Catechol[4]arene: The Missing Chiral Member of the Calix[4]arene Family

Article abstract of DOI:10.1021/acs.orglett.0c01864

A missing, inherently chiral member of the calix[4]arene family denoted catechol[4]arene was synthesized. Its properties were studied and compared to the ones of its close relatives resorcin[4]arene and pyrogallol[4]arene. This novel supramolecular host exhibits binding capabilities that are superior to its sister molecules in polar media. The enantiomerically pure forms of the macrocycle display modest recognition of chiral ammonium salts.

Full text of DOI:10.1021/acs.orglett.0c01864

pubs.acs.org/OrgLett
Letter
Catechol[4]arene: The Missing Chiral Member of the Calix[4]arene
Family
Suren J. Nemat, Hanna Jędrzejewska, Alessandro Prescimone, Agnieszka Szumna,
and Konrad Tiefenbacher*
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ABSTRACT: A missing, inherently chiral member of the calix[4]arene
family denoted “catechol[4]arene” was synthesized. Its properties were
studied and compared to the ones of its close relatives resorcin[4]arene and
pyrogallol[4]arene. This novel supramolecular host exhibits binding
capabilities that are superior to its sister molecules in polar media. The
enantiomerically pure forms of the macrocycle display modest recognition of
chiral ammonium salts.
The latter two systems are of particular interest as they are
known to self-assemble in apolar media, resulting in the
formation of hexameric capsules held together by hydrogen
bond networks.7 The emerging enclosed space supplemented
with its capability to take up neutral and cationic guests
resembles enzymatic pockets to some extent.8 In the case of RS,
these properties have been successfully applied to the catalysis of
a growing number of reaction classes.9
While there are examples of successful asymmetric catalysis
employing achiral RS, these reactions exclusively rely on the
presence of an optically active cocatalyst to carry the chiral
information.10 One way of overcoming this limitation would be
the use of inherently chiral building blocks. In contrast to the
inherently chiral pillararenes, the calix[4]arene family of
macrocycles is achiral. Interestingly, a missing chiral relative
( )-1 (Figure 1b) can be envisioned, we propose the name
catechol[4]arene, which to the best of our knowledge has not
been reported so far. This inherently chiral constitutional isomer
of RS could potentially open access to a range of applications
known from other inherently chiral macrocycles, such as
asymmetric catalysis, chiral molecular recognition, and chiral
self-assembly.11
n the broad field of supramolecular chemistry, macrocycles
1
Ihave always played a key role. Phenol-based macrocycles
have been explored intensively due to their facile preparation on
large scale and the ease of functionalization. Important members
of this class of macrocycles are calixarenes,2 cyclotriveratry-
lenes,3 and pillararenes4 (Figure 1a). Among these synthetic
macrocycles, the calix[4]arene family stands out as one of the
most functional and versatile ones.5 Calix[4]arene along with its
sister molecules resorcin[4]arene (RS) and pyrogallol[4]arene
(PG) are rigid, bowl-shaped, and easily derivatizable macro-
cyclic structures that enabled a variety of applications across the
fields of material sciences, molecular sensing, and drug delivery.6
Received: June 3, 2020
Figure 1. (a) Structures of important phenol-based macrocycles. (b)
Inaccessible one-pot route toward catechol[4]arene and proposed
stepwise approach from C4-rersorcin[4]arene.
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The known calix[4]arene family can be easily obtained
through electrophilic aromatic substitution of the respective
phenols with aldehydes.12 However, the directing effects in
catechol prevent the direct formation of 1. Catechol derivatives
reacting with formaldehyde under acidic conditions yield mainly
the tricyclic cyclotriveratrylenes (Figure 1a), and no formation
of catechol[4]arene has been reported.3a We here report the
synthesis, characterization, and application of the new,
inherently chiral, macrocyclic host 1 in its racemic and optically
pure form.
large excess of nBuLi and TMEDA, as well as long reaction times
and a precise temperature program, were required. As a result of
these optimizations, the yield for the tetrahydroxylated product
( )-5, obtained by subsequent borylation and oxidation to the
phenol,16 was increased to 47% while at the same time ensuring
scalability of the reaction. At this stage, it was possible to readily
separate the enantiomers by preparative, chiral HPLC to give
optically pure M-(−)-1 and P-(+)-1 (Scheme 1b, Supporting
Information (SI), Figure S12). In the final step, the methyl
protecting groups were removed using boron tribromide,
followed by a final purification by column chromatography to
yield either ( )-1 or enantiopure M-(−)-1 and P-(+)-1 in yields
>90%. Catechol[4]arene was extensively characterized by ESI-
HRMS, NMR- and IR-spectroscopy, as well as X-ray
crystallography (Scheme 1a) to confirm the macrocyclic
structure.
