Anion-p Catalysis: Focus on Nonadjacent Stereocenters
Xiang Zhang, Le Liu, Javier L
opez-Andarias, Chao Wang, Naomi Sakai, and Stefan Matile*
Department of Organic Chemistry, University of Geneva, Quai Ernest Ansermet 30, CH-1211 Geneva 4, Switzerland,
In Memory of Gilbert Stork
Anion-p interactions have been recently introduced to catalysis with the idea to stabilize anionic intermediates on
p-acidic surfaces. Realized examples include enolate, enamine and iminium chemistry, domino processes and Diels–
Alder reactions. Moving on from the formation of contiguous stereogenic centers on p-acidic surfaces, herein we
report the ﬁrst asymmetric anion-p catalysis of cascade reactions that afford nonadjacent stereocenters. Conjugate
addition-protonation of achiral disubstituted enolate donors to 2-chloroacrylonitrile generates 1,3-nonadjacent
stereocenters with moderate enantioselectivity and diastereoselectivity. The explored catalysts operate with
complementary naphthalenediimide and fullerene surfaces with highly positive quadrupole moments and high
polarizability, respectively, and proximal amine bases. We ﬁnd that anion-p catalysts can increase the
diastereoselectivity of the reaction beyond the maximal 1:4.0 dr with conventional catalysts to maximal 5.3:1 dr on
the large fullerene surfaces. The enantioselectivity of anion-p catalysts, best on the conﬁned naphthalenediimide
surfaces with strong quadrupole moment, exceed the performance of conventional catalysts except for comparable
results with a new, most compact, surprisingly powerful bifunctional control catalyst. Simultaneously increased rates
and stereoselectivities compared to control catalysts without p-acidic surface support that contributions of anion-p
interactions to the catalytic cascade process are signiﬁcant.
Keywords: anion-p catalysis, asymmetric catalysis, supramolecular chemistry, unorthodox interactions, fullerenes.
Complementary to cation-p interactions which have
been widely accepted in chemistry and biology for a
[1 – 8]
anion-p interactions are much
younger but are attracting rapidly increasing atten-
[9 – 18]
Contributions from anion-p interactions
have been reported for anion binding,
[22 – 25]
and, since 2015, also
The integration of anion-p
interactions into catalysis is based on the idea to sta-
bilize anionic transition states or negatively charged
reactive intermediates on p-acidic surfaces, thus
decrease the transition state energy and accelerate
the rate of the reaction.
Moreover, by manipulating
asymmetric auxiliaries, contributions from anion-p
interactions could be expanded from chemoselectivity
to stereoselectivity. These have been well exempliﬁed
by anion-p catalysis in asymmetric enamine
and Diels–Alder reactions.
biotin-streptavidin technology provided access to the
ﬁrst anion-p enzyme.
Remote control of
heterogeneous anion-p catalysis on electrodes by
electric ﬁelds has been reported as well.
the asymmetric transformations that have been real-
ized with anion-p catalysis so far all generate contigu-
ous stereogenic centers.
Moving one step
further, the next target was to introduce anion-p catal-
ysis to the formation of more demanding nonadjacent
stereocenters in acyclic molecules from achiral
To construct two nonadjacent stereocenters in
acyclic molecules, the typical strategy is to apply a
multistep process which generates two stereocenters
Direct creation of both stereocenters
from achiral substrates in one step via an asymmetric
cascade reaction is fundamentally more efﬁcient and
The catalytic domino conjugate addi-
tion-protonation reaction involing trisubstituted car-
bon donors 1 and a-substituted Michael acceptors 2
was attractive for anion-p catalysis not ony because
the generated 1,3-tertiary-quaternary stereocenters in
product 3 are widely present in numerous natural
[38 – 40]
but also because the stabilization of
the anionic intermediates on p-acidic surfaces is
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DOI: 10.1002/hlca.201700288 Helv. Chim. Acta 2018, 101, e1700288 © 2018 The Authors. Helvetica Chimica Acta Published by Wiley-VHCA AG.
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