Gold(I)-catalyzed synthesis of functionalized cyclopentadienes

Article abstract of DOI:10.1002/anie.200604006

(Chemical Equation Presented) ... or a touch of gold: Electrocyclization of the pentadienyl cation produced on coordination of cationic phosphinegold(I) to vinyl allenes results in the regioselective formation of highly functionalized cyclopentadienes. Th

Full text of DOI:10.1002/anie.200604006

Communications
DOI: 10.1002/anie.200604006
Cyclopentadiene Synthesis
Gold(I)-Catalyzed Synthesis of Functionalized Cyclopentadienes**
Jun Hee Lee and F. Dean Toste*
Table 1: Catalyst optimization.
The rearrangement of vinyl allene oxides (1, X = O) is a key
transformation in the metabolic pathway that converts
arachidonic acids into cyclopentenones (3, X = O)
[Eq (1)].[1] These rearrangements can proceed by two distinct
Entry
Catalyst
T [8C]
t [min]
Yield [%][a]
1
2
3
4
5
6
2% P 3PAuCl/h2% AgSbF6
2% P 3PAuCl/h2% AgSbF6
1% P 3PAuCl/h1% AgSbF6
5% P 3PAuCl h
5% AgSbF6
5% AuCl3
0
À20
0
23
0
1
5
1
180
5
5
97
93
96
0[b]
0[c]
30[d]
0
[a] Yield of isolated product after column chromatography. [b] Starting
material was recovered. [c] Decomposition occurred. [d] Determined by
1H NMR spectroscopy against an internal standard (1,2,3-trimethoxy-
benzene).
mechanistic pathways:[2] a concerted rearrangement (path a)
involving direct addition of the olefin on the epoxide or a
stepwise mechanism (path b) through a Nazarov cyclization
of an oxypentadienyl cation (2, X = OÀ).[3] The regioselectiv-
ity of the cyclization is dictated by donation of the oxyanion
into the resulting cation leading to the formation of a ketone.
Recently, stabilization of developing positive charge through
back-bonding from phosphinegold(I) complexes has been
implicated in a number of rearrangement reactions.[4] There-
fore, we hypothesized that coordination of cationic phos-
phinegold(I) complexes to a vinyl allene might mimic these
reaction pathways through similar back-bonding, leading to
metal–carbenoid intermediate 3 (X = R3PAu+).[5] These inter-
mediates would further rearrange into substituted cyclo-
pentadienes, important building blocks in organic and organ-
ometallic chemistry.[6,7]
In light of our recent success in using [Ph3PAuCl] with
AgSbF6 in dichloromethane for carbon–carbon bond-forming
reactions,[4c] we chose this system for preliminary studies of
the proposed cycloisomerization (Table 1). Treatment of vinyl
allene 4 with 2 mol% cationic triphenylphosphinegold(I)
afforded the desired cyclopentadiene 5 as a single regioisomer
in 97% yield after 1min at 0 8C (Table 1, entry 1). Similar
results were obtained when a lower temperature or lower
catalyst loading were used (Table 1, entries 2 and 3). Control
experiments employing either 5 mol% [Ph3PAuCl] or
5 mol% AgSbF6 as the sole catalyst did not lead to any
conversion of 4 into 5 (Table 1, entries 4 and 5). Other
transition-metal complexes showed no catalytic activity;
however, gold(III) chloride rapidly consumed 4 to afford a
small amount of 5 (Table 1, entry 6).[8]
With optimal conditions in hand, the scope of the gold(I)-
catalyzed cycloisomerization of vinyl allenes was examined.[9]
We were pleased to find that the reaction allowed for the
regiospecific synthesis of functionalized cyclopentadienes in
high yields with a variety of substitution patterns (Table 2).
