Optimized iminium-catalysed 1,4-reductions inside the resorcinarene capsule: achieving >90% ee with proline as catalyst

Article abstract of DOI:10.1039/d1ra04333a

In previous work, we demonstrated that iminium-catalysed 1,4-reductions inside the supramolecular resorcinarene capsule display increased enantioselectivities as compared to their regular solution counterparts. Utilizing proline as the chiral catalyst, enantioselectivities remained below 80% ee. In this study, the reaction conditions were optimized by determining the optimal capsule loading and HCl content. Additionally, it was found that alcohol additives increase the enantioselectivity of the capsule-catalysed reaction. As a result, we report enantioselectivities of up to 92% ee for iminium-catalysed 1,4-reductions relying on proline as the sole chiral source. This is of high interest, as proline is unable to deliver high enantioselectivities for 1,4-reductions in a regular solution setting. Investigations into the role of the alcohol additive revealed a dual role: it not only slowed down the background reaction but also increased the capsule-catalysed reaction rate.

Full text of DOI:10.1039/d1ra04333a

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Optimized iminium-catalysed 1,4-reductions inside
the resorcinarene capsule: achieving >90% ee with
proline as catalyst†
Cite this: RSC Adv., 2021, 11, 24607
a
ab
*
Daria Sokolova
and Konrad Tiefenbacher
In previous work, we demonstrated that iminium-catalysed 1,4-reductions inside the supramolecular
resorcinarene capsule display increased enantioselectivities as compared to their regular solution
counterparts. Utilizing proline as the chiral catalyst, enantioselectivities remained below 80% ee. In this
study, the reaction conditions were optimized by determining the optimal capsule loading and HCl
content. Additionally, it was found that alcohol additives increase the enantioselectivity of the capsule-
catalysed reaction. As a result, we report enantioselectivities of up to 92% ee for iminium-catalysed 1,4-
reductions relying on proline as the sole chiral source. This is of high interest, as proline is unable to
deliver high enantioselectivities for 1,4-reductions in a regular solution setting. Investigations into the
role of the alcohol additive revealed a dual role: it not only slowed down the background reaction but
also increased the capsule-catalysed reaction rate.
Received 4th June 2021
Accepted 5th July 2021
DOI: 10.1039/d1ra04333a
rsc.li/rsc-advances
Our understanding of capsule I-catalysis improved
substantially over the last years. For instance, the importance
Introduction
of HCl as a co-catalyst for a selection of reactions inside I was
elucidated.31 However, the inuence of HCl on iminium-
catalysed reactions inside I remains unknown. This work
aimed at (1) elucidating the role of HCl for the iminium
catalysis inside I; (2) reducing the amount of capsule catalyst
required, as originally 26 mol% were utilized; (3) optimizing
the reaction conditions to improve the enantioselectivity. We
The self-assembled resorcinarene hexamer I (Fig. 1a), rst re-
ported by Atwood1 in the solid state in 1997, comprises one of
the easiest to access molecular containers based on hydrogen
bonds. It assembles from six resorcinarene units 1, readily
accessible in one step on a large scale, and eight water mole-
cules.1–3 Due to its dynamic nature, it can entrap guest mole-
cules temporarily inside its cavity.2,4–9 The properties of I in
solution were studied in detail, mainly by the groups of Rebek
and Cohen.2–7,9–15 More recently, this container has started
being explored as a container for other catalysts16 or as
a catalyst itself.17,18 The eld has been reviewed,19–23 and novel
applications have been found very recently.24–27 In 2016, our
group reported that iminium-catalysis can be performed
inside capsule I (Fig. 1b).28,29 Later work by the Neri group
extended iminium catalysis inside I to cycloadditions.30 The
a,b-unsaturated aldehyde rst forms an iminium species with
the chiral amine catalyst L-proline (3a). This iminium species
is encapsulated due to the high affinity of the capsule I for
cationic species. The subsequent reduction with Hantzsch
ester 2, therefore, has to take place inside the conned envi-
ronment of the capsule, delivering much higher enantiose-
lectivities than in the absence of container I.28,29
aDepartment of Chemistry, University of Basel, 4058 Basel, Switzerland. E-mail:
konrad.tiefenbacher@unibas.ch
bDepartment of Biosystems Science and Engineering, ETH Zurich, 4058 Basel,
¨
Switzerland. E-mail: tkonrad@ethz.ch
Fig. 1 (a) Self-assembly of monomer 1 into hexameric capsule I. (b)
General scheme of iminium catalysed 1,4-reduction inside capsule I.
