Gold-catalyzed cycloisomerization of cyclopropyl alkynyl acetates: A versatile approach to 5-, 6-, and 7-membered carbocycles

Article abstract of DOI:10.1002/anie.200804202

Nonclassical chirality transfer? Depending on the substitution pattern of propargyl acetates, a gold-catalyzed homologous Rautenstrauch reaction generates either 5- or 6-membered ring systems (see scheme). The stabilization of cationic intermediates is crucial for this reaction to succeed. The underlying principle for the good chirality transfer observed could be gold-stabilized nonclassical carbocations having configurational stability.

Full text of DOI:10.1002/anie.200804202

Communications
DOI: 10.1002/anie.200804202
Homogeneous Catalysis
Gold-Catalyzed Cycloisomerization of Cyclopropyl Alkynyl Acetates:
AVersatile Approach to 5-, 6-, and 7-Membered Carbocycles**
Yue Zou, David Garayalde, Quanrui Wang,* Cristina Nevado,* and Andreas Goeke*
In memory of Yoshihiko Ito
During the last decade, late-transition-metal-catalyzed cyclo-
isomerizations have emerged as a powerful tool to access
unprecedented structural and mechanistic diversity.[1] In this
context, a rapidly developing area involves the use of
propargylic esters, preferably acetates, in which the carbonyl
unit acts as a nucleophile onto the metal-activated alkyne
complex I (Scheme 1). Two distinct mechanistic scenarios
rangement to form allenyl acetate V, which can be addition-
ally activated in the presence of the metal catalyst to give VI,
triggering an extensive palette of transformations.[4,5]
Intermediates of type III were proposed by Rauten-
strauch et al. for the Pd-catalyzed cycloisomerization/in situ
hydrolysis of vinyl propargyl acetates to give 2-cyclopent-
enones.[6] Recently, Toste and co-workers expanded the scope
of this cyclopentenone synthesis by application of cationic AuI
catalysts.[7,8] To access the Rautenstrauch rearrangement
products of larger ring sizes we decided to construct a
homologous system such as 1a (Scheme 2).[9] The reaction in
the presence of catalytic amounts of AuCl3 was aimed to
Scheme 1. 1,2- versus 1,3-acetate migration.
arise from this intermediate.[2] If terminal alkynes are used,
1,2 migration of the acetate affords vinyl metal species II,
which can result in the formation of “carbenoid” III.[3] In
contrast, internal alkynes undergo a [3,3]-sigmatropic rear-
[*] Y. Zou, Prof. Dr. Q. Wang
Department of Chemistry, Fudan University
220 Handan Road, Shanghai 200433 (PR China)
E-mail: qrwang@fudan.edu.cn
Scheme 2. Au-catalyzed homo-Rautenstrauch rearrangement.
D. Garayalde, Prof. Dr. C. Nevado
Organisch-chemisches Institut, Universitꢀt Zꢁrich
Zꢁrich (Switzerland)
Fax: (+41)446-356-891
E-mail: nevado@oci.uzh.ch
probe the behavior of canonical carbenoid 2 which could
subsequently arise from the Au-promoted 1,2-acetate migra-
tion.[3] However, a look at intermediate 2 in light of the
recently discussed nonclassical carbocationic nature of carbe-
noid-like intermediates of gold-catalyzed enyne cycliza-
tions[1b,g] would be more insightful. Resonance structures
3–6 visualize the possibilities for consecutive cyclizations
more clearly. Intermediate 2 could lead to 7-membered ring
products by a Cope (divinylcyclopropane) rearrangement,
and allylcations 5 or 6 may cyclize to give 6- or 8-membered
ring systems, respectively. We were pleased to find that
compound 1a exclusively led to cyclohexadienyl acetate 7a.
Herein, we report our investigation on this novel gold-
catalyzed homo-Rautenstrauch rearrangement and hope it
Y. Zou, Dr. A. Goeke
Shanghai Givaudan Ltd, Fragrances
298 Li Shi Zhen Road, Shanghai 201203 (PR China)
Fax: (+86)21-5080-0269
E-mail: andreas.goeke@givaudan.com
[**] C.N. and D.G. thank Givaudan and the Swiss National Science
Foundation for support. We are indebted to Prof. Dr. W. Hug and P.
Oulevey for ROA measurements of compounds 8k and 19e, and to
Dr. G. Brunner for help on NMR analyses. Dr. P. Gygax, Prof. Dr. G.
Frꢂter, and Dr. S. Derrer are also acknowledged for fruitful
discussions and proof reading of the manuscript.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804202.
