Turning Cucurbit[8]uril into a Supramolecular Nanoreactor for Asymmetric Catalysis

Article abstract of DOI:10.1002/anie.201505628

Chiral macromolecules have been widely used as synthetic pockets to mimic natural enzymes and promote asymmetric reactions. An achiral host, cucurbit[8]uril (CB[8]), was used for an asymmetric Lewis acid catalyzed Diels-Alder reaction. We achieved a remarkable increase in enantioselectivity and a large rate acceleration in the presence of the nanoreactor by using an amino acid as the chiral source. Mechanistic and computational studies revealed that both the amino acid-Cu²⁺ complex and the dienophile substrate are included inside the macrocyclic host cavity, suggesting that contiguity and conformational constraints are fundamental to the catalytic process and rate enhancement. These results pave the way towards new studies on asymmetric reactions catalyzed in confined achiral cavities.

Full text of DOI:10.1002/anie.201505628

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201505628
German Edition: DOI: 10.1002/ange.201505628
Host–Guest Catalysis
Turning Cucurbit[8]uril into a Supramolecular Nanoreactor for
Asymmetric Catalysis
Lifei Zheng, Silvia Sonzini, Masyitha Ambarwati, Edina Rosta, Oren A. Scherman,* and
Andreas Herrmann*
Abstract: Chiral macromolecules have been widely used as
synthetic pockets to mimic natural enzymes and promote
asymmetric reactions. An achiral host, cucurbit[8]uril (CB[8]),
was used for an asymmetric Lewis acid catalyzed Diels–Alder
reaction. We achieved a remarkable increase in enantioselec-
tivity and a large rate acceleration in the presence of the
nanoreactor by using an amino acid as the chiral source.
Mechanistic and computational studies revealed that both the
amino acid–Cu2+ complex and the dienophile substrate are
included inside the macrocyclic host cavity, suggesting that
contiguity and conformational constraints are fundamental to
the catalytic process and rate enhancement. These results pave
the way towards new studies on asymmetric reactions catalyzed
in confined achiral cavities.
[n]urils, CB[n], have been shown to promote both photo-
chemical and thermochemical reactions, entailing rate accel-
erations as well as improving stereo- and chemo-selectiv-
ities.[3] However, unlike some analogues, such as cyclodex-
trins,[4] calixarenes,[5] and nanocages,[6] employing CB[n] in
asymmetric catalysis remains a challenge. The main reasons
are related to the intrinsic achirality of cucurbiturils and the
nontrivial synthetic efforts in constructing chiral supramolec-
ular assemblies.[7] To the best of our knowledge, only one
example has been reported, showing a marginal increase of ee
values from 16% to 18% when CB[8] was added to the
reaction mixture.[8]
Moreover, cucurbiturils not only exhibit a hydrophobic
cavity, which has been extensively applied for improving
reactivity and selectivity, but they also possess two carbonyl
rims with a known affinity for both organic and inorganic
cations.[3,9] Nevertheless, CB[n] binding to metal ions, espe-
cially for catalysis, has not been fully exploited.[3d,e]
To address these challenges, we herein present a novel
design of a supramolecular CB[n]-based system forming
a chiral nanoreactor by the combination of three components:
amino acids, Cu2+, and CB[8]. Here, amino acids were applied
as a source of chirality, and Cu2+ acted as a potential active
site to expand the reaction scope from conventional photo-
and thermo-chemical reactions to new types of transforma-
tions, such as the Lewis acid catalyzed Diels–Alder (D-A)
reaction shown in Scheme 1. CB[8] can bind the chiral copper
R
eaction pockets are considered to be responsible for the
origin of enhanced rates and high selectivities in enzyme-
catalyzed transformations. Although the detailed working
mechanism is often unclear, stabilization of the transition
state and binding of the substrate in a beneficial orientation
and conformation within the pocket appear to be fundamen-
tal.[1] Inspired by nature, supramolecular systems with con-
fined hydrophobic cavities where apolar reactants are recog-
nized by host–guest interactions are potential candidates for
the development of efficient enzyme mimetics.[2] Among
them, the pumpkin-shaped family of macrocycles cucurbit-
[*] Dr. L. Zheng,[+] M. Ambarwati, Prof. Dr. A. Herrmann
Department of Polymer Chemistry,
Zernike Institute for Advanced Materials,
University of Groningen
Nijenborgh 4, 9747 AG Groningen (The Netherlands)
E-mail: a.herrmann@rug.nl
S. Sonzini,[+] Prof. Dr. O. A. Scherman
Melville Laboratory for Polymer Synthesis, Department of Chemistry,
Cambridge University
Lensfield Road, Cambridge CB2 1EW (UK)
E-mail: oas23@cam.ac.uk
Scheme 1. Asymmetric D-A reaction; L stands for the amino acid used
as ligand to create the asymmetric copper catalyst.