† Electronic supplementary information (ESI) available: Experimental details, and
copies of GC spectra. See DOI: 10.1039/d1ra04333a
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here report the results of this effort. As a highlight of these capsule exerts a detrimental effect on the ee (background
studies, unprecedented enantioselectivities of up to 92% were iminium reaction, <12 mol%, entries 1 and 2 of Table S1†); (2)
achieved for the 1,4-reduction of a,b-unsaturated alde- at higher capsule loadings, the racemic background reaction
hydes32–34 inside capsule I using simple proline as the sole catalysed by capsule I itself starts dominating (>12 mol%,
source of chiral information. This is of high interest as proline entries 4–10 of Table S1†). This background reaction is caused
in a regular solution setting is unable to deliver high enan- by the activation of the aldehyde substrate by the capsule itself
tioselectivities for 1,4-reductions.34
(without proline) and leads to a racemic product as described
in our previous work.28 Therefore, 12 mol% I was selected for
further studies.
Results and discussion
In the previous work of our group, it was already demon-
strated that Hantzsch ester 2 and L-proline (3a) are the most
suitable hydride source and chiral catalyst, respectively.28,29 In
this study, different L-proline loadings were evaluated with the
newly optimized capsule I loading of 12 mol%. As can be seen in
Table S2,† the optimum was found at 20 mol% of L-proline.
Next, the inuence of HCl on the enantioselectivity of the
standard reaction was explored. It was studied for two
different capsule loadings: the optimized 12 mol% and the
previously utilized 26 mol%.28,29 As can be seen in Fig. 2b, the
enantioselectivity of the reaction does not benet from HCl traces.
Contrarily, larger HCl loadings (>5 mol%) even lead to a drop in
enantioselectivity, presumably via an acid-catalysed racemic
background reaction (Table S3†). A similar trend is observed for
reactions with 26 mol% of I. Hence, the addition of HCl is not
required for the iminium-catalysed 1,4-reductions inside capsule I.
This nding is in line with our previous report that not all reac-
tions inside I depend on an acid co-catalyst.31
As a rst step, we aimed at reducing the unusually high
capsule loading (26 mol%). This loading was initially
selected28 to ensure complete uptake of proline (20 mol%) and
its iminium species. Utilizing the standard reaction condi-
tions with substrate A1 (1 equiv. of A1, c(A1) ¼ 0.15 M in
chloroform, 1.5 equiv. of reducing agent 2, 0.2 equiv. of amine
catalyst 3a; Section 3.2 in ESI†), the inuence of the capsule
loading (8–26 mol%) was explored (Fig. 2a). Interestingly,
a peak selectivity (80% ee) was found at 12 mol%, which
deteriorated both for increasing and decreasing loadings. This
surprising nding may be a result of two opposing effects: (1)
at low capsule loadings, the iminium reaction outside of the
Aer having established the optimal capsule (12 mol%) and
proline (20 mol%) loadings, and HCl content (none), further
additives were investigated. Of particular interest were alcohol
additives, as their interactions with the resorcinarene capsule
are well documented.15,35–37 The Cohen group investigated the
incorporation of different alcohols into the resorcinarene
capsule in solution and demonstrated that they can replace
water molecules of the hydrogen bond network.15,36 Addition-
ally, in the solid state it was reported that the incorporation of
nPrOH into the hydrogen network of the resorcinarene hex-
amer results in 25% larger assemblies.38 These reports
prompted us to investigate the inuence of different alcohol
additives on the iminium catalysis inside I. Indeed, initial
Table 1 Optimization of the alcohol additive under the standard
reaction conditions: 1 equiv. A1, c(A1) ¼ 0.15 M, 12 mol% of I, 1.5 equiv.
