[2]Catenane Synthesis via Covalent Templating

Article abstract of DOI:10.1002/chem.202004925

After earlier unsuccessful attempts, this work reports the application of covalent templating for the synthesis of mechanically interlocked molecules (MiMs) bearing no supramolecular recognition sites. Two linear strands were covalently connected in a perpendicular fashion by a central ketal linkage. After subsequent attachment of the first strand to a template via temporary benzylic linkages, the second was linked to the template in a backfolding macrocyclization. The resulting pseudo[1]rotaxane structure was successfully converted to a [2]catenane via a second macrocyclization and cleavage of the ketal and temporary linkages.

Full text of DOI:10.1002/chem.202004925

Accepted Article
Accepted Article
Title: [2]Catenane Synthesis via Covalent Templating
Authors: Jan Herman Van Maarseveen, Steen Ingemann Jørgensen,
and Simone Pilon
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To be cited as: Chem. Eur. J. 10.1002/chem.202004925
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[2]Catenane Synthesis via Covalent Templating
[
a]
[a]
[a]
Simone Pilon, Steen Ingemann Jørgensen and Jan H. van Maarseveen*
This communication is dedicated to Professor Gottfried Schill on the occasion of his 90th birthday.
[
a]
Prof. dr. J. H. van Maarseveen
Van ‘t Hoff Institute for Molecular Sciences
University of Amsterdam
Science Park 904, 1098XH Amsterdam, The Netherlands
E-mail: j.h.vanmaarseveen@uva.nl
Supporting information for this article is given via a link at the end of the document
Abstract: After earlier unsuccessful attempts, we report the
application of covalent templating for the synthesis of mechanically
interlocked molecules (MiMs) bearing no supramolecular recognition
sites. Two linear strands were covalently connected in a perpendicular
fashion by a central ketal linkage. After subsequent attachment of the
first strand to a template via temporary benzylic linkages, the second
was linked to the template in a backfolding macrocyclization. The
resulting pseudo[1]rotaxane structure was successfully converted to
a [2]catenane via a second macrocyclization and cleavage of the ketal
and temporary linkages.
The development of covalent templated approaches, where
reversible covalent bonds are employed to enforce the desired
topology, can help widen the structural diversity of MiMs and open
up new avenues.
Although less common, several covalent templates have recently
seen application in MiMs synthesis. Drawing inspiration from
passive metal templating, Godt developed a carbonate template
for the synthesis of [2]catenanes and polymeric catenanes.[
12–14]
Höger
successfully
modified
its
terephthalic
ester
macrocyclization template to obtain MiMs, and our group later
investigated this method as well.[15–18] Other functional groups
used for templating include esters[19–22] and imines.[23,24]
Over the last forty years, the field of mechanically interlocked
molecule (MiM) synthesis has been dominated fully by non-
covalent templated approaches.[1–3] Taking advantage of specific
supramolecular interactions, such as metal templating[4–6], -
stacking[7] or hydrogen bonding , two or more molecular building
blocks are preorganized into the desired topology, which is then
fixed via covalent modifications. This results, as compared to
covalent approaches, in shorter and relatively higher yielding
syntheses of MiMs, which explains the widespread application of
these strategies in other fields, such as that of molecular
machines.[9] In addition, new non-covalent approaches are being
developed, such as radical and halogen bonding templation.[10,11]
However, the structural motifs required for supramolecular
recognition tend to shape a large portion of the resulting MiMs, as
well as their properties.
For this work however, we were specially inspired by Schill, who,
by the synthesis of a catenane, prepared a MiM for the first time
[
25–
and pioneered the field of covalently templated MiM synthesis.
[8]
27]
In one study (Scheme 1, route A), he took advantage of a
directing ketal group to join a macrocycle (in red) to a properly
functionalized linear thread (in blue) in a perpendicular fashion.[
The resulting intermediate can adopt two conformations, a
prerotaxane-like one 1, with the thread positioned within the ring,
and a trivial one 1’, which are in an equilibrium lying far to the left.
Upon alkylation with bulky stopper groups, this equilibrium was
frozen, and the two distinct compounds could be separated.
28]
Scheme 1. Comparison of Schill’s statistical [2]rotaxane synthesis (A) with our covalent template backfolding strategy (B).