Dr. E. Rosta
Department of Chemistry, King’s College London, Britannia House
7 Trinity Street, London SE1 1DB (UK)
[+] These authors contributed equally to this work.
complex and further serves as the recognition site for
substrates. A catalytic amount of the CB[8]-reactor was
enough to achieve both rate acceleration (up to 9.5 times) and
enhanced diastereoselectivity and enantioselectivity, yielding
ee values of the products of up to 92%. To the best of our
knowledge, this is the first demonstration of achiral cucurbi-
turils playing an active role in substantially affecting enantio-
selectivity during a catalytic reaction.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505628. Underlying data
for this article can be accessed at http://www.repository.cam.ac.uk/
handle/1810/250356.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
Following our design strategy, we prepared the catalytic
assembly using different CB[n], including CB[6], CB[7], and
Angew. Chem. Int. Ed. 2015, 54, 13007 –13011
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
13007

.
Angewandte
Communications
the Cu2+–aromatic amino acids adducts, decreased enantio-
selectivities were observed compared to the pristine amino
acid catalyst system. Upon addition of CB[8], nearly no effect
was found for phenylalanine (b) and tyrosine (c), but,
remarkably, both assemblies CB[8]·d·Cu2+ and CB[8]·e·Cu2+
gave the same product with highly increased diastereo- and
enantioselectivities compared to d and e alone (Table 1). The
catalyst system consisting of CB[8]·e·Cu2+ resulted in 92% ee.
These results show that the size of the hydrophobic cavity is
a crucial factor in influencing the catalytic performance. It has
to be large enough to incorporate the chiral moiety and still
leave sufficient space for accommodating the substrates.[15]
To further elucidate the catalytic activity, the apparent
second-order rate constants (kapp) of the D-A reactions
mediated by different copper complexes were measured
from the initial decrease in UV absorption of 1a (Table 2;
Figure 1. Components for the screening of the supramolecular system
catalyzing the D-A reaction. Top row: CB[6], CB[7], and CB[8] as well as
their outer diameters. Bottom row: a) lysine, b) phenylalanine, c) tyro-
sine, d) tryptophan, and e) abrine.
Table 2: Kinetic data and isobaric activation parameters at 298 K for the
Diels–Alder reactions.[a]
CB[8], and different amino acids, which are known to bind to
specific members of the cucurbituril family.[9] As previously
reported, CB[6] shows reasonable affinity towards positively
charged aliphatic chains, such as those present in lysine, while
CB[7] and CB[8] form inclusion complexes with aromatic
amino acids (Figure 1).[9]
d·Cu2+
CB[8]·d·Cu2+
e·Cu2+
CB[8]·e·Cu2+
kapp (molsÀ1
Keq(mÀ1
kcat (molsÀ1
DG°(kcalmolÀ1
DH°(kcalmolÀ1
TDS°(kcalmolÀ1
)
0.022
1.77”103
0.252
19.7
4.4
À15.3
0.089
2.07”104
0.184
18.9
7.2
À11.7
0.050
2.31”103
0.451
19.2
2.6
À16.6
0.48
1.91”104
1.04
17.9
5.3
)
)
)
)
)
The three members of the CB[n] family were then
combined with different amino acids (Figure 1, compounds
a–e) and the resulting supramolecular host–guest systems
were tested in the benchmark Cu2+-catalyzed D-A reaction of
azachalcone (1a) with cyclopentadiene (2) under optimized
conditions (Supporting Information, Section S3).[10] We chose
this particular reaction as a proof-of-concept because the
cycloaddition was known to be highly sensitive to the
presence of other macromolecules, such as DNA,[11] anti-
bodies,[12] cyclodextrin,[13] and molecular capsules.[14] As
expected, CB[n]·Cu2+ adducts formed racemic products,
indicating that enantioselectivity only can be induced by the
chiral amino acids (Table 1). Upon using lysine as a ligand
alone, 2% ee was achieved, and no higher ee values were
obtained when this amino acid was combined with CB[6]. In
contrast, when Cu2+ was complexed with amino acids bearing
aromatic side chains (b–e), higher enantioselectivities (13–
72% ee) were obtained (Table 1). When CB[7] was added to
À12.6
[a] Fixed ratio of amino acids to Cu2+ 1.5:1. In the presence of CB[8],
CB[8]:d/e:Cu2+ =2:1.5:1.
