Gold-catalyzed [3+2] cycloaddition/hydrolytic Michael addition/retro-aldol reactions of propargylic esters tethered to cyclohexadienones

Article abstract of DOI:10.1002/anie.201104028

A golden dance! A series of symmetric and nonsymmetric propargylic esters tethered to cyclohexadienones were found to undergo the title reaction sequence under mild reaction conditions through gold catalysis. The product cyclohexenones or cyclohexanones having a γ-quaternary center arise from simultaneous multiatom transpositions with complete stereochemical control. Copyright

Full text of DOI:10.1002/anie.201104028

DOI: 10.1002/anie.201104028
Homogeneous Catalysis
Gold-Catalyzed [3+2] Cycloaddition/Hydrolytic Michael Addition/
Retro-Aldol Reactions of Propargylic Esters Tethered to
Cyclohexadienones**
Shunyou Cai, Zheng Liu, Weibin Zhang, Xinyang Zhao, and David Zhigang Wang*
Functionalized cyclohexenones and cyclohexanones repre-
sent two recurring structural motifs found in many bioactive
natural products.[1] Synthetically, a very important approach
for accessing these compounds is to take advantage of the
oxidative de-aromatization/conjugate addition sequence
using the corresponding phenolic precursors.[2] In this context,
a number of highly efficient catalysis methods have been
established and can deliver the desired conjugate addition
event with excellent reactivity and selectivity.[3] However,
these methods usually fail when a putative nucleophile
contains a hard and sterically demanding quaternary carbon
center. Up to the present, there appears to be no generally
useful method reported to adequately address this difficult
problem.[4] A possible approach for the facile preparation of
such cyclohexenones or cyclohexanones bearing a g-quater-
nary stereogenic carbon center (Scheme 1) would therefore
propargylic-acetate-tethered cyclohexadienones 1 at room
temperature with equal amounts (5% mol each) of
[PPh3AuCl] and AgSbF6 in toluene under an atmosphere of
air (i.e., not predried), it was found that the cyclohexenone
products 2, functionalized with a g-quaternary ketoester, were
formed in 20–30% yield upon isolation and with complete
diastereomeric control (Scheme 2). As suggested by a mech-
Scheme 2. Gold-catalyzed multiatom transposition reaction sequence
leading to cyclohexenones functionalized with g-quaternary center.
anistic analysis (see below), it was remarkable that in this
desymmetrization transformation up to four carbon atoms
and three oxygen atoms appeared to have been formally
transpositioned in a highly orchestrated multiple-bond rear-
rangement sequence.[5]
Scheme 1. Cyclohexenones or cyclohexanones bearing stereogenic
g-functionalized quaternary centers.
invite consideration of new catalysis scenarios. Ideally, such
an approach, once defined, would not only yield cyclohex-
enone or cyclohexanone rings with g-quaternary moieties in
high regio- and stereocontrol, but also enable the operation to
be applied to related quaternary carbon residues (FG1 and
FG2) for additional structural and functional editing.
In an attempt to improve the catalysis efficiency under
similar reaction conditions, we screened other potential
catalyst systems for carbon–carbon triple bond p activation,
including AgOTf (Tf = trifluorosulfonyl),[6] PtCl2,[7] and PtCl2/
CO (1 atm)[7], but all resulted in failures. Fortunately, an
interesting and useful “aryl effect” next emerged from the
observation that the simple replacement of the acetate with
benzoate (see structure 3 in Table 1) resulted in much cleaner
reaction. By using this aryl propargylic ester as a new
substrate, subsequent optimizations on the reaction revealed
[PPh3AuCl]/AgOTf to be the optimal catalyst combination,
and that there was an important solvent effect. When the
solvent was THF, MeCN, or 1,4-dioxane, the process was
completely inhibited under otherwise identical reaction
conditions; when the solvent was Et2O or CH2Cl2, the product
yield was improved to 62% and 78%, respectively; and when
the solvent was 1,2-dichloroethane (DCE), the yield was
markedly increased to greater than 90%. The catalyst loading
could be reduced to 2% mol without affecting the reaction,
but we decided to employ 4 mol% so as to achieve a practical
reaction time and product yield. Interestingly, the reprodu-
ciblity of the reaction necessitated water as the reaction
yielded no product when run under a nitrogen atmosphere or
We report herein our recent discovery of a formal gold-
catalyzed tandem [3 + 2] cycloaddition/hydrolytic Michael
addition/retro-aldol sequence that offers
a surprisingly
simple and efficient solution to the above challenge under
very mild reaction conditions. Upon treating the prochiral
[*] S. Y. Cai, Z. Liu, W. B. Zhang, X. Y. Zhao, Prof. D. Z. Wang
Key Laboratory of Chemical Genomics, School of Chemical Biology
and Biotechnology, Shenzhen Graduate School of Peking University
Shenzhen University Town, Shenzhen 518055 (China)
E-mail: dzw@szpku.edu.cn
[**] We thank the National Natural Science Foundation of China (Grants
20872004 and 20972008), the national “973 Project” of the State
Ministry of Science and Technology, the Shenzhen Bureau of
Science and Technology, and the Shenzhen “Shuang Bai Project” for
financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104028.
