An Auxiliary Approach for the Stereoselective Synthesis of Topologically Chiral Catenanes

Article abstract of DOI:10.1016/j.chempr.2019.03.008

Catenanes, molecules in which two rings are threaded through one another like links in a chain, can form as two structures related like an object and its mirror image but otherwise identical if the individual rings lack bilateral symmetry. These structure

Full text of DOI:10.1016/j.chempr.2019.03.008

Article
An Auxiliary Approach for the Stereoselective
Synthesis of Topologically Chiral Catenanes
Mathieu Denis, James E.M.
Lewis, Florian Modicom,
Stephen M. Goldup
s.goldup@soton.ac.uk
HIGHLIGHTS
First stereoselective synthesis of a
topologically chiral catenane
First absolute stereochemical
assignment of a topologically
chiral catenane
First example of an auxiliary
approach to topologically chiral
catenanes
Catenanes, molecules comprising two rings held together like links in a chain, can
exist as two mirror-image forms if the rings lack bilateral symmetry. These
‘‘topological enantiomers’’ are unusual because they cannot be interconverted by
stretching or bending chemical bonds. To date, their synthesis has required the
separation of mirror-image structures by specialist techniques. We present a
simple method to allow the synthesis of topologically chiral catenanes, opening
them up to investigation in catalysis, sensing, and materials science.
Denis et al., Chem 5, 1–9
June 13, 2019 ª 2019 The Author(s). Published
by Elsevier Inc.
https://doi.org/10.1016/j.chempr.2019.03.008

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Article
An Auxiliary Approach
for the Stereoselective Synthesis
of Topologically Chiral Catenanes
Mathieu Denis,1 James E.M. Lewis,1,2 Florian Modicom,1 and Stephen M. Goldup1,3,
*
SUMMARY
The Bigger Picture
Chiral molecules have occupied a
special place in chemistry since
Pasteur reported the painstaking
separation of mirror-image
crystals of tartaric acid salts in
1848. In the 21st century, chiral
molecules remain a major
Catenanes, molecules in which two rings are threaded through one another like
links in a chain, can form as two structures related like an object and its mirror
image but otherwise identical if the individual rings lack bilateral symmetry.
These structures are described as ‘‘topologically chiral’’ because, unlike most
chiral molecules, it is not possible to convert one mirror-image form to the other
under the rules of mathematical topology. Although intriguing and discussed as
early as 1961, to date all methods of accessing molecules containing only this
topological stereogenic element require the separation of the mirror-image
forms via chiral stationary phase high-performance liquid chromatography,
which has limited their investigation to date. Here, we present a simple method
that uses a readily available source of chiral information to allow the stereose-
lective synthesis of topologically chiral catenanes.
scientific focus because of their
importance in biology and their
emerging applications in
materials science. However,
topologically chiral molecules,
such as the catenanes described
here, have received little attention
because they are hard to make;
preparative chiral stationary
phase high-performance liquid
chromatography allows the
separation of their mirror-image
forms but only on a very small
scale. Here, we demonstrate the
synthesis of topologically chiral
catenanes by using standard
synthetic techniques, marking
their transition from ‘‘inaccessible
curiosities’’ to valid synthetic
targets for investigation in
INTRODUCTION
Chiral molecules occupy a special place in synthetic chemistry because of their ubiq-
uity in biological systems and emerging applications in materials science.1 A tetra-
hedral carbon atom bearing four different substituents is the archetypal unit that
can give rise to molecular chirality.2–4 However, chirality in organic molecules can
arise because of a number of different covalent structural features in addition to
such stereogenic centers, the most common examples of which are in molecules
where atoms are arranged suitably around a fixed axis (commonly referred to as
‘‘axially chiral’’) such that they facially desymmetrize an oriented plane (‘‘planar chi-
ral’’) or are displayed in a helical arrangement (‘‘helically chiral’’).5,6 Regardless of the
structural origin of molecular chirality, the key challenge in the synthesis of chiral
molecules is the production of pure samples of one mirror-image form (enantiomer)
of the product; because the different enantiomers of a chiral molecule by definition
have identical properties under most circumstances, they must either be produced
selectively or separated by specialist techniques. Thus, a significant amount of effort
has been devoted to achieving these goals efficiently over the past century of syn-
thetic chemistry research.
catalysis, sensing, medicinal
chemistry, and materials science.
