Iminium Catalysis inside a Self-Assembled Supramolecular Capsule: Scope and Mechanistic Studies

Article abstract of DOI:10.1021/jacs.7b08976

Although iminium catalysis has become an important tool in organic chemistry, its combination with supramolecular host systems has remained largely unexplored. We report the detailed investigations into the first example of iminium catalysis inside a supramolecular host. In the case of 1,4-reductions of α,β-unsaturated aldehydes, catalytic amounts of host are able to increase the enantiomeric excess of the products formed. Several control experiments were performed and provided strong evidence that the modulation of enantiomeric excess of the reaction product indeed stems from a reaction on the inside of the capsule. The origin of the increased enantioselectivity in the capsule was investigated. Furthermore, the substrate and nucleophile scope were studied. Kinetic investigations as well as the kinetic isotope effect measured confirmed that the hydride delivery to the substrate is the rate-determining step inside the capsule. The exploration of benzothiazolidines as alternative hydride sources revealed an unexpected substitution effect of the hydride source itself. The results presented confirm that the noncovalent combination of supramolecular hosts with iminium catalysis is opening up new exciting possibilities to increase enantioselectivity in challenging reactions.

Full text of DOI:10.1021/jacs.7b08976

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Article
Iminium Catalysis inside a Self-Assembled
Supramolecular Capsule: Scope and Mechanistic Studies
Thomas Braeuer, Qi Zhang, and Konrad Tiefenbacher
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b08976 • Publication Date (Web): 01 Nov 2017
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Iminium Catalysis inside a Self-Assembled Supramolecular
Capsule: Scope and Mechanistic Studies
Thomas M. Bräuera, Qi Zhanga, Konrad Tiefenbachera,b*
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a Department of Chemistry, University of Basel, BPR 1096, Postfach 3350, Mattenstrasse 24a, CH-4002 Basel, Switzerland
b Department of Biosystems Science and Engineering, ETH Zürich, Mattenstrasse 26, CH-4058 Basel, Switzerland
ABSTRACT: Although iminium catalysis has become an important tool in organic chemistry, its combination with supramolecular host
systems has remained largely unexplored. We report the detailed investigations into the first example of iminium catalysis inside a supramo-
lecular host. In the case of 1,4-reductions of ,-unsaturated aldehydes, catalytic amounts of host are able to increase the enantiomeric
excess of the products formed. Several control experiments were performed and provided strong evidence that the modulation of enantio-
meric excess of the reaction product indeed stems from a reaction on the inside of the capsule. The origin of the increased enantioselectivity
in the capsule was investigated. Furthermore, the substrate and nucleophile scope were studied. Kinetic investigations, as well as the kinetic
isotope effect measured confirmed that the hydride delivery to the substrate is the rate-determining step inside the capsule. The exploration
of benzothiazolidines as alternative hydride sources revealed an unexpected substitution effect of the hydride source itself. The results pre-
sented confirm that the non-covalent combination of supramolecular hosts with iminium catalysis is opening up new exciting possibilities
to increase enantioselectivity in challenging reactions.
Introduction
Catalysis inside self-assembled supramolecular containers is gain-
ing interest in the scientific community.10 It offers the potential to
observe substrate- and product-selectivities not observed in regular
solution experiments and, additionally, could facilitate multicata-
lyst tandem reactions.11 Recent examples included a Kemp elimi-
nation,12 reductive elimination,13 gold catalyzed reactions,14 epoxi-
dations,15 and an allylic oxidation/Diels–Alder cycloaddition se-
quence.16
The field of intermolecular enantioselective enamine1 and imin-
ium1b-d, 2 organocatalysis has flourished since the seminal reports in
the year 2000 by List3 and MacMillan,4 respectively. Iminium ca-
talysis is now regularly used for the construction of chiral building
blocks via mainly 1,4-addition and cycloaddition; while enamine
catalysis is a potent tool for the construction of α-functionalized
carbonyl compounds. Although these fields were heavily investi-
gated and still receive tremendous attention, efforts to combine
these activation modes with supramolecular assemblies have been
very limited. The Rebek group investigated a Knoevenagel reac-
tion accelerated by an amine catalyst bound to an open cavitand.5
A series of rotaxane-based switchable aminocatalysts were pre-
pared by the Leigh group and used for iminium and enamine catal-
ysis.6 Recently, an additional rotaxane-based organocatalyst was re-
ported by the Leung group.7 In all of these cases, the supramolecu-
lar structure functioned as the amine catalyst itself or entrapped the
catalyst in an open cavity. The reactions themselves were still tak-
ing place in solution. In other words, the supramolecular structure
just modified the catalyst and did not allow entrapping the reactive
intermediates. The groups of Raymond and Bergman did encapsu-
late an iminium species inside a supramolecular container but did
not observe conversion.8 Recently, our group reported the first ex-
ample of an iminium catalyzed reaction taking place inside a supra-
molecular container.9 Due to the binding of the reactive iminium
species on the inside of the capsule, the enantiomeric excess of the
product was increased as compared to the reaction in solution un-
der otherwise identical conditions. We now report the full details
concerning this reaction including substrate scope, mechanistic
details and also expand the reaction to further nucleophiles.