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Communications
strictly in dry air. However, when water was purposefully
introduced into the solvent, the reaction gave rise to complex
reaction mixtures. Thus, moist air was elected as a practically
simple source of water. Under these conditions, the product
could be obtained in 92% yield in 8 hours.[8]
This technology could be readily extended to a series of
other aryl propargylic-ester-tethered cyclohexadienones 3,
and the results are compiled in Table 1. The reactions
Scheme 3. Reactivity of the bromo-substituted cyclohexadienone 5.
Table 1: Survey of the reaction scope.
leading to the final ring-opened product, but also suggested
the possibility of intercepting the reaction course for the
purposeful preparation of such synthetically interesting and
useful tricyclic ring skeletons.[9] A comparison on the
structures of 6 and 7 showed the incorporation of an oxygen
atom from an apparently external source, which in this system
is the moist water. Accordingly, the dihydrofuran ring-open-
ing seemed to have involved a gold-promoted hydrolytic
conjugate addition and subsequent retro-Aldol event.[10]
Indeed, when the reactions were run under a strictly dry
nitrogen atmosphere, the corresponding dihydrofuran-fused
cyclohexenone products 8 were consistently isolated in good
to excellent yields, and again with virtually complete diaste-
reomeric control. Moreover, it was discovered that the
reactions were significantly accelerated with Cu(OTf)2 as a
cocatalyst. Thus, with this new [PPh3AuCl]/Ag(OTf)/Cu-
(OTf)2 three-component catalyst system, the reactions were
typically complete within just 1–1.5 hours. The results are
summarized in Table 2. The steric influence of the R1/R2
substituents of 3 upon the reactivity was found to parallel
those observed previously for the substrates in Table 1, but
the formation of 8 was evidently more tolerant of variations
on the ester substituent R4. A variety of substrates carrying
Entry
4
R1
R2
R3
Yield [%][a]
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4 f
4g
4h
4i
H
H
H
a Me
b Me
H
H
H
Me
Et
iPr
Me
Me
Me
Me
Me
Me
p-Me
p-Me
p-Me
p-Me
p-Me
p-OMe
p-F
p-Cl
1-naphthalenyl
92
89
70
90
91
88
87
89
85
H
[a] Yield of isolated product.
generally finished in 8–12 hours and yielded the desired
products containing two well-differentiated g-quaternary
carbon residues (acyl and ester) in good to excellent yields
upon isolation(70–92%). The reactions appeared to be
stereospecific because in each of the cases examined, the
corresponding product was as a single diastereomer. The R2
substituent on the substrateꢀs prochiral allylic carbon center
had an influence on the catalysis efficiency; from 4a to 4b and
4c, a decrease of product yield was observed with the increase
in the steric bulk of R2 (Table 1, entries 1–3). When unsym-
metrical R1-substituted cyclohexadienones were used, such as
those in the cases of 4d and 4e (Table 1, entries 4 and 5),
reaction was regiospecific and took place at the less-substi-
tuted enone double bonds. The electronic characteristics of
the substituents (R3) on the aromatic ring on the benzoates
also played a significant role in affecting the reaction: when
R3 is electron releasing in nature (R3 = Me, OMe, F, Cl, or
Ph), the corresponding products (4a and 4 f–4i) were all
obtained in high yields (Table 1, entries 1, and 6–9); when R3
is a strong electron-withdrawing group, such as NO2 or CF3,
the reactions gave complicated mixtures. Analogous aliphatic
esters (such as iPr, tBu, and cyclohexyl esters) also gave
relatively low product yields (< 30%).
Table 2: Preparation of dihydrofuran-fused cyclohexenones.
