Full Paper
Abstract: Herein, we report the development of biohybrid
catalysts that are capable of catalyzing the aldol reaction.
The use of biotinylated imidazolium salts in combination
with racemic or enantiomerically pure catalytic anions al-
lowed us to study the adaptive and cooperative positioning
of the anionic catalyst inside the protein. Supramolecular en-
capsulation of the biotinylated catalyst into avidin resulted
in good selectivity for the aldol reaction performed in ionic
liquid/water mixtures.
Introduction
cally modified, even if this requires some time through long
methods in order to optimize the environment around the cat-
alyst. Imidazolium salts, best known as ionic liquids (ILs), have
gained major interest in the world of organic synthesis as
promising “green solvents” as they display many interesting
characteristics in terms of supramolecular architecture, non-
toxicity, atom economy, and protein stabilization.[11–13] More re-
cently, ILs have been used in asymmetric catalysis and biocatal-
ysis, either as solvents or as actual catalysts. Their potential as
solvents for the aldol reaction has been widely reported in the
literature, and their superior efficiency as catalysts was recently
highlighted.[14] Whereas catalysis using the cations of ILs has
been widely reported in the literature, use of the anions of or-
ganic salts as catalysts is still a developing topic.[15] We previ-
ously reported the use of an imidazolium salt bearing a chiral
catalytic anion that can be the source of stereoinduction in the
aldol and Michael reactions.[16] Moreover, having demonstrated
the beneficial effect of the second coordination sphere provid-
ed by the presence of a cyclodextrin unit in a supramolecular
complex,[17] we were interested in determining the influence of
a host protein on the activity and stereoselectivity of a hybrid
system composed of an imidazolium-based biotinylated
anchor and a nonchiral organocatalytic anion. The biotinylated
imidazolium cation therefore plays an important role, not only
in modulating the steric and electronic properties of the orga-
nocatalytic anion (first-coordination-sphere interactions), but
also in its position inside the protein and therefore in defining
the second coordination sphere.
Enzymes are evolved entities with supramolecular structures
possessing highly catalytic functions, which are usually accom-
panied by a variety of conformational states. It has been clearly
demonstrated that the motion of the enzyme structure confers
catalytic efficiency during catalysis.[1] Recent progress in host–
guest chemistry has allowed chemists to use noncovalent an-
choring strategies to build supramolecular complexes with
proteins that behave as biohybrid catalysts. These supramolec-
ular complexes show intricate and hierarchical architectures, as
well as dynamic features, all of which are required parameters
for the development of catalytic systems.
Over the last decade, the development of artificial hybrid
biocatalysts inspired by natural ones has been of great interest
in the field of stereoselective synthesis. Ranging from synthetic
macrocyclic compounds to self-assembled nanometer-sized
objects, such complexes have been exploited as scaffolds to
design supramolecular biohybrid systems.[2] The supramolec-
ular anchoring strategy relies on noncovalent interactions be-
tween small molecules and the biomolecular scaffold. The cru-
cial point of this strategy is the affinity of the guest molecule
for the host biomolecular scaffold. For example, Harada et al.
used the high affinity of antibodies for the creation of an artifi-
cial hydrogenase.[3] In the same spirit, Keinan et al. presented
an antibody–metalloporphyrin assembly that catalyzed enan-
tioselective oxidations.[4] In an early report, Whitesides et al. de-
scribed the creation of an artificial metalloenzyme based on
the very high affinity of biotin for avidin and streptavidin.[5]
Since 2003, the Ward research group has intensively explored
the biotin–(strept)avidin technology for the creation of artificial
metalloenzymes, ranging from those mimicking natural en-
zymes to the design of efficient unnatural metalloenzymes.[6–10]
The presence of the biomolecular scaffold offers an additional
advantage for the optimization of the artificial metalloenzyme.
Whereas chemical optimization can be achieved by modifying
the ligand or by introducing a spacer between the biotin
anchor and the metal, the biomolecular scaffold can be geneti-
The use of biotinylated imidazolium salts in combination
with racemic or enantiomerically pure anions allowed us to
study the adaptive and cooperative positioning of the anionic
catalyst inside the protein (Scheme 1). We report the prepara-
tion of a new type of biohybrid catalysts active in IL/H2O mix-
tures and mechanistic insights into its organocatalysis by using
the aldol reaction as an example. To the best to our knowl-
edge, this is the first example of a biohybrid catalyst that is
able to function in an ionic liquid medium.
Results and Discussion
[a] V. Gauchot, Prof. Dr. A. Schmitzer
Avidin is a glycosylated protein that is naturally present in egg
white.[18] Avidin is a tetrameric eight stranded b-barrel protein
that binds up to four biotins with high affinity. The interaction
between biotin and avidin is extremely tight with Ka =1.7ꢁ
1015 mÀ1. This high value ensures a quasi-irreversible anchoring
of biotinylated compounds in the protein pocket as a result of
numerous interactions between the biotin and the protein,
such as hydrophobic interactions,[19] Van der Waals interactions,
Departement de Chimie, Universitꢀ de Montrꢀal
C. P. 6128 Succursale Centre-Ville, Montrꢀal, Quꢀbec H3C 3 J7 (Canada)
[b] Dr. M. Branca
Present address: Laboratoire d’Electrochimie Molꢀculaire
UMR 7591 CNRS, Universitꢀ Paris Diderot, Sorbonne Paris Citꢀ
15 rue Jean-Antoine de Ba¨ıf, 75205 Paris Cedex 13 (France)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303865.
Chem. Eur. J. 2014, 20, 1530 – 1538
1531
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim