Mechanical Chirality of Rotaxanes: Synthesis and Function

S S symmetry

Review Mechanical Chirality of Rotaxanes: Synthesis and Function

Kazuko Nakazono * and Toshikazu Takata * School of Materials and Chemical Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8503, Japan * Correspondence: [email protected] (K.N.); [email protected] (T.T.)

Received: 26 November 2019; Accepted: 7 January 2020; Published: 10 January 2020

Abstract: Mechanically chiral molecules have attracted considerable attention due to their property and function based on its unique interlocked structure. This review covers the recent advances in the synthesis and function of interlocked rotaxanes with mechanical chirality along with their dynamic and complex stereochemistry. The application of mechanically chiral rotaxanes to control the polymer helical structure is also introduced, where ampliﬁcation of mechanical chirality appears to cause the macroscopic polymer property change, suggesting the potential applicability of mechanical chirality in polymer systems.

Keywords: mechanical chirality; rotaxane; mechanically interlocked molecules; chiral rotaxane; helical polymer

1. Introduction Mechanically interlocked molecules (MIMs) consist of multiple molecular components entangled via mechanical bonds. Early research on MIMs started from the viewpoint of statistical synthesis and molecular topology, which has been followed by strategic synthesis based on host–guest chemistry and the active metal template method. Thus, catenanes and rotaxanes with various molecular structures have become presently available [1]. These molecules offer interesting properties that are based on the cooperative effect between their subcomponents, which can be altered at the mechanical bonds. Recently, various applications of the characteristic properties of MIMs have been actively studied by utilizing not only small molecules, but also polymer materials [2]. Although a variety of MIMs can be synthesized, research on the basic chirality of MIMs is still in its infancy. It is well known that chiral MIMs are obtained by introducing some classical chiral units to MIMs, whereas chirality also appears when combining Cs symmetrical components (Figure1). Such chirality stems from the di fference in the spatial arrangement of the components at the mechanical bond, and it is therefore called “mechanical chirality” or “topological chirality.” Theoretical studies on this subject were reported in the 1960s [3–5]; thereafter, the first synthesis of mechanically chiral catenane and rotaxane was achieved in the late nineties by Sauvage et al. [6] and Vögtle et al. [7,8]. With the development of strategic synthetic methodologies, MIMs with different types of molecular chirality have been reported [1], and recently, the stereochemistry of MIMs has also been consolidated based on the concepts of “co-conformation” and “co-configuration” [9–12]. This stereoisomerism is generated not only by the orientation, sequence, and arrangement of multiple components, but also by their relative position. Moreover, the chirality arises from the combination of achiral components. These may or may not be convertible between the stereoisomers, depending on the mechanical bond movement; furthermore, it is sometimes possible to induce the switching between chiral and achiral structures. Therefore, the chirality of MIMs includes complex but interesting concepts, and special characteristics that cannot be found in conventional chiral molecules are expected. In the future,

Symmetry 2020, 12, 144; doi:10.3390/sym12010144 www.mdpi.com/journal/symmetry Symmetry 2020, 12, 144 2 of 14 the variety of chiral MIMs derived by co-conformational changes could be used to create switchable molecular devices for various chiral applications. Thus, fundamental research on the chirality of MIMs is an important subject not only for basic science, but also for applications exploiting the nature of MIMs. Recently, some excellent reviews on chiral MIMs have been reported [13–15] that widely cover various compounds with chiral aspects. This review focuses on chiral rotaxanes and their applications directed toward an extensive analysis of mechanical chirality. In general, rotaxane can be synthesized easier than catenane, and has wide structural diversity, depending on the number and kind of components. Rotaxanes can exhibit some dynamic modes based on the intercomponent motions such as shuttling, circumrotation, and ﬂipping around the mechanical bond, which leads to signiﬁcant co-conformational changes and at times to a change in the chemical property of the functional groups in it [9]. In fact, a variety of molecular switches including a chiroptical switch system have been investigated by utilizing the rotaxane component’s mobility. Not only have small molecules received considerable research attention, but also the polymeric systems possessing rotaxane moieties. The combination of polymer and rotaxane increases the structural and conformational diversity accompanied by the appropriate polymer property changes such as morphology or other physical properties according to the rotaxane’s dynamicSymmetry 2020 behavior., 12, x FOR Therefore, PEER REVIEW we would like to focus on the potential of chiral rotaxane as a new chiral2 of 15 molecular motif.

Figure 1. Mechanically chiral catenane (a) and rotaxane (b). Figure 1. Mechanically chiral catenane (a) and rotaxane (b). 2. Mechanically Chiral Rotaxanes With the development of strategic synthetic methodologies, MIMs with different types of Rotaxanes consist of macrocyclic components, so called wheels, threaded by axle components. molecular chirality have been reported [1], and recently, the stereochemistry of MIMs has also been As shown in Figure2, the combination of unsymmetrical components inherently derives enantiomers. consolidated based on the concepts of “co-conformation” and “co-configuration” [9–12]. This Their chirality is related to the spatial arrangements of unsymmetrical component parts linked stereoisomerism is generated not only by the orientation, sequence, and arrangement of multiple by a mechanical bond, and is different from the classical chirality based on covalent bonding. In fact, components, but also by their relative position. Moreover, the chirality arises from the combination these enantiomers cannot be interconverted unless a mechanical bond breaks and is then re-formed. of achiral components. These may or may not be convertible between the stereoisomers, depending To express this characteristic chirality of mechanical bonded molecules, several terms have been on the mechanical bond movement; furthermore, it is sometimes possible to induce the switching proposed to properly represent this to date [16], but recently, an appropriate method has been between chiral and achiral structures. Therefore, the chirality of MIMs includes complex but established. Goldup proposed “mechanically planar chirality” as the more suitable description to interesting concepts, and special characteristics that cannot be found in conventional chiral molecules express the stereochemistry of the rotaxane’s molecular chirality [17]. To describe the chirality based are expected. In the future, the variety of chiral MIMs derived by co-conformational changes could on the spatial arrangement of components parts, he proposed adding “mp” to the “R” and “S” be used to create switchable molecular devices for various chiral applications. Thus, fundamental as “R ” and “S ”. “mp” stands for mechanical planar, which means that the central plane of researchmp on the chiralitymp of MIMs is an important subject not only for basic science, but also for chirality corresponds to the plane including the wheel that is located at the vertical position to the applications exploiting the nature of MIMs. Recently, some excellent reviews on chiral MIMs have axle component. As shown in Figure2a, first the orientations of each component are defined based on been reported [13–15] that widely cover various compounds with chiral aspects. This review focuses the ordinary used priority rule, respectively. Then, the directions of the components are combined on chiral rotaxanes and their applications directed toward an extensive analysis of mechanical and determine the enantiomers as R or S . On the other hand, the co-conformational change chirality. In general, rotaxane can bemp synthesizedmp easier than catenane, and has wide structural by moving the relative position of the wheel on the axle derives a different chiral stereoisomer. The diversity, depending on the number and kind of components. Rotaxanes can exhibit some dynamic co-conformational change, as shown in the bottom of Figure2a, results in a drastic change in the spatial modes based on the intercomponent motions such as shuttling, circumrotation, and flipping around arrangement of component parts around the intersection of components, even though the orientations the mechanical bond, which leads to significant co-conformational changes and at times to a change of the individual components do not change. It would not be surprising if such a co-conformational in the chemical property of the functional groups in it [9]. In fact, a variety of molecular switches including a chiroptical switch system have been investigated by utilizing the rotaxane component’s mobility. Not only have small molecules received considerable research attention, but also the polymeric systems possessing rotaxane moieties. The combination of polymer and rotaxane increases the structural and conformational diversity accompanied by the appropriate polymer property changes such as morphology or other physical properties according to the rotaxane’s dynamic behavior. Therefore, we would like to focus on the potential of chiral rotaxane as a new chiral molecular motif.

2. Mechanically Chiral Rotaxanes Rotaxanes consist of macrocyclic components, so called wheels, threaded by axle components. As shown in Figure 2, the combination of unsymmetrical components inherently derives enantiomers.

Symmetry 2020, 12, 144 3 of 14 change resulted in the inversion of the circular dichroism (CD) signal. Such an apparent chiral inversion is signiﬁcantly interesting from the view of chiroptical switching, but these co-conformers are not static, but dynamic, and usually have a structural distribution. If the isomerization barrier between these co-conformers is not high as to detect each co-conformer, it should be discussed by using the averaged structure based on the co-conformational distribution. In fact, when the rotaxanes are synthesized by utilizing local intramolecular interactions, the co-conformation is biased in a speciﬁc distribution even though the mechanical bond is movable. Whereas, when the intramolecular interaction of rotaxane

Symmetryis removed, 2020, 12 a, x stable FOR PEER conformational REVIEW distribution is spontaneously changed based on the updated3 of 15 potential gradient.

Figure 2. Mechanically planar chirality in rotaxane. Co-conformational stereoisomerization in Figure[2]rotaxane 2. Mechanically having a rotationally planar chirality unsymmetrical in rotaxane wheel. andCo-conformational an axle with two stereoisomerization nonequivalent ends (ina), [2]rotaxaneand achiral-chiral having interconversiona rotationally unsymmetrical in [2]rotaxane havingwheel and rotationally an axle with unsymmetrical two nonequivalent wheel and ends an ( axlea), andwith achiral-chiral two equivalent interconversion ends (b). in [2]rotaxane having rotationally unsymmetrical wheel and an axle with two equivalent ends (b). In addition to this, the dynamic stereoisomerization in a rotaxane means it is possible to control the achiral–chiralTheir chirality chiropticalis related to switching the spatial in arrangements a [2]rotaxane, of which unsymmetrical consists of component a symmetrical parts axle linked and byunsymmetrical a mechanical bond, wheel and (Figure is different2b). Once from the the wheelclassical moves chirality from based the centralon covalent position bonding. of the In axle,fact, thesemechanically enantiomers planar cannot chirality be interconverted is induced, depending unless a me onchanical the co-conformation bond breaks fromand is achiral then re-formed. (prochiral). ToHowever, express ifthis the characteristic wheel can move chirality freely of on mechanical the axle (i.e., bonded the racemization molecules, several is too fastterms to detecthave been each proposedenantiomer), to properly it can be regardedrepresent asthis an achiralto date molecule.[16], but recently, an appropriate method has been established.As above-mentioned, Goldup proposed mechanical“mechanically chirality planar chirality” is generated as the asmore the suitable result description of a static to expressmechanostereoisomerism the stereochemistry during of the therotaxane’s synthetic molecu process,lar chirality but it is possible[17]. To describe to access the various chirality chiroptical based onstates the spatial by their arrangement dynamic stereoisomerism of components property.parts, he proposed From this adding point “mp” of view, to the mechanically “R” and “S chiral” as “rotaxanesRmp” and “ areSmp an”. “mp” attractive stands chiral for moleculemechanical with planar, unique which dynamic means property. that the central plane of chirality corresponds to the plane including the wheel that is located at the vertical position to the axle component.2.1. Mechanically As shown Planar in Chiral Figure Rotaxanes: 2a, first the Stereochemistry, orientations of Synthesis, each component and Optical are Resolution defined based on the ordinaryIn 1997,used priority Vögtle andrule, Okamoto respectively. reported Then, thethe directions ﬁrst synthesis of the and components HPLC optical are combined resolution and of determinemechanically the enantiomers chiral rotaxanes as Rmp that or consistedSmp. On the of other an unsymmetrical hand, the co-conformational axle and macrocyclic change components by moving the(Figure relative3a) [ position7,8]. They of succeededthe wheel inon isolating the axle the derives enantiomerically a different purechiral [2]rotaxane stereoisomer.(Smp The/Rmp co-)-1, conformationalfollowed by transforming change, as shown it to [1]rotaxane in the bottom(Smp of/R Figump)-1re0 by2a, bridgingresults in the a drastic components change via in the linking spatial the arrangementsulfonamide moietiesof component with an oligoethyleneparts around spacer the in (Figuretersection3b). Theof CDcomponents, spectra of (Sevenmp)-1 thoughand (R mpthe)-1 orientationsbecome a mirror of the image,individual and components the enantiomeric do not relationship change. It iswould also maintainednot be surprising after conversionif such a co- to conformational[1]rotaxane (Smp change/Rmp)-1 resulted0, respectively. in the inversion of the circular dichroism (CD) signal. Such an apparent chiral inversion is significantly interesting from the view of chiroptical switching, but these co-conformers are not static, but dynamic, and usually have a structural distribution. If the isomerization barrier between these co-conformers is not high as to detect each co-conformer, it should be discussed by using the averaged structure based on the co-conformational distribution. In fact, when the rotaxanes are synthesized by utilizing local intramolecular interactions, the co- conformation is biased in a specific distribution even though the mechanical bond is movable. Whereas, when the intramolecular interaction of rotaxane is removed, a stable conformational distribution is spontaneously changed based on the updated potential gradient. In addition to this, the dynamic stereoisomerization in a rotaxane means it is possible to control the achiral–chiral chiroptical switching in a [2]rotaxane, which consists of a symmetrical axle and unsymmetrical wheel (Figure 2b). Once the wheel moves from the central position of the axle, mechanically planar chirality is induced, depending on the co-conformation from achiral (prochiral). However, if the wheel can move freely on the axle (i.e., the racemization is too fast to detect each enantiomer), it can be regarded as an achiral molecule.

Symmetry 2020, 12, x FOR PEER REVIEW 4 of 15

As above-mentioned, mechanical chirality is generated as the result of a static mechanostereoisomerism during the synthetic process, but it is possible to access various chiroptical states by their dynamic stereoisomerism property. From this point of view, mechanically chiral rotaxanes are an attractive chiral molecule with unique dynamic property.

2.1. Mechanically Planar Chiral Rotaxanes: Stereochemistry, Synthesis, and Optical Resolution In 1997, Vögtle and Okamoto reported the first synthesis and HPLC optical resolution of mechanically chiral rotaxanes that consisted of an unsymmetrical axle and macrocyclic components (Figure 3a) [7,8]. They succeeded in isolating the enantiomerically pure [2]rotaxane (Smp/Rmp)-1, followed by transforming it to [1]rotaxane (Smp/Rmp)-1′ by bridging the components via linking the sulfonamide moieties with an oligoethylene spacer (Figure 3b). The CD spectra of (Smp)-1 and (Rmp)- Symmetry1 become2020 a, mirror12, 144 image, and the enantiomeric relationship is also maintained after conversion4 of 14to [1]rotaxane (Smp/Rmp)-1′, respectively.

FigureFigure 3.3. FirstFirst synthesizedsynthesized andand separatedseparated mechanicallymechanically planarplanar chiralchiral rotaxanes:rotaxanes: [2]rotaxane (a)) andand [1]rotaxane[1]rotaxane ((bb).). The stereochemistrystereochemistry S mp andand RRmpmp isis applied applied based based on on Goldup’s Goldup’s method. method.

InIn theirtheir paper,paper, thethe authorsauthors usedused thethe termterm “cycloenantiomeric”“cycloenantiomeric” toto describedescribe thethe chiralitychirality ofof thethe rotaxanesrotaxanes accordingaccording toto Schill’sSchill’s nomenclaturenomenclature [[16],16], which is basedbased onon thethe stereochemistrystereochemistry ofof cycliccyclic peptidespeptides asas reportedreported byby PrelogPrelog [[4].4]. Based on the idea of cycloenantiomerism, VögtleVögtle etet al.al. determined thethe directiondirection ofof thethe wheelwheel (i.e.,(i.e., theythey appliedapplied thethe prioritypriority rulerule toto thethe sulfonamidesulfonamide groupgroup inin thethe wheelwheel toto decidedecide thethe clockwiseclockwise oror anticlockwise).anticlockwise). At that time, they did not discuss in R or SS forfor absoluteabsolute structure,structure, butbut ifif Goldup’sGoldup’s methodmethod isis appliedapplied here,here, thethe enantiomersenantiomers cancan bebe determineddetermined asas( S(Smpmp)-1)-1 and ((RRmpmp)-1)-1,, respectively, respectively, as as shown shown in in Figure Figure 3a.3a. However, However, no no one one has has ever ever succeeded succeeded in indetermining determining the theabsolute absolute configuration configuration of oftwo two actually actually separated separated enantiomer enantiomer samples. samples. To To determine determine the absoluteabsolute configuration,configuration, singlesingle crystalcrystal structurestructure analysisanalysis oror computationalcomputational simulationsimulation wouldwould bebe requiredrequired asas thethe usualusual method,method, howeverhowever itit isis stillstill aa didifficultfficult subjectsubject now.now. Moreover,Moreover, theythey alsoalso synthesizedsynthesized [3]rotaxanes,[3]rotaxanes, whichwhich havehave anan additionaladditional wheelwheel componentcomponent comparedcompared withwith [2]rotaxane [2]rotaxane (Figure (Figure4)[ 4)18 ].[18]. As wellAs we as increasingll as increasing the number the number of components, of components, the number the ofnumber stereoisomers of stereoisomers is also increased. is also increased. In [3]rotaxane, In [3]r thereotaxane, are three there stereoisomers are three stereoisomers that depend that on di dependfferent combinationson different ofcombinations the orientations of ofthe the orientations two wheels. of As the shown two in Figurewheels.4, twoAs enantiomericshown in Figure [3]rotaxanes 4, two withenantiomeric antiparallel [3]rotaxanes orientated with wheels antiparallel(Rmp, Smp orientated)-2 and (S wheelsmp, Rmp (R)-2mpand, Smp the)-2 and achiral (Smpmeso, Rmp-[3]rotaxane)-2 and the withachiral parallel meso-[3]rotaxane oriented wheels with (Rparallelmp, Rmp oriented/Smp, Smp wheels)-2 have (R beenmp, Rmp/ obtainedSmp, Smp in)-2 1:1:2 have in been a statistical obtained ratio. in In1:1:2 these in a rotaxanes, statistical theratio. co-conformation In these rotaxanes, is fixed the byco-conformation hydrogen bonds is fixed here, by but hydrogen a more complicatedbonds here, stereoisomerizationbut a more complicated system stereoisomerization is expected, if it is possiblesystem tois expected, combine the if it co-conformational is possible to combine isomerization. the co- Considering such a potentiality, these pioneering studies have contributed significantly to the creation of mechanostereoisomerization chemistry today. The first attempt toward the asymmetric synthesis of a mechanically planar chiral rotaxane was reported by Takata et al. [19] (Scheme1). They have already developed an e ffective rotaxane synthesis including an end-capping reaction of semi[2]rotaxane generated in situ from crown ether and dialkylammonium salt using a bulky anhydride and tributylphosphane catalyst. Therefore, they utilized a chiral catalyst instead of the tributylphosphane in hope of the mechanical chirality selective ester formation reaction. Symmetry 2020, 12, x FOR PEER REVIEW 5 of 15

conformational isomerization. Considering such a potentiality, these pioneering studies have contributed significantly to the creation of mechanostereoisomerization chemistry today.

Symmetry 2020, 12, x FOR PEER REVIEW 5 of 15

Symmetryconformational2020, 12, 144 isomerization. Considering such a potentiality, these pioneering studies have5 of 14 contributed significantly to the creation of mechanostereoisomerization chemistry today.

Figure 4. Mechanostereoisomers of [3]rotaxane composed of two wheels and a single axle component.

The first attempt toward the asymmetric synthesis of a mechanically planar chiral rotaxane was reported by Takata et al. [19] (Scheme 1). They have already developed an effective rotaxane synthesis including an end-capping reaction of semi[2]rotaxane generated in situ from crown ether and dialkylammonium salt using a bulky anhydride and tributylphosphane catalyst. Therefore, they utilizedFigureFigure a chiral 4. 4.Mechanostereoisomers Mechanostereoisomers catalyst instead of ofthe of [3]rotaxane [3]rotaxane tributylphos composedcomposedphane of in two twohope wheels wheels of the and and mechanical a asingle single axle axle chirality component. component. selective ester formation reaction. The first attempt toward the asymmetric synthesis of a mechanically planar chiral rotaxane was reported by Takata et al. [19] (Scheme 1). They have already developed an effective rotaxane synthesis including an end-capping reaction of semi[2]rotaxane generated in situ from crown ether and dialkylammonium salt using a bulky anhydride and tributylphosphane catalyst. Therefore, they utilized a chiral catalyst instead of the tributylphosphane in hope of the mechanical chirality selective ester formation reaction.

SchemeScheme 1.1. Catalytic asymmetric synthesis of of a a me mechanicallychanically planar planar chiral chiral rotaxane. rotaxane.

