Supramolecular Catalysis of the oxa-Pictet–Spengler Reaction with an Endohedrally Functionalized Self-Assembled Cage Complex

Article abstract of DOI:10.1002/anie.202009553

An endohedrally functionalized self-assembled Fe₄L₆ cage complex can catalyze oxa-Pictet—Spengler cyclizations of tryptophols and various aldehyde derivatives, showing strong rate accelerations and size-selectivity. Selective molecular recognition of substrates controls the reactivity, and the cage is capable of binding and activating multiple different species along the multistep reaction pathway. The combination of a functionalized active site, size-selective reactivity, and multistep activation, all from a single host molecule, illustrates the biomimetic nature of the catalysis.

Full text of DOI:10.1002/anie.202009553

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Accepted Article
Title: Supramolecular Catalysis of the Pictet-Spengler Reaction with an
Endohedrally Functionalized Self-Assembled Cage Complex
Authors: Courtney Ngai, Colomba M. Sanchez-Marsetti, W. Hill
Harman, and Richard J. Hooley
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202009553
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Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Biomimetic Catalysis
Supramolecular Catalysis of the Pictet-Spengler Reaction with an
Endohedrally Functionalized Self-Assembled Cage Complex**
Courtney Ngai, Colomba M. Sanchez-Marsetti, W. Hill Harman and Richard J. Hooley*
Abstract: An endohedrally functionalized self-assembled Fe4L6 cage
complex can catalyze Pictet-Spengler cyclizations of tryptophols and
various aldehyde derivatives, showing strong rate accelerations and
size-selectivity. Selective molecular recognition of substrates controls
the reactivity, and the cage is capable of binding and activating
multiple different species along the multistep reaction pathway. The
combination of a functionalized active site, size-selective reactivity
and multistep activation, all from a single host molecule, illustrates
the biomimetic nature of the catalysis.
with supramolecular host catalysts,[1],[4b],[8] combining all of them in
a single system is still a challenge. Here we show that an acid-
functionalized self-assembled cage complex is capable of catalysing
the multi-step Pictet-Spengler cyclization of tryptophols and various
aldehyde derivatives, showing strong rate accelerations and size-
selectivity. This requires the binding and activation of multiple
different species along a multistep reaction pathway, which is not
trivial for rigid, inflexible synthetic hosts.
T
he confined interior spaces of self-assembled host molecules can
be exploited for a variety of catalytic processes.[1] Enhanced effective
concentration in a cavity confers enhanced rates, and guest
confinement can force unusual regioselectivities.[2] Still, many
reactions promoted and/or catalyzed by capsular hosts are, by
necessity, relatively simple one or two step reactions such as
cycloadditions or rearrangements.[3] More complex, multistep
processes require supersized cavities that can bind many substrates.
Suitable nanosized superstructures include M12L24 cages[4] and
resorcinarene hexamers,[5] which can perform cationic
rearrangements[5] and metal-mediated cyclizations[4b] via the use of
cofactor-like reagents bound in the spacious inner cavities of the
capsules. Smaller hosts can bind their guests more tightly, allowing
size-selectivity and “enzyme-like” catalysis,[1c] but these smaller
cavities have limits, either showing poor coencapsulation properties
or limited turnover. The exception is Raymond’s Ga4L6 catecholate
cages, which are capable of multistep reactions exploiting
organometallic reagents as cofactors.[1a],[6],[7]
While many advances in supramolecular catalysis have been
achieved, enzymes are still far more capable at catalysing complex,
multistep processes inside active sites. The reasons are obvious: the
more complex the reaction, the more species need to be bound in the
active site, either at the same time or sequentially. The enzyme
provides the binding pocket, displays reactive functional groups to its
substrates, and is capable of selective molecular recognition and
turnover. While each of these individual traits have been achieved
[]
C. Ngai, C. M. Sanchez-Marsetti, Prof. W. H. Harman, Prof. R. J.
Hooley.
