Iminium Catalysis inside a Self-Assembled Supramolecular Capsule: Modulation of Enantiomeric Excess

Article abstract of DOI:10.1002/anie.201602382

The noncovalent combination of a supramolecular host with iminium organocatalysis is described. Due to cation–π interactions the reactive iminium species is held inside the host and reacts in this confined environment. The products formed differ up to 92 % ee from the control experiments without added host. A model rationalizing the observed difference is presented.

Full text of DOI:10.1002/anie.201602382

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International Edition: DOI: 10.1002/anie.201602382
German Edition: DOI: 10.1002/ange.201602382
Host–Guest Systems
Hot Paper
Iminium Catalysis inside a Self-Assembled Supramolecular Capsule:
Modulation of Enantiomeric Excess
Thomas M. Bräuer, Qi Zhang, and Konrad Tiefenbacher*
Abstract: The noncovalent combination of a supramolecular
host with iminium organocatalysis is described. Due to cation–
p interactions the reactive iminium species is held inside the
host and reacts in this confined environment. The products
formed differ up to 92% ee from the control experiments
without added host. A model rationalizing the observed
difference is presented.
C
atalysis in self-assembled supramolecular structures has
Figure 1. Structure of resorcinarene 1 and capsule I.
attracted great interest.[1] Chemists are intrigued by the
possibility of performing reactions in small spaces (nm3 scale),
in which the reactivities and selectivities differ from those in
solution.[2] In artificial systems, product inhibition poses
a great challenge. Nevertheless, a variety of reactions includ-
ing hydroformylations,[3] hydrolysis,[4] hydrations,[5] hydro-
alkoxylations,[6] aza-Cope rearrangements,[7] Diels–Alder
reactions, Nazarov[8] and, Prins[9] cyclizations, isomeriza-
tions,[10] and terpene cyclizations[11] were catalyzed success-
fully. The majority of these examples involve monomolecular
reactions, or reactions catalyzed by an encapsulated metal
catalyst. We herein report the catalysis of a complex multi-
molecular reaction inside the supramolecular host I. Capsule
I, first reported by the Atwood group,[12] self-assembles from
six resorcinarene units
1 and eight water molecules
(Figure 1).[13] Its behavior in solution was studied exten-
sively.[14]
Figure 2. Proposed pathway of the iminium-catalyzed reaction inside
capsule I.
Recently, we reported that I acts as a Brønsted acid[4g] and
is able to catalyze cationic reactions.[6c,11] We now explored
the possibility of controlling iminium reactions[15] inside this
host. If the reaction is to occur inside the cavity of I, rapid
encapsulation of the reactive iminium species 4 (Figure 2) is
essential. Since capsule I displays a high affinity towards
ammonium ions due to cation–p interactions,[14b,c,e–h,m] we
speculated that a suitably sized iminium species would also be
an excellent guest to yield complex A. After uptake of
a nucleophile (complex B) and reaction (complex C),
hydrolysis would regenerate the catalysts amine 2 and capsule
I.
To the best of our knowledge, no iminium catalysis has
been reported inside supramolecular structures. The Rebek
group reported the acceleration of a Knoevenagel reaction by
an amine catalyst bound to a cavitand, where the reaction
took place outside of the open cavity.[16] The Bergman and
Raymond groups reported the stabilization of an iminium ion
inside a supramolecular container but no conversion.[17] The
fact that intramolecular cation–p interactions can play a sig-
nificant role in iminium catalysis was demonstrated by the
Gilmour group.[18] We herein show that intermolecular
cation–p stabilization and the resulting encapsulation inside
a supramolecular host can dramatically influence the reac-
tion.
[*] M. Sc. T. M. Bräuer, M. Sc. Q. Zhang
As a model reaction, the organocatalytic reduction of a,b-
unsaturated aldehyde 3a (Figure 3) was investigated.[19] The
Department of Chemistry, Technical University of Munich
Lichtenbergstrasse 4, 85747 Garching (Germany)
Prof. Dr. K. Tiefenbacher
Department of Chemistry, University of Basel
St. Johannsring 19, CH-4056 Basel (Switzerland)
E-mail: konrad.tiefenbacher@unibas.ch
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201602382.
Figure 3. Iminium-catalyzed 1,4-reduction investigated.
7698
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reactions were carried out with and without 26 mol% capsule
No significant Dee values were observed in these cases,
I. Reactions with catalysts carrying a sterically shielding
group in a-position (entries 1 and 2, Table 1) did not display
significant differences when capsule I was present. However,