AsAs shownshown inin SchemeScheme1 1,, they they utilizedutilized anan opticallyoptically activeactive chiralchiral ditopic phosphane as as the the catalyst catalyst andand confirmed confirmed thatthat thethe mechanicallymechanically chiral [2]rotaxane 3 was obtained obtained in in 4.4 4.4 ee% ee% by by chiral chiral stationary stationary phasephase highhigh performanceperformance liquidliquid chromatographychromatography (HPLC)(HPLC) separationseparation analysis. Unfortunately, Unfortunately, the the enantiomerenantiomer excessexcess waswas significantlysignificantly low, but this is a meaningful first first result. result. As As it it is is surprising surprising that that thesethese enantiomersenantiomersScheme areare 1. only onlyCatalytic didifferentff erentasymmetric in the synthesis substitutionsubstitu oftion a me position positionchanically on onplanar the the chiralbenzene benzene rotaxane. ring ring of of the the wheel wheel component,component, despitedespite thethe factfact thatthat thethe components ca cannotnnot be be fixed fixed in in a a specific specific relative relative arrangement arrangement As shown in Scheme 1, they utilized an optically active chiral ditopic phosphane as the catalyst duringduring thethe end-capend-cap reaction due due to to the the dynamic dynamic nature nature of ofmechanical mechanical bonding. bonding. A typical A typical strategy strategy for and confirmed that the mechanically chiral [2]rotaxane 3 was obtained in 4.4 ee% by chiral stationary forthe the asymmetric asymmetric synthesis synthesis is based is based on how on how to fix to the fix spatial the spatial arrangement arrangement of the of substrates the substrates around around the phase high performance liquid chromatography (HPLC) separation analysis. Unfortunately, the thechiral chiral catalyst; catalyst; some some breakthroughs breakthroughs would would be be required required toward toward effective effective asymmetric asymmetric synthesis synthesis in in enantiomer excess was significantly low, but this is a meaningful first result. As it is surprising that dynamicdynamic mechanicallymechanically chiralchiral rotaxane.rotaxane. these enantiomers are only different in the substitution position on the benzene ring of the wheel HiroseHirose reportedreported aa uniqueunique syntheticsynthetic method to prepare prepare mechanically mechanically chiral chiral [2]rotaxanes [2]rotaxanes utilizing utilizing component, despite the fact that the components cannot be fixed in a specific relative arrangement enantiopureenantiopure prerotaxanesprerotaxanes [[20]20] (Scheme(Scheme2 2).). during the end-cap reaction due to the dynamic nature of mechanical bonding. A typical strategy for thePrerotaxane asymmetric consistssynthesisof is abased wheel on componenthow to fix the and spatial a half-structured arrangement of axle the connectedsubstrates around to the the inner spacechiral of thecatalyst; wheel. some After breakthroughs separation into would enantiomerically be required toward pure prerotaxanes effective asymmetric4 by HPLC synthesis with a chiral in stationarydynamic phase, mechanically these were chiral converted rotaxane. to [2]rotaxanes (Rmp/Smp)-5 by planar selective aminolysis of the esterHirose group reported using 3,5-dinitrobenzylamine a unique synthetic method without to prepare chiral mechanically inversion or chiral degradation. [2]rotaxanes utilizing enantiopureAs described prerotaxanes above, chiral [20] stationary(Scheme 2). phases have been indispensable in the optical resolution of mechanically chiral rotaxanes thus far; however, a breakthrough has recently been reported toward a more efficient separation of enantiomers. Thus, Goldup et al. achieved a practical optical resolution method by applying diastereomeric resolution to the synthesis of a mechanically chiral rotaxane (Scheme3)[17].

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Symmetry 2020, 12, 144 6 of 14 Symmetry 2020, 12, x FOR PEER REVIEW 6 of 15

Scheme 2. Mechanically planar chiral [2]rotaxane synthesis from prerotaxane enantiomers. The

structures of 41st (first elution) and 42nd (second elution) are tentatively determined configurations.

Prerotaxane consists of a wheel component and a half-structured axle connected to the inner space of the wheel. After separation into enantiomerically pure prerotaxanes 4 by HPLC with a chiral stationary phase, these were converted to [2]rotaxanes (Rmp/Smp)-5 by planar selective aminolysis of the ester group using 3,5-dinitrobenzylamine without chiral inversion or degradation. As described above, chiral stationary phases have been indispensable in the optical resolution of mechanically chiral rotaxanes thus far; however, a breakthrough has recently been reported towardSchemeScheme a more 2.2. MechanicallyMechanicallyefficient separation planar chiralof enantiomers. [2]rotaxane Thus, synthesis Goldup from et prerotaxanepr al.erotaxane achieved enantiomers. a practical The Theoptical

resolutionstructuresstructures method ofof4 41st1st by(ﬁrst(first applying elution) and anddiastereomeric 442nd2nd (second(second elution) resolution elution) are are tentatively to tentatively the synthesis determined determined of a configurations. mechanically conﬁgurations. chiral rotaxane (Scheme 3) [17]. Prerotaxane consists of a wheel component and a half-structured axle connected to the inner space of the wheel. After separation into enantiomerically pure prerotaxanes 4 by HPLC with a chiral stationary phase, these were converted to [2]rotaxanes (Rmp/Smp)-5 by planar selective aminolysis of the ester group using 3,5-dinitrobenzylamine without chiral inversion or degradation. As described above, chiral stationary phases have been indispensable in the optical resolution of mechanically chiral rotaxanes thus far; however, a breakthrough has recently been reported toward a more efficient separation of enantiomers. Thus, Goldup et al. achieved a practical optical resolution method by applying diastereomeric resolution to the synthesis of a mechanically chiral rotaxane (Scheme 3) [17].

SchemeScheme 3.3. EEffectiveﬀective approachapproach to an enantiomerically pure pure mechanically mechanically chiral chiral rotaxane rotaxane via via practical practical resolutionresolution ofof thethe diastereomericdiastereomeric precursor.precursor.

AA [2]rotaxane[2]rotaxane containing containing a aCCs symmetricals symmetrical wheel, wheel, an achiral an achiral half halfaxle, axle,and the and enantiopure the enantiopure end- end-capcap group group 6 was6 was synthesized synthesized byby the the copper-assisted copper-assisted az azide–acetyleneide–acetylene cycloaddition cycloaddition reaction. reaction. The The diastereomersdiastereomers( D(D, R, mpRmp)-7)-7and and(D (,DS,mp Smp)-7)-7were were generated generated in ain 1:1 a ratio1:1 ratio and separatedand separated by classical by classical column chromatographycolumn chromatography using an using achiral an resin.achiral The resin. chiral The chiral end-cap end-cap was replaced was replaced with with an achiral an achiral end-cap end-8 viacap the 8 via substitution the substitution reaction reaction to generate to generate the mechanically the mechanically chiral chiral [2]rotaxane [2]rotaxane enantiomers enantiomers(Smp )-9(Smpand)- (R9 mpand)-9 (,R respectively.mp)-9, respectively. The conﬁguration The configuration of 9 was of changed 9 was changed from that from of 7, however,that of 7, thishowever, is because this theis directionbecauseScheme the of thedirection 3. Effective axle determined of approach the axle todetermined according an enantiomerically to according the priority pure to the rulemechanically priority changed rule chiral after changed rotaxane the reaction, after via practicalthe not reaction, the real stereoinversionnot theresolution real stereoinversion of of the mechanical diastereomeric of chirality.mechanical precursor. This chirality. catalytic This ester-amide catalytic ester-amide exchange reaction exchange can reaction achieve can the stopper exchange reaction without dethreading of components to maintain the mechanical chirality. Moreover,A [2]rotaxane they containing increased thea Cs stereoselectivity symmetrical wheel, of the an diastereomeric achiral half axle, mechanically and the enantiopure planar rotaxane end- bycap changing group 6 thewaschiral synthesized end-cap by group the copper-assisted (Scheme4)[ 21 az].ide–acetylene By using the cycloaddition readily available reaction.α-amino The acid-deriveddiastereomers azide (D, (RS)-10mp)-7as and the ( end-capD, Smp)-7 moiety, were diastereomericgenerated in a mechanically1:1 ratio andplanar separated chiral by [2]rotaxane classical column chromatography using an achiral resin. The chiral end-cap was replaced with an achiral end- (S, Rmp/Smp)-11 was obtained in a diastereomeric ratio of 98:2. The obtained diastereomers 11 can be cap 8 via the substitution reaction to generate the mechanically chiral [2]rotaxane enantiomers (Smp)- transformed into an enantiomeric mechanically planar chiral [2]rotaxane (Rmp/Smp)-12 by converting the9 and chiral (Rmp end-cap)-9, respectively. to an achiral The group, configuration and the enantiomeric of 9 was changed excess from is unchanged. that of 7, Inhowever, their rotaxanes, this is because the direction of the axle determined according to the priority rule changed after the reaction, not the real stereoinversion of mechanical chirality. This catalytic ester-amide exchange reaction can