2, 0.2 equiv. 3aa
Entry
Alcohol
Yield (%)
Conversion (%)
ee (%)
1
2
3
4
5
6
—
89 ꢀ 1
89 ꢀ 1
89 ꢀ 3
90 ꢀ 1
91 ꢀ 1
89 ꢀ 2
93 ꢀ 1
93 ꢀ 1
94 ꢀ 2
94 ꢀ 2
94 ꢀ 2
94 ꢀ 2
77 ꢀ 1 (S)
80 ꢀ 2 (S)
80 ꢀ 2 (S)
80 ꢀ 2 (S)
83 ꢀ 2 (S)
80 ꢀ 2 (S)
MeOH
EtOH
nPrOH
iPrOH
nBuOH
Fig. 2 (a) Optimization of the capsule I loading (8–26 mol%) under the
standard reaction conditions using aldehyde A1: 1 equiv. A1, c(A1) ¼
0.15 M in chloroform, 1.5 equiv. 2, 0.2 equiv. 3a. The optimal amount of
I (12 mol%) is highlighted. (b) Influence of the HCl content on the
standard reaction utilizing either 12 or 26 mol% of capsule I. Enan-
tiomeric excesses were determined with chiral GC measurements. The
values reported refer to measurements after 72 h of reaction time.
a
Conversions, yields, and enantiomeric excesses were determined with
achiral and chiral GC measurements. The values reported refer to
measurements aer 72 h of reaction time. Reactions were performed
in triplicate and standard deviations were determined
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tests revealed that alcohol additives increased the enantiose- effect of the capsule on substrate A5 was lower than in the
lectivity of the standard reaction. An initial screening indi- other four cases; most likely due to the lack of an aromatic
cated that the best results were obtained with 9 equiv. of moiety that facilitates p–p interactions with the capsule walls.
alcohol per capsule (Table S4†). Subsequently, several alcohol Most interestingly, for two substrates (A2 and A3), enantiose-
additives were screened (Table 1). As shown in Table 1 addi- lectivities >90% ee were achieved. This is remarkable, as
tion of each of the tested alcohols led to a slight increase of the proline is unable to deliver high enantioselectivities for 1,4-
ee, with iPrOH performing slightly better than the alternatives reductions in a regular solution setting.34 Only in combination
concerning yield and ee. Although the change in ee was not with the capsule catalyst and iPrOH, these high selectivities
very big (6% ee, see entries 1 and 5 in Table 1), it was fully are observed.
reproducible. The effect of the iPrOH additive was studied with
How does iPrOH inuence the enantioselectivity of the
a series of substrates (Table 2). In all cases, the combination of capsule-catalysed reaction? Initially, we investigated the inu-
capsule I and iPrOH resulted in higher enantioselectivities. As ence of iPrOH on the capsule structure and size, as it was re-
reported in our previous work on the substrate scope,29 the ported that alcohol incorporation can increase the size of the
Table 2 Results of reactions with different substrates under optimized conditions: 1 equiv. A, c(A) ¼ 0.15 M in chloroform, 12 mol% I, 1.5 equiv. 2,
0.2 equiv. 3a, 9 equiv. iPrOH, (bright-green). Comparison to reactions in the presence of 12 mol% of capsule I, but the absence of iPrOH (dark-
green); reactions in the absence of capsule I, and the presence of 9 equiv. of iPrOH (dark-grey); reactions in the absence of both capsule I and
iPrOH (light-grey)a
a
Conversions, yields, and enantiomeric excesses were determined by GC measurements. The values reported refer to measurements aer 72 h of
reaction time. Reactions were performed in triplicate and standard deviations were determined
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Fig. 3 Non-linear effects study of iminium catalysed 1,4-reduction
under optimized conditions using aldehyde A5: 1 equiv. A5, c(A5) ¼
0.15 M in chloroform, 1.5 equiv. 2, 0.2 equiv. of proline (mixtures of L-
and D-proline of different ratios). Different reaction conditions
(absence/presence of I and/or iPrOH) were explored. Enantiomeric
excesses were determined by chiral GC measurements. For more
details, see Section 3.7 of the ESI.†
capsule by 25%, at least in the solid state.38 However, DOSY-
NMR data indicates that the size of the capsule does not
change upon the addition of iPrOH (see Section 5 of the ESI† for
diffusion coefficients). This is in line with observations in
solution from the Cohen group, who reported the replacement
of water molecules in the hydrogen bond network by iPrOH
without a signicant change in the assembly size.36
Another hypothesis centered on the idea that the alcohol additive
might inuence proline–proline interactions in the capsule.
If such interactions play a role, non-linear effects (NLE)
should be observable. Therefore, a NLE study was performed.