Our group9, 17 and the groups of Scarso and Strukul18 have utilized
the supramolecular capsule I, first reported by the Atwood group,19
successfully as catalyst. Container I self-assembles from six resor-
cinarene units 1 and eight water molecules in non-competitive sol-
vents like chloroform. With an internal volume of approx. 1.4 nm3
it is one of the largest hydrogen bond-based molecular capsules
available.20 Guest exchange, which is believed to occur via a portal
mechanism, is facile.21 Cationic molecules, for instance alkyl am-
monium ions bind strongly to the cavity of I due to cation-π inter-
actions.19b, 22 We reported that capsule I acts as a reasonable strong
Brønsted acid.17a This acidity, in combination with the capsule’s
ability to stabilize cationic intermediates/transition states, is re-
sponsible for its catalytic activity. However, in some cases, addi-
tional external acid is required.17e, 18d A very closely related supra-
molecular assembly is capsule II, which self-assembles from pyro-
gallolarene units 2.23 We recently reported that capsule II is catalyt-
ically inactive for terpene cyclizations,24 most likely due to its ina-
bility to encapsulate ion pairs.17e Its potential for iminium catalysis,
however, remained unexplored.
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Figure 1: Structures of resorcinarene (1) and pyrogallolarene (2) and their respective self-assembled hexameric capsules I and II.
(Fig. 2b). If the in situ formed iminium species is encapsulated fast
enough within I, its conversion with a nucleophile might indeed
Results and discussion
take place inside the restricted environment of the capsule. This
might lead to different substrate- and stereoselectivities than ob-
served in a regular solution experiment. To validate these consid-
erations, two competition experiments were initially investigated
in the presence of capsule I. We investigated the size selectivity of
the enamine-catalyzed addition of propanal (3) to differently sized
nitroolefins 4a and 4b. If the reaction takes place inside the cavity
of I, a selectivity towards the smaller addition product would be ex-
pected, as the larger nitro olefin 4b is too large for encapsulation.17a-
c However, even a slight preference for the larger addition product
6b was observed, indicating that the reaction took place outside of
the container.
Enamine vs. Iminium catalysis. At the outset of the investigation,
we tried to evaluate the potential of enamine and iminium organo-
catalysis inside aromatic supramolecular containers. In the case of
enamine catalysis, the reactive species is certainly the enamine,
which is in situ formed from the aldehyde substrate and the amine
catalyst. Amines and also enamines are only encapsulated in their
protonated forms inside capsule I,17a therefore, enamine catalysis
will be inhibited inside the container and only take place outside in
solution. In contrast, the reactive species in iminium catalysis is the
charged iminium species that should display a high affinity towards
the interior of capsule I due to strong cation-π interactions
Figure 2: Cycles for enamine and iminium catalysis.
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Figure 3: Size selectivity experiments for enamine and iminium ion catalysis in the presence and absence of capsule I.
experiment under otherwise identical conditions (Table 1, entries
Without I both addition products are also formed in approx. equal
amounts (Fig. 3a). Additionally, no significant difference in the op-
tical purity of product 6a was observed when the reaction was run
with (97% ee) or without capsule (98% ee). As an example for imin-
ium catalysis, the 1,4-reduction of an α,β-unsaturated aldehyde uti-
lizing Hantzsch ester as a hydride equivalent was utilized (Fig. 3b).
