Facial Selectivity in Mechanical Bond Formation: Axially Chiral Enantiomers and Geometric Isomers from a Simple Prochiral Macrocycle

In 1971, Schill recognized that a prochiral macrocycle encircling an oriented axle led to geometric isomerism in rotaxanes. More recently, we identified an overlooked chiral stereogenic unit in rotaxanes that arises when a prochiral macrocycle encircles a prochiral axle. Here, we show that both stereogenic units can be accessed using equivalent strategies, with a single weak stereodifferentiating interaction sufficient for moderate to excellent stereoselectivity. Using this understanding, we demonstrated the first direct enantioselective (70% ee) synthesis of a mechanically axially chiral rotaxane.


■ INTRODUCTION
Early in the development of the chemistry of the mechanical bond, 1 Schill recognized that when a macrocycle containing a prochiral center such that its faces are distinguishable encircles an axle with distinguishable ends, the rotaxane can exist as distinct geometric isomers even though the individual components are stereochemically trivial. 2 Although molecules that correspond to the type 1 3 mechanical geometric isomers (MGI-1) of rotaxanes have been reported, the vast majority where the mechanical bond provides the sole stereogenic unit 4 are constructed from calixarenes 5 or similar macrocycles 6 whose facial dissymmetry arises from the fixed cone-shaped conformation of the threaded ring. 7The same is true of the corresponding catenane stereogenic unit first reported by Gaeta and Neri. 8In these cases, facial dissymmetry is expressed over the whole macrocycle, which has been shown to lead to the stereoselective formation of the corresponding rotaxanes.However, to our knowledge, the only MGI-1 rotaxanes in which a single covalent prochiral center differentiates the faces of the ring, 9 as envisaged by Schill, were reported by Bode and Saito, 10 where no stereoselectivity was reported.
More recently, 11 we identified that when a facially dissymmetric macrocycle encircles a prochiral axle, an overlooked mechanically axially chiral (MAC) 12 stereogenic unit arises that is analogous to the MAC stereogenic unit of catenanes identified by Wasserman and Frisch over 60 years earlier. 13Having made this observation, we demonstrated that such molecules can be synthesized using a diastereoselective co-conformational chiral auxiliary 14 active template 15 Cu-mediated alkyne−azide cycloaddition (AT-CuAAC) 16,17 approach with a ring whose facial dissymmetry arises from a single prochiral sulfoxide unit.
If we consider a schematic AT-CuAAC retrosynthesis of MGI-1 isomers (Figure 1a) and MAC enantiomers (Figure 1b), in which the axle is divided into two components that couple through the macrocycle in the forward synthesis, the common challenge involved in the stereoselective synthesis of both becomes obvious; we must control which face of the macrocycle is oriented toward which half-axle component in the mechanical bond-forming step.
Here, by re-examining our stereoselective synthesis of MAC rotaxanes, we identify that a single H-bond between the sulfoxide unit and one of the two half-axle components appears to play a key role in the reaction outcome.We use this understanding to develop a stereoselective approach to rotaxane MGI-1 isomers that can be extended directly to their catenane counterparts.Finally, we apply these principles to the direct synthesis of MAC rotaxanes without the need to produce diastereomeric intermediates.
The effect of the temperature on the stereoselectivity of the reactions of 1a and 1d was more complicated.Whereas reducing the reaction temperature in the synthesis of 4a from rt (entry 1) to −40 °C (entry 8) and −78 °C (entry 9) increased the observed selectivity, that for 4d was higher at −40 °C (entry 10) and then fell at −78 °C (entry 11).We suggest that this slightly counterintuitive observation can be rationalized in broad terms by considering that the AT-CuAAC reaction takes place over several steps, 21 which include an    equilibrium between diastereomeric azide/acetylide complexes I, followed by irreversible formation of the corresponding triazolides II (Scheme 2). 22The observed stereoselectivity is thus a composite function of the pre-equilibrium step (K eq ) and the relative rates (k RR , k SR ) at which intermediates I progress to triazolides II.The effect of temperature on the reaction to produce 4d suggests the pre-equilibrium and kinetic resolution steps respond differently to changes in temperature, resulting in the observed behavior. 23 Stereoselective Synthesis of MGI-1 Rotaxanes.Having demonstrated that a single H-bond between the sulfoxide unit and one of the incoming half-axle components appears to be important in the synthesis of rotaxanes 4, we turned our attention to the synthesis of analogous rotaxanes expressing the MGI-1 stereogenic unit.