Furthermore, this work will inspire
efforts to access other neglected
classes of chiral interlocked
molecules.
Much less widely known, and even less well explored, are the stereogenic elements
that can arise in systems where two or more covalent subcomponents with suitable
symmetry properties are permanently held together in a defined orientation by
threading through one another to create a mechanical bond.7–10 The first of these
to be identified, the ‘‘topologically chiral’’ catenanes (Figure 1), were discussed by
Wasserman and Frisch in their seminal 1961 work on chemical topology.11 This ster-
eogenic unit is extremely unusual in that it is invariant when treated under the rules of
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1
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Figure 1. Schematic of Our Proposed Approach to Topologically Chiral Catenanes
mathematical topology; in contrast to simple covalent stereogenic units, the enan-
tiomers of which can be interchanged by relaxing the Euclidean properties of molec-
ular bonding (i.e., fixed bond lengths and angles) while maintaining atomic connec-
tivity, topological stereoisomers cannot be exchanged without breaking and
reforming atomic connections and are thus topologically invariant.12,13
Over two decades passed between the identification of the potential for topological
chirality in catenanes and the first isolation of the enantiomers of topologically
chiral catenanes; Sauvage and Okamoto succeeded in separating the topological
enantiomers of a catenane by using preparative chiral stationary phase high-
performance liquid chromatography (PCSP-HPLC),14 a technique that allows the
purification of small quantities of chiral molecules. Unfortunately, the techniques
used to selectively produce chiral molecules based on covalent stereogenic
units in a scalable manner have not been applied successfully to topologically
chiral catenanes. As a result, the examples of enantiopure catenanes in which
the mechanical bond provides the only fixed stereogenic unit all make use of
PCSP-HPLC to separate the enantiomeric products.14,15 This has prevented their
investigation in enantioselective catalysis and sensing and materials science, even
as examples of chiral interlocked molecules based on covalent stereogenic
units15–19 and other chirotopic mechanical stereogenic elements20,21 have begun
to show promise in these areas.8
1School of Chemistry, University of Southampton,
Highfield, Southampton SO17 1BJ, UK
propose a new approach to enantiopure topologically chiral catenanes (Figure 1).
2Department of Chemistry, Imperial College
Building on our previous approach to mechanically planar chiral rotaxanes,22,23 we
Our proposed methodology makes use of the properties of molecules that contain
London, Molecular Sciences Research Hub, 80
Wood Lane, London W12 0BZ, UK
two stereogenic units, one of which is a classical covalent stereogenic center and the
3Lead Contact
other of which is the mechanical topological element that arises from the enchained
rings. Our proposed chiral auxiliary approach,24 including a covalent stereogenic
*Correspondence: s.goldup@soton.ac.uk
https://doi.org/10.1016/j.chempr.2019.03.008
center of fixed configuration in one of the rings in an active template coupling, gives
2
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Scheme 1. Synthesis of Diastereomeric Catenanes 3
Reagents and conditions: (i) slow addition (4 h) of (R)-1 to macrocycle 2, [Cu(MeCN)4]PF6, NiPr2Et,
CHCl3-EtOH (1:1) at 60ꢀC; (ii) KCN and CH2Cl2-MeOH (1:1). (R,R/Smt)-3a: n = 2, 1:1 inseparable
mixture, 72% combined isolated yield; (R,R/Smt)-3b: n = 1, 2:1 separable mixture favoring (R,Smt)-
3b, 89% combined isolated yield; (R,R/Smt)-3c: n = 0, 1:1 inseparable mixture: ꢁ23% conversion of
2c by 1H NMR analysis of the unpurified reaction mixture.
rise to two possible interlocked products that differ only in the configuration of the
mechanical bond. These diastereomers can be separated, at least in principle, by
simple chemical means (e.g., silica gel chromatography) because they are no longer
related as object and mirror image and thus have distinct physical properties. Once
they are separated, ‘‘deleting’’ the covalent stereogenic unit from the catenanes
would give rise to the separated mirror-image catenanes as single isomers,
completely circumventing the need for enantiomer separation.