Symmetry 2020, 12, x FOR PEER REVIEW 7 of 15 Symmetry 2020, 12, x FOR PEER REVIEW 7 of 15 achieve the stopper exchange reaction without dethreading of components to maintain the achieve the stopper exchange reaction without dethreading of components to maintain the mechanical chirality. mechanical chirality. Moreover, they increased the stereoselectivity of the diastereomeric mechanically planar Moreover, they increased the stereoselectivity of the diastereomeric mechanically planar rotaxane by changing the chiral end-cap group (Scheme 4) [21]. By using the readily available α- rotaxane by changing the chiral end-cap group (Scheme 4) [21]. By using the readily available α- amino acid-derived azide (S)-10 as the end-cap moiety, diastereomeric mechanically planar chiral amino acid-derived azide (S)-10 as the end-cap moiety, diastereomeric mechanically planar chiral [2]rotaxaneSymmetry 2020 ,(S12, ,R 144mp/Smp)-11 was obtained in a diastereomeric ratio of 98:2. The obtained diastereomers7 of 14 [2]rotaxane (S, Rmp/Smp)-11 was obtained in a diastereomeric ratio of 98:2. The obtained diastereomers 11 can be transformed into an enantiomeric mechanically planar chiral [2]rotaxane (Rmp/Smp)-12 by 11 can be transformed into an enantiomeric mechanically planar chiral [2]rotaxane (Rmp/Smp)-12 by converting the chiral end-cap to an achiral group, and the enantiomeric excess is unchanged. In their converting the chiral end-cap to an achiral group, and the enantiomeric excess is unchanged. In their rotaxanes,it can be assumed it can be that assumed the short that axle the probably short axle helps probably to reduce helps the co-conformational to reduce the co-conformational dynamic degree rotaxanes, it can be assumed that the short axle probably helps to reduce the co-conformational dynamicof freedom degree to enhance of freedom the reactivity to enhance of speciﬁcthe reac mechanicaltivity of specific chirality. mechanical chirality. dynamic degree of freedom to enhance the reactivity of specific mechanical chirality.

SchemeScheme 4. 4. Stereoselective Stereoselective synthesis synthesis of of diastereomeric me mechanicallychanically planarplanar chirchir chiralalal [2]rotaxane[2]rotaxane and and its its transformationtransformation into into enan enantiomericenantiomerictiomeric [2]rotaxane. [2]rotaxane.

Although,Although, as as has has been been described describeddescribed here, here, the synthesi synthesiss and and opticaloptical optical resolutionresolution resolution of of mechanically mechanically mechanically chiral chiral rotaxanesrotaxanes are are still still underunder development, development, thethe intense intense on ongoinggoing research research inin in thisthis this fieldfield field will will yield yield not not only only asymmetricasymmetric synthesis,synthesis, but butbut also also higher higher order and complicated topologicallytopologically chiralchiral rotaxanesrotaxanes in in the the not-so-distantnot-so-distant future. future. 2.2. Chiroptical Switching via Co-Conformational Interconversion of Mechanically Chiral Rotaxanes 2.2.2.2. Chiroptical Chiroptical Switching Switching viavia Co-ConformationalCo-Conformational Interconversion ofof MechanicallyMechanically ChiralChiral Rotaxanes Rotaxanes In this section, the rotaxane chirality is discussed from the perspective of co-conformation. Chiral InIn this this section, section, the the rotaxane rotaxane chiralitychirality isis discussed from thethe perspectiveperspective of of co-conformation. co-conformation. Chiral Chiral information in MIMs can be transferred between components via mechanical bonds. In this context, informationinformation in in MIMs MIMs cancan bebe transferredtransferred betweenbetween components viavia mechanicalmechanical bonds.bonds. In In this this context, context, Leigh and coworkers reported a chiroptical switching behavior in [2]rotaxane as the first example LeighLeigh and and coworkers coworkers reported reported aa chiropticalchiroptical switching behavior inin [2]rotaxane[2]rotaxane asas the the first first example example of of of through-space chirality transfer (Scheme5)[ 22]. In [2]rotaxane 13, the wheel is located on the through-spacethrough-space chiralitychirality transfertransfer (Scheme(Scheme 5) [22]. In [2]rotaxane 1313,, thethe wheelwheel isis locatedlocated onon thethe fumaramide moiety through hydrogen bonding, and no CD signal was observed. In contrast, after the fumaramidefumaramide moiety moiety throughthrough hydrogenhydrogen bonding,bonding, and no CD signalsignal waswas observed.observed. InIn contrast, contrast, after after photoisomerization of fumaramide, the wheel moves closer to the stereogenic center of the axle as 14, thethe photoisomerization photoisomerization ofof fumaramide,fumaramide, thethe wheel moves closer toto thethe stereogenicstereogenic center center of of the the axle axle giving rise to a CD signal. This chiroptical switch in the CD spectrum occurred simultaneously with asas 14 14, ,giving giving rise rise to to a a CD CD signal.signal. ThisThis chiropticalchiroptical switch in thethe CDCD spectrumspectrum occurredoccurred simultaneously simultaneously the reversible co-conformational change induced by photoisomerization, and suggests that the spatial withwith the the reversible reversible co-conformational co-conformational changechange induced by photoisomerization, andand suggests suggests that that the the arrangement of components around the mechanical bonding is fixed in the specific configuration in spatialspatial arrangementarrangement ofof componentscomponents aroundaround the mechanical bondingbonding isis fixedfixed inin thethe specificspecific each co-conformer by hydrogen bonding between the components. configurationconfiguration in in each each co-conformer co-conformer byby hydrogenhydrogen bonding between thethe components.components.

SchemeScheme 5.5. Through-spaceThrough-space chirality transfer of point chirality chirality on on the the axle-to-wheel axle-to-wheel component. component. Scheme 5. Through-space chirality transfer of point chirality on the axle-to-wheel component. Such a structure-constraining effect around the mechanical bonding also applied circularly polarized luminescence (CPL) control. Cuerva and Blanco designed a [2]rotaxane consisting of a wheel incorporating a 2,20-bipyrene unit as the emissive part and an axle bearing point chiral stereogenic center nearby the sec-ammonium moiety (Scheme6)[ 23]. This rotaxane is capable of on–off switching the CPL (i.e., the crown ether positioned on the sec-ammonium neighboring chiral stereogenic center induces CPL on (15), while the crown ether move to the triazolium moiety by deprotonation of ammonium makes CPL off (16)). In this way, the structure and chemical property of each component Symmetry 2020, 12, x FOR PEER REVIEW 8 of 15 Symmetry 2020, 12, x FOR PEER REVIEW 8 of 15 Such a structure-constraining effect around the mechanical bonding also applied circularly polarizedSuch luminescence a structure-constraining (CPL) control. effect Cuerva around an dthe Blanco mechanical designed bonding a [2]rot alsoaxane applied consisting circularly of a polarized luminescence (CPL) control. Cuerva and Blanco designed a [2]rotaxane consisting of a wheel incorporating a 2,2′-bipyrene unit as the emissive part and an axle bearing point chiral wheel incorporating a 2,2′-bipyrene unit as the emissive part and an axle bearing point chiral stereogenic center nearby the sec-ammonium moiety (Scheme 6) [23]. This rotaxane is capable of on– stereogenic center nearby the sec-ammonium moiety (Scheme 6) [23]. This rotaxane is capable of on– off switching the CPL (i.e., the crown ether positioned on the sec-ammonium neighboring chiral off switching the CPL (i.e., the crown ether positioned on the sec-ammonium neighboring chiral stereogenic center induces CPL on (15), while the crown ether move to the triazolium moiety by stereogenic center induces CPL on (15), while the crown ether move to the triazolium moiety by deprotonationSymmetry 2020, 12 ,of 144 ammonium makes CPL off (16)). In this way, the structure and chemical property8 of 14 deprotonation of ammonium makes CPL off (16)). In this way, the structure and chemical property of each component are deeply related to each other, and their intramolecular cooperative behavior of each component are deeply related to each other, and their intramolecular cooperative behavior makes it possible to transform the point chirality to axial chirality, depending on the co- aremakes deeply it relatedpossible to to each transform other, and the their point intramolecular chirality to cooperativeaxial chirality, behavior depending makes iton possible the co- to conformational change. transformconformational the point change. chirality to axial chirality, depending on the co-conformational change.

