10.1002/anie.201708355
Angewandte Chemie International Edition
spirooxindole 10 in excellent yield and with 81% ee (Scheme 4).
Importantly, the ester function offers a synthetic handle that can be
easily manipulated in compound collection synthesis.
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Having biaryl groups in syn-configuration at 2´- and 4´-position
on the 3,3´-piperidinoyl spirooxindole bequeaths anticancer activity
to the molecules (Scheme 1).[7e] No enantioselective synthesis to this
class of scaffold is yet known. Using magnesium salt with ligand G,
the reaction of oxindole E-11 bearing a phenyl substituted olefin and
2-ASB 2a, afforded diphenyl substituted 3,3´-piperidinoyl
spirooxindole 12 in very high yield and with excellent
enantioselectivity and thus demonstrated the broader synthetic
utility of the asymmetric HDA reaction (Scheme 4).
Mechanistically, ligand G acts as a tetradentate ligand to
trivalent Dy(III) and along with alkylidene oxindole forms a
distorted octahedral complex. N,N-oxides as well as the amide
carbonyls of G stabilize the highly congested exo-transition state
that strictly permits 2-ASB to approach only the si-face of cyano-
olefin and form the exo-adduct 4 exclusively (Scheme 5a). However,
the transition state of a relatively puckered divalent magnesium
complex with ligand G and dicyano-alkylidene oxindole 3´ gets the
si-face of olefin completely blocked and therefore azadiene
approaches it from the re-face.[14] In this situation, 2-ASBs lacking
4-alkyl group (R = H) successfully form the 3,4´-piepidinoyl
spirooxindole 6a. However, 1,4-disubstituted 2-ASBs (e.g. R = Me)
face steric hindrance from aryl groups of amide functions in ligand
G and thus prefer to form 3,3´-piperidinoyl-spirooxindole 4a´ and
exo-8 (in case of disubstituted olefin (E)-7) via a flipped azadiene
approach where we assume that the - interaction of aryl groups of
diene and dienophile stabilize the complex (Scheme 5b-c).
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[11] At a fourteen times higher scale, a reaction of 2a (1.05 mmol) with 3a
(0.07 mmol) deleivered 4a in 99% yield and with 95% ee.
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Scheme 5. a) A transition state for exo-selective HDA reaction of mono-cyano
alkylidene oxindoles 3 with 2-ASBs; b) a transition state for enantioselective
HDA reaction of 2-ASBs (2´) with dicyano- (3´) and c) cyano, ester substituted
alkylidene oxindoles (7).
In summary, we have developed highly enantioselective and
easily tunable hetero-Diels-Alder reactions of 2-aza-silyloxy-1,3-
butadienes with alkylidene oxindoles. In this rarely explored class of
cycloaddition reactions, chiral N,N-dioxide ligand G in complex
with dysprosium or magnesium metal salts regaled a facile and
selective construction of 3,3´- and 3,4´-piperidinoyl-spirooxindoles
respectively that represent scaffolds of biologically intriguing
synthetic and natural small molecules. The disclosed asymmetric
cycloaddition reaction can create molecular scaffolds beholding a
number of consecutive chiral centers including all-carbon-
quaternary centers in a very efficient manner and therefore can offer
various applications in asymmetric organic synthesis of complex
small molecules.
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Keywords: hetero-Diels-Alder reaction • piperidones • azadienes •
spirooxindoles • asymmetric synthesis
4
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