Chiral Catenanes and Rotaxanes: Fundamentals and Emerging Applications

Abstract Molecular chirality provides a key challenge in host–guest recognition and other related chemical applications such as asymmetric catalysis. For a molecule to act as an efficient enantioselective receptor, it requires multi‐point interactions between host and chiral guest, which may be achieved by an appropriate chiral 3D scaffold. As a consequence of their interlocked structure, catenanes and rotaxanes may present such a 3D scaffold, and can be chiral by inclusion of a classical chiral element and/or as a consequence of the mechanical bond. This Minireview presents illustrative examples of chiral [2]catenanes and [2]rotaxanes, and discusses where these molecules have been used in chemical applications such as chiral host–guest recognition and asymmetric catalysis.


Introduction
Any undergraduate chemistry student will be familiarw ith the concept of chirality,a nd specifically that chiral molecules are non-superimposable on their mirror image. Many processes in the natural world rely on the ability to recognize chiral molecules, and this, in part at least, inspires chemists to study chiral host-guest recognition and relatedthemes such as asymmetric catalysis. [1] It is generally accepted that a3 Da rrangemento fa t least three interactions (one of which needs to be stereochemically dependent)m ust exist between ac hiral host and its chiral guest to achieve chiral recognition. [2] As ac onsequence of their interlocked structures, catenanes [3,4] (molecules consisting of two or more interlocked macrocyclic rings, Figure 1a) and rotaxanes [5] (molecules consisting of stoppered axle(s) components threaded through one or more macrocyclic rings, Figure 1b)c ould form the basis of useful 3D scaffolds for chiral hosts.
It is now well-established that template synthesis provides a versatile route to interlocked molecules, [6] relying on the preorganization of components prior to final covalent bond formation to trap the interlocked species. [7] Classicalt emplatings trategies using metal cations, [8] p-p stacking [9] and hydrogen bonding [10] have been supplemented by more recent work on anionic, [11] radical-radical [12] and halogen bond [13] templation.Althoughs ynthetic methodology is still being developed, research is increasingly being focused on exploiting mechanically interlocked moleculesi nc hemical applications, [14] such as hostguest recognition [15] or catalysis. [16] Some researchers have made use of the 3D geometries created by interlocked molecular structures to achieve guest selectivity,a nd someh ave exploitedt he stimulus-controlled motion of interlocked components to make examples of molecular machines [17] which were celebrated by the 2016 Nobel Prize in Chemistry. [18] Ac atenane or rotaxanem ay be made chiralb yt he inclusion of ac lassical chiral motif. Alternatively,c hirality may arise as a consequence of the mechanical bond. Although examples of chiral interlockedm olecules have been known for some time (as evidenced by previousr eviews), [19,20] it is perhaps only now that this research field has begun to genuinely flourish, as significant progress is not only made in their preparation,b ut also in the applicationo ft heset opologically and stereochemically exotic species. This Minireview sets out to provide an informed overview of examples of chiral catenanes and rotaxanes, before detailing their use in emerging chemical applications. As aM inireview,t his article is not designed to be an exhaustivecollection of every chiral catenane or rotaxane, and instead ar ange of illustrative examples will be presented, focusingp rincipally on chiral examples of [2]catenanes and [2]rotaxanes,a nd those that exhibit useful chemical application. For progress in the relatedc lass of molecular knots,i nterested readers are referred to an excellent review that has just been published. [21] 2. Chirality Arising from Classical Chiral Elements As traightforward way to create ac hiral catenaneo rr otaxane is by incorporating ac lassical chiral element, such as ac hiral centre,a xis or plane into at least one of the componentst hat make up the interlocked molecule. However,c are is neededi n certainc ases. For example, for ah omocircuit [2]catenane (a catenane where the two interlocked rings are identical), if one ring hasastereocentrew ith an R configurationa nd the other an S,t hen the catenane is achiral (it is the meso diastereomer of the R,R and S,S enantiomeric pair,see Figure 2).