Supporting Information).[10] In the presence of CB[8],
a modest 4-fold rate increase was found for d·Cu2+. A more
pronounced 9.5-fold rate acceleration was observed in the
case of e·Cu2+. The results produced by CB[8]·e·Cu2+ clearly
indicate the common trend between reactivity and selectivity,
namely, the most active combination also gave rise to the
highest enantioselectivities.
Encouraged by these data, the origin of this rate accel-
eration was further investigated using the methods described
previously by Engberts and co-workers.[16] The proposed
catalytic cycle where the nanoreactor is expected to influence
the rate of the D-A reaction is depicted in the Supporting
Information, Scheme S1. In the first step, the reversible
association between nanoreactor and dienophile generates
a readily activated substrate for the reaction with the diene;
then the D-A reaction occurs irreversibly. Finally, the product
has to depart from the active site, regenerating the catalyst for
the next cycle. In total, the overall rate of the reaction (kapp) is
determined by three constants: Keq, kcat, and kd. Since the
kinetic measurements were performed with a large excess of
catalyst, the contribution from kd can be ignored under this
condition. The equilibrium constant, Keq, was measured
independently from a series of UV/Vis absorption titration
experiments (Supporting Information, Figure S2). The cata-
lytic rate constant, kcat, was then calculated according to the
determined apparent rate constant (kapp) and Keq (Supporting
Information, Section S4.3). As listed in Table 2, for both
d·Cu2+ and e·Cu2+, Keq in the presence of CB[8] showed an
increase of around one order of magnitude; however, the kcat
Table 1: Enantiomeric excesses of Diels–Alder products using different
copper catalyst assemblies.[a]
Ligand
a
b
c
d
e
–
0
1
0
2
2
–
–
13
–
9
32
–
10
32
31 (90:10)[b]
72 (90:10)[b]
CB [6]
CB [7]
CB [8]
–
13
–
55
12
73 (96:4)[b]
92 (97:3)[b]
[a] General conditions: 1a (1.5 mmol), 2 (4 mL), Cu2+ (3% mol), a–
e (4.5% mol), CB[n] (6% mol) in 1 mm phosphate buffer (PBS) with
pH 7.4, for 24 h at 68C. Data were obtained from the crude product on
chiral phase HPLC. The ee values are averaged over two experiments and
are reproducible within Æ2%. [b] Endo/exo ratios are in parentheses. In
all reactions, conversions determined by HPLC are >99%. The absolute
configuration of the main products were identified as the (2R,3R)-
enantiomer.
13008 www.angewandte.org
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 13007 –13011

Angewandte
Chemie
does not change significantly. These results clearly show that
the observed rate enhancement in the presence of CB[8] is
mainly on account of an increased affinity of the dienophile to
the cucurbit[8]uril–copper complex.
were also calculated (Supporting Information, Table S3). As
expected, approach from the same side as the amino acid was
disfavored both with and without CB[8]; however, the
difference in energy between diene approach from the same
side versus the opposite side of the amino acid was higher in
the presence of the macrocyle, namely 3.1 vs 6.5 kcalmolÀ1
(Supporting Information, Table S3). These results provided
a possible explanation for the observed higher enantioselec-
tivity in the presence of CB[8] and fully supported the
hypothesis of the substrate binding to the d·Cu2+ complex
within the host cavity.