Figure 1. Cage-catalyzed Pictet-Spengler cyclizations. a) Structure of FeII4L6 acid
cage 1, unfunctionalized cage 2, control acid 3 and a minimized structure of the
S4 isomer of 1 (SPARTAN, semi-empirical calculations); b) summary of Pictet-
Spengler reaction and scope of substrates used.
Department of Chemistry and the UCR Center for Catalysis,
University of California - Riverside, Riverside, CA, 92521, U.S.A.
E-mail: richard.hooley@ucr.edu.
[]
The authors would like to thank the National Science Foundation
(CHE-1752876 to W.H.H., CHE-1708019 to R.J.H.) for support.
Self-assembled Fe4L6 host complex 1 (Figure 1a), which displays
twelve carboxylic acid groups towards a host cavity, is a highly
effective host catalyst. [9] The complex exists as a mixture of two
metal-centered isomers, and can catalyze simple acid-mediated
1
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/anie.201xxxxxx.
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10.1002/anie.202009553
Angewandte Chemie International Edition
processes such as acetal solvolysis[9] and thioetherification of
activated alcohols.[10] Small, neutral guests can be bound in the cavity
with affinities up to 105 M-1, and display fast in/out exchange,
allowing turnover and catalysis in acetonitrile solvent. The reactions
tested to date have been quite rudimentary, however, such as acid-
mediated dissociative substitutions with mild nucleophiles. As such,
we were interested in investigating the ability of host 1 to catalyze
more complex, multistep reactivity. The choice of reaction is
important: self-assembled Fe-iminopyridine complexes[11] are poorly
tolerant to strong nucleophiles, coordinating anions (even some as
mild as hydroxide or chloride) and strong acids. They are often
insoluble in hydrocarbon solvents, and are restricted to CH3CN,
DMSO or, in some cases, water.[12]
The Pictet-Spengler reaction (Figure 1b) is the cyclization of
tryptophol derivatives with aldehydes, and is readily catalyzed by
strong Lewis acids such as BF3•Et2O or AlCl3.[13] Enantioselectivity
is possible with organocatalysts such as chiral amine-appended
thioureas.[14] It is challenging for a host-catalyzed reaction, however.
The reaction is usually performed in anhydrous, non-coordinating
solvents. In addition, the catalyst must activate the substrate twice for
reaction to proceed: both the indole and alcohol groups of the
tryptophol must attack the carbonyl carbon of the electrophile. This
is not a problem for small molecule Lewis acids in non-coordinating
solvents, as they freely coordinate to different atoms in the system. A
host must bind and activate both the small electrophile and larger
intermediate in a fixed, inflexible cavity, while not suffering from
product inhibition. This is not simple, nor is it common among self-
assembled cage hosts.
and oxocarbenium ions, when compared to carboxylic acids in free
solution. Benzaldehyde dimethyl acetal 5a can be activated by 1 at
room temperature in acetonitrile,[9] so this was applied as the initial
test case for Pictet-Spengler reaction with tryptophol 4a as
nucleophile. Both 4a and 5a (1:1.25 molar ratio) were combined in
distilled CD3CN with 5% cage 1, and the reaction course monitored
by 1H NMR, using dioxane as internal standard. As can be seen from
Table 1, the Pictet-Spengler cyclization between 4a and 5a was
successfully catalyzed by only 5% 1, with 87% yield of product 6a
present after 24 h. Control experiments show that acid cage 1 is
required for catalysis. If the host is replaced with 5% unfunctionalized
cage 2, no reaction is seen after 24 h, nor is the any reaction observed
with 30% of the carboxylic acid control 3. While 3 shows some minor
ability to catalyze a small amount of solvolysis of 5a,[9] it is not active
enough to catalyze the more complex Pictet-Spengler cyclization. It
is notable that the hydrolysis of 5a to benzaldehyde occurs faster than
the Pictet-Spengler cyclization, and undried CD3CN gives rise to
mainly aldehyde byproduct rather than product 6a. The cage is not
capable of catalyzing cyclization between 4a and aldehydes, and any
aldehyde formed is retained throughout the reaction. Fortunately,
using distilled CD3CN is all that is needed, and the reaction can be
performed in air, with no precautions taken to prevent exposure of the
reaction to water. A small amount of solvolysis is seen, but as 1.25
mol.-eq. of the acetal are used, this does not limit the yield of 6a.