Entry
8
R1
R2
R4
Yield [%][a]
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8 f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
p-MeC6H4
Ph
91
90
89
92
83
65
85
91
75
82
52
72
85
90
86
65
83
68
p-ClC6H4
p-FC6H4
p-OMeC6H4
p-NO2C6H4
1-naphthalenyl
o-MeC6H4
furanyl
thiophenyl
iPr
cyclohexyl
tBu
9
10
11
12
13
14
15
16
17
18
iPr
When the bromo-substituted cyclohexadienone 5 was
examined, the reaction was found to proceed cleanly but in
addition to the expected product 6 (isolated in 38% yield), a
new species, which we spectroscopically assigned to be the
dihydrofuran-fused cyclohexenone 7, was also obtained in
26% yield (Scheme 3). The result not only implied that 7
might serve as an intermediate under catalysis conditions
Me
Me
Me
Me
iPr
=
trans-CH CHPh
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
a Me
b Me
Me
[a] Yield of isolated product.
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Angew. Chem. Int. Ed. 2011, 50, 11133 –11137

electron-releasing (8a–8e and 8o–8r) and electron-with-
drawing (8 f) aryl substituents worked smoothly (Table 2,
entries 1–6, and 15–18). Furthermore, naphthalenyl (8g),
ortho-substituted phenyl (8h), heterocyclic (8i–8j), aliphatic
(8k–8m), as well as olefinic esters (8n) were all comparably
efficient (Table 2, entries 8–14). Interestingly, it merits a note
here that, in terms of steric effects, a larger R4 group seemed
to be beneficial, but not detrimental, to the observed
reactivity. For example, for electronically similar systems,
such as aromatic esters 8a and 8h, or aliphatic ones 8k, 8l,
and 8m, the reactions are comparable and even favorable
with the increasing steric bulk of R4. This trend is rather
unexpected since, regardless of the detailed mechanistic
pathways, the 1,2-acyloxy migration of R4C(O) towards an
intramolecular nucleophilic attack on the gold-activated
triple bond seems to be an inevitable step. These results, in
conjunction with the aforementioned moist air versus water
effect, implied a delicate operation of the interplay between
kinetic and thermodynamic control in these systems.
Scheme 5. Reactivity of propargylic-ester-linked acyclic enones.
tetrahydrofuran (or pyrrolidine) dihydrofuran motifs fre-
quently found in many bioactive natural products,[11] but also
stereochemically fascinating “inherently chiral” alkenes (hel-
ical chirality) that are generated by the steric overcrowding of
the double bond substituents (with helical diastereomeric
ratios ranging from 4.2:1 to 0.4:1).[12] These products do not
undergo further ring-opening because of the apparent loss of
planar geometry on their corresponding enone units (for
example, the enone carbonyl in 11c was found to have a
significantly downfield-shifted resonance at d = 201.0 ppm).
Mechanistically, we believe that these experimental find-
ings collectively point to a cascade catalysis network that
might involve a rare gold-promoted [3+2] cycloaddition/
hydrolytic Michael addition/retro-aldol reaction sequence.
Such a proposal is illustrated in Scheme 6. With the substrate
3a as a model system that is electronically and sterically
unbiased in its local propargylic positions,[13a–b] the cascade is
triggered by electrophilic activation of the alkyne triple bond
A single crystal of 8a was successfully obtained and
subjected to X-ray diffraction analysis, thus confirming
unambiguously its stereochemical assignment (Scheme 4).
Scheme 4. X-ray crystal structure[18] and synthetic elaborations of 8a.
The thermal ellipsoids are shown at 30% probablilty.
Notably, 8a was found to be stable for days upon exposure to
water with or without AgOTf, but was quickly converted into
4a in quantitative yield when treated again with the standard
catalysis conditions (i.e., 4% mol of [PPh3Au]/AgOTf and
moist air), thus suggesting the critical role of the gold catalyst
during the ring-opening event. Additionally, the enone
double bond in 4a was readily hydrogenated by Pd/C reagent,
thus leading to the functionalized cyclohexanone 9 in 97%
yield upon isolation.
It should be noted that although the cyclohexadienone-
containing substrates 3 are highly attractive for additional
structural manipulations, neither the cyclic enone moiety nor
the oxygen atom linker is a structural requisite for the cascade
reactivity outlined above. Simpler propargylic-ester-linked
acyclic enones work with comparable efficiencies, thus
significantly expanding the synthetic utility of the method.
As shown in Scheme 5, the linear substrates 10a–d readily
cyclize to give 11a–d, which feature not only the cis-fused
Scheme 6. Mechanistic proposal.