1
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Acidic hydrolysis of the ketal moiety then gave a mixture of the
separate ring and axle for the major intermediate and a
observation inspired us to pursue the synthesis of 10b, an analog
of catenane 10a in which the amides have been replaced by
ethylidene groups.
[2]rotaxane for the very minor one (0.08–0.12% yield). Despite the
poor yields, it was not only proven that the prerotaxane
conformation is possible, but also that it can in principle lead to an
interlocked species.
We recently devised a somewhat similar approach to MiMs
termed “templated backfolding” (Scheme 1, route B). Starting
from two linear strands joined together at the center by a ketal, a
suitable template is connected via temporary linkages (dashed
lines) to give 6. Next the first macrocycle is formed by linking the
template to its opposing strand (in red) in a “backfolding” fashion.
Thanks to the covalent temporary linkages, the unfavored
pseudorotaxane conformation of 1 is the only one available to 7.
From 7, a second macrocycle (in blue) is formed, and final
cleavage of the temporary linkages and the ketal selectively
results in a [2]catenane. The efficacy of the backfolding approach
was proven by the synthesis of both a quasi[1]rotaxane and a
quasi[1]catenane, featuring irreversible bonds between the axle
and ring fragments.[29] The next step was to make the bond to the
central quaternary spiro-carbon reversible, by introducing a ketal
group. With this purpose, target [2]catenane 10a was addressed.
Scheme 3. Model study to assess reactivity of the central ketal linkage.
For this, ketone 17 was prepared first from known alcohol 15[32] in
three steps (Scheme 4). The alkene groups were converted to
alkynes via a bromination-elimination protocol, which proceeds in
good selectivity under anhydrous conditions.
Scheme 2. Planned ketal hydrolysis from precatenanes 9a and 9b.
By following the backfolding templated strategy as outlined in
Scheme 1B and using the powerful Cu(I)-catalyzed azide-alkyne
cycloaddition (CuAAC) and ring-closing metathesis (RCM) as the
key macrocyclization steps, precatenane 9a was successfully
obtained. However, to our surprise but even more disappointment,
all attempts at hydrolyzing the acid labile ketal group failed.[30]
Initially this was attributed to steric shielding within the very
congested precatenane architecture. In order to gather
experimental evidence of this, model compound 11 was
synthesized, which closely matches the electronic environment of
precatenane 9a (Scheme 3). Treatment ketal of 11 with
concentrated aqueous HCl in MeOH at room temperature showed
even after 28 h only trace amounts of the hydrolysis products.
Hydrolysis of ketal 11 could only be accomplished after stirring in
concentrated HCl and MeOH at 50°C for several hours. This
indicates that besides the catenane effect that clearly plays a role
in the remarkable stability of ketal 9a, other factors play a role. In
contrast, ketal 12, an early intermediate in synthesis of 9a, could
be hydrolyzed at room temperature in only 4 h under otherwise
identical conditions. The positive influence of amide groups on the
stability of nearby ketals has been reported before[31] and this
Scheme 4. Synthesis of precatenane 23b, the common [2]catenane and
[
2]rotaxane precursor.
2
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This was followed by oxidation of the alcohol group by PCC. As
already found in our previous studies, direct coupling of ketones
such as 17 and (+)-dimethyl tartrate proceeds sluggishly. This
could be overcome by transformation of the ketone to the
dimethoxy ketal, followed by transketalization with (+)-dimethyl
tartrate to give functionalized ketal 18 in 58% yield. Although more
viable, this procedure suffers from incomplete conversion, likely
due to the difficulties in completely removing water from the
reactants, but nonetheless allows for recovery of ketone 17 in high
yield (90% brsm). Assembly of the second macrocycle follows,
by saponification of the methyl esters and coupling of the resulting
diacid with amine 19, which also includes the temporary linkages.
At this stage, transesterification of template 21 with the two
phenolic groups in 20 affords the backfolding macrocyclization
precursor 22b. To initiate this key step using the CuAAC reaction,
To further assess the influence of the catenane effect on the
stability of the ketal group in precatenanes 9a and 9b, we set out
to synthesize their respective regular spiro topoisomers and
subjected them to ketal hydrolysis conditions (Scheme 6).
