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olfactory properties. Structures 3 and 4 both superimpose well
on the leads 1 and 2, and these compounds thus constitute
Cashmeran odorants bearing quaternary stereocenters.
As shown in the retrosynthetic analysis (Scheme 1), our
strategy for the construction of 3 and 4 involves a regioselec-
tive and enantioselective Michael addition of tert-butyl vinyl
ketone (7a) to the monoprotected 2-methylcyclohexan-1,4-
lack of selectivity in the formation of the most substituted
enamine has to be considered. To overcome this limitation,
and inspired by the concerted acid–base mechanism found in
enzymatic enolization,[15] we envisioned a shift from enamine
to enol catalysis through a Brønsted acid catalyzed Michael
reaction between 6a and 7a (Scheme 2). Acid-catalyzed
enolizations are well documented[16] and we hypothesized that
Scheme 1. Retrosynthetic analysis of the targets 3 and 4.
dione 6a as the key step, followed by an intramolecular
McMurry coupling to install the double bond. The flattened
dienone structure 4, which corresponds better to the planar
ring system of Cashmeran (1), should then be accessible
through a Saegusa–Ito reaction or a related oxidation.
The key transformation is challenging and requires
selective modification at the more hindered position of a-
substituted ketone 6a. This problem has previously been
addressed by Pfau and dꢀAngelo, who reported the use of
preformed imines derived from (+)-a-methylbenzylamine.[5]
Recently, Carter and coworkers[6] disclosed a thiourea-based
primary amine catalyzed formation of a-quaternary stereo-
centers from a-alkyl-substituted cycloalkanones and electron-
deficient alkenes, excluding vinyl ketones. In both reports,
tautomerization to the thermodynamically favored enamine
was observed. However, despite our efforts, the latter
methodology gave very poor conversions, whereas the
former afforded products with good e.r. values (91:9) but
required stoichiometric amounts of enantiopure amine and
two additional steps (imine formation/imine cleavage, see the
Supporting Information). The limited success of both meth-
ods with the challenging substrate combination of the O,O-
acetal analogue of 6a and the bulky vinyl ketone 7a prompted
us to develop a novel strategy.
Despite the versatility of enantiopure all-carbon a,a-
disubstituted cyclohexanones as building blocks in organic
synthesis, only a limited number of catalytic systems for their
synthesis have been reported. In most cases, they involve
allylation reactions via p-allyl palladium intermediates[7] or
Michael reactions on activated substrates, for example, b-
ketoesters or diketones.[8] The formation of isomeric enolates
on a-branched ketones is still a major challenge and some
allylation protocols have circumvented it with preformed
enolates[9] or decarboxylative allylic alkylation[10] under Pd0
catalysis.[11] Organocatalytic approaches to these stereogenic
centers mainly rely on phase transfer[12] or enamine catalysis,
and they have almost exclusively been applied to dicarbonyl
compounds,[13] and only very recently to a-branched alde-
hydes.[14] The limited applicability to other substrates, such as
simple a-substituted ketones, can be attributed to the difficult
formation of the sterically constrained enamine intermediate.
Furthermore, when the b-ester functionality is removed, the
Scheme 2. Design of an asymmetric Brønsted acid catalyzed Michael
addition.
chiral phosphoric acids,[17] for example, (S)-TRIP,[18] could
accelerate both the enolization and the activation of the
electrophile and the nucleophile through their Brønsted
ꢀ
=
acidic P OH and Brønsted basic P O moieties, respectively.
Chiral Brønsted acids have indeed recently been used in the
Robinson annulation of b-ketoester derivatives of 1-indanone
with methyl vinyl ketone.[19] Furthermore, simple unsubsti-
tuted ketones have been activated by chiral phosphoric acids
in aldol reactions with glyoxylate, and in one example
a quaternary stereocenter is formed albeit with limited
enantioselectivity.[20] However, we are unaware of any
successful direct methods that can be used to regio- and
enantioselectively form an all-carbon quaternary a-stereo-
center on ketones.
We started our investigation by treating ketone 6a with an
excess of enone 7a in the presence of 10 mol% of different
chiral BINOL-derived phosphoric acids or disulfonimides[21]
bearing different substituents in the 3 and 3’ positions of the
backbone (see the Supporting Information). Thioacetal 6a
was preferred over the corresponding O,O-acetal, which
proved unstable under the acidic reaction conditions. When
the reaction mixture was heated above 708C, most of the
phosphoric acids afforded the desired products in moderate
yields and with good to excellent enantioselectivity. (S)-TRIP,
which bears 2,4,6-iPr3C6H2 groups, was found to be superior
and interestingly, the enantioselectivity proved to be little
influenced by reaction conditions, which allowed the reaction
to be run at 1008C with methylcyclohexane as the solvent.
Radical polymerization of the enone was found to be an
undesired side reaction, but upon employing 3 equiv of the
electrophile and adding of 0.1 equiv of BHT as a radical
scavenger, the desired product 5a could be isolated in 79%
yield with 97.5:2.5 e.r. after 3 days. Gratifyingly, diketone 5a
gave crystals suitable for X-ray analysis,[22] which were used to
determine the absolute configuration of the products (see the
Supporting Information).
We carried out a preliminary investigation into the
substrate scope of our new reaction (Scheme 3). Six-mem-
bered rings bearing different alkyl chains in the a-position
2
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
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