present for entries 8-10.
c There are many byproducts in small quantities for entries 3-4 and 8-10.
d Yields of products are given after separation from silica column.
b Yields were reported after separation from a silica column.
substrates 33-35 affect the cyclization chemoselectivity. We
prepared dienynol substrates 39-46 bearing a five-membered
ring to assess the generality of bicyclo[4.1.0]heptenone synthesis
using 5% PtCl2/CO. For alcohol 39 bearing a cyclopentyl ring,
the corresponding PtCl2 catalysis gave desired ketones 47 in
80% yield. The stereoselectivity of this cyclization is shown
by dienynol 40 bearing a cis-phenyl group, which selectively
afforded bicyclic ketone 48;22 its structure was established with
1H NOE spectroscopy.12 In contrast, its trans-phenyl analogue
41 led to polymerization under similar conditions. In the
presence of MgO additive,23 this bicyclic ketone synthesis is
(OTf)2 to ensure complete dehydration of the primary alcohol
product (I). In the absence of MS 4 Å, we obtained alcohol
product 37-I in good yields (75-78%),11 in addition to
reorganized styrene 37 using AuCl or AuCl3 catalysts; the
structure of alcohol product 37-I was characterized by 1H NOE
spectroscopy.11 A similar platinum catalysis on oxacyclic
substrate 35 gave a 78% yield of aromatized product 38, of
which the 1H NOE spectroscopy verifies a novel 1,3-isopropy-
lidene shift in this transformation.21
2.2.1. Formation of Bicyclo[4.1.0]heptenones. The prelimi-
nary results in Table 3 indicate that the ring sizes of alcohol
(22) For stereoselective formation of cyclopropane products in metal-catalyzed
cycloisomerization of enynes, see refs 2b, 3f,e, 4d, and (a) Bruneau, C.
Angew. Chem., Int. Ed. 2005, 44, 2328. (b) Johansson, M. J.; Gorin, D. J.;
Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002. (c) Fu¨rstner,
A.; Hannen, P. Chem. Commun. 2004, 2546.
(21) Prior to our studies, a 1,3-alkylidene shift in the cycloisomerization of
enynes is only reported for metathesis-type reactions,1a,d whereas a 1,2-
alkylidene shift is only reported for one instance.7
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Skeletal Rearrangement of Cyclized Products
A R T I C L E S
Table 5. PtCl2-Catalyzed Synthesis of Stryrene Products via
Scheme 4
Cyclization of Alcohols Bearing a Bridging Cyclohexyl Ring
Scheme 5
Scheme 6
a [substrate] ) 0.8 M, 80 °C, 5 mol % PtCl2, 1 atm CO, toluene, 1 h.
b Yields are given after separation from a silica column. c MgO was added.
Table 6. Effects of the Alkyne on the PtCl2-Catalyzed Cyclization
of Alcohols Bearing a Bridging Benzene Ring
extendible to dienynol analogues 42 and 43 bearing an internal
alkyne (R3 ) Me, Ph); the yields of resulting ketones 49 and
50 were 78% and 85%, respectively. The benzothienyl species
44-46 are also suitable for this bicyclo[4.1.0]heptenone syn-
thesis; the resulting ketones 51-53 were obtained in 77-89%
yields. The five-membered rings of alcohols 39-40 and 42-
46 apparently direct the cycloisomerization toward bicyclic
ketone formation regardless of the types of tethered alkynes.
The cyclopentyl and benzothienyl groups of alcohols 33, 39-
40, and 42-46 gave exclusively bicyclo[4.1.0]heptenones
products 36a, 47-48, and 49-53 (Tables 3 and 4), regardless
of the internal or terminal alkynes. The stereoselectivity in the
production of bicyclo[4.1.0]heptenone 48 from alcohol 40
indicates that platinum-π-alkyne species E bears carbenoid
character,22 as represented by species E′ (Scheme 4). This
carbenoid captures its tethered olefin to form bicyclo[4.1.0]-
heptenyl carbene F, which ultimately forms a bicyclo[4.1.0]-
heptenone core via a 1,2-hydrogen shift. Although 5-exo-dig
cyclization occurs more frequently than the 6-endo-dig route
a [substrate] ) 0.6 M, 60 °C, 5 mol % PtCl2, 1 atm CO, toluene, 1 h.
b Product yields are given after separation from a silica column.
(23) In the absence of MgO, the internal alkynes 42 underwent dehydration
reaction to give the following byproduct:
in the cycloisomerization of 1,6-enynes containing a terminal
alkyne,24 the former is not suitable to alcohol substrate
E containing a cyclopentyl group because the resulting car-
bene intermediate F′ bears a strained [3.3.0]-octenol frame-
work.