2
2b was stirred at high dilution with Cu(MeCN)
4
BF
4
as catalyst
and TBTA as ligand. Refluxing in CH Cl for 3 days gave cage
2 2
compound 23b in 24% yield. Compared to 23a[30], 23b is formed
1
in lower yield and showed a much simpler H-NMR spectrum, with
only minor splitting of the signals corresponding to chemically
equivalent protons. These surprising differences suggest the
presence of substantial interactions between the macrocycle
amides and the tartrate core in 23a, resulting in rigidification of the
macrocycle (in red) and slowing down conformational exchange.
With the ketal and two macrocycles in place, the two terminal
alkenes are positioned such as to allow the second
macrocyclization to give the precatenane skeleton. This is done
2 2
via RCM, performed in CH Cl
at 40°C using Grubbs’ 2nd
generation catalyst (Scheme 5). The resulting product, obtained
in 57% yield as an inseparable mixture of E and Z isomers, is then
converted to a single compound 24b-H
double bonds by catalytic hydrogenation. To liberate the
2]catenane, first the temporary linkages were broken via
2
after saturation of the
[
solvolytic transesterification of the lactone groups, followed by
protolytic cleavage of the benzylic tertiary amides using TFA in
the presence of Et
was hydrolyzed under strongly acidic conditions, liberating
2]catenane 10b in 60% yield.
3
SiH as cation scavenger. Finally, the ketal core
[
Scheme 6. Formation of trivial rings 29 and 28b.
This was done by simply altering the order of the final steps that
were used for the syntheses of precatenanes 9a and 9b. Thus
starting from prerotaxane 23a, instead of first carrying out the
RCM macrocyclization reaction, the sequence of reactions started
by solvolysis of the temporary ester linkages in 23a to give
macrocycle 25a’ as an intermediate, followed by a concomitant
spontaneous unwinding process, yielding 25a. Subsequent
subjection of 25a to RCM, catalytic hydrogenation conditions and
final protolytic removal of the benzylic appendages gave a
compound with different spectral properties from precatenane 9a,
supporting the proposed regular spiro topology of 27a thus
obtained.
Scheme 5. Synthesis of [2]catenane 10b.
3
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1
As shown in Figure 1, a comparison of the H-NMR spectra of 27a
and 9a shows marked differences for several key peaks. These
were assigned for 27a based on integral and multiplicity, and their
identity was confirmed by COSY and HSQC NMR (see supporting
information). Most striking, is the splitting of the diastereotopic
benzylic protons (d), which is significantly increased in
precatenane 9a. Similarly, the aliphatic signals between 1.5 and
stabilizing amide groups in 9a, in this case ketal cleavage is
completely blocked.
3
ppm as well as the amide NH signals display much more
complex patterns in 9a. This is likely the result of slower
conformational movements in the sterically more congested
precatenane macrocycles.[33] In addition, the aromatic template
signal (c) is shifted downfield by 0.34 ppm, indicating additional
shielding in 27a due to ring-current effects arising from the triazole
moieties.[34] This interaction is reduced in 9a as the intra-annular
fragment limits the ability of the ketone macrocycle (in red) to fold.
These findings are consistent with observations made on similar
inverted spiro architectures previously synthesized via our
backfolding approach.[29,35]
1
Figure 2. Comparison of H-NMR spectra of catenane 10b (II) with an equimolar
6
mixture of trivial rings 28b and 29 (I) in DMSO-d . For proton assignments, see
Schemes 5 and 6.
Analysis by 1H-NMR revealed marked differences between
catenane 10b and a 1:1 mixture of its separate and non-
interlocked components 28b and 29, as shown in Figure 2. The
benzylic protons (d) appear equivalent in 28b, and become
diastereotopic in 10b. In addition, the overall chemical shift of the
aliphatic proton signals is significantly reduced. This points to
increased shielding and is common for methylene chains
entrapped within macrocycles bearing aromatic rings.[33,36,37]
However, the most striking difference is the downfield shift of 0.56
and 0.11 ppm respectively, of the template aromatic (c) and
methyl ester (g) protons. As was observed for precatenane 9a and
trivial bicycle 27a, this is probably due to the rigid conformation of
the interlocked rings in [2]catenane 10b preventing the
macrocycles from collapsing. Furthermore, the NMR spectrum of
catenane 10b shows that the signals of both the terephthalate
protons (c) and triazole protons (a) appear as double singlets
Figure 1. Comparison of 1H-NMR spectra of trivial spiro bicycle 27a (I) and
precatenane 9a (II) in CDCl . For proton assignments, see Scheme 6.