Angew. Chem. Int. Ed. 2011, 50, 11133 –11137
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Communications
in the AuI-complexed intermediate 12, upon which a subse-
exclusively from the back face of the enolate (unshielded by
the p–p stacking effect) to give 6 with the indicated relative
stereochemistry.[17]
quent attack by the ester carbonyl group and [3,3] rearrange-
ment/[2,3]-shift[13] generates the gold-coordinated allene
species 14. Carbonyl addition to this allene and concomitant
allylic elimination of the gold catalyst yields a 1,3-dipole
which then undergoes [3+2] cycloaddition[14] with the enone
double bond via the transition-state 16 to give the vinyl ketal
17.[15] The significant rate acceleration effect brought about by
the Lewis acidic cocatalyst Cu(OTf)2 in reactions of Table 2
may thus be rationalized by its activation to the enone system.
Next, strain release drives a vinyl ketal fragmentation in 17 to
generate the putative zwitterionic intermediate 18, in which a
rapid intramolecular proton-transfer event produces the
dihydrofuran-fused cyclohexenone 19. Therefore in the
absence of any moisture, 19 was the experimentally observed
product. The conversion of 19 into the final product 4a
requires the participation of both water and AuI catalysis. The
activation of 19 by the soft gold metallic center likely
proceeded through the complexation of its enone p system
with the catalyst (20a), and nucleophilic attack to the enone
by water would yield the labile hemiketal species 21, which
upon a retro-aldol collapse produces 4a. It should be
emphasized here that the above-mentioned aryl effect upon
promoting this catalysis is seen in the transformation of 19
into 4a, a transformation that was found to depend on the
presence of a phenyl group. We have found that when R4 is a
heterocyclic (furanyl or thiophenyl) or an aliphatic group
(Table 2, entries 9 and 10), the resultant products 8 could not
be converted cleanly into their final ring-opened g-function-
alized compounds 4. These results may imply that an
electronically highly polarized (therefore considerably soft)
enone–phenyl extended p system is critical for its complex-
ation with the gold center and subsequent electrophilic
activation. This electronic polarization effect, in conjunction
with the unique bowl-shaped tricyclic skeletal twisting in 19,
may in turn suggest an alternative possibility that the initial
enone–gold p activation could stimulate charge separation to
give a new zwitterionic intermediate, that is, the gold–enolate/
oxonium 20b.[16] The compound 20b then reacts with water to
yield 4a following the same retro-aldol pathway.
In summary, by subjecting a series of propargylic-ester-
tethered cyclohexadienones and acyclic enones to gold
catalysis under mild reaction conditions, we discovered a
unique cascade process that leads to simultaneous multiatom
transpositions in an essentially stereospecific manner. The
mechanistic course is believed to follow a highly orchestrated
sequence: enone [3+2] cycloaddition/hydrolytic Michael
addition/retro-aldol collapse. Other p-activating transition-
metal catalysts were found inactive under otherwise similar
reaction conditions, thus suggesting that the judicious combi-
nation of highly polarized enone–aryl p systems with AuI
catalysts are important for synergistic electrophilic activation.
By modulating the participation of water, the methodology
can be diverted to purposeful construction of either dihydro-
furan-fused cyclohexenones, or cyclohexenones and cyclo-
hexanones bearing a g-quaternary stereogenic carbon center
amenable to additional structural editing. Given the impor-
tance of these common structural skeletons that are present in
bioactive natural products, and the simplicity in implementing
such cascade catalysis methodologies, it can be anticipated
that these technologies will find their synthetic utility in the
stereoselective preparations of pharmaceutically meaningful
compounds and libraries of their structural mimics. Ongoing
efforts along these lines will be reported in due course.
Received: June 12, 2011
Revised: July 30, 2011
Published online: September 29, 2011
Keywords: cycloaddition · gold · heterocycles ·
.
homogeneous catalysis · synthetic methods
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[10] The resistance of 7 towards hydrolytic dihydrofuran ring opening
should originate from the bromo substitution that likely retards
activation of the enone carbonyl group by gold (analogous to
structures 20a–b) through competitive steric and/or electronic
Br–Au interactions.
[16] For the first report on the X-ray structure of a gold enolate, see:
a) Y. Ito, M. Inouye, M. Suginome, M. Murakami, J. Organomet.
Chem. 1988, 342, C41 – C44; for catalysis involving an oxonium/
Au/enolate species, see: b) J.-M. Tang, T.-A. Liu, R.-S. Liu, J.
Org. Chem. 2008, 73, 8479 – 8483.
[17] For an example of enolate chemistry involving p – p stacking,
see: M. Stefano, G. N. Ana, F. M. Carlos, J. Org. Chem. 2009, 74,
6888 – 6890.
[18] CCDC 845089 (8a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif
[11] For some illustrative examples, see: a) B. Zhao, J. Chang, Q.
Wang, Y. Du, K. Zhao, Synlett 2008, 2993 – 2996; b) R. W. Fitch,
Angew. Chem. Int. Ed. 2011, 50, 11133 –11137
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