Having shown the catalytic abilities of the cage, we expanded the
scope of the process by varying the individual components, using the
same conditions as above (distilled CD3CN on the benchtop in air).
As well as being experimentally simple, allowing small amounts of a
competitive nucleophile (water) to the reaction gives additional
insight into the reaction mechanism for different substrates (see
below). The tryptophol and acetal reactants were varied in both size
and reactivity: the structures of the reactants are shown in Figure 1b
(see Supporting Information for the structures of products 6a-k - these
products were independently synthesized to corroborate the
assignment). The size of the acetal can be varied at two points, the
alcoholic leaving groups R2 (5a-c, with R2 = Me, Et, n-Bu,
respectively), or the R3 group (5d, 5e, R3 = naphthyl, anthryl).
Increasing the size of the R2 leaving groups had minimal effect on the
catalysis, and 80% yield of product 6a was observed in both cases
(Table 1, entries 4, 5). However, increasing the size of the R3 group
in the acetal significantly reduced the reaction yield, with naphthyl
product 6d forming in 25% yield and anthryl product 6e in only 15%
yield after 24 h. Notably, the amount of solvolysis of 5a-e varied as
well, with 25% yield of naphthaldehyde seen, but only 13%
anthraldehyde (entries 6,7), as opposed to only 7% benzaldehyde.
Aromatic dimethyl acetals with more electron poor rings than 5a
(bromophenyl 5f, pyrimidine 5h) were, as expected, poor substrates
for the reaction. Neither Pictet-Spengler cyclization nor solvolysis
were seen for the very electron poor 5h and only minimal reaction
was seen for 5f (Table 1, entries 8, 10). Alkyl acetals 5i and 5j and
benzophenone ketal 5k were also poor substrates. Dimethylamino-
phenyl acetal 5g is an interesting outlier, though: the acetal is quite
reactive, both towards solvolysis (22%) and Pictet-Spengler reaction,
with 56% yield observed after 24 h. Finally, varying the size of the
tryptophol derivatives was possible by using 5-bromo- or 7-ethyl
indole. The tryptophol substrate 4c was synthesized in two steps via
literature methods (4b was commercially available)[16] and reacted
with acetal 5a and host 1 as before. The larger tryptophols were not
well-tolerated by the cage, with ethyltryptophol 4b showing only 39%
reaction with 5a, and no Pictet-Spengler reaction occurring with 4c.
Table 1. Pictet-Spengler Cyclization via Supramolecular Catalysis.[a]
Control yield
Product
Aldehyde
Yield (%)
(with CSA
Indole Acetal
Catalyst
catalyst, %)[b]
Yield (%)
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
5a
5a
5a
5b
5c
5d
5e
5f
cage 1
cage 2
diacid 3
cage 1
cage 1
cage 1
cage 1
cage 1
cage 1
cage 1
cage 1
cage 1
cage 1
cage 1
cage 1
87
0
7
0
90
N/A
N/A
84
87
62
47
53
15
0
0
0
80
80
26
15
17
56
0
11
10
25
13
9
5g
5h
5i
22
0
12
0
14
0
52
0
5j
5k
5a
5a
0
8
63
62
0
39
0
19
29
[a] 293 K, CD3CN, [4] = 15.8 mM, [5] = 19.8 mM, [1,2] = 0.8 mM; [3] = 4.74 mM. [b]
5 % camphorsulfonic acid (CSA) used as catalyst. Yield determined by integration
against dioxane as standard (7.9 mM).