RESULTS AND DISCUSSION
We recently reported an improved25,26 active-template27 Cu-mediated azide-alkyne
cycloaddition28,29 (AT-CuAAC)30 methodology for the synthesis of sterically crowded
catenanes in excellent yield.31 We selected this methodology to demonstrate our pro-
posedchiralauxiliaryapproachtotopologicallychiralcatenanesbecausediastereomeric
small crowded molecules, in which the topological and covalent elements of stereo-
chemistry are held in close proximity and thus interact strongly, are a priori more likely
to be separable. The required precursors, azide or alkyne pre-macrocycle (R)-1 (which
contains a fixed stereogenic center derived from an enantiopure amino acid) and macro-
cycles 232 were synthesized in a straightforward manner from readily available building
blocks (see Supplemental Information).
When pre-macrocycle (R)-1 was added slowly to a solution of macrocycle 2a and a
copper catalyst (Scheme 1), catenanes 3a were formed in high isolated yield (72%)
as a 50:50 mixture of two interlocked products, the analytical data (nuclear mag-
netic resonance [NMR] and liquid chromatography-mass spectrometry [LC-MS])
of which were consistent with diastereomers. Disappointingly, we were unable to
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Figure 2. Characterization of Catenanes 3b
(A) Solid-state structure of major diastereomer (R,Smt)-3b35 with selected intercomponent
˚
interactions highlighted (selected distances [A]: Hu$$$N = 2.35, OH$$$N = 2.28).
(B) CD spectra of (35 mM in CHCl3) (R,Smt)-3b and (R,Rmt)-3b.
(C) Partial stacked 1H NMR spectra (500 MHz, 298 K, CDCl3) of (i) the corresponding non-interlocked
triazole macrocycle derived from (S)-1, (ii) catenane (R,Rmt)-3b, (iii) catenane (R,Smt)-3b, and (iv)
macrocycle 2b. Selected signals are assigned and color coded (see Scheme 1). Signals
corresponding to macrocycle 2b are all shown in blue for clarity.
separate the stereoisomers of catenane 3a by using simple chemical techniques;
although diastereomers can theoretically be separated, this is not always practically
true. Pleasingly, replacing macrocycle 2a with smaller macrocycle 2b gave rise to
catenane 3b, and in this case, the isomers were separable in good yield (57% ma-
jor, 32% minor, and 89% combined yield). Moreover, the two possible products
were formed in unequal amounts in a ratio of ꢁ2:1 as judged by 1H NMR analysis
of the unpurified reaction mixture, selectivity that increases the overall yield of the
major isomer. It is important to note that selectivity and separability are not related
in a simple manner to the size of the bipyridine-containing ring; when smaller mac-
rocycle 2c was used, catenane 3c was formed with no selectivity as an inseparable
mixture.33,34
4
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Scheme 2. Cleavage of the Chiral Auxiliary from Catenane (R,Smt)-3b to Give Catenane (Smt)-6b
Reagents and conditions: (i) (COCl)2, DMSO, NEt3, and CH2Cl2 at room temperature (RT); (ii) AcOH
and CHCl3 at RT. 6b was isolated in 68% yield over two steps.
In order to assign the absolute stereochemistry of the interlocked products, we grew
single crystals of a racemic35 sample of the major isomer of 3b and subjected them to
X-ray diffraction analysis (Figure 2A). This allowed us to determine the relative orienta-
tion ofthe interlockedrings. Weassignedabsolute stereochemical labels byconsidering
the relative orientation of each macrocycle’s polar vectors, which followed a path from
the highest-priority atom (A, assigned by the Cahn-Ingold-Prelog method) to the high-
est-priority ligand (B) of that atom. Once we assigned these vectors, we determined the
absolute stereochemistry by orienting the assembly with the polar vector of one ring
passing away from the observer through the cavity of the other and observing the orien-
tation of the second polar vector; clockwise was assigned Rmt, and anticlockwise was
assigned Smt, and we propose that the ‘‘mt’’ suffix be used to highlight the mechanical
topological origin of the stereochemistry.7 Using this approach, we determined the
absolute stereochemistry of the major isomer to be (R,Smt)-3b and, by a process of
elimination, the minor isomer determined to be (R,Rmt).