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J. AM. CHEM. SOC. VOL. 129, NO. 50, 2007 15681

A R T I C L E S
Scheme 7
Tang et al.
2.2.2. Formation of Reorganized Styrene Derivatives. In
the cycloisomerization of alcohols 34-35 to styrene deriva-
tives 37-38, as depicted in Table 3, this rearrangement pro-
ceeds via an atypical 1,3-isopropylidene migration. To assess
the generality, we prepared various alcohol substrates
54-60 bearing either a cyclohexane or an acyclic framework;
PtCl2/CO (5%) was used as the catalyst (Table 5). Treatment
of alcohols 54-55 gave styrene products 61-62 in 86-87%
yields (entries 1-2); 1H NOE spectra of cyclized products 63-
64 (entries 3-4) confirm a 1,3-alkylidene migration. Acyclic
alcohols 58 and 59 conformed to the same chemoselec-
tivity to give styrene products 65-66 in good yields (78-82%).
For alcohol 60 bearing an internal alkyne, this PtCl2 catalysis
led to undesired Nazarov cyclization to give cyclopent-
enyl derivative 67 in 86% yield, even in the presence of
MgO additive. This information indicates that formation of
species 67 was actually initiated by PtCl2 rather than Brønsted
acid.
As the Nazarov cyclization observed for alcohol 60 failed to
clarify the preferred chemoselectivity of internal alkynes in the
cyclohexyl system, we examined the cycloisomerization of
substrates 68-76, of which the benzene group is expected to
inhibit Nazarov cyclization. The results in Table 6 clearly show
the pronounced influence of the alkynyl substituent on the
cyclization chemoselectivities; substrates 68, 72, and 74 bearing
a terminal alkyne afforded styrene products 77, 82, and 84,
whereas their internal alkyne analogues 69-71, 73, and 75-
76 gave bicyclo[4.1.0]heptenone products 78, 80-81, 83, and
85-86 efficiently. We used the 1H NOE effect to elucidate the
structure of compound 78. The reaction patterns here are distinct
from those observed for alcohols 39-46 bearing a five-
membered cyclopentane or benzothienyl ring, which provided
only bicyclo[4.1.0]heptenones for both terminal and internal
alkynes (see Table 4).
which undergoes an atypical 1,2-cyclopropyl migration to
generate species G, and ultimately produces reorganized styrene
product 37. However, our calculations (B3LYP/LAN2DZ)
reveal that the two alcohols 33 (n ) 1) and 34 have activation
energies (11.9-12.3 kcal/mol) in the 1,2-hydrogen shifts
(species Ff H) much lower than a 1,2-cyclopropyl shift (F f
G).26 This information suggests that 6-endo-dig cyclization is
inapplicable to alcohol 34, and thus we revise the mechanistic
interpretation.
The cyclizations of alcohols 34 and 68 bearing both a six-
membered ring and a terminal alkyne are expected to proceed
via the common 5-exo-dig cyclization,24 as depicted in Scheme
7. The carbenoid character of the π-alkyne I is represented by
species I′, which initiates 5-exo-dig cyclization to form species
J. This species is commonly proposed to undergo a 1,2-alkyl
shift to form species K in the enyne metathesis-type reactions,
but we obtained reorganized styrenes 37 and 77 rather than the
metathesis product N.27 Hence, we seek the mechanistic solution
through calculation, and gratifyingly we find a new low-barrier
rearrangement for species J (path b), to generate allyl or benzyl
cation L, which ultimately provides the desired styrenes 37 and
77 through intermediate M.
We performed a theoretical calculation to estimate activation
energies for path a and its competitive path b to compare their
relative feasibility; the results are depicted in Scheme 8.
According to the B3LYP/LANL2DZ calculation, path a has an
activation energy of +16.49 kcal/mol, which is very close to
that of +16.90 kcal/mol for path b. In addition, the proposed
path b in Scheme 7 is supported by the transition-state structure
(TS-L) connecting the intermediates J and L at the B3LYP/
LANL2DZ level of theory. Notably, intermediate L given from
path b is much more stable than species K (from path a) by a
large margin (-36.97 kcal/mol) in energy; the metathesis route
(path a) is thus unlikely to occur according to this energy profile.