It was decided to synthesize this elusive member through
derivatization of the literature known compound ( )-4
(Scheme 1).13 The route toward tetramethoxy resorcin[4]arene
a
Scheme 1. Synthesis of Catechol[4]arene (1)
Single crystals suitable for X-ray crystallography were
obtained from a solution of ( )-1 in DMSO at room
temperature. The crystal structure analysis of catechol[4]arene
(space group: P-1) revealed a pseudoboat conformation (C2v
symmetry, Figure 2). While this deviation from ideal C4-
Figure 2. X-ray crystal structure of ( )-1 with the distances a and b and
the tetrahedral angle α. Values for a, b, and the maximum variability of
the tetrahedral angle Δαmax for 1, RS, and PG.17
symmetric crown conformation is observed for its sister
molecules RS and PG in the solid state, it is slightly more
pronounced in the case of 1.17 This is reflected in the distances
between the phenolic units of the macrocycle, for which 1
exhibits both the shortest (a = 7.73 Å) and longest (b = 9.31 Å)
distance between two opposing aromatic faces across all three
systems (Figure 2; SI, Figures S4, S9−S11 and Appendix B for
details). Further structural differences between 1, RS, and PG
are observed for the distortion of the tetrahedral angles α at the
bridging methane carbons. While for the latter two systems,
these four angles vary by less than 1.5°, 1 shows considerable
variability of Δαmax = 4.7°. These findings suggest a decreased
rigidity of the framework that enables a more flexible
conformation in comparison to its sister macrocycles.
To investigate the chiral properties of 1 in solution, its
enantiomers were analyzed by CD-spectroscopy and optical
rotation measurements. These characterization methods along
with DFT calculations18 allowed to assign the axial chirality and
optical activity for M-(−)-1 and P-(+)-1 (Figure 3, SI, Chapter
2.5).19
After having confirmed the structure, its ability to self-
assemble was explored. ( )-1 turned out to be poorly soluble in
chloroform, and no evidence for the formation of larger self-
assembled structures was obtained by NMR spectroscopy (SI,
Chapter 2.2). Also forcing conditions like prolonged heating,
ultrasonication, templating, and ball-milling failed to induce any
form of soluble higher structure.20 The same was true for the
optically active forms, M-(−)-1 or P-(+)-1. We suspect that the
a
R = C11H23. (a) Racemic synthesis and X-ray crystal structure of
( )-1. (b) Separation of enantiomers of 5 and synthesis of M-(−)-1/
P-(+)-1. Reagents and conditions: (i) Tf2O, pyridine, DCM, 0 °C to
rt, 16 h, 94%; (ii) NEt3, formic acid, Pd2[dba]3 (10 mol %), rac-
BINAP (20 mol %), toluene, 120 °C, 40 h, 86%; (iii) nBuLi,
TMEDA, Et2O, −78° to rt, 16 h, then B(OMe)3, −78° to rt, 8 h, then
NaOH/H2O2, −78° to rt, 16 h, 47%; (iv) BBr3, DCM, −78° to rt, 16
h, 91% (M-(−)-1, 96%; P-(+)-1, 97%).
( )-4 starts from the readily available racemic ( )-2, which can
be prepared on the decagram scale in good yields from O-
methylresorcinol and lauric aldehyde in the presence of the
Lewis acid BF3·Et2O within a day.14
( )-2 is converted to the tetratriflate ( )-3 in 94%, using
literature conditions.13 After optimization of the reported
conditions,13 it was possible to remove the triflates in high
yield using Pd2[dba]3, rac-BINAP, and formic acid to give ( )-4
(86%). The crucial step of the synthesis of ( )-1 involved the
tetrafunctionalization of ( )-4, which was achieved through
ortho-lithiation. Ortho-lithiations of resorcin[4]arene deriva-
tives are known15 but typically require two O-alkylated directing
groups per lithiation site. To achieve reasonable yields with the
single methoxy directing group per aromatic moiety in ( )-4, a
B
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Figure 3. (a) Experimental CD spectra of enantiomers M-(−)-1 and P-
(+)-1 in chloroform; (b) calculated CD spectrum for M-(−)-1 (TD
DFT B3LYP/6-31G(d,p)) in chloroform.
absence of hydrogen bonds between the aromatic units of the
macrocycle, which stabilize the crown conformation in case of
RS and PG, is detrimental to its aptitude for self-assembly. In
polar solvents, such as acetone, diethyl ether, or methanol, 1
exhibited good solubility. The latter solvent is particularly
interesting, as RS and PG are practically insoluble in alcoholic
solvents, explaining their use for the recrystallization of these
macrocycles.21 The solvation of 1 is presumably facilitated
through the increased flexibility of the macrocyclic framework.