SchemeSchemeScheme 6. 6.6. On–off On–oOn–offﬀ switching switchingswitching of of CPL CPL emission emission by by contro controllinglling thethe through-spacethrough-space chiralitychirality transfer. transfer.

OnOn the the other other hand,hand, co-conformationalco-conformational chiroptical switching ofof mechanically mechanically planarplanar chirality chirality in in rotaxanesrotaxanes was was reported reported byby SaitoSaito andand coworkerscoworkers (Scheme(Scheme7 7))[ [24].24].

SchemeScheme 7.7. Co-conformational mechanical chirality chirality in in [2]rotaxanes. [2]rotaxanes. Scheme 7. Co-conformational mechanical chirality in [2]rotaxanes.

This kind of chirality is generated when a symmetrical axle is combined with a wheel with Cs symmetry. In other words, when the wheel is located at the center of the axle component, the molecule is prochiral (17), whereas when the wheel is located at a biased position (18), mechanical chiralitySymmetry 2020 is induced., 12, 144 Regardless of which side the wheel moves from the center of the axle, its shuttling9 of 14 energy is the same. Thus, if the partition group in the middle of the axle is sufficiently bulky, the enantiomers can be separated without racemization. In fact, the authors achieved the separation of enantiomericallypure [2]rotaxanes, pure which [2]rotaxanes, displayed which a mirror displayed image CDa mirror spectra. image The CD relationship spectra. The between relationship these betweenenantiomers these involves enantiomers a chiral involves inversion a chiral like “turning inversio overn like the “turning rubber gloves”over the [ 25rubber,26]. Agloves” catenane [25,26]. with Asimilar catenane chirality with wassimilar also chirality reported was by Sauvagealso reported et al. by [25 Sauvage]. et al. [25]. In rubber-glove-likerubber-glove-like chirality, chirality, there there is no is potentialno potential bias tobias determine to determine the wheel’s the shuttlingwheel’s shuttling direction directionon the axle on in the general. axle in Credi general. and BaronciniCredi and et Baro al.ncini achieved et al. a one-directionalachieved a one-directional selective shuttling selective by shuttlingutilizing aby diastereomeric utilizing a diastereomeric salt system (Scheme salt system8)[27 (Scheme]. 8) [27].

Scheme 8. 8. InterconversionInterconversion between between two two diastereomeric diastereomeric ion ion pairs pairs containing containing a chiral a chiral anion anion with with co- conformationalco-conformational mechanical mechanical chirality chirality [27]. [27 ].

[2]Rotaxane 2020, ,derived derived from from prochiral prochiral [2]rotaxane [2]rotaxane 19,19 potentially, potentially has hasmechanical mechanical chirality, chirality, but thesebut these are aredynamic dynamic racemic racemic mixtur mixtureses because because the the wheel wheel component component can can move move freely freely on on the the axle, axle, having a symmetrical structure. Th Thee authors authors aimed aimed to unbalance the populations of the wheel at the equivalent two triazolium stations stations by by using an op opticallytically active counter anion such as the camphor sulfonate anion (CS) instead of achiral iodonium. As As a a result, result, they achieved an approximately 85:15 diastereomeric ratio. The The authors authors suggested suggested that that the the encircled encircled triazo triazoliumlium site site does not influence inﬂuence the site selectivity;selectivity; thethe recognition recognition between between the the wheel wheel and anotherand another triazolium triazolium station station that directly that interactsdirectly interactswith the with optically the optically active counter active anioncounter seems anion to seems be the toprimary be the primary reason forreason this for selectivity. this selectivity. When Whenthe counter the counter anion isanion exchanged is exchanged with the with iodonium the iodo ionnium instead ion instead of the opticallyof the optically active CS,active the CS, biased the biasedexistence existence of diastereomers of diastereomers is canceled is canceled as a racemic as a racemic mixture. mixture. Moreover, Moreover, once the once central the amino central group amino is groupprotonated, is protonated, the crown the ether crown is localized ether atis thelocalized prochiral at positionthe prochira by strongl position hydrogen by strong bonding, hydrogen thus it bonding,becomes achiralthus it rotaxane becomes19 .achiral These interconversionsrotaxane 19. These and inversionsinterconversions of the mechanicaland inversions chirality of the are mechanicaldemonstrated chirality in the are solution demonstrated state, so unfortunately,in the solutionthe state, separation so unfortunately, of the diastereomers the separation would of the be diastereomersimpossible in thiswould system be impossible as there is noin barrierthis system to inhibit as there the racemizationis no barrier to via inhibit shuttling the motion.racemization via shuttlingRecently, motion. Takata and Ishiwari achieved the chiral–achiral interconversion system [28]. As shown in Scheme9, they derived mechanically chiral [2]rotaxane (Smp/Rmp)-22 from prochiral (achiral) + [2]rotaxane 21 PF6 by N-ethylation of the nitrogen atom located at the symmetrical center of • − the axle. Symmetry 2020, 12, x FOR PEER REVIEW 10 of 15

Recently, Takata and Ishiwari achieved the chiral–achiral interconversion system [28]. As shown in Scheme 9, they derived mechanically chiral [2]rotaxane (Smp/Rmp)-22 from prochiral (achiral) + − Symmetry[2]rotaxane2020, 1221, 144•PF6 by N-ethylation of the nitrogen atom located at the symmetrical center of10 the of 14 axle.

SchemeScheme 9.9. Chiral–achiralChiral–achiral reversible control of ro rotaxanestaxanes with a a symmetrical symmetrical axle axle [28]. [28].