Next, the Eyring equation was employed for the calcu-
lation of isobaric activation parameters by measuring kapp at
various temperatures (Supporting Information, Figure S3).
This revealed that the enhanced rate constant in the presence
of CB[8] is largely driven by the gain in entropy, which is
partially compensated by a negative effect on enthalpy. This
favorable effect on DS° suggests that classical hydrophobic
interactions are responsible for expelling surface-bound water
molecules from both the hydrophobic cavity and from the
non-polar substrate, and therefore are most likely a major
driving force for rate acceleration.[12b, 17]
As the experimental data suggested the formation of
a supramolecular catalyst capable of binding and orienting
the substrate efficiently, the nanoreactor cavity and its
interaction with the diene were further investigated using
a computational approach (Supporting Information, Sec-
tion S5). First, the most stable conformation of the active
catalytic complex was determined, resulting in the trans-cisoid
structure (Supporting Information, Table S2 and Figure S4a).
Importantly, the same conformer was previously suggested to
be the most stable.[18]
Once obtained, the stability of the complex inside the
CB[8] cavity was verified. Moreover, the complex appeared
to be almost completely buried inside the host, with only the
vinylbenzene unit of the azachalcone protruding towards the
solvent, and thus accessible for the diene approach (Support-
ing Information, Figure S4b). Since these results were in full
agreement with the experimental data, the relative energies
and the structure of the nanoreactor in the presence of
cyclopentadiene were also calculated. The structures
obtained (Figure 2) showed a biased interaction between
the catalytic complex and the diene: when the cyclopenta-
diene approached from the same side as the amino acid the
complex needed to twist and open slightly, to accommodate
the diene, with a subsequent energetic cost. This process,
which also appeared to take place in the absence of CB[8]
(Supporting Information, Figure S5c), was even more unfav-
orable in the presence of the macrocycle on account of the
space constraints introduced by the host cavity. The relative
energies for the complex with and without CB[8] when
cyclopentadiene was approaching from different directions
To gain a further understanding of how the supramolec-
ular asymmetric nanoreactor assembles, structural studies on
the catalyst assembly as well as the molecular recognition
between nanoreactor and dienophile were carried out with
the aid of 1H NMR, fluorescence, and UV/Vis spectroscopies,
and isothermal titration calorimetry (ITC). First, the inclusion
of d·Cu2+ and e·Cu2+ within the CB[8] cavity was evaluated
1
through H NMR (Supporting Information, Figures S7–S10).
The addition of CB[8] into either a solution of d·Cu2+ or
e·Cu2+ resulted in an upfield shift of the aromatic signals,
which corroborated the inclusion of the indole ring inside the
hydrophobic cavity of the macrocycle. Further evidence of
binding was obtained from fluorescence measurements,
where both fluorescence quenching as well as a distinct
blue-shift (ca. 20 nm) were observed upon addition of CB[8]
to d·Cu2+ or e·Cu2+ solutions (Supporting Information, Fig-
ure S12). Moreover, ITC experiments demonstrated the
presence of a binding event between d·Cu2+ or e·Cu2+ and
CB[8] with a stoichiometry of only 1:1 instead of a homoter-
nary 2:1 complex previously reported for Trp2CB-
[8][9b](Supporting Information, Figures S15c and S16c).
Subsequently, the binding behavior of azachalcone to the
ternary catalyst complex was investigated. Both 1H NMR and
fluorescence measurements suggested the inclusion of each of
the amino acids and 1a in the presence of Cu2+, yielding
CB[8]·d·Cu2+·1a and CB[8]·e·Cu2+·1a. The analysis of the
1
aromatic region of the H NMR spectra revealed that the
signals from both the amino acids and 1a were shifted upfield
when CB[8] and Cu2+ were both present (Supporting
Information, Figures S7–S10). Furthermore, the emission of
both d and e were blue-shifted. However, as azachalcone 1a
was present, quenching was also observed in the study of the
full catalytic system (Supporting Information, Fig-
ure S12a,b). These data suggest that the amino acids and 1a
are indeed in close proximity and included in the CB[8] cavity.