catalysts with hydrogen-bond acceptor groups (entries 3–5,
Table 1) provided products with different enantiomeric excess
when the capsule was present. For instance, with proline
benzyl ester 2e a Dee value of 32% was observed. Employing
catalysts with hydrogen-bond acceptor and donor function-
alities (entries 6 and 7, Table 1), resulted in even higher Dee
values. In the case of proline 2g (entry 7, Table 1), 67% ee (S)
was obtained in the presence of I, while only 23% ee (S) were
observed in its absence.
Control experiments (Supporting Information (SI) chap-
ters 8.1–8.6) with a very large Hantzsch ester, amine catalyst,
and aldehyde were performed. Due to their size, the
formation of the reactive complex B (Figure 2) is prevented
and, therefore, the reaction has to occur outside in solution.
providing strong evidence that encapsulation is indeed
responsible for the strong modulation of the ee. Further
evidence is provided by a control experiment, in which the
cavity was blocked by a strongly binding inhibitor. Evidence
for the encapsulation of an iminium species of 2g was
obtained by NMR spectroscopy (SI chapters 8.7–8.10).
Furthermore, we found that in the case of the carboxylic
acid 2g the addition of acid additive is not necessary. Without
TFA, even a higher modulating effect of capsule I was
observed (Dee of 65%). Also other catalysts with acidic
protons, thioproline (2h) and proline tetrazole 2i,[20] exhib-
ited relatively large Dee values (43% and 51%, respectively).
Inside the confined environment of I, strong substrate
selectivity is to be expected. Therefore, a series of unsaturated
aldehydes were investigated with 2g as the catalyst (Table 2).
Table 2: Results of the iminium catalyzed 1,4-reduction of different
aldehydes 3 utilizing proline (2g).
Table 1: Results of the iminium-catalyzed 1,4-reduction of aldehyde 3a
utilizing different catalysts.
[a] Determined by GC analysis. [b] Determined by GC analysis on a chiral
stationary phase.
The addition of a methyl group at different positions of the
phenyl substituent of the substrate (entries 1–3, Table 2) had
a pronounced influence on the reaction inside the capsule: the
Dee value observed increased from 9% (para-) to 92%
(ortho-substitution). Similarly, the ortho-methoxy substrate
was also converted much more selectively in the presence of
capsule (Dee of 69%). To gauge the influence of the phenyl
group, the cyclohexyl derivative was investigated. Only
a reduced modulating effect of capsule I was observed (Dee
of 26%), indicating that interactions of the phenyl ring
contribute to the phenomenon observed.
Inspection of all experiments reveals that the enantio-
meric distribution of the product tends towards an S configu-
ration inside I, when compared to the corresponding results in
[a] Determined by GC analysis. [b] Determined by GC analysis on a chiral
stationary phase. Bn=benzyl, TFA=trifluoroacetic acid, TMS=trime-
thylsilyl.
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Figure 4. Hypothesis for the different selectivity inside capsule I.
solution. We propose that the iminium species binds to the
interior wall of the cavity via cation–p interactions from the
less hindered side (Figure 4a). Therefore, the hydride is
preferentially delivered syn to group Y. In the case of
directing groups[15a,21] (groups that can act as hydrogen-bond
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the container (SI chapter 6.2). This is due to the fact that the
reactive iminium species is sequestered from the nucleophile
by encapsulation.
In summary, it has been demonstrated that an iminium-
catalyzed 1,4-reduction can be performed inside a supra-
molecular host. The intermolecular, noncovalent interactions
inside the host system dramatically improve the enantiose-
lectivity for several amine catalysts. As expected for a reaction
inside a confined environment, a high substrate selectivity was
observed. To some extent, the presented system mimics
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cofactor inside an enzyme pocket. Conceptually, this novel
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Acknowledgements
We thank Prof. Thorsten Bach for his support. T.M.B. thanks
the National Research Fund, Luxembourg for an AFR
fellowship. Further support was provided by the Bayerische
Akademie der Wissenschaften, Fonds der Chemischen Indus-
trie, and the TUM Junior Fellow Fund. We thank M.Sc.
Johannes Richers for graphical design.
Keywords: enantioselectivity · host–guest systems ·
iminium catalysis · organocatalysis · supramolecular chemistry
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Received: March 8, 2016
Revised: April 22, 2016
Published online: June 3, 2016
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