DespiteDespite thethe N-ethylN-ethyl groupgroup beingbeing size-complementalsize-complemental to the wheel, they they achieved achieved separation separation of of thethe enantiomers enantiomers inin opticaloptical puritiespurities overover 80 ee% by carrying out out chiral chiral HPLC HPLC resolution resolution at at a a lower lower temperaturetemperature than than room room temperature. temperature. In In fact, fact, the the mirror mirror imaged imaged CD CD spectra spectra were were observed observed at at 10−10C °C to − ◦ supportto support that that these these were were enantiomers. enantiomers. The The racemization racemization behavior behavior viavia the shuttling overcoming overcoming the the centralcentral N-ethyl N-ethyl group group waswas alsoalso indicatedindicated byby thethe CD decay at 0 °C.◦C. By By utilizing utilizing the the protonation protonation of of the the + + − N-ethylN-ethyl group, group, [2]rotaxane [2]rotaxane 21 is 2 also1 is capable also capable of being of the being achiral the form achiral23 CF form3COO 23,•CF not racemization.3COO , not • − Thisracemization. chiral–achiral This reversiblechiral–achiral interconversion reversible interconversion is like the case is inlike Scheme the case8, however,in Scheme setting 8, however, up an appropriatesetting up an barrier appropriate at the centerbarrier of at the the axle center would of the be axle the would key to thebe the further key to application the further of application switchable mechanicallyof switchable chiral mechanically rotaxanes. chiral rotaxanes. AsAs indicated indicated fromfrom thesethese studies,studies, the stereoinversionstereoinversion of mechanically chiral chiral rotaxane rotaxane by by shuttling shuttling isis similar similar to to the the chirality chirality of of axially axially chiral chiral biphenyl biphenyl compounds. compounds. This This implies implies that that the the rubber-glove-like rubber-glove- chiralitylike chirality of rotaxane of rotaxane is the is spatio-temporalthe spatio-temporal characteristics. characteristics. In caseIn case of of rotaxane, rotaxane, which which is is capable capable of stereoinverting,of stereoinverting, if some if some interaction interaction is induced is induced to fix to the fix wheel the wheel on the on center the center atom of atom the axle, of the the axle, chirality the disappearschirality disappears and becomes and achiral. becomes However, achiral. the However, ring components the ring components that are not covalentlythat are not bonded covalently on the centerbonded of theon axlethe center are still of movable the axle on are the still axle. movable Therefore, on wethe cannot axle. Therefore, precisely distinguish we cannot the precisely racemic statedistinguish and prochiral the racemic state because state and the prochiral detected state averaged because structure the detected is almost averaged the same, structure irrespective is almost of the variedthe same, degree irrespective of shuttling of andthe circumrotationvaried degree of along shuttling the axle and if thecircumrotation averaged structure along the coincides axle if withthe theaveraged prochiral structure one. coincides with the prochiral one. ThroughThrough thesethese above-mentionedabove-mentioned studies, it is consideredconsidered that chiral rotaxanes rotaxanes potentially potentially have have chiropticalchiroptical switching switching properties properties such such as on–o as ffon–offswitching switching or switching or switching the handedness the handedness of enantiomers of enantiomers induced by various stimuli. The above-mentioned on–off switching of the CPL emission induced by various stimuli. The above-mentioned on–off switching of the CPL emission system system in Scheme 6 is not attributed to the mechanical chirality, but is a highly suggestive study in Scheme6 is not attributed to the mechanical chirality, but is a highly suggestive study toward toward applications in optical devices with a chiroptical switching property. In the near future, if a applications in optical devices with a chiroptical switching property. In the near future, if a method method of controlling mechanical chirality involving co-conformation is established, a good example of controlling mechanical chirality involving co-conformation is established, a good example of CPL of CPL emission attributable to mechanical chirality will be achieved. It is expected that not only emission attributable to mechanical chirality will be achieved. It is expected that not only chiral chiral achiral switching, but also stereo inversion, is possible, considering the chiroptical diversity achiral switching, but also stereo inversion, is possible, considering the chiroptical diversity due to the due to the co-conformational diversity. Furthermore, several interesting application studies on co-conformational diversity. Furthermore, several interesting application studies on dynamic helical dynamic helical polymers have been reported. These are discussed in the next section. polymers have been reported. These are discussed in the next section.

2.3. Helical Structure Control by Chiral Rotaxanes Helical structure is a chiral structure universally found in polymers including biological macromolecules such as proteins, DNA, and RNA. The functions of these macromolecules are deeply Symmetryrelated to2020 their, 12, 144helical structure, and therefore the construction of well-ordered helical structures11 ofhas 14 attracted a great deal of attention. Polymers with a dynamic structure exhibit various physical properties such as crystallinity and glass transition temperature, which depend on their conformation has attracted a great deal of attention. Polymers with a dynamic structure exhibit various physical of either a random coiled conformation or a highly ordered helical conformation. In this decade, properties such as crystallinity and glass transition temperature, which depend on their conformation significant advances have been made in the control of the structure of dynamic helical polymers and, of either a random coiled conformation or a highly ordered helical conformation. In this decade, recently, in the study of the application of their dynamic property as stimuli responsive chiral systems significant advances have been made in the control of the structure of dynamic helical polymers [29]. The chirality of a dynamic helical polymer is determined by various chiral factors such as and, recently, in the study of the application of their dynamic property as stimuli responsive chiral catalyst, solvent, or interactive molecules as well as by the optically active group inside the polymer systems [29]. The chirality of a dynamic helical polymer is determined by various chiral factors such chain. More interestingly, the screw sense and helical pitch of the helical structure are affected by as catalyst, solvent, or interactive molecules as well as by the optically active group inside the polymer small changes in solvent polarity [30]. Thus, by controlling the dynamic helical structure of polymers, chain. More interestingly, the screw sense and helical pitch of the helical structure are affected by their chirality can be amplified from that of small or easily obtained chiral sources to higher order small changes in solvent polarity [30]. Thus, by controlling the dynamic helical structure of polymers, chirality. Another question of interest yet to be resolved is the prediction of the sense of a helical their chirality can be amplified from that of small or easily obtained chiral sources to higher order structure on a dynamic helical polymer from an enantiomerically pure chiral molecule that serves as chirality. Another question of interest yet to be resolved is the prediction of the sense of a helical a monomer, catalyst, or solvent. Although computational simulation might help in this regard, this structure on a dynamic helical polymer from an enantiomerically pure chiral molecule that serves as a is a challenging task because the structure usually depends on multiple environmental stimuli. monomer, catalyst, or solvent. Although computational simulation might help in this regard, this is a Despite the large number of examples of polymers with a switchable helical structure, those challenging task because the structure usually depends on multiple environmental stimuli. Despite the exhibiting controlled reversible helicity inversion in one pot are still scarce. In this context, Takata et large number of examples of polymers with a switchable helical structure, those exhibiting controlled al. achieved a rational control of the helical structure of polyacetylene with chiral [2]rotaxanes (Figure reversible helicity inversion in one pot are still scarce. In this context, Takata et al. achieved a rational 5) [31]. control of the helical structure of polyacetylene with chiral [2]rotaxanes (Figure5)[31].