The 1H NMR spectra of separated diastereomeric catenanes 3b were clearly
different from those of the corresponding non-interlocked components (Figure 2C);
in both interlocked products, triazole resonance Hu appeared at higher ppm than the
corresponding non-interlocked macrocycle, consistent with a H bond between this
polarized C–H and a bipyridine N, as observed in the solid-state structure of racemic
(R,Smt)-3b,36 and many other signals (e.g., flanking aromatic ring protons HD, HE, HL,
and HM) shifted to lower ppm, consistent with the crowded environment of the me-
chanical bond. Mechanical bond formation also rendered several geminal methy-
lene signals of the bipyridine macrocycle diastereotopic; protons HF, HK, HP, and
HN, which are single environments in macrocycle 2b, split apart into diastereotopic
sets in catenanes 3b.
Despite these gross similarities, the separated isomers of 3b were clearly chemically
distinct by 1H NMR; benzylic protons He appeared as an AB quartet in catenane
(R,Smt)-3b and as separated doublets in (R,Rmt)-3b. Similarly, HD, HE, HL, and HM
appeared close to one another in (R,Rmt)-3b but were more widely dispersed in dia-
stereomer (R,Smt)-3b. The circular dichroism (CD) spectra of the diastereomers were
also clearly distinct: compared with the minor diastereomer (R,Rmt)-3b, the major
(R,Smt)-3b diastereomer displayed an additional peak (Figure 2B). Perhaps surpris-
ingly, aside from the additional peak and a slight shift in the lower-wavelength
signal, the CD traces of (R,Smt)-3b and (R,Rmt)-3b were roughly mirror images of
one another, suggesting that the topological element of stereochemistry dominates
the appearance of the CD spectra.
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Figure 3. Characterization of Catenanes 6b
(A) Analytical chiral stationary phase HPLC chromatograms (RegisCell, 98:2 hexane-iPrOH,
0.5 mL/min) of (Rmt)-6b (blue), (Smt)-6b (green), and racemic 6b (orange).
(B) CD spectra (35.0 mM in CHCl3, 293 K) of (Rmt)-6b (blue), (Smt)-6b (green), and racemic 6b (orange).
(C) Partial stacked 1H NMR spectra (500 MHz, 298 K, CDCl3) of (i) the corresponding non-
interlocked triazole macrocycle of catenane 6b, (ii) catenane (Smt)-6b, and (iii) macrocycle
2b. Selected signals are assigned and color coded (see Schemes 1 and 2). Signals
corresponding to macrocycle 2b are all shown in blue for clarity.
Having demonstrated the synthesis and separation of topologically epimeric cate-
nanes 3b, we turned our attention to removing the covalent stereogenic element in
order to produce enantiomeric catenanes 6b (Scheme 2). The chiral auxiliary unit
bore a striking resemblance to the achiral para-methoxybenzene (PMB) protecting
group, and our original intention was to remove it in an analogous manner to a PMB
group either by treatment with acid or by oxidation.37 However, treatment of
(R,Smt)-3b with trifluoroacetic acid or oxidation with Ce(IV) led to extensive decom-
position, and LC-MS showed cleavage of the triazole-containing macrocycle. Ulti-
mately, the covalent stereogenic unit was cleaved from (R,Smt)-3b by a stepwise
process of oxidation and hydrolysis inspired by the Amadori rearrangement of imi-
nosugars;38,39 treatment of (R,Smt)-3b under Swern40 conditions gave aldehyde 4b,
which was not isolated but immediately treated with acetic acid. Acetic acid cata-
lyzed the removal of the auxiliary to give catenane 6b presumably by isomerization
6
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of a-amino aldehyde catenane 4b to the a-hydroxy iminium tautomer 5b with sub-
sequent hydrolysis.
Catenane 6b no longer contained a covalent stereogenic unit, and thus the
topological stereogenic unit was the only remaining fixed stereochemical feature.41
The stereochemical purity of the products was confirmed by analytical CSP-HPLC
(Figure 3A). A racemic sample of 6b displayed two clear peaks in the chromatogram,
whereas single peaks (<1:99 purity) were observed for the separated enantiomers.
To assign the topological stereogenic unit, we considered that the relative orienta-
tion of the two rings remained unchanged during the cleavage of the auxiliary and
applied the same approach discussed above for catenanes 3; thus, (R,Smt)-3b
gave rise to (Smt)-6b. The mirror-image isomer (Rmt)-6b was synthesized starting
from (S)-1. Analysis of catenanes (Rmt)-6b (Figure 3C) and (Smt)-6b by 1H NMR
confirmed that they were chemically identical with the exception of the topological
element of stereochemistry; the spectra of the isomers were identical and,
compared with their non-interlocked components, exhibited the expected changes
in chemical shift. Hu shifted to higher ppm; HD, HE, HL, and HM shifted to lower ppm;
and protons Hs and Ht, which are singlets in the non-interlocked macrocycle, were
split into diastereotopic signals in the interlocked structure. CD spectroscopy (Fig-
ure 3B) confirmed the enantiomeric nature of the structures by revealing identical
but mirror-image spectra for the two enantiomers.