We further explored the role of copper in the complex
formation by UV/Vis spectroscopy (Figure 3). Upon binding
to the amino acids, the absorption maximum of the dienophile
(326 nm) displayed a red-shift (375 nm), while the amino acid
absorbance at 275 nm exhibited a fine structure and increased
in value (Figure 3a,b). Notably, titration of CB[8]·d·Cu2+ or
CB[8]·e·Cu2+ into the substrate resulted in a large dienophile
absorbance at 375 nm, while the absorbance at 326 nm was
drastically decreased (Figure 3c,d). Moreover, the amino acid
absorbance was also red-shifted and the entire spectra
generally broadened. These data indicated that the presence
of CB[8] dramatically increases the extent of Cu2+ bound to
Figure 2. Nanoreactor–1a complex with cyclopentadiene approaching
from a) the opposite side and b) the same side of the amino acid in
the endo direction.
Angew. Chem. Int. Ed. 2015, 54, 13007 –13011
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 13009

.
Angewandte
Communications
Figure 4. Different substrates employed for the D-A reaction catalyzed
by d·Cu2+ and CB[8]·e·Cu2+. Yields are given (values for CB[8]·e·Cu2+
are shown in brackets).
Figure 3. Titration of a) d·Cu2+, b) e·Cu2+, c) CB[8]·d·Cu2+, and
d) CB[8]·e·Cu2+ to azachalcone 1a (50 mmol in 1 mm PBS buffer)
followed by UV/Vis spectroscopy.
Information, Figure S13). Unlike 1a, in the presence of
CB[8], the absorption of 1b remained unchanged. Further-
more, the distinct red-shift was not observed. These results
suggest that 1b is most likely not included inside the cavity of
CB[8], which can be explained by the steric hindrance from
the additional methyl group in close proximity to the metal
center. Therefore, these results not only support that pre-
inclusion of the substrate is necessary to achieve enantiomeric
enhancement, but also suggest that the pyridine ring is
included in the cavity during catalysis, while the phenyl ring of
the substrate is protruding out of the cavity. These exper-
imental data are also in full agreement with the computa-
tional studies performed.
1a in solution and suggested the formation of a strong charge-
transfer adduct.
Based on the qualitative data obtained through spectro-
scopic techniques, we further evaluated the interaction of
CB[8]·d·Cu2+ and CB[8]·e·Cu2+ with 1a through ITC. The
titration of a mixture of amino acid and Cu2+ into the
dienophile solution resulted in a low-affinity interaction
(Supporting Information, Figures S15a and S16a), while the
titration of CB[8]·d·Cu2+ and CB[8]·e·Cu2+ into 1a showed
a strong binding event for both systems (Supporting Infor-
mation, Figure S17). Although the Keq values obtained from
the ITC analyses were one order of magnitude higher than
those measured by UV/Vis (Table 2), the trend was exactly
the same (Supporting Information, Figures S15,S16).
All of the spectroscopic and calorimetric analyses indi-
cated the occurrence of a binding event between both the
nanoreactor systems and the substrate 1a. The UV/Vis data
also suggested the occurrence of a strong charge-transfer
interaction between the substrate and the aromatic amino
acid within the cucurbit[8]uril cavity, as predicted by the
computational calculations and corroborated by the binding
constants measured by ITC. Therefore, as a consequence, one
of the two faces on which the diene can approach the
dienophile is more shielded, which is, again, in agreement
with the results obtained by the computational study and
explains the enhanced enantioselectivity achieved in the
presence of CB[8].
In conclusion, we have demonstrated the first example of
employing achiral cucurbit[8]uril as a nanoreactor in asym-
metric catalysis. Using a single amino acid as the chiral source,
Cu2+ as the Lewis acid, and CB[8] as the host, we obtain
a complex that is able to catalyze D-A reactions with high
enantioselectivities of up to 92% ee, which are comparable to
other bio-inspired catalytic systems containing much larger
DNA or protein scaffolds.[15,19] The high selectivities are also
accompanied by a large 9.5-fold rate acceleration of the
1
reaction. With the help of computational studies, H NMR,
optical spectroscopic measurements, and ITC, information
about the most likely catalytic mechanism was discerned.