In cases of [2]catenanes, in which both rings possess chiral elements, researchers have sometimes observed evidenceo f diastereoselectivityi ns ynthesis. For example, when racemic binaphthyl crown ether 2 and enantiopure (R)-binapthyl bis-pyridinium precursor 3 were used, the R,R and S,R stereoisomers of the catenane were obtained in ad iastereomericr atio of 67:33 in favour of R,R ( Figure 4). [23] For catenane 6 4 + (PF 6 À ) 4 ( Figure 5), both rings may possess elements of planar chirality,w hen the pair of binaphthyl spacers in each ring are staggered with respectt oo ne other. In solution, twelve stereoisomers of this catenane are possible (six diastereomers, each existing as pairs of enantiomers), many of which are in exchange with one another through low energy conformational and co-conformational processes. Althought his catenane exhibits complex dynamic stereochemical behaviour in solution, the researchers reportedt hat crystallization afforded enantiopure single crystals of the SS, SS enantiomer. [24] 2.2. Rotaxanes that possess classical chiral elements Amongst early work, Vçgtle and co-workers prepared charge assisted p-p donor-acceptor rotaxanes possessing chiralt etraacetyl glucose stoppers (such as 7 4 + (PF 6 À )i nF igure 6a). [25] In addition, the same group prepared examples of hydrogen bond templated rotaxanes stoppered with tetrabenzoyl glucose units (such as 8 in Figure 6b). [26] In the latter case, the ro-     taxanese xhibited amplified circular dichromism (CD) compared to the free axle.
Subsequently,L eigh andc o-workers have prepared as eries of hydrogen bond templatedr otaxanes incorporating l-amino acids ( Figure 7). [27] In chloroform,t he rotaxanes 9 exhibit CD signals, but the corresponding non-interlockedc hiral axles do not. Detailedi nvestigations revealed that chirality is transmitted from the chiral centre on the axle via the interlocked macrocycle to the C-terminal stopper of the rotaxane. Further,t his induced circulard ichroism (ICD) may be modulated by varying solvent, temperature or size of the chiral substituent.F or example,s witching the solventt oh ydrogen bond competitive methanol leads to ad ramatic reduction in CD signal for any given rotaxanea st he macrocycle can freelyr otate and hence does not communicatethe chiral information efficiently.
In follow-up work, the same group reported on the use of light-controlled E/Z isomerism in ar elated rotaxane 10 to create ac hiroptical switch ( Figure 8). [28] When the fumaramide C=Ci strans,t hen the macrocycle preferentially resides over this functional group. Isomerization of the double bond to cis geometry,c auses the macrocycle to shuttle to the glycine-leucine station, which, incorporatingachiral substituent, allows for the switching on of achiral opticalresponse (that is the appearance of as ignal in the CD spectrum). [29] 3. Chirality Arising as aConsequence of the Mechanical Bond Exciting opportunities are possible because of the mechanical bond,f or chirality may arise in catenanes and rotaxanes even when the interlocked components are themselves achiral. This may be described as "mechanical chirality", at ermt hat has recently been defined specifically by Bruns and Stoddart as "a non-classicalf orm of chirality resulting from the spatial arrangements of component parts connected by mechanical bonds". [30,31] Mechanical chirality may arise in [2]catenanes from directionality in both rings ( Figure 9a)o rf rom facially unsymmetric rings ( Figure 9b). Catenanes possessing directionality in both rings may be described as topologically chiral. Mechanical chirality originates in [2]rotaxanes from both the axle and the macrocycle being directional( Figure 9c)o rw hen am acrocycle is trapped on one side of what would be ap rochiral centre of the non-interlocked axle component-in am anner with parallels to atroposiomerism (Figure 9d).