Conclusions
We have demonstrated that by combining a covalent stereogenic unit with a topo-
logical element of stereochemistry, it is possible to stereoselectively produce sepa-
rable topological catenane epimers. Subsequent cleavage of the covalent stereo-
genic element from the separated products gave enantiopure topologically chiral
catenane products. Although Sanders,42 Gagne,43 and Trabolsi44 have previously
reported isolated examples of the serendipitous stereoselective synthesis of topo-
logical homo[2]catenane diastereomers under thermodynamic control, the multiple
elements of covalent stereochemistry used to direct the stereochemical outcome of
the reaction remained in the final product, whereas our chiral auxiliary approach
gives access to molecules in which the mechanical bond provides the sole fixed
stereogenic unit.41 Our chiral auxiliary concept is technically simple and, given the
generality of the AT-CuAAC catenane-forming reaction,31 makes functionalized
topologically chiral catenanes in which the mechanical bond provides the only
stereogenic unit available for the first time without the need for CSP-HPLC
separation.
DATA AND SOFTWARE AVAILABILITY
The accession number for the solid-state structure of (R,Smt)-3b reported in this pa-
per is CCDC: 1885204. Processed compound characterization data (NMR, circular
dichroism, HPLC, and MS) are available freely from the University of Southampton
repository (https://doi.org/10.5258/SOTON/D0828).
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2019.03.008.
ACKNOWLEDGMENTS
S.M.G thanks the European Research Council (Consolidator Grant agreement no.
724987) and Leverhulme Trust (ORPG-2733) for funding. M.D. and F.M. thank the
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Engineering and Physical Sciences Research Council for doctoral prize funding (EP/
N509747/1 and EP/R513325/1, respectively). J.E.M.L. thanks the European Union’s
Horizon 2020 Research and Innovation Programme for a Marie Skłodowska-Curie
Fellowship (grant agreement no. 660731). The authors thank Reach Separations
for assistance with analytical CSP-HPLC.
AUTHOR CONTRIBUTIONS
S.M.G. conceived the project and secured project funding. M.D., J.E.M.L., and F.M.
contributed equally to the design of experiments and methodology and their execu-
tion. S.M.G. wrote the manuscript with input from all authors. M.D., J.E.M.L., and
F.M. contributed equally to the reviewing and editing of the manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: December 15, 2018
Revised: January 14, 2019
Accepted: March 15, 2019
Published: April 11, 2019
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Please cite this article in press as: Denis et al., An Auxiliary Approach for the Stereoselective Synthesis of Topologically Chiral Catenanes, Chem
(2019), https://doi.org/10.1016/j.chempr.2019.03.008
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Supplemental Information for further details)
suggests that, as previously observed,23
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stereochemical bias observed, significantly
more detailed modeling, including the
identification of a suitable transition state and
the inclusion of explicit solvent, alongside
extensive corroborating experimental data,
would be required in order to fully elucidate
and hopefully optimize the stereoselectivity of
the reaction.
41. Although the mechanical stereogenic element
is the only remaining fixed source of
stereochemistry in 6b, as with most molecules,
multiple sources of dynamic stereochemistry,
including the stereogenic sp3 hybridized N
atom, are present, and these can undergo
inversion between R and S configurations and
conformational stereoisomerism as a result of
rotation of C–C bonds, for example, between
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two macrocycles.
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35. Attempts to grow single crystals of enantiopure
(R,Smt)-3b failed. Both enantiomers were
observed in the solid-state structure of racemic
(R*,S*mt)-3b (see Supplemental Information
for details; asterisks indicate that the
assigned stereochemistry is relative rather
than absolute). The 1H NMR spectrum of
(R*,S*mt)-3b was identical to that of
(R,Smt)-3b.
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33. The conversion of macrocycle 2c to catenanes
3c was extremely low, and as a result, it was not
possible to isolate the interlocked product.
However, 1H NMR analysis of the crude
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reaction mixture revealed signals consistent
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