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
[1] For bioactive natural products having cyclohexenone or cyclo-
hexanone substructures, see: a) J.-T. Zhang, X.-P. Cao, J. Org.
2001, 64, 892 – 895.
Within the above mechanistic framework, the reaction in
Scheme 4 involving the bromo-substituted substrate 5 clearly
requires a refined pathway as an intramolecular proton-
transfer event in 18!19 would become impossible. A
plausible proposal (Scheme 7) may leverage on the stabiliza-
tion of the initially formed cation 22a by the bromonium ion
resonance structure 22b. The subsequent water trapping
followed by charge separation would yield the new bromo-
enolate species 23, in which a protonation event occurrs
[2] For some applications of phenol oxidative dearomatization/
conjugate addition methods, see: a) G. Lemiꢁre, J. Clayden,
Chem. Commun. 2011, 47, 3745 – 3747; b) Q.-F. Wu, S.-L. You,
[3] For a recent review on asymmetric conjugate additions, see:
R. H. Syuzanna, D. H. Tim, G. Koen, J. M. Adriaan, L. F. Ben,
Chem. Rev. 2008, 108, 2824 – 2852.
[4] Examples of natural products containing g-functionalized qua-
ternary centers of cyclohexenones or cyclohexanones: a) B.
Victoria, B. Gonzalo, C. Luz, G. BegoÇa, R. P. Josꢂ, J. Nat. Prod.
[5] For recent reviews on gold catalysis, see: a) A. S. K. Hashmi,
Scheme 7. Refined reaction pathway leading to 6.
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 11133 –11137