Topologically chiralcatenanes
The first topologically chiral catenane was prepared by Mitchell and Sauvage by use of Cu I cation templation. [32] Inclusion of a phenyl substituent at position 4o ft he phenanthrolineg roup of both rings leads to the creation of enantiomers( Figure 10). The chirality of catenane 11 (whichw as prepared as ar acemate) wasc onfirmed by use of Pirkle's reagent (S-(+ +)-2,2,2-trifluoro-1-(p-anthryl)ethanol) and careful 1 HNMR spectroscopic analysis. Subsequently,p artial separation of the enantiomers   was achieved by HPLC to allow forr ecording of mirror image CD spectra (in collaboration with Okamoto and co-workers). [33] An alternative source of directionality in metal templated mechanically chiral catenanes has been illustrated in an example of ab imetallic [2]catenane ( Figure 11). [34] In the solid state, crystal structures reveal that only one of the imine nitrogen atoms is coordinating to the Zn II cation, thus generating directionality in each of the interlocked rings. However,i ns olution, catenane 12 is fluxional, with cleavagea nd formation of coordination bonds occurring. Such processes are forbidden when considering topology,and so in solution (at least) this catenane cannotbec onsidered topologically chiral.

Facially unsymmetric chiral catenanes
The first facially unsymmetric chiral catenanesw ere reported by Puddephatt in 2002 ( Figure 12). [35,36] As et of [2]catenanes 13 were preparedu sing aurophilic templation.C hirality arises from the orientation of the bromo-aromatic substituents, in a manner similar to how chirality arises in appropriately substituted allenes. Bruns and Stoddart have therefore proposed the use of the term "mechanically axial chirality" and the stereochemicall abels R ma and S ma to describe the chirality in such catenanes. [30] AC u I -templated catenane has been prepared by Marinetti and co-workersthat also exhibits facially unsymmetric mechanical chirality (Figure 13). [37] In this case, facial dissymmetry arises from incorporation of phosphine oxides in each ring. In addition to the mechanical chirality there are stereogenic carbon atoms. By use of an enantiopure macrocycle to generate the catenane, the resulting diastereomers of demetallated catenane 14 were separableb yp reparative HPLC to give optically pure diastereomers.  The stereochemical labels R and S are assigned thus:inthe direction of an arrow pointing from the highest priority atom (labelled 1) to its highest priority neighbour (labelled 2), interlocked rings that are disposedi naclockwise manner are R,those in an anticlockwise manner are S.

Mechanically planar chiral rotaxanes
In 1997, Vçgtle andO kamoto reported upon the preparation and HPLC resolution of an amide-sulfonamide [2]rotaxane,t hat is chiral by consisting of directional axle and macrocyclic components ( Figure 14). [38] Although the researchers successfully separated the enantiomers of rotaxane 15 and recorded mirror-imageC Ds pectra, they were unable to assign the absolute configurationo ft he two enantiomeric samples.
The authors of this paper used the term "cycloenantiomeric" to describe the chirality of 15,b ut it has since been proposed that the term "mechanically planar chiral" is possibly am ore appropriate descriptor. [39] Goldup has also suggested an omenclature for describing the enantiomersofamechanicallyp lanar chiral rotaxane, as illustrated for rotaxane 15 in Figure 14.
The key synthetic challenge in exploiting mechanically planar chiral rotaxanes is to preparee nantiopure examples on ap reparative scale. An illustration of the challenge involved is reflectedb yT akata's report on attempts to achievec atalytic asymmetrics ynthesis of ap lanar chiralr otaxane consisting of a substituted 18-dibenzocrown-6 macrocycle and secondary ammonium salt axle ( Figure 15). [40,41] The rotaxanes were prepared by an acylativee nd-capping using ac hiral bisphosphine catalyst. Unfortunately,t he maximum observed enantiomer excess was only 4.4 %.
Acritical breakthrough in accessing enantiopure mechanically chiralr otaxanes wasa chieved in the elegantw ork of Bordoli and Goldup (Figure 16). [39,42] Using aC uAAC" click"-active metal templates ynthesis, [43] they constructed rotaxane 24 from directional macrocycle 21 and two half threads-achiral alkyne 22 and the othere nantiopure azide 23.T he diastereomers of 24 weref ormedi na ne ssentially 1:1r atio, butc rucially they could be separated by standard flash chromatography.S ubsti-  The stereochemical labels R mp and S mp are assigned thus:View the rotaxane along its axle from the highest priority atom in the axle (A1) to that atom's highest priorityn eighbour (A2). If in the macrocyclethe highestp riority neighbour (M2)isd isposedclockwise from the highest priority atom (M1), then the stereochemical label is R mp ;ifi ti sd isposed anticlockwise thent he label is S mp .