During catalysis, the aromatic side chain of the amino acid
and the pyridine ring of the dienophile both complexed to
copper are located inside the cavity of CB[8], while the
vinylbenzene unit is protruding towards the solvent. This
spatial arrangement is not only responsible for face-prefer-
ential attack of the diene but also for the rate acceleration,
since ordered water molecules are regained by the bulk from
the dienophile as well as from the hydrophobic CB[8] cavity.
The design of an asymmetric supramolecular catalytic system
containing a chiral transition-metal complex and a non-chiral
macrocyclic pocket is described herein, which is distinct from
the traditional concept of introducing an achiral catalyst into
an existing chiral scaffold.[20] An obvious advantage of the
current approach is the dramatically decreased quantity of
expensive chiral resources. As such, we believe that this work
will pave the way towards more types of asymmetric reactions
involving achiral cucurbit[n]uril and other synthetic hosts
exhibiting strong binding of auxiliary chiral guests.
Taking the best performing combination CB[8]·e·Cu2+,
the scope of the reaction was investigated using other
chalcones 1b–d under the optimized conditions (Figure 4).
Different behaviors of the catalytic system were observed
with the varying substrates. Introducing a substituent on the
phenyl ring (1c and 1d) had little influence on the reaction,
meaning that the presence of CB[8] enhanced the enantio-
selectivity by around 20% ee. However, when a substituent is
introduced on the pyridine ring as in 1b, the presence of
CB[8] did not result in an obviously increased selectivity. To
clarify the possible reasons for this finding, we performed the
same spectroscopy studies as described before for substrate
without substitution on the aromatic heterocycle (Supporting
13010 www.angewandte.org
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 13007 –13011

Angewandte
Chemie
[8] C. Yang, T. Mori, Y. Origane, Y. H. Ko, N. Selvapalam, K. Kim,
Acknowledgements
Y. Inoue, J. Am. Chem. Soc. 2008, 130, 8574 – 8575.
[9] a) S. W. Heo, T. S. Choi, K. M. Park, Y. H. Ko, S. B. Kim, K. Kim,
H. I. Kim, Anal. Chem. 2011, 83, 7916 – 7923; b) L. M. Heit-
mann, A. B. Taylor, P. J. Hart, A. R. Urbach, J. Am. Chem. Soc.
2006, 128, 12574 – 12581; c) M. E. Bush, N. D. Bouley, A. R.
Urbach, J. Am. Chem. Soc. 2005, 127, 14511 – 14517; d) S.
Sonzini, S. T. J. Ryan, O. A. Scherman, Chem. Commun. 2013,
This research was supported by the European Union Euro-
pean Research Council Starting Grants ASPiRe 240629
(O.A.S.) and NUCLEOPOLY 240080 (A.H.) and STREP
project MICREAGENTS, the Netherlands Organization for
Scientific Research (NWO-Vici Grant), and the Zernike
Institute for Advanced Materials. E.R. acknowledges com-
putational support from the NIH Biowulf cluster, the EPSRC
UK NSCCS cluster, and the ARCHER UK National Super-
computing Service via CCPBioSim. The authors thank Dr.
Duncan Howe for the help in performing and analyzing the
NMR samples.
˝
49, 8779 – 8781; e) F. Tian, M. Cziferszky, D. Jiao, K. Wahlstrom,
J. Geng, O. A. Scherman, Langmuir 2011, 27, 1387 – 1390; f) M.
Rowland, E. Appel, R. J. Coulston, O. A. Scherman, J. Mater.
Chem. B 2013, 1, 2904 – 2910; g) P. Rajgariah, A. R. Urbach, J.
Inclusion Phenom. Macrocyclic Chem. 2008, 62, 251 – 254.
[10] a) S. Otto, G. Boccaletti, J. B. F. N. Engberts, J. Am. Chem. Soc.