Again, two differently sized substrates (trans-2-hexenal (7a) and
trans-2-tridecenal (7b)) were utilized to detect a potential size se-
lectivity imposed by capsule I. Indeed, a significant selectivity to-
wards the smaller product 9a (10:1.0) was observed in the pres-
ence of catalytic amounts of I (26 mol%). This is in stark contrast
to the reaction without capsule under otherwise identical reaction
conditions, where even a slight selectivity towards the larger prod-
uct was detected (1.0:1.2). These initial results confirmed our as-
sumption that indeed iminium catalysis is feasible in the inside of
capsule I and that the transiently formed reactive iminium species
are encapsulated fast enough to efficiently suppress the back-
ground reaction outside in solution. Intrigued by these results, we
decided to explore enantioselective iminium catalysis inside the
capsule. Since the enantiotopos-differentiating step, the attack of
the nucleophile onto the encapsulated iminium ion, would be re-
quired to take place inside the densely packed environment of the
host, we expected to observe an alteration in enantioselectivity as
compared to the solution experiment. Preliminary results confirm-
ing this hypothesis were published last year by our group.9
1-2). The experiment using D-proline delivered, as expected, the
opposite result of the experiment using L-proline (5b) as organo-
catalyst (77% ee (R)). The closely related pyrogallolarene capsule
II, on the other hand, did not display this modulation effect on the
enantioselectivity observed (no ∆ee was observed; Table 1, entry
3).
Table 1: Comparison of the resorcinarene I and the pyrogallolarene II
capsule in the 1,4-reduction of (E)-3-phenyl-2-butenal (10a).
The known enantioselective 1,4-reduction of -substituted α,β-un-
saturated aldehydes with Hantzsch ester 8a (1.5 equiv) as a reduc-
ing agent was utilized as a starting point in this investigation (Table
1).25 In the initial screening,9 L-proline (5b, 20 mol%) was identi-
fied as the most promising organocatalyst for this study. Interest-
ingly, in the presence of catalytic amounts of capsule I (26 mol%),
a much higher enantioselectivity (74% ee (S) vs. 9% ee (S); corre-
sponding to a ∆ee of 65%) was observed than in a regular solution
[a] determined by GC analysis; [b] determined by chiral GC analysis.
Control experiments. To learn more about these results, we first
aimed at understanding where the reaction takes place. Several
control experiments were performed to elucidate the role of cap-
sule I. Separate reactions were run with either a large Hantzsch es-
ter (Table 2, 8b), a large organocatalyst 5c or a large aldehyde 10b
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instead of the respective standard reactants (Table 1). Molecular
modulation of enantiomeric excess is observed (Δee of 0%) These
modeling26 indicated that reactions involving one of these enlarged
reactants/reagents would not be possible inside the confined envi-
ronment of I. Therefore, such reactions would have to occur out-
side in the solution and/or on the outer surface of capsule I. In all
these three cases, ∆ee values well below ±10% were observed,
much lower than the value of 65% observed under the regular con-
ditions. In an ideal control experiment of this kind, no ∆ee would
be expected. We attribute the small modulating effect observed in
these control reactions to a (weak) interaction of the reactive imin-
ium species to the outside of the capsule; this seems likely since it
is known that tetraalkyl ammonium ions are able to bind weakly to
the outside of capsule I.27
five control experiments provide convincing evidence that the
strong modulation of enantiomeric excess indeed stems from an
encapsulation effect inside host I.
Source of ee-modulation. The modulation of enantioselectivity in-
side I is even more intriguing when taking into account that the
building blocks of capsule I, resorcinarene 1 (Fig. 1) and water, are
achiral. This means that no additional chiral information is added
to the experiment. The different enantioselectivity observed within
I may stem from altered reactivities of the respective E- and Z-al-
kene isomers of the iminium ion (Fig. 4a). It was reported by Mac-
Millan that both alkene isomers of aldehyde 10a are converted to
the same product enantiomer.25c This stereoconvergence is at-
tributed to a rapid iminium-catalyzed ZE isomerization and a se-
lective hydride delivery to the E-isomer. We, therefore, decided to
investigate the isomerization in the presence of the supramolecular
system in detail. In solution, when starting from the E-isomer, the
unreacted starting material 10a displayed an E/Z ratio of 1.95 after
8 h under the standard reaction conditions (Table 3, entry 1 with-
out capsule). A similar ratio was reached after 8 h when starting
from the Z-isomer (entry 2 without capsule). This indicates that
an equilibrium distribution of approx. 1.8 between the E- and Z-
isomer is reached in the solution experiment (for details see SI).