Fortunately, cage 1 is a promiscuous host, capable of binding and
activating multiple species of various sizes,[9],[10] as has also been seen
with other Fe-iminopyridine cages.[15] The host shows ~1000-fold
rate accelerations of simple reactions that proceed via benzyl cations
2
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10.1002/anie.202009553
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These results were then compared to the reaction with a strong
small molecule acid as catalyst, camphorsulfonic acid (CSA, see
Table 1 and S-1). The reaction conditions were chosen so that the
conversion of 5a + 4a was identical under both conditions, allowing
a comparison of relative conversion between the cage and a “free”
acid as catalyst. The reactivity with CSA was far less dependent on
whether 1:1 or 2:1 binding was most likely. It is clear that most of the
substrates were capable of binding in the host in a 2:1 manner, but
that only four guests clearly favored 2:1 binding over 1:1. As would
be expected, the smallest guests 5a-5d fit best to a 2:1 model, whereas
larger species fit best to a 1:1 model. Some guests such as the large
anthryl product 6e had very high errors in the 2:1 fit and were clearly
structure than with cage 1. The phenyl acetals 5a-c were most reactive, only bound in a 1:1 manner, whereas “intermediate-sized” species
giving 84-90% (± 3%) yield under the chosen conditions. The
unreactive acetals 5h and 5j again gave no conversion. The rest of the
acetals mostly cyclized with yields between 47-63%, irrespective of
size, stabilizing groups, etc.
were more ambiguous. The binding affinities of the various substrates
were all strong (> 103 M-1), and varied in magnitude between ~2-12
x 103 M-1 for the 1:1 substrates. The 2:1 substrates showed a 7-fold
variation in the first binding affinity K1, with butyl acetal 5c bound
most strongly. The coencapsulation process was negatively
cooperative in each case.[18] In general, the affinities of the
components are all quite similar, which is to be expected as they are
of broadly similar sizes and do not have any strongly coordinating
groups. This (along with the rapid rate of in/out exchange) aids
effective catalysis, as one species does not dominate the binding in 1
at any one time.
The most interesting observations were with the larger acetals:
electrophiles 5d-5f were cyclized with 4a in 47-62% yield with CSA,
far more than the 12-26% yield seen with the cage. The alkyl acetal
5i was cyclized much more slowly in the cage, in only 12% yield,
whereas 52% yield was obtained with CSA. The larger tryptophol 4b
was a more effective nucleophile outside the cage, reacting with 5a
in 62% yield (as opposed to 39% in the cage). The most surprising
observation was with acetal 5g, which showed accelerated reaction
with 4a in the cage: whereas 56% yield was seen with 5% 1, only
15% yield was observed with 5% CSA. The clearest example of
selectivity was with the large ketal 5k: this is a perfectly good partner
for cyclization with 4a and CSA, with 63 % yield seen after 24 h, but
showed absolutely no Pictet-Spengler reactivity in cage 1. A small
amount of solvolysis was seen, but no cyclization.
Table 2. Binding affinities between substrates and cage 1.[a]
1:2
K1 x 103 M-1
K2 x 103 M-1
α (4K2/K1)
Substrate
5a
5b
5c
5d
8.6 ± 0.8
20.0 ± 0.7
34.0 ± 1.3
4.7 ± 0.4
0.08 ± 0.002
0.03 ± 0.001
0.40 ± 0.01
0.70 ± 0.04
0.04
0.06
0.05
0.60
1:1
Ka x 103 M-1
1:1 Substrate
Ka x 103 M-1
Substrate
4a
4b
4c
5e
5f
3.9 ± 0.1
4.1 ± 0.1
7.4 ± 0.3
4.0 ± 0.2
12.0 ± 0.6
1.9 ± 0.04
5h
5i
9.6 ± 0.4
12.0 ± 1.0
8.3 ± 0.3
4.4 ± 0.5
6.2 ± 0.3
2.9 ± 0.1
5j
5k
6a
6e
5g
[a] in CH3CN, [1] = 3 μM, absorbance changes measured at 300/330nm.[10],[18]
These results indicate that cage-catalyzed process is strongly
affected by size and shape matching in the cavity. As such, we
investigated the binding affinities of the substrates 4, 5 and some of
the products 6 with 1 via UV/vis absorbance titrations. This is an
effective method of interrogating binding in porous hosts such as 1
and 2, which show rapid in/out exchange of neutral guests.[9],[10],[17]
Guests were titrated into a CH3CN solution of 1, and absorbance
changes at 300nm and 330 nm were fitted using the Nelder-Mead
method with both 1:1 and 2:1 binding models,[18] to determine the
affinity and stoichiometry of the process. The results are shown in
Table 2. The errors in each binding model were assessed to determine
Figure 2. a) Proposed mechanistic cycle of the cage-catalyzed Pictet-Spengler
cyclization; minimized structures (SPARTAN, semi-empirical calculations) of host
1 binding: b) substrate 4a (incompletely filling the cavity); c) intermediate 7a.