Figure 5. Control of reversible helicity inversion triggered by chiral rotaxane side chain co-conformationalFigure 5. Control switching,of reversible and helicity the corresponding inversion triggered circular by dichroism chiral rotaxane (CD) and side UV chain spectra co- (chloroform,conformational 0.14 switching, mM, 293 K).and Thethe insetscorrespondi are theng expanded circular CDdichroism spectra (350–500(CD) and nm, UVtop spectra) and the(chloroform, reversible 0.14 change mM, in 293 CD intensityK). The insets (500 nm) are withthe expanded various additives CD spectra (bottom (350–500). nm, top) and the reversible change in CD intensity (500 nm) with various additives (bottom). Polyacetylene is a typical dynamic helical polymer that has prompted several studies on the control of itsPolyacetylene higher order structures. is a typical As dynamic shown in helical Figure 5polymer, the side that chain-type has prompted polyrotaxane severalpoly-( studiesR)-24 onwas the preparedcontrol of by its the higher polymerization order structures. of chiral As [2]rotaxaneshown in Figure with an5, the acetylene-terminated side chain-type polyrotaxane axle and a crown poly- ether(R)-24 containing was prepared an optically by the polymerization active binaphthyl of chiral unit. In[2]rotaxane this system, with the an distance acetylene-terminated between the chiral axle wheelsand a crown and the ether polymer containing main an chain optically is precisely active tunedbinaphthyl by the unit. reversible In this system, co-conformational the distance change between of rotaxanethe chiral in wheels the polymer and the sidepolymer chain. main The chain CD and is pr ultraviolet-visibleecisely tuned by the absorption reversible (UV-Vis) co-conformational spectra of poly-(R)-24, which has a tert-amine-bearing axle, show a Cotton effect attributable to the polymer main chain absorption region, supporting the induction of the single-handed helical structure on the polymer backbone. After protonation of the tert-amine to give poly-(R)-24H, the Cotton effect completely disappeared. This indicates that the polymer main chain becomes a random helix because the chiral Symmetry 2020, 12, x FOR PEER REVIEW 12 of 15 change of rotaxane in the polymer side chain. The CD and ultraviolet-visible absorption (UV-Vis) spectra of poly-(R)-24, which has a tert-amine-bearing axle, show a Cotton effect attributable to the polymer main chain absorption region, supporting the induction of the single-handed helical Symmetry 2020, 12, 144 12 of 14 structure on the polymer backbone. After protonation of the tert-amine to give poly-(R)-24H, the Cotton effect completely disappeared. This indicates that the polymer main chain becomes a random wheelshelix because are fixed the by chiral hydrogen wheels bonding are fixed at by the hydrogen ammonium bonding moiety, at whichthe ammonium is sufficiently moiety, far fromwhich the is polymersufficiently main far chain.from the Such polymer a change main in thechain. helical Such structure a change of in the the polymer helical mainstructure chain of occurs the polymer in one potmain in chain response occurs to in acid one or pot base in response treatment, to indicatingacid or base that treatment, the helical indicating structure that is the induced helical with structure good reproducibility.is induced with This good result reproducibility. shows the potential This result of “through-space shows the potential chirality of transfers “through-space and amplification” chirality fromtransfers the mechanicallyand amplification” linked from chiral the wheel mechanically to the polymer linked backbonechiral wheel by to utilizing the polymer the intramolecular backbone by chiropticalutilizing the switching intramolecular ability chiroptical of the rotaxane switching side chain. ability of the rotaxane side chain. More recently, TakataTakata etet al.al. achieved the inductioninduction of a single-handed helical structure from the mechanical chirality of the rotaxane side chains (Figure(Figure6 6))[ 32[32].].

Figure 6. ControlControl of the polymer helical structure by mechanically chiral rotaxane side chains.

They synthesized three types of polyrotaxanes—poly-(Rmp/Smp)-25, poly-(Rmp/Smp)-26, They synthesized three types of polyrotaxanes—poly-(Rmp/Smp)-25, poly-(Rmp/Smp)-26, and poly- and poly-(S,Rmp/S,Smp)-27—with different rotaxane side chains depending on the mechanical chirality (S,Rmp/S,Smp)-27—with different rotaxane side chains depending on the mechanical chirality of of rotaxanes of how to link with the polymer backbone. The polymer shown on the left of Figure6 rotaxanes of how to link with the polymer backbone. The polymer shown on the left of Figure 6 has has an enantiomerically pure mechanically chiral rotaxane side chain linked to the polymer backbone an enantiomerically pure mechanically chiral rotaxane side chain linked to the polymer backbone via via the wheel, whereas the polymer shown in the center of the figure is linked via the axle. In both the wheel, whereas the polymer shown in the center of the figure is linked via the axle. In both cases, cases, the polymer obtained from each enantiomer exhibited a mirror image CD spectrum in the the polymer obtained from each enantiomer exhibited a mirror image CD spectrum in the absorption absorption region of the main chain for the opposite sense of the helical structure. The structural region of the main chain for the opposite sense of the helical structure. The structural difference difference between the enantiomers are quite small, and it is interesting to determine which of the between the enantiomers are quite small, and it is interesting to determine which of the adjacent adjacent carbon atoms of the benzene ring are substituted. When viewed from the polymer backbone, carbon atoms of the benzene ring are substituted. When viewed from the polymer backbone, it is it is noteworthy that the chirality of the helical structure is induced even though the wheel components noteworthy that the chirality of the helical structure is induced even though the wheel components are not chiral and are not fixed in a specific conformation because of the flexibility of the mechanical are not chiral and are not fixed in a specific conformation because of the flexibility of the mechanical bond. Furthermore, an additional point of chirality on the wheel component in the side chain does bond. Furthermore, an additional point of chirality on the wheel component in the side chain does not influence the helicity of the polymer, as in (S,Rmp/S,Smp)-27. This result clearly indicates that not influence the helicity of the polymer, as in (S,Rmp/S,Smp)-27. This result clearly indicates that mechanically chiral rotaxanes, despite having a dynamic nature, can be used as efficient chiral sources, mechanically chiral rotaxanes, despite having a dynamic nature, can be used as efficient chiral sometimes even in a more effective manner than classical chirality in which the configuration is fixed. sources, sometimes even in a more effective manner than classical chirality in which the configuration It has also been confirmed that the reversible helical chirality inversion depends on both is fixed. temperature and solvent. Although the role of mechanical chirality in the induction of single-handed It has also been confirmed that the reversible helical chirality inversion depends on both helical structures is not fully understood, this inversion in the polymer probably stems from the temperature and solvent. Although the role of mechanical chirality in the induction of single-handed occurrence of a conformational change due to the movement of mechanical bonds as a result of helical structures is not fully understood, this inversion in the polymer probably stems from the environmental stimuli. These results introduce an important concept that opens the door to a new chiral chemistry and could result in the development of novel applications. Symmetry 2020, 12, 144 13 of 14

3. Conclusions and Outlook Nowadays, rotaxane is an easily accessible molecule that possesses a variety of potential applications as an innovative small molecular device, catalyst, and molecular sensing. However, the fundamental aspects of rotaxanes such as their stereochemistry are not yet fully understood at the present time. The determination of the absolute configuration of mechanically chiral rotaxanes is still a challenging task. Considering that this issue remains unsolved even for simple rotaxanes, the problem becomes more complicated when increasing the number of components, which leads to more complex isomers including conformational isomers. Therefore, further fundamental study is absolutely required. Furthermore, the application to the catalysis and molecular sensing of mechanically chiral molecules should be helpful in understanding how the mechanical chirality works to other environmental molecules, along with the development of the asymmetric synthetic method. In addition, through study including molecular assemblies, we will be able to gain deeper insights into the properties and functions of the mechanical bonds and its chirality from the viewpoints of both chemical and physical consideration. These application studies through collaboration across fields would bring great benefits to the fundamental research of MIMs. We hope that chemists from various fields including supramolecular chemistry will have interest in mechanical chirality and develop new aspects of chemicals, materials, and related science areas.

Author Contributions: Writing—original draft preparation and visualization, K.N.; Writing—review and editing, T.T. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the JSPS KAKENHI (No. 19K05417), the Naito Foundation and the CREST program (JST, JPMJCR1522). Acknowledgments: K.N. acknowledges funding from JSPS KAKENHI (No. 19K05417) and The Naito Foundation. T.T. and K.N. thank the CREST program (JST, JPMJCR1522) for financial support. Conflicts of Interest: The authors declare no conflicts of interest.

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