Interestingly, the capsule experiments displayed contrasting re-
sults. In both cases, the purity of the alkene isomer added was re-
tained rather efficiently. After 8 h, the ratios were still 8.16 and
0.09, respectively. Nevertheless, also in the capsule experiments a
stereoconvergence of the final product was observed, indicating
that an isomerization took place after iminium formation but be-
fore hydride addition in the case of the Z-alkene isomer. This likely
indicates that once a Z-iminium species is formed and encapsu-
lated, it is isomerized to the E-iminium species and predominantly
converted to the product without hydrolysis in between, thereby
retaining the substrate isomer ratio in solution. In a regular solu-
tion experiment, however, the formed iminium is predominantly
hydrolyzed again after isomerization, resulting in the fast equilibra-
tion of the added alkene isomers. This interpretation of the results
is also in line with observations with a different supramolecular
host which is able to protect iminium ions from hydrolysis.8 There-
fore, altered reactivities of the respective E- and Z-alkene isomers
of the iminium ion inside the capsule cannot explain the modula-
tion of ee observed.
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Table 2: Performed control experiments involving a large Hantzsch es-
ter 8b, a large catalyst 5c, a large aldehyde 10b and hexamethonium
bromide (12).
An alternative explanation for the observed modulation of enanti-
oselectivity inside I may involve the chirality of I. Although, as
stated before, the building blocks of I are achiral, the assembly of I
itself is chiral due to the twisted arrangement of the subunits (Fig.
1).19a Nevertheless, the capsule is present as racemate. It was re-
cently shown that encapsulated chiral tertiary amines (good guests
due to protonation by the capsule I)17a induce optical activity onto
the capsule itself.28 It is likely that the chiral iminium ion formed
during iminium catalysis would impose a similar induction onto I.
However, the weak chiral field produced by the slight twists of the
capsule components is not the most likely source of the effect ob-
served. Also the pronounced differences in ee-modulation for very
similar substrates (vide infra, Table 4) is supporting another mech-
anism. It is more likely that the modulation stems from a binding
effect.
[a] determined by GC analysis; [b] determined by chiral GC analysis.
Additionally, a control experiment was performed in which the
cavity of I was blocked by hexamethonium bromide (12), a bis am-
monium salt (Table 2, entry 4). In previous publications of our
group, we successfully blocked capsule I with tetrabutyl ammo-
nium bromide. In this project, however, the usage of singly charged
ammonium salts would not suppress the uptake of the iminium
species efficiently. Due to its higher charge, we expected 12 to out-
compete the iminium species efficiently. Indeed, this control ex-
periment also resulted in a greatly reduced ∆ee. In another control
experiment, we added DMSO to the experiment with capsule.
DMSO destroys the hexameric structure of capsule I by interrupt-
ing the hydrogen bond network. Also in this control experiment no
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Table 3: Study of the influence of the alkene isomer 10a utilized in the reduction experiments.
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Values after 8 h; [a] determined by GC analysis; [b] determined by chiral GC analysis.
Figure 4: (a) E-iminium and Z-iminium ion of (E)-3-phenyl-2-butenal (10a); (b) Hypothesis for the increased enantioselectivity inside capsule I.
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Our hypothesis is that the iminium preferentially binds to the inner
walls of capsule I from the less hindered side (anti to the carboxylic
acid of proline, Fig. 4b). This arrangement then facilitates the at-
tack of the nucleophile from the top face (syn to the carboxylic
acid), which preferentially produces the (S)-product in case of L-
proline. This mechanism is in accordance with the selectivities ob-
served and with our current understanding of the system.
produced only low to modest selectivity differences inside the cap-
sule. However, the ortho-derivative (10f) displayed a very high Δee
of 92%. These dramatic differences for the methyl derivatives 10d-
f support our hypothesis that the binding of the iminium species to
the capsule walls is responsible for the selectivity increase. In the
case of 10f, however, only a yield of 12% was obtained. To examine
if the ortho-position generally delivers poor yields, we tested the
ortho-methoxy derivative 10g. To our delight a high yield of 96%
and a noteworthy Δee of 69% were obtained. Further ortho-substi-
tuted derivatives were investigated: All halogenated substrates
10h-j displayed high ∆ee values, indicating that indeed ortho-sub-
stituted derivative in general display better selectivities inside the
capsule. The decrease in yield and conversion in the series 10h to
10j indicates that a large ortho-substituent is slowing down the re-
action considerably. The smaller fluoro-substituted aldehyde 10h
produced a good yield of 76%, whereas the much larger bromo-
substituted aldehyde 10j formed the respective product 11j in only
14%. The even larger nitro-compound 10k also followed the ob-
served trend.