Substrate A5 was chosen since it yields the highest ee in the
absence of the capsule (Table 2) and thus facilitates the obser-
vation of changes. In all the cases, linear graphs were obtained
(Fig. 3). Accordingly, we can exclude iPrOH-effected changes in
the proline–proline interactions as the source of the increased
enantioselectivity.
Fig. 4 Influence of iPrOH on the initial rates and enantiomeric
excesses of the reaction under optimized conditions using aldehyde
A2: 1 equiv. A2, c(A2) ¼ 0.15 M in chloroform, 1.5 equiv. 2, 0.2 equiv. 3a.
Conversions and ees were determined with achiral and chiral GC
measurements, respectively. (a) Conversions of reactions in the
presence/absence of capsule I (12 mol% if present); the presence/
absence of alcohol additive (9 equiv. if present). (b) Enantiomeric
excesses of reactions in the presence/absence of capsule I (12 mol% if
present); the presence/absence of alcohol additive (9 equiv. if present).
For more details, see Section 3.8 of the ESI.†
Subsequently, we decided to investigate the initial rates and
initial ee of the reaction, in order to elucidate the role of the
iPrOH additive. Substrate A2 was chosen for this study as it
displays the fastest kinetics. Four reactions (presence/absence of
capsule I; presence/absence of alcohol additive) were studied in
parallel. The capsule-free reactions turned out to be faster than the
capsule-mediated ones, although they plateaued at approx. 40–
50% conversion (Fig. 4a). Slowed down kinetics for iminium
catalysis inside the capsule is to be expected as the Hantzsch ester
and the iminium species have to be co-encapsulated for conver-
sion. More interestingly, the alcohol additive suppressed the
reaction rate in the absence of capsule; however, it increased the
rate in the presence of capsule I. A different trend was observed
when following the initial enantioselectivity of the reaction
(Fig. 4b). While the inuence of alcohol additive was negligible for
the reactions without capsule, the capsule-mediated reaction
beneted from the additive (92% ee vs. 84% ee).
capsule is likely a consequence of two effects. (1) The reduced
background reaction of the free iminium species (compare grey
lines in Fig. 4a) that yields low ees. (2) The increased reaction
rate in the capsule (compare green lines in Fig. 4a). The accel-
eration of the reaction in the presence of alcohol additive and
capsule (light-green line in Fig. 4a) likely stems from faster
exchange kinetics of the reagents in/out of the capsule, as it is
known that polar additives destabilize the hydrogen-bonding
network.2 These results indicate that the proline-catalysed
reaction inside capsule I is highly enantioselective, and is only
reduced to some extent by the background reaction outside of
the capsule that delivers basically racemic product.
Conclusions
We present optimized reaction conditions for the iminium-
We interpret the results the following way: the increased catalysed 1,4-reduction of a,b-unsaturated aldehyde inside the
enantioselectivity in the presence of alcohol additive and supramolecular capsule I. The capsule loading was successfully
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reduced from 26 to 12 mol%. Furthermore, it was established
that HCl is not required as a co-catalyst. Most interestingly, it
was found that alcohol additives have a benecial role con-
cerning the enantioselectivities observed. In two cases, products
with 92% ee were formed. To our knowledge, this is the rst
time that such high enantioselectivities were observed for
iminium-catalysed 1,4-reductions utilizing proline as the sole
chiral source. While proline performs poorly in solution, the
increased interactions inside the conned space of I lead to
a dramatic increase in enantioselectivity. According to our
initial hypothesis,28,29 this ee-increase stems from a selective
shielding of one side of the iminium species by the inner wall of
capsule I. This study demonstrates that this enantioselectivity
6 L. Avram and Y. Cohen, Effect of a cationic guest on the
characteristics of the molecular capsule of resorcinarene:
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7 M. Yamanaka, A. Shivanyuk and J. Rebek, Kinetics and
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Author contributions
12 E. S. Barrett, T. J. Dale and J. Rebek, Assembly and exchange
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14 S. Slovak and Y. Cohen, In-out interactions of different
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K. T. conceived the original idea and supervised the project. D.
S. carried out and analysed the experiments. D. S. and K. T.
compiled the manuscript.
Conflicts of interest
There are no conicts to declare.
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Acknowledgements
This work was supported by funding from the European
Research Council Horizon 2020 Programme [ERC Starting
Grant 714620-TERPENECAT]. We also thank Suren Nemat for
helpful discussions.
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