The takeaway from the fitting data is that cage 1 is a promiscuous
host, capable of binding each substrate. In addition, the host is large
enough to bind the products, any intermediates and, most importantly,
3
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10.1002/anie.202009553
Angewandte Chemie International Edition
both substrates at once. This allows some mechanistic analysis, as
shown in Figure 2. At the beginning of the reaction, any of the
substrates can bind in cage 1. Binding the acetal 5a allows loss of
electrophile and nucleophile is essential for effective cyclization.
While the flexible alkyl chains on the acetals (R2) are not important,
larger R3 groups disfavor the cyclization reaction and species such as
methanol after protonation, giving the oxocarbenium ion intermediate. ketal 5k are unable to react with tryptophol in the cage at all, despite
This is possible for all substrates, but the selectivity is seen in the next
step: Pictet-Spengler cyclization is only possible if the acetal and the
tryptophol nucleophile 4 can be bound in the cavity. Small acetals
allow this, but larger acetals such as 5d, 5e, 5i and especially 5k are
too big to allow further reaction to give intermediate 7a. Once the
mixed acetal 7a is formed, it must then bind inside 1 and be activated
a second time, forming a second oxocarbenium intermediate, which
can then cyclize to form product 6a and be released, allowing
turnover. Figures 2b and c show minimized structures of the S4 isomer
of cage 1 binding tryptophol 4a and the putative intermediate 7a.
Each guest can fit inside the spacious cavity, and 4a does not fully fill
the host by itself.
being good substrates for reaction in free solution. Increasing the size
of the tryptophol also disfavored the reaction in the cage. Size and
shape matching in the intermediate does not explain everything,
however. Why acetal 5g is more reactive in the cage than with CSA
is not clear at all, and these observations indicate that the multistep
process is affected by more than just shape-fitting. This delicate
sensitivity to structure illustrates the “enzymatic” behavior of host 1.
It can bind and activate two different substrates in a single active site,
and shows differential reactivity that is dependent on proper size and
shape fitting of the intermediate — not necessarily the “base”
reactivity of the substrate.
Other experiments support this mechanistic postulate: the
intermediate 7a can be observed during the reaction. The reaction
between tryptophol 4a and acetal 5a with 5% 1 was monitored at
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
1
discrete time intervals by H NMR. The acetal region of the spectra
Keywords: Supramolecular chemistry · Self-assembly · Catalysis · Enzyme
models · Molecular recognition
is shown in Figure 3, and the full spectra are shown in Figure S-11.
After only 30 mins reaction time, two new peaks appear in the δ 5.2-
6.0 ppm region, corresponding to the benzylic proton (red dot) in
product 6a and a small amount of an intermediate product that can be
assigned as the mixed acetal 7a. Over time, acetal 5a is converted to
product 6a, and the mixed acetal concentration slowly lowers, until it
is negligible after 24 h. Finally, the reaction was tested in the presence
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Figure 3. In situ monitoring of the reaction between 4a and 5a. Acetal region of
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10.1002/anie.202009553
Angewandte Chemie International Edition
Biomimetic Catalysis
Courtney Ngai, Colomba M. Sanchez-
Marsetti, W. Hill Harman and Richard J.
Hooley* _______ Page – Page
Supramolecular Catalysis of the Pictet-
Spengler Reaction with an Endohedrally
Functionalized Self-Assembled Cage
Complex
An endohedrally functionalized self-assembled Fe4L6 cage complex can catalyze
Pictet-Spengler cyclizations of tryptophols and various aldehyde derivatives,
6
This article is protected by copyright. All rights reserved.