We prepared 13C-enriched samples C(3)-34 and C(6)-34
with 10% 13C content at the C(3)- and C(6)-carbons, respec-
tively, of alcohol 34. As depicted in Scheme 5, treatment
of C(3)-34 with PtCl2 produced styrene C(1)-37 with 13C content
at the C(1)-carbon according to 13C-1H HMQC and HMBC
spectra,25 whereas alcohol C(6)-34 gave product C(4)-37
with the 13C content at the C(4)-carbon. These labeling results
reconfirm the occurrence of a 1,3-isopropylidene shift for
alcohol 34.
Acylic alcohols 58-59 and the six-membered-rings contain-
ing alcohols 34-35, 54-57, 62, 68, and 74, bearing a terminal
alkyne, gave only reorganized styrene products 37-38, 61-
66, 77, 82, and 84 (Tables 3 and 5-6). In our original
mechanism11 as depicted in Scheme 6, we proposed a 6-endo-
dig cyclization for alcohol 34 (n ) 2) to form intermediate F,
In Table 6, the alkynyl effects of alcohols 68-76 on their
cyclization chemoselectivities are unclear at present. In gold
catalysis,28 there are reported similar observations that internal
alkynes prefer 6-endo-dig cyclization, whereas terminal alkyne
analogues lead to 5-exo-dig routes. We propose tentatively that
(24) For the 5-exo-dig cyclizations of 1,6-enynes, see refs 2a, 3d, 4d, and selected
examples: (a) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem.
Soc. 2000, 122, 11553. (b) Nevado, C.; Ca´rdenas, J.; Echavarren, A. M.
Chem. Eur. J. 2003, 9, 2627. (c) Amijs, C. H. M.; Ferrer, C.; Echavarren,
A. M. Chem. Commun. 2007, 698. (d) Charruault, L.; Michelet, V.; Taras,
R.; Gladiali, S.; Genet, J.-P. Chem. Commun. 2004, 850.
(25) The 1H-13C-correlated HMQC and HMBC spectra of compound 37 were
provided in the communication, see ref 11.
(26) See Scheme S1 in Supporting Information for the results of calculations.
(27) See refs 2a, 3c,g, 7, 20a, and selected examples: (a) Fu¨rstner, A.; Szillat,
H.; Gabor, B.; Mynott, R. J. Am. Chem. Soc. 1998, 120, 8305. (b) Fu¨rstner,
A.; Stelzer, F.; Szillat, H. J. Am. Chem. Soc. 2001, 123, 11863.
(28) Shapiro, N.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 4160.
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15682 J. AM. CHEM. SOC. VOL. 129, NO. 50, 2007

Skeletal Rearrangement of Cyclized Products
A R T I C L E S
Scheme 8
case of terminal alkynes, 5-exo-dig route is more likely to occur
than 6-endo-dig for formation of a monocyclic product.
3. Conclusions
Gold and platinum catalysts implement catalytic cycloisomer-
izations of cis-4,6-dien-1-yn-3-ols in various modes and enable
structural reorganization of cyclized products chemoselectively.
For 6-substituted cis-4,6-dien-1-yn-3-ols, the AuCl3-catalyzed
cyclizations were initiated with a 6-exo-dig pathway to give
allyl cations, which subsequently underwent a pinacol rear-
rangement to give a cyclopentenyl aldehyde core. We observed
reasonable chirality using chiral alcohol substrates. For 7,7-
disubstituted cis-4,6-dien-1-yn-3-ols, their PtCl2-catalyzed cy-
clizations gave either bicyclo[4.1.0]heptenones or reorganized
styrene products, depending on the types of substrate. On the
basis of the chemoselectivity/structure relationship, we conclude
that bicyclo[4.1.0]heptenone products result from 6-endo-dig
cyclization of alcohols bearing a five-membered ring, whereas
reorganized styrene products are derived from 5-exo-dig cy-
clization of alcohols bearing both a six-membered ring and a
terminal alkyne.
Scheme 9
Acknowledgment. We thank the National Science Council,
Taiwan for supporting this work.
Supporting Information Available: Experimental procedures
for synthesis of cis-4,6-dien-1-yn-3-ol substrates and catalytic
operations, NMR spectra, spectral data of new compounds, and
X-ray structural data of compound 24a. This material is available
free of charge via the Internet at http://pubs.acs.org.
such chemoselectivity is attributed to alternating the charge
polarization of Pt-π-alkyne moiety, as depicted in Scheme 9.
In both cases, the vinyl cations are generated preferably on the
alkynyl carbon bearing a more electron-donating group. In the
JA076175R
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J. AM. CHEM. SOC. VOL. 129, NO. 50, 2007 15683