1998, 120, 4238 – 4239; b) S. Otto, J. B. F. N. Engberts, J. Am.
Chem. Soc. 1999, 121, 6798 – 6806.
[11] A. J. Boersma, J. E. Klijn, B. L. Feringa, G. Roelfes, J. Am.
Chem. Soc. 2008, 130, 11783 – 11790.
[12] a) J. Xu, Q. Deng, J. Chen, K. N. Houk, J. Bartek, D. Hilvert,
I. A. Wilson, Science 1999, 286, 2345 – 2348; b) J. Chen, Q. Deng,
R. Wang, K. N. Houk, D. Hilvert, ChemBioChem 2000, 1, 255 –
261.
Keywords: asymmetric catalysis · Diels-Alder reaction · host–
guest systems · macrocycles · supramolecular chemistry
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13007–13011
Angew. Chem. 2015, 127, 13199–13203
[13] D. C. Rideout, R. Breslow, J. Am. Chem. Soc. 1980, 102, 7816 –
7817.
[1] a) L. Pauling, Am. Sci. 1948, 36, 51 – 58; b) W. P. Jencks, Catalysis
in Chemistry and Enzymology, McGraw-Hill, New York, 1969;
c) D. Ringe, G. A. Petsko, Science 2008, 320, 1428 – 1429.
[2] a) M. D. Pluth, R. G. Bergman, K. N. Raymond, Acc. Chem. Res.
2009, 42, 1650 – 1659; b) J. J. Rebek, Acc. Chem. Res. 2009, 42,
1660 – 1668; c) M. Raynal, P. Ballester, A. Vidal-Ferranab,
P. W. N. M. van Leeuwena, Chem. Soc. Rev. 2014, 43, 1734 –
1787; d) T. S. Koblenz, J. Wassenaar, J. N. H. Reek, Chem. Soc.
Rev. 2008, 37, 247 – 262; e) T. Murase, S. Horiuchi, M. Fujita, J.
Am. Chem. Soc. 2010, 132, 2866 – 2867.
[3] a) S. Y. Jon, Y. H. Ko, S. H. Park, H.-J. Kim, K. Kim, Chem.
Commun. 2001, 1938 – 1939; b) W. L. Mock, T. A. Irra, J. P.
Wepsiec, M. Adhya, J. Org. Chem. 1989, 54, 5302 – 5308; c) N. i.
Saleh, A. L. Koner, W. M. Nau, Angew. Chem. Int. Ed. 2008, 47,
5398 – 5401; Angew. Chem. 2008, 120, 5478 – 5481; d) A. L.
Koner, C. Mµrquez, M. H. W. Dickman, M. Nau, Angew.
Chem. Int. Ed. 2011, 50, 545 – 548; Angew. Chem. 2011, 123,
567 – 571; e) X. Lu, E. Masson, Org. Lett. 2010, 12, 2310 – 2313;
f) B. C. Pemberton, R. Raghunathan, S. Volla, J. Sivaguru,
Chem. Eur. J. 2012, 18, 12178 – 12190; g) F. Biedermann, I. Ross,
O. A. Scherman, Polym. Chem. 2014, 5, 5375 – 5382; Other
review articles on supramolecular properties of cucurbiturils:
h) J. W. Lee, S. Samal, N. Selvapalam, H.-J. Kim, K. Kim, Acc.
Chem. Res. 2003, 36, 621 – 630; i) J. Lagona, P. Mukhopadhyay, S.
Chakrabarti, L. Isaacs, Angew. Chem. Int. Ed. 2005, 44, 4844 –
4870; Angew. Chem. 2005, 117, 4922 – 4949; j) H.-J. Buschmann,
E. Cleve, L. Mutihac, E. Schollmeyer, J. Inclusion Phenom.
Macrocyclic Chem. 2009, 65, 293 – 297; k) Special issue on
cucurbitruils: Isr. J. Chem. 2011, 51, 485 – 678; l) K. I. Assafa,
W. M. Nau, Chem. Soc. Rev. 2015, 44, 394 – 418.
[14] a) J. Kang, J. J. Rebek, Nature 1997, 385, 50 – 52; b) M. Yoshi-
zawa, M. Tamura, M. Fujita, Science 2006, 312, 251 – 254.