The DFT calculations of 1 suggest a conformation with C2v
symmetry as major species in solution (SI, Figure S15, Table S3,
and Appendix C). Nevertheless, the 1H NMR spectra suggest a
well-defined C4 symmetric macrocycle, independent of the
solvent and devoid of any signal splitting typically expected for
C2v symmetry. Consequently, it can be proposed that two rapidly
interconverting pseudoboat conformers are present in solution
(SI, Figure S3). Similar observations have been made for a
related system.22
Figure 4. Host−guest interactions of ( )-1 with guests G1 and G2. (a)
Partial 1H NMR spectra of G2; ( )-1 + G2 (1:1, 4 mM); ( )-1; ( )-1
+ G1 (1:1, 4 mM); G1. (b,c) NMR shifts Δδ of ( )-1 signals with
increasing equivalents of G1 and G2 and their corresponding binding
constants Ka for ( )-1⊂G1 and ( )-1⊂G2. All spectra were recorded
in acetone-d6.
In light of the systematic differences between 1 and its sister
macrocycles, the question arose to which extent their guest
binding capability differs. We investigated the binding of organic
ammonium guests. Acetone was chosen as solvent due to the
good solubility of all three hosts (SI, Figure S5). Initial
experiments with ( )-1 and varying concentrations of
methylpyridinium guests G1 and G2 showed considerable shifts
of the host and guest signals indicating the formation of host−
guest complexes in fast exchange on the NMR time scale (Figure
4; SI, Chapter 3.1).
Figure 5. Binding constants Ka of ( )-1, RS, and PG and the
corresponding guest (M−1), determined by 1H NMR titration in
acetone-d6. Titrations performed at 4 mM of host. n.d.: Ka could not be
determined by means of NMR titration.
Interestingly, binding of G1 and G2 was substantially higher
than in RS and PG. A small library of five achiral guest molecules
was investigated, comprising mono- and dicationic (G1, G2)
methylpyridinium salts, as well as benzylic (G3) and phenylic
(G4, G5) tri- and dimethylammonium salts. The hexafluor-
ophosphate counterion ensured good solubility of these salts in
acetone. As all three macrocycles were in fast exchange with their
respective guests, the binding constants Ka for the host−guest
and P-(+)-1. Initial tests were performed with (S)-G6, a
methylated derivative of 1-indamine, an important drug
intermediate.25 The H NMR in acetone-d6 of a 1:2 mixture
1
of ( )-1 and (S)-G6 demonstrated two distinguished sets of
signals for each of the diastereomeric complexes M-(−)-1⊂(S)-
G6 and P-(+)-1⊂(S)-G6 (Figure 6b). An exact assignment of
the peaks was accomplished by comparison with spectra of pure
P-(+)-1 and (S)-G6 (Figure 6c).
To identify any form of enantioselective binding, a library of
four chiral ammonium salts was compiled and the binding
constants Ka for each host−guest pair were determined via 1H
NMR titration in acetone-d6 (Figure 7; SI, Chapter 3.2).
For the structurally related guests (S)-G6, (R)-G7, and (R)-
G8, a trend for selectivity of M-(−)-1 toward S and P-(+)-1
toward R configured guests was observed. In the case of the
1
complexes were determined by means of H NMR titration in
acetone-d6 (Figure 5).23
While all host−guest complexes showed only weak to
moderate binding affinities, ( )-1 outperformed the other
systems in every case tested. Surprisingly, RS demonstrated the
weakest binding capabilities, which stands in stark contrast to its
properties as a hexameric capsule in apolar solvents.8a,e The
binding ability of ( )-1 to G1 is comparable to the
pillararenes.24
Upon assessing the achiral binding capabilities, we shifted our
attention toward chiral recognition using enantiopure M-(−)-1
C
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PG. In contrast to RS and PG, no evidence for the formation of
larger self-assembled structures was found. However, ( )-1
exhibited guest binding capabilities in polar solvents which
exceeded those of RS and PG. This property may be attributed
to its more flexible conformation that adapts to maximize the
interaction with the individual guests. The enantiomers M-
(−)-1 and P-(+)-1 were accessed by preparative, chiral HPLC,
and their absolute configuration was assigned by CD spectros-
copy and quantum mechanical calculations. The optically active
macrocycles showed modest chiral recognition of optically
active ammonium salts. We believe that 1 could serve as a readily
available, inherently chiral macrocyclic platform for further
derivatization and applications in chiral recognition, asymmetric
catalysis and chiral self-assembly.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01864.