Substitution at the allene terminus was well tolerated,
encompassing linear alkyl (Table 2, entries 8 and 9), oxy-
genated (entries 3–7), secondary benzyl (entry 1), and phenyl
substituents (entry 2). Notably, the gold(I)-catalyzed reaction
can be easily carried out on a gram scale albeit with a slightly
diminished yield (Table 2, entry 1). Furthermore, the stability
of acid-labile protecting groups, such as tetrahydropyranyl
(Table 2, entry 9) and silyl ethers (entries 3, 4, 6, and 7),
isopropylidene acetal (entry 5), and an N-Boc amine
(entry 6), is a testament to the mildness of the reaction
conditions. Bicyclic cyclopentadienes are readily produced
from the cycloisomerization of vinyl allenes containing cyclic
alkenes (Table 2, entries 1–6). Additionally, the gold(I)-
catalyzed reaction can be employed for the synthesis of
cyclopentadienes with a quaternary carbon center (Table 2,
entries 2 and 3). The use of a more electron-rich gold(I)
complex, [tBu3PAuCl], as a catalyst gave improved yields for
some vinyl allenes (Table 2, entries 5, 6, 8, and 9). For
example, switching the gold catalyst from [Ph3PAuCl] to
[tBu3PAuCl] resulted in an improved yield for the formation
of cyclopentadiene 21 (Table 2, entry 8).
[*] Dr. J. H. Lee, Prof. Dr. F. D. Toste
Department of Chemistry
University of California
Berkeley, CA 94720 (USA)
Fax: (+1)510-643-9480
E-mail: fdtoste@uclink.berkeley.edu
[**] We gratefully acknowledge the University of California, Berkeley,
NIHGMS (R01 GM073932-01), Merck Research Laboratories,
Bristol-Myers Squibb, Amgen Inc., DuPont, GlaxoSmithKline, Eli
Lilly & Co., Pfizer, AstraZeneca, and Roche for financial support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
912
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Table 2: Gold(I)-catalyzed cyclopentadiene synthesis.[a]
through loss of either of two in-
equivalent protons (Ha or Hb) in
allyl cation 25, only a single regio-
isomer of the cyclopentadiene is
formed. The formation of a sole
cyclopentadiene product is consis-
tent with gold(I)–carbenoid inter-
mediate 26 undergoing an intramo-
Entry
Vinyl allene
Cyclopentadiene
Yield [%][b]
98 (88)[d]
1
6[c]
7[c]
2
3
4
8
9
92
63
86
lecular
rather than a mechanism involving
deprotonation/protonation of
1,2-hydrogen
shift,[4b,c]
10
11
a
vinyl gold intermediate. This path-
way is further supported by the
observation of complete deuterium
incorporation into [D]-5 and the
lack of crossover in a deuterium-
labeling experiment using vinyl
allenes [D]-4 and 12 [Eq. (3)].
We envisioned that the 1,2-
hydrogen shift in cationic inter-
mediate 26 could be replaced by
alternative reactions. To this end,
we were pleased to find that fully
substituted tricyclic cyclopenta-
diene 28 was generated in excellent
yield by reacting bicyclic vinyl
allene 27 with 2 mol% cationic
triphenylphosphinegold(I) at 08C
for 5 min [Eq. (4)]. Additionally,
we were intrigued by the possibility
12
13
5
6
7
14[c]
16
15[c]
17
78[e]
53[e]
72
18
19
8
9
20: R=Bn
22: R=THP
21
23
39 (78)[e]
87[d]
[a] Reaction conditions: [Ph3PAuCl] (1.0 or 2.0 mol%), AgSbF6 (1.0 or 2.0 mol%), vinyl allene in CH2Cl2
(0.05m), 08C, 5 min. [b] Yield of isolated product after column chromatography. [c] 1:1 mixture of
diastereomers. [d] 5.3-mmol scale. [e] [tBu3PAuCl] (2.0 mol%) was employed. TBS=tert-butyldimethyl-
silyl, TBDPS=tert-butyldiphenylsilyl, Boc=tert-butyloxycarbonyl, Bn=benzyl, THP=tetrahydropyranyl.
In analogy to the rearrangement of allenoxides, the two
mechanistic possibilities shown in Equation (1) were consid-
ered. To distinguish between these potential mechanisms,
gold(I)-catalyzed cycloisomerization of enantioenriched vinyl
allene 10 was examined [Eq. (2)].[10] Treatment of vinyl allene
Scheme 1. Proposed mechanism for gold(I)-catalyzed cyclopentadiene
synthesis.