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Table 2: Scope of the AuI-catalyzed 2-cyclohexenone synthesis.[a]
will help to further unravel the mechanistic blur of gold
catalysis.
To provide insight into this initial result several optimi-
zation and control reactions were carried out (Table 1). The
primary product, 7a, is a sensitive dienol acetate and it was
generally converted into 2-hexenone 8a by an in situ meth-
anolysis. To investigate the cationic gold(I) complexes for
Entry Substrate
Product
t [min][b] Yield [%][c]
1
2
3
4
5
1b: R1 =R2 =Et,
8b
5
10
10
10
10
78
R3 =H
1c: R1 =H,
R2 =nPr, R3 =H
1d: R1 =CH3,
R2 =Et, R3 =H
8c
8d
62
Table 1: Catalyst optimization.
82
1e: R1 =H, R2 =Et, 8e
R3 =CH3
96
1 f: R1 =H, R2 =Ph, 8 f
R3 =CH3
88[10]
Entry
Catalyst (mol%)
t [min]
Yield [%][a]
1
2
3
4
5
6
7
AuCl3 (2)
360
2
30
5
360
5
360
75
85
80
0[b]
0[c]
0[b]
0[b]
[Au(PPh3)]SbF6 (1)
[Au(PPh3)]SbF6 (0.1)
[Au(PPh3)]OTf (5)
[Au(PPh3)]Cl (5)
AgSbF6 (5)
6
7
10
10
56
71
[PdCl2(MeCN)2] (5)
[a] Yield of isolated product 8a after column chromatography.
[b] Decomposition occurred. [c] Starting material was recovered.
8
9
360
60
90
alkyne activation, compound 1a was treated with a variety of
catalysts (Table 1). Using 1 mol% of the pregenerated
cationic complex [Au(PPh3)]SbF6 in CH2Cl2 produced acetate
7a within 2 minutes, and the product was isolated in an 85%
yield after hydrolysis (Table 1, entry 2). Even at a catalyst
loading of 0.1 mol%, the reaction was fast and no significant
decrease in yield was observed (Table 1, entry 3). Interest-
ingly, decomposition of substrate 1a was observed when the
70[d]
[a] Reaction conditions: 1) Substrate (10 mmol, 1m in CH2Cl2), [Au-
(PPh3)]SbF6 (1 mol% in CH2Cl2), RT. 2) K2CO3 (20 mmol), MeOH
(10 mL), RT, 30 min. [b] Reaction time for the first step with 100%
conversion determined by GC-MS methods. [c] Yield of isolated products
after 2 steps. [d] Yield of isolated product after the first step.
counterion was changed from SbF6 to TfOÀ (Table 1,
À
entry 4). Control experiments employing either 5 mol%
[Au(PPh3)]Cl or 5 mol% AgSbF6 as the sole catalyst did not
lead to product 7a (Table 1, entries 5 and 6). Notably, under
the original reaction conditions reported by Rautenstrauch
et al.,[6] decomposition of 1a was observed (Table 1, entry 7).
With good working conditions in hand, the scope of the
gold(I)-catalyzed cycloisomerization of 1-cyclopropyl-prop-
argyl esters 1 was examined (Table 2). The reactions were all
carried out on gram scale under very mild conditions.[9] Alkyl
(Table 2, entries 1–4) and aryl (Table 2, entry 5) substituents
on the double bonds were tolerated, and the products (8)
were obtained in good to excellent yields. As expected,
sterically hindered substrate 1i resulted in a slower reaction,
but full conversion was achieved after 6 hours, giving bicyclic
compound 8i in an excellent yield of 90% upon isolation
(Table 2, entry 8). The cyclopropyl ring cleavage can be also
stabilized by a para-methoxyphenyl substituent (1j), afford-
ing 7j in good yield (Table 2, entry 9).
low yield (Scheme 3). Likewise, the simple cyclopropyl
derivative 11 did not cyclize but rearranged to allene 12.
We also extended this process to homopropargyl acetates
(Scheme 4), which have been reported to undergo acetate
migration to the internal position of the alkyne, even though
serious limitations were observed when restricted conforma-
tions were not achieved.[11] To our delight, cyclization of
Apparently, the stabilization of positive charge in inter-
mediates 3 and 5 (Scheme 2) is essential for a smooth
conversion of 1 into the cyclization products (7); even under
harsh conditions, secondary acetate 9 did not cyclize but
instead ring-opened to trienone 10 after hydrolysis, albeit in
Scheme 3. Side reactions of the cycloisomerization.
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Additional investigations (Table 3) revealed that the cycliza-
tion also tolerates a variety of differently substituted sub-
strates.