In any case, why is the modulation effect not observed with capsule
II? Recent findings from our group indicate that capsule II does not
encapsulate ion pairs due to the absent stabilization of anions
within its cavity.24 Since the iminium ion formed is present as an
ion pair in an apolar solvent like chloroform, it is likely that indeed
failure of uptake into its cavity is the reason for the lack of modula-
tion with II.
Aldehyde substrate scope. Next, the aldehyde substrate scope was
investigated in detail. The cyclohexyl derivative 10c showed a re-
duced Δee of only 26%, which might indicate that the aromatic
moiety of the aldehyde plays an important role in binding of the
iminium species inside I via π-π interactions. Subsequently, three
methyl derivatives of (E)-3-phenyl-2-butenal (10a) were investi-
gated. Interestingly, the results differed dramatically: The para-de-
rivative (10d, Δee = 9%) and meta-derivative (10e, Δee = 41%)
Mechanistic studies. To gain a better insight into the 1,4-reduction
inside capsule I at hand, mechanistic studies were performed by us-
ing the initial rate method. Under the standard reaction conditions,
pseudo first order consumption of the α,β-unsaturated aldehyde
was observed (Fig. 4a). Additionally, the activation parameters
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were measured by performing the reaction at different tempera-
the rate determining step of the reaction inside capsule I. Addi-
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tures (Fig. 4b).
tional evidence was sought by investigating the kinetic isotope ef-
fect for the hydride transfer. The known d2-Hantzsch ester 8c29
(Fig. 6) was synthesized from d2-paraformaldehyde utilizing the
classical Hantzsch ester synthesis. The experiments utilizing the
regular and deuterated Hantzsch ester 8a and 8c, respectively, were
Table 4: Results of the iminium catalyzed 1,4-reduction of different al-
dehydes 10 utilizing proline (5b) as catalyst.
run in triplicate. A primary kinetic isotope effect of kH/kD
=
I
Capsule
Yield
(%)a
enantiomeric
excessb
Entry
1
Aldehyde
ee
1.90±0.05 was observed, providing strong evidence that indeed the
hydride transfer is the rate determining step.
present?
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O
yes
no
89±8 63±1% ee (S)
73±1 37±1% ee (S)
26%
10c
O
yes
no
67±2 18±1% ee (S)
26±2 9±2% ee (S)
2
3
4
5
6
7
8
9
9%
10d
O
yes
no
89±3 61±1% ee (S)
37±2 20±5% ee (S)
41%
92%
69%
74%
80%
66%
38%
10e
O
yes
no
12±0 73±1% ee (S)
10±1 19±2% ee (R)
10f
O
yes
no
OMe
96±4 78±2% ee (S)
28±12 9±1% ee (S)
10g
O
F
yes
no
76±1 78±0% ee (S)
17±1 4±0% ee (S)
10h
O
O
yes
no
Figure 5: (a) Initial rates at 303 K, 313 K and 323 K; (b) Eyring plot.
Cl
40±1 77±3% ee (S)
10±1 3±0% ee (R)
Alternative hydride sources. Since transfer of the hydride is the rate
determining step, changing the hydride source potentially has a
strong impact on the selectivities observed. Therefore, we investi-
gated alternative hydride sources. Our interest turned to benzothi-
azolidines, which were shown to reduce imines in a phosphoric
acid-catalyzed transfer hydrogenation.30
10i
yes
no
Br
14±0 69±2% ee (S)
5±1
3±2% ee (S)
10j
O
O
O
yes
no
NO2
10±0 40±2% ee (S)
8±0 2±1% ee (S)
5b (20 mol%)
R
R
EtO2C
Me
CO2Et
Me
I
capsule (26 mol%)
10k
(CDCl3)
N
R
30 °C, 0.15 M
H
8a
8c
11a
11l
(R = H)
(R = D)
(R = H)
(R = D)
[a] determined by GC analysis; [b] determined by chiral GC anal-
ysis.
10a
1 equiv
1.5 equiv
The obtained parameters for the capsule-mediated 1,4-reduction
reaction are ΔH≠ = 21.10±0.16 kcal/mol, ΔS≠ = -9.57±0.49 J/mol
and ΔG≠ = 24.00±0.02 kcal/mol. The negative entropy of activa-
tion observed may indicate that the bimolecular hydride transfer is
kinetic isotope effect : kH/kD = 1.900.05
Figure 6: Kinetic isotope effect of the examined 1,4-reduction.