[15] D. Coqui›re, J. Bos, J. Beld, G. Roelfes, Angew. Chem. Int. Ed.
2009, 48, 5159 – 5162; Angew. Chem. 2009, 121, 5261 – 5264.
[16] S. Otto, F. Bertoncin, J. B. F. N. Engberts, J. Am. Chem. Soc.
1996, 118, 7702 – 7707. In principle, the current system in the
presence of CB[8] is complicated because of the multiple binding
equilibriums involved. However, the investigation of the origin
of the rate acceleration can be rationally simplified based on two
assumptions: 1) the equilibrium constant between CB[8] and d/
e·Cu2+ is around 105, therefore, under the experimental con-
ditions, it is justified to simplify the catalytically active copper
specie as only CB[8]·d/e·Cu2+; 2) other potentially existing
equilibria, such as CB [8] + 1a, CB[8] + d/e, CB [8] + 2 1a, and
CB[8] + 2 d/e, do not form the reactive species, and accordingly
will not contribute to the observed increase of kapp. Therefore,
those equilibria can be ignored when studying the catalytic cycle.
[17] a) W. Blokzijl, J. B. F. N. Engberts, Angew. Chem. Int. Ed. Engl.
1993, 32, 1545 – 1579; Angew. Chem. 1993, 105, 1610 – 1650;
b) E. A. Meyer, R. K. Castellano, F. Diederich, Angew. Chem.
Int. Ed. 2003, 42, 1210 – 1250; Angew. Chem. 2003, 115, 1244 –
1287; c) F. Biedermann, V. D. Uzunova, O. A. Scherman, W. M.
Nau, A. De Simone, J. Am. Chem. Soc. 2012, 134, 15318 – 15323;
d) F. Biedermann, M. Vendruscolo, O. A. Scherman, A. De Si-
mone, W. M. Nau, J. Am. Chem. Soc. 2013, 135, 14879 – 14888.
[18] S. Otto, Ph. D. Thesis, University of Groningen, 1998.
[19] a) G. Roelfes, B. L. Feringa, Angew. Chem. Int. Ed. 2005, 44,
3230 – 3232; Angew. Chem. 2005, 117, 3294 – 3296; b) M. Reetz,
N. Jiao, Angew. Chem. Int. Ed. 2006, 45, 2416 – 2419; Angew.
Chem. 2006, 118, 2476 – 2479; c) L. Zheng, A. Marcozzi, J. Y.
Gerasimov, A. Herrmann, Angew. Chem. Int. Ed. 2014, 53,
7599 – 7603; Angew. Chem. 2014, 126, 7729 – 7733.
[4] a) A. Schlatter, M. K. Kundu, W. D. Woggon, Angew. Chem. Int.
Ed. 2004, 43, 6731 – 6734; Angew. Chem. 2004, 116, 6899 – 6902;
b) S. Hu, J. Li, J. Xiang, J. Pan, S. Luo, J. Cheng, J. Am. Chem.
Soc. 2010, 132, 7216 – 7228.
[5] a) S. Shirakawa, S. Shimizu, Eur. J. Org. Chem. 2009, 1916 – 1924;
b) C. Dieleman, S. Steyer, C. Jeunesse, D. Matt, J. Chem. Soc.
Dalton Trans. 2001, 2508 – 2517.
[20] M. E. Wilson, G. M. Whitesides, J. Am. Chem. Soc. 1978, 100,
306 – 307.
[6] a) C. J. Brown, R. G. Bergman, K. N. Raymond, J. Am. Chem.
Soc. 2009, 131, 17530 – 17531; b) Y. Nishioka, T. Yamaguchi, M.
Kawano, M. Fujita, J. Am. Chem. Soc. 2008, 130, 8160 – 8161.
[7] V. Mandadapu, A. Day, A. Ghanem, Chirality 2014, 26, 712 –
723.
Received: June 18, 2015
Revised: August 10, 2015
Published online: September 7, 2015
Angew. Chem. Int. Ed. 2015, 54, 13007 –13011
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 13011