Point mechanical chiral rotaxanes
Mechanical chirality may arise in rotaxanes-which is more appropriately termed point mechanical chirality-when am acrocycle is trapped on one side of what would be ap rochiral centre of the non-interlocked axle component. This has been demonstrated in ar otaxanep repared by Leigh and co-workers ( Figure 17). [44] At room temperature, the macrocycle of the achiral [2]rotaxane 27 can move between the two fumaramide functional groups on as ymmetrical axle. However, if the alcohol at the centre of the axle is benzoylated, the macrocycle becomest rapped at one end of the axle, and the carbon atom attached to the benzoylated alcohol group becomes as tereogenic centre. If DMAP is used to catalyze the benzoylation reaction, ar acemateoft he point mechanically chiral rotaxane 29 is generated. However,u se of ac hiral catalysta llows for enantioselectivity,w ith rotaxane 29 being isolatedw ith an enantiomeric ratio of 67:33 (S:R).

Chiral Catenanes and Rotaxanes in Application
Mechanically interlockedm olecules are increasingly being put towardss ome form of functional application. [14] For example, the three dimensional structures of certain catenanes and rotaxanesh ave been used to achieve selectivity in the binding and sensing of ionic and small molecular guest species. [15] Meanwhile, others have been shown to act as catalysts, including examples for whichc ontrolled motiono ft he interlocked components is used to switchc atalytic activity on and off. [16] Examples of chiral catenanes and rotaxanes being used in such applicationsh ave been somewhat rare, but are now growing in number.

Chiralhost-guest recognition
In 2006, Kametaa nd Hiratani reported upon the chiral sensing of phenylalaninol by am echanically planar chiral rotaxane (Figure 18). [45] The racemate of rotaxane 30 was prepared by a covalentb ondf ormation (rather than template synthesis) ap-proach. [46] 1 HNMR and fluorescences pectroscopic experiments provided evidencet hat l-phenylalaninol was selectivelyb ound through hydrogen bonding by one of the enantiomerso ft he rotaxane, and d-phenylalaninol by the other in chloroform.
Being studied as the racemate, the Kameta and Hiratani system is somewhat limited as an enantioselective host. To avoid this issue, Niemeyer and co-workers prepared an enantiopure catenane by use of macrocyclic components containing an axially chiral binaphthyl-phosphoric acid unit ( Figure 19). [47] Followingr emoval of the calcium cation used to template the formationo ft he catenane, the researchers demonstrated that catenane 31 (as the bis-tetrabutylammonium salt) possessed enantioselectivity for bis-HCls alts of chiral diamine guestsi nD MSO. While the levels of enantioselective guest recognition were modest (K fav /K disfav = 1.4-1.6), they were greater than for the non-interlocked macrocycle.    Figure 20). [48] Prepared by active-metal templating, both macrocycle and axle components possess iodotriazoles that can halogen bond to anionic guests in solution. By 1 HNMR titrations, they demonstrated that rotaxanes 32 + PF 6 À and 33 + PF 6 À can bind chiral anionsw ith enantioselectivities( K fav /K disfav )o fu p to 2.9 and3 .4 respectively ( Table 1). Notably rotaxane 34 + PF 6 À exhibits negligible enantioselective behaviour towards any of the chiral anionsi nvestigated (K fav /K disfav < 1.2), meaning,f or these rotaxanes, that the presence of ac hiralm acrocyclic component is essential to achieve reasonable levels of guest enantiodiscrimination.