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Table 5: Results of the iminium catalyzed 1,4-reduction utilizing different benzothiazolidines 13.
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[a] determined by GC analysis; [b] determined by chiral GC analysis; [c] 1.5 equiv of reducing agent and concentration of 0.15 M; [d] 1 equiv of
reducing agent and concentration of 0.075 M.
The phenyl- (13a), methyl- (13b) and naphthyl- (13c) derivatives
of this class of reducing agents were investigated (Table 5). As with
Hantzsch ester 8a as hydride donor, L-proline (5b) displayed good
enantioselectivity in the presence of capsule (78% R) with benzo-
thiazolidine 13a. However, the other enantiomer is formed! To
rule out mistakes, the absolute configuration of L-proline was
checked by measuring the optical rotation. Additionally, the exper-
iments were repeated in triplicate, confirming this surprising result
(entry 1, Table 5). Unfortunately, and although starting material
was converted, no ∆ee value could be determined since the corre-
sponding solution experiment did not yield the desired product
11a at all. In general, the yields using benzothiazolidines as reduc-
ing agents were only low to modest, although the conversion of the
starting material was good. Investigations revealed that the starting
material (the α,β-unsaturated aldehyde) as well as the product al-
dehyde underwent trans-N,S-acetalization with the benzothiazoli-
dine (see SI-Fig. S14 – S16). Although these side reactions unfor-
tunately reduced the yield, the results obtained are, in our opinion,
nevertheless of high conceptual interest. When utilizing proline de-
rivative 5d, a ∆ee value near 0% was observed with benzothiazoli-
dine 13a. Like in the case of L-proline, a preference towards the R-
enantiomer was also observed with proline amide 5e (∆ee of -18%)
and L-thioproline (5f, ∆ee of -73%) as organocatalysts. This is the
first time we observed selectivity towards the R-enantiomer inside
the capsule when utilizing the S-configured secondary amines uti-
lized for this study. What causes this tendency towards the R-enan-
tiomer? There might be additional π-π interactions of the aromatic
benzothiazolidine 13a with the capsule walls or, alternatively, cat-
ion-π interactions between the iminium ion and the hydride
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source. Such interactions could override the proposed binding of
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the iminium species (Fig. 4b) and, therefore, lead to opposite en-
antioselectivites. With proline tetrazole 5g, which features an elec-
tron poor aromatic surface, this effect is not detected (∆ee of 47%).
To learn more about these surprising observations, catalysts 5f and
5g were further investigated using other benzothiazolidines. First
benzothiazolidine 13b, which carries a methyl group instead of a
phenyl substituent was tested. With L-thioproline (5f) as catalyst
and 13b as hydride donor, a high ∆ee of 67% is observed, whereas
18% are obtained with 5g. In both cases the expected (S)-product
is formed preferentially inside I again. This supports the notion
that indeed the additional phenyl ring in reducing agent 13a caused
the observed preference for the R-configured product inside the
capsule, since the methyl derivative 13b did not display this effect.
When using the larger naphthyl-benzothiazolidine 13c, the size
limit of capsule I is reached and only very low yields of product are
observed in these cases. The investigations into the benzothiazoli-
dine revealed how subtle non-covalent interactions between the re-
actants and the capsule can lead to complete changes in the optical
activity of the reduction product. Although these modulation ef-
fects are not predictable at this stage, we believe that further inves-
tigations with additional supramolecular structures are justified.
The increased enantiomeric excess observed within capsule I will
be especially helpful in examples of iminium catalysis where no sat-
isfactory enantiocontrol can be achieved with regular solution
chemistry so far.31
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by funding from the Swiss National Science
Foundation as part of the NCCR Molecular Systems Engineering and
the Bayerische Akademie der Wissenschaften (Junges Kolleg). T. M.
B. thanks the National Research Fund, Luxembourg for an AFR fel-
lowship. We thank Dr. Johannes Richers for graphical design.
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Conclusion
In summary, detailed investigations into the first example of imin-
ium catalysis inside a supramolecular host are described. The dif-
ferences in influencing enamine and iminium catalyzed reactions
inside capsule I were explored. Several control experiments were
performed and provided strong evidence that the modulation of
enantiomeric excess of the reaction product indeed stems from a
reaction on the inside of capsule I. The origin of the increased en-
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confirmed that the hydride delivery to the substrate is the rate-de-
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ASSOCIATED CONTENT
Supporting Information. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Author
konrad.tiefenbacher@unibas.ch / tkonrad@ethz.ch
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