Figure 6. 1H NMR spectra of (a) (S)-G6; (b) 4 mM ( )-1 and 8 mM
(S)-G6; (c) 4 mM P-(+)-1 and 8 mM (S)-G6; (d) 4 mM P-(+)-1. All
spectra were recorded in acetone-d6.
Experimental details, NMR spectra of new compounds
and computational and crystallographic data (PDF)
Accession Codes
CCDC 1999713 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Figure 7. Binding constants Ka of M-(−)-1 and P-(+)-1 and the
corresponding guest (M−1), determined by 1H NMR titration in
acetone-d6. Titrations performed at 4 mM of host.
Corresponding Author
Konrad Tiefenbacher − Department of Chemistry, University of
Basel, 4058 Basel, Switzerland; Department of Biosystems Science
and Engineering, ETH Zurich, 4058 Basel, Switzerland;
orcid.org/0000-0002-3351-6121;
structurally closely related guests (S)-G6 and (R)-G7, a chiral
binding preference is detectable with Ka(M)/Ka(P) values
amounting to 1.23:1 and 1:1.24, respectively. The overall
binding affinity increased with the dicationic guest (S)-G9 in
accordance to our previous findings with G1. At the same time,
binding selectivity with (S)-G9 became almost negligible. This
observation may be explained by examining the binding motifs
of this particular guest. While (S)-G9 possesses two cationic
sites, our results from titration of the achiral guests G2 and G5
with racemic ( )-1 suggest (S)-G9 to primarily bind via its
methylpyridinium moiety. Because the chiral information,
located on the pyrrolidinium moiety, points away from the
chiral cavity of 1, the selectivity might be lost. The strongest
chiral recognition was observed for (R)-G8. In this case, the
chiral center at the benzylic position displays a high degree of
rotational freedom, which may be translated into an enhanced
adaptability toward the chiral environment of the host, thus
expressing the highest selectivity.
Email: konrad.tiefenbacher@unibas.ch, tkonrad@ethz.ch
Authors
Suren J. Nemat − Department of Chemistry, University of Basel,
4058 Basel, Switzerland; orcid.org/0000-0002-1894-4021
Hanna Jędrzejewska − Institute of Organic Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland
Alessandro Prescimone − Department of Chemistry, University
of Basel, 4058 Basel, Switzerland; orcid.org/0000-0002-
3631-5210
Agnieszka Szumna − Institute of Organic Chemistry, Polish
Academy of Sciences, 01-224 Warsaw, Poland
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01864
Author Contributions
In summary, we have developed a short, high yielding (39%
overall yield), and scalable synthesis of a missing member of the
calix[4]arene family denoted “catechol[4]arene”. This new,
inherently chiral macrocycle was characterized in detail and
compared to its sister molecules resorcin[4]arene and
pyrogallol[4]arene. Macrocycle 1 is well soluble in alcohols
while showing poor solubility in apolar solvents such as
chloroform, which sets it apart from its close relatives RS and
K.T. supervised the project. S.J.N. and K.T. conceived and
planned the project. S.J.N. carried out all experimental work. H.J.
and A.S. performed and interpreted the DFT calculations. A.P.
performed the X-ray crystallography. The first draft of the
manuscript was compiled by S.J.N. and K.T.
Notes
The authors declare no competing financial interest.
D
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ACKNOWLEDGMENTS
■
This work was supported by funding from the Swiss National
Science Foundation (SNF: 200021_178714), by the NCCR
Molecular Systems Engineering, and by the Wroclaw Centre for
Networking and Supercomputing (no. 299). We thank Dr.
Michael Pfeffer for HR-MS analysis as well as Severin F. Merget
and Fabian Bissegger for their contributions to the NMR
experiments.
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