(S)-10 with 2 mol% [Ph3PAuCl] and 2 mol% AgSbF6 in
dichloromethane at À208C for 20 h furnished cyclopenta-
diene 11 in 55% yield and with 0% enantiomeric excess. In
light of recent examples of excellent chirality transfer in gold-
catalyzed additions of nucleophiles to enantioenriched
allenes,[11] the poor chirality transfer observed in the cyclo-
pentadiene synthesis suggests that the reaction does not
proceed through a pathway that involves direct addition of
the olefin on a coordinated allene.[12]
On the basis of this result, a plausible mechanism for this
transformation is proposed in Scheme 1. Coordination of a
cationic phosphinegold(I) to the allene results in the forma-
tion of an achiral pentadienyl cation, 24, that undergoes
electrocyclization to give the cationic intermediate 25.[13]
While regioisomeric cyclopentadienes could be formed
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Communications
g) M. J. Johansson, D. J. Gorin, S. T. Staben, F. D. Toste, J. Am.
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of trapping the cationic intermediate through intramolecular
addition of a pendant nucleophile. To examine this possibility,
vinyl allenes 29 and 30 bearing a primary alcohol were
subjected to the conditions of the gold(I)-catalyzed reaction.
While the gold(I)-catalyzed reaction of 29 bearing a hydrogen
at the allene terminus afforded cyclopentadienyl carbinol 31
as the sole product in 77% yield, the reaction of 30 bearing a
methyl group at the allene terminus led to the formation of
tetrahydrofuran derivative 32 [Eq. (5)].
[5] For mercury- and thallium-promoted rearrangements of vinyl
allenes to cyclopentenones, see: a) F. Delbecq, J. GorØ, Tetrahe-
dron Lett. 1976, 3459; b) R. Baudouy, F. Delbecq, J. GorØ,
Tetrahedron 1980, 36, 189; c) R. Baudouy, J. Saartoretti, F.
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[6] For reviews, see: a) Metallocenes (Eds.: A. Togni, R. L. Halter-
man), Wiley-VCH, New York, 1998; b) R. L. Halterman, Chem.
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[7] For examples of cyclopentadiene synthesis, see: a) S. Datta, A.
Odedra, R.-S. Liu, J. Am. Chem. Soc. 2005, 127, 11606; b) W.
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10, 3444; d) Z. Xi, Q. Song, J. Chen, H. Guan, P. Li, Angew.
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[8] No reaction was observed upon treatment of 4 with PtCl2,
[PdCl2(CH3CN)2], or CuI under the following conditions:
5 mol% catalyst, 0.05m 4 in CH2Cl2, 238C, 3 h.
[9] For thermal cycloisomerization of vinyl allenes, see: a) M.
Murakami, S. Ashida, T. Matsuda, J. Am. Chem. Soc. 2004,
126, 10838; b) D. J. Pasto, W. Kong, J. Org. Chem. 1989, 54, 4028;
For Pd-catalyzed reactions of vinyl allenes see: c) P. H. Lee, K.
Lee, Y. Kang, J. Am. Chem. Soc. 2006, 128, 1139.
In conclusion, we have developed a gold(I)-catalyzed
cycloisomerization of vinyl allenes for the synthesis of
cyclopentadienes. The mild reaction conditions of this
gold(I)-catalyzed carbon–carbon bond-forming reaction pro-
vide a regiospecific method for the synthesis of highly
functionalized cyclopentadienes, including tricyclic structures
through a tandem cycloisomerization/ring-enlargement reac-
tion sequence. Application of the gold(I)-catalyzed reaction
to the preparation of optically active metallocenes and
asymmetric catalysis is ongoing in our laboratory and will
be reported in due course.
[10] Enantioenriched vinyl allene was prepared from the correspond-
ing propargylic alcohol according to Myersꢀ procedure (see
Supporting Information): A. G. Myers, B. Zheng, J. Am. Chem.
Soc. 1996, 118, 4492.
Received: September 29, 2006
Published online: December 14, 2006
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[12] Alternatively, rapid allene racemization followed by direct
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material 10 was also recovered with complete loss of enantio-
meric excess.
Keywords: allenes · cycloisomerization · cyclopentadienes ·
electrocyclic reactions · gold
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