3
[30]
Remarkably, solvolysis of the ester linkages in 23b gave
intermediate 25b’ as a stable compound at room temperature,
which required extensive heating to unwind to the
thermodynamically favored conformer 25b. Molecular mechanics
modeling of structures 25b’ and 25a’ suggest that the benzylic
groups (in black) could hamper this process, as they barely fit in
the macrocycle cavity according to space filling representations
(Figure 3). This points to the presence of two diastereomeric
forms of catenane 10b, likely resulting from a combination of
central chirality, emerging from the tartrate moiety, and planar
chirality of the red macrocycle. The AB system displayed by the
benzylic protons (d) suggests in fact that rotation of the p-
cyclophane-type terephthalate moiety is hindered, resulting in two
different conformations of the macrocycle, which are mirror
images of each other (Figure 3, III).
(see supporting information). However, so far we have no sound
explanation for the exceptional differences in the kinetics of this
step between 25a’ and 25b’. From unwound macrocycle 25b, the
trivial spiro bismacrocycle 26b was obtained after RCM and
catalytic hydrogenation.
Similarly to what was observed for precatenanes 9a and 9b, the
final hydrolysis of the linking ketals in the regular spiro compounds
2
6b and 27a gave a completely different outcome (Scheme 6).
Starting from 26a, the benzylic groups could be selectively
cleaved in TFA in the presence of Et SiH, giving 27a, which failed
3
to hydrolyze to the desired separate macrocycles even under
forcing conditions (not shown). In stark contrast, 26b partially split
into the separate macrocycles 29 and 28b already by TFA
addition. This process was brought to completion by treatment
2
with HCl in MeOH/H O at room temperature. The relatively mild
Figure 3. Detail of the 1H-NMR spectra of catenane 10b (II) and an equimolar
mixture of trivial rings 28b and 29 (I) in DMSO-d showing splitting of the
6
aromatic peaks. The proposed structure of the two diastereoisomers of 10b is
shown (III).
conditions required underscore that the high stability of the ketal
in precatenanes 9a,b emerges to a great extent from the
catenane effect. Due to the presence of the additional ketal
4
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[
30] L. Steemers, M. J. Wanner, B. R. C. van Leeuwen, H. Hiemstra, J. H. van
Maarseveen, Eur. J. Org. Chem. 2018, 2018, 874–878.
Conversely, the non-interlocked macrocycle 28b, which lacks the
steric constraints of the mechanical bond, displays a sharp singlet
signal for the benzylic (d) protons, indicating that the terephthalic
moiety can rotate freely. So far, all attempts to separate the
eventual diastereomers of 10b by several symmetric and
asymmetric HPLC methods failed.
In conclusion, despite the strong stabilizing catenane effect
experienced by the pivotal ketal link, small structural changes
allowed its hydrolysis liberating the mechanically interlocked
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[2]catenane. As
a
consequence, the covalent template
backfolding approach was, for the first time, successfully
employed in the synthesis of a mechanically interlocked molecule.
Currently, we are focusing on reducing the footprint of the
template and further improving the versatility of the temporary
linkages to expand the structural diversity within the class of
mechanically interlocked molecules.
Acknowledgements
The authors would like to thank The Netherlands Organization for
Scientific Research (NWO-CW, ECHO grant number
711.012.007 to J.v.M). E. Zuidinga and D. S. Tromp (University of
Amsterdam) are acknowledged for mass spectrometry and NMR
assistance.
Keywords: Catenanes • Planar chirality • Synthetic methods •
Template synthesis • Covalent template
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5
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Entry for the Table of Contents
A novel covalent template strategy for the synthesis of mechanically interlocked molecules has been successfully employed to give a
2]catenane. This approach results in a [2]catenane devoid of supramolecular recognition sites. An inverted spiro intermediate is
[
formed due to the action of a covalent template, which enforces an otherwise unfavorable macrocyclization. The trapped thread could
be clipped into a second macrocycle giving a precatenane and, upon cleavage of the covalent templating linkages, the [2]catenane
architecture.
6
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