Asymmetricc atalysis
In 2004, Takata reported upon the use of rotaxanes possessing axially chiral binaphthyls to create ac hiral environmentt o asymmetrically catalyze benzoinc ondensations ( Figure 21). [49] Good yields (up to 90 %), but with rather modest enantiomeric excesses (< 32 % ee), were observed for rotaxanes, for which the chiral group was either part of the axle, or more impressively when the chiral group was part of the macrocycle (as depicted in Figure 21), thus transmitting the chirali nformation between thei nterlocked components to the thioazolium on the axle. Leigh andc o-workersh ave since reportedo nanumber of chiral rotaxanesf or asymmetricc atalysis. [50][51][52] For instance, an active metal template synthesized rotaxanep ossessing ac hiral C 2 symmetric trans-cyclohexanediaminem acrocycle, for use in enantioselective nickel-catalyzedc onjugate addition reactions ( Figure 22). [50] In comparison to an analogous acyclic ligand, rotaxane( R,R)-38 exhibited am uch better enantiomeric ratio of product (93:7 compared to 68:32), but considerably slower reaction times (27 vs. 2days for full conversion as determined by 1 HNMR spectroscopy). These observations are consistent with the rotaxanei mproving expression of chirality arising from the two stereogenic carbon atoms (by reducing degrees of freedom),b ut also restricting access to the cation (since it is buriedw ithin the rotaxane structure while coordinated to the nitrogen amine atoms), thusreducing the rate of reaction.   The same group has also exploited ap oint mechanical chiral rotaxane( S)-42 in catalysis ( Figure 23). [51] As econdary amine on the axle component may participate in enantioselective Michael addition and enamine reactions. The recorded enantiomeric ratio of productsw as somewhat low (68:32 and 71:29 were the best reported for the two types of reaction)-this is partly due to rotaxane (S)-42 being preparedi no nly 84 % eebut the proof of principle was clearly demonstrated (enantio-meric ratios of 50:50 being observed in all cases where the achiral axlewas used in place of the rotaxane).
The researchers have also demonstrated that as witchable rotaxanem ay asymmetrically catalyzer eactions in ac ontrolled fashion ( Figure 24). [52] Rotaxane (R)-46 + PF 6 À includes two stations:i na cidic conditions,t he central secondary amine of the axle is protonated and the crown ether macrocycle resides over the resulting ammoniumg roup, preventing the substrate from accessing the Na tom. Once the amine is deprotonated, the crown ether moves to an alternative methyl triazoliums tation;s ubstrates can then access the amine (whichi sb onded to as tereogenic carbon atom) and catalytic reactivity is thus turned on. This process may be reversed by addition of acid to reprotonate the amine, leading to translation of the macrocycle back over the reformed ammonium group. In its deprotonated state, rotaxane (R)-46 + PF 6 À can catalyzea symmetric Michael additions with reasonable conversion( 60-70 %) and high enantiomeric ratios of products (up to 94:6).
Very recently,N iemeyera nd co-workers have reportedu pon the use of binaphthyl-phosphoric acid catenane (S,S)-31 (de-    Figure 19) as ac atalyst in asymmetric transfer hydrogenationr eactions ( Figure 25). [53] Impressively, using catenane (S,S)-31 as the catalyst led to dramatically increased stereoselectivity comparedt ou sing the non-interlocked macrocycle, with comparable yields (although notably slower reaction times). Detailed computational calculations provide evidence that the high stereoselectivities observed with the catenane are ad irect result of its interlocked nature.

Conclusions
Future investigations into the preparation and studyo fc hiral catenanes and rotaxanes have great potential. As highlighted in the Introduction, much progress has been made in developing new synthetic methodologies to prepare interlocked molecules since the early work on chiral catenanes and rotaxanes by the groups of Sauvage, Stoddart and Vçgtle.R ecent demonstrations of the application of chiral interlocked molecules in host-guest recognition and catalysis provide significant encouragementf or researchers to work towards overcoming unresolved challenges in the field such as directly accessing enantiopure mechanically chiralc atenanes andr otaxanes through enantioselective synthesis. By overcoming such challenges,wec an look forwardt or ealizing the full potential of interlocked molecules as useful three-dimensional scaffolds in real-worldc hiral applications.