The interesting question of a possible chirality transfer in
these systems was addressed using optically active substrates
1k and 15e, which are both easily available from optically
pure (1S,3S)-(À)-trans-chrysanthemum acid (99% ee;
Scheme 5).[9,12] Cycloisomerization of 1k (d.r. 6:4, 99% de)
under standard conditions ([Au(PPh3)]SbF6, CH2Cl2, RT)
cleanly afforded (R)-8k after methanolysis, albeit with only
Scheme 4. Homopropargyl acetate cycloisomerization.
substrate 13 occurred smoothly affording cycloheptenone 14
in 72% yield.
As shown in Scheme 1, substitution at the terminal
position of the acetylene unit may initiate a 6-endo-dig-like
1,3 migration of the carboxylate group.[2,4] We envisioned that
treatment of substrates, such as 15a, with [Au(PPh3)]SbF6
would generate cyclopropylalkyl carbenium ion 16a, which is
mesomeric to intermediate 17a (Table 3). Cyclization of these
species at the allyl cationic positions may occur, but only
trienyl acetate 18a was obtained in almost quantitative yield
as a mixture of cis and trans isomers. Methanolysis and
concomitant isomerization led to 19a as a single isomer.
Table 3: Scope of the AuI-catalyzed 1-cyclopentenylketone synthesis.[a]
Scheme 5. Chirality transfer of compounds 1k and 15e to 6- and 5-
membered ring products.
27% ee. Lowering the temperature to À208C only increased
the reaction time to 24 hours without significantly improving
the ee value (31% ee). Performing the reaction in various
solvents also did not improve these results. Surprisingly, using
AuCl3 as the catalyst retained the enantioselectivity most
effectively, leading to (R)-8k with 87% ee. In contrast,
[Au(PPh3)]SbF6-promoted cycloisomerization of compound
15e delivered acetylcyclopentenone (R)-19e with good
chirality transfer (89% ee; Scheme 5). The absolute config-
uration of both enantiomerically enriched samples was
unequivocally determined by Raman optical activity (ROA)
measurements.[13]
Entry
1
Substrate
Product
t [min][b]
Yield [%][c]
5
88
In our view, these results disfavor mechanisms of chirality
transfer through the stereogenic propargyl ester unit as
reported earlier for other systems:[8] the stereochemical
information at the 2’-position in substrate 1k (Scheme 5)
does not overrule that which is inherent at C1 and C3.[14] In
contrast, the reaction clearly depends on the stabilization of a
positive charge, particularly at positions 3 and 2’ in 1k (see
Scheme 3 and reference [10]), but only to an extent that
prevents formation of achiral cation 5 (Scheme 2). We
propose a more concerted mechanism, wherein carbene 2k
can be redefined as a nonclassical carbonium ion[1b,15] complex
3k or, under participation of the vinyl/gold unit species 5k,[16]
as the intermediate that preserves the enantioselectivity
(Scheme 6). Depending on the electronic stabilization and
geometry, these species display a certain configurational
stability by which stereochemical information is retained
throughout the reaction.
2
3
2
87
10
90[d]
[a] Reaction conditions: 1) Substrate (10 mmol, 1m in CH2Cl2), [Au-
(PPh3)]SbF6 (1 mol% in CH2Cl2), RT. 2) K2CO3 (20 mmol), MeOH
(10 mL), RT, 16 h. [b] Reaction time of first step with 100% conversion
determined by GC-MS methods. [c] Yield of isolated product after
column chromatography. [d] Yield of isolated product 18d after column
chromatography.
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Angewandte
Chemie
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Scheme 6. Proposed nonclassical intermediates for the chirality trans-
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[8] Herein, an interesting chirality transfer from an optically active
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oxonium ion similar to mechanisms proposed for such con-
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[9] For the preparation of new compounds and additional exper-
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[10] When the reaction was performed using AuCl3 and MeOH as
solvent, substrate 1 f reacted through a 1,2-acetate shift and
solvolysis of the cyclopropane unit to give a methoxy adduct:
In conclusion, we have found a new Au-catalyzed homo-
Rautenstrauch rearrangement of 1-cyclopropylpropargylic
esters to give cyclohexenones 8 and cyclopentenyl ketones
19 under mild conditions. In addition, enantiomerically
enriched cyclohexenones and cyclopentenyl ketones can be
prepared by the gold-catalyzed cyclization of optically active
propargyl acetates. Although the rearrangements are cationic
in nature, the high degree of chirality transfer in these
reactions suggests that gold-stabilized nonclassical carboca-
tions with a certain configurational stability are involved.
Received: August 26, 2008
Revised: October 14, 2008
Published online: November 21, 2008
Keywords: alkynes · carbocations · gold · rearrangement
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