Intrigued by the small but measurable stereoselectivity observed in the formation of 4e, which cannot arise due to the proposed stereodifferentiating NH•••O interaction, we exam-ined the AT-CuAAC coupling between macrocycle 2, and halfaxles 3 and 5, neither of which contain a directing group.At rt in CH 2 Cl 2 (Scheme 3a, entry 1), geometric isomers (E m )-6 and (Z m )-6 were formed in low but significant stereoselectivity (24% de), confirming that the AT-CuAAC reactions of 2 are not only biased by the H-bond identified in the case of rotaxanes 4. 24 Analysis of the separated isomers of 6 by SCXRD allowed their absolute stereochemistry to be determined (Figure 3a,b).Replacing the solvent with THF marginally improved the selectivity (28% de, entry 2), as did lowering the reaction temperature to −20 °C (40% de, entry 3), but, as with 4d, reduced selectivity was observed at lower temperatures (entries 4 and 5).Using EtOH as a solvent was comparable to THF (entry 6). 25  Although the selectivities observed in the formation of 4e and 6 are consistent with some inherent facial bias between the azide and alkyne half-axles in the mechanical bond-forming step, when a propargylic alkyne was employed with aryl azide 5 to generate rotaxane 7, no stereoselectivity was observed (Scheme 3b).In contrast, the reaction of an alkyl azide and aryl acetylene 3 to give rotaxane 8 proceeded in an appreciable stereoselectivity (14% de).Thus, although it is clearly possible to achieve low selectivities in the AT-CuAAC reactions of 2 in the absence of obvious directing interactions, this is highly substrate-dependent, and its origins are unclear at this time. 26eturning to our H-bonding-directed approach, when a propargylic amide was reacted with 2 to give 9, significantly improved stereoselectivity (54% de) was obtained, which was reduced in EtOH (40% de).The corresponding N-methyl amide gave rise to rotaxane 10 in low selectivity (13% de).The AT-CuAAC coupling of 3 and an alkyl azide bearing a simple amide gave rotaxane 11 in moderate stereoselectivity (40% de), which was reduced in EtOH (19% de).Thus, the amide can be placed in either coupling partner.Finally, rotaxane 12, whose amide NH is expected to be more polarized than that of 11, was produced in good selectivity (72% de) at rt, which was improved (90% de) when the same reaction was conducted at −40 °C.Reducing the temperature further did not improve the observed stereocontrol and led to a slow reaction.Replacing the reaction solvent with EtOH once again led to reduced selectivity (26% de).
As in the case of rotaxanes 4, the high selectivity observed in the synthesis of 9, 11, and 12 is consistent with the key role of an NH•••O interaction between the macrocycle and half-axle in controlling the facial selectivity in the AT-CuAAC reactions of macrocycle 2. However, we previously observed 11 this interaction in the solid-state structures of both diastereomers of epimeric MAC catenanes even though, in principle, in one diastereomer, the S−O bond could be expected to project away from the NH unit, which is possible due to the flexible nature of macrocycle 2. The major isomers of rotaxanes 9 and 11 determined by SCXRD (Figure 3c,d, respectively) highlight the importance of this flexibility; although both were formed selectively, counterintuitively, the ring is oriented in opposite directions with respect to the amide in the major diastereomer of each.Thus, although the NH•••O interaction appears able to direct the synthesis of MGI-1 isomers, the major product depends on the detailed structure of the half-axles used. 27We also note that whereas an NH•••O interaction is observed in the SCXRD structure of 4d, in the case of 9 and 11, this is replaced by an NH•••N interaction between the amide proton and one of the bipyridine N atoms, with the SO unit instead interacting with the polarized C−H of the triazole moiety in an inter-or intramolecular manner, respectively, presumably because the NH unit is geometrically accessible to the macrocycle in rotaxanes 9 and 11 whereas it is not in the case of 4d.
Stereoselective Synthesis of an MGI Catenane.Having established that a polarized NH unit appears sufficient to control the synthesis of MGI-1 rotaxanes with macrocycle 2, we briefly investigated whether the same approach could be applied to the related isomers of catenanes.Pre-macrocycle 13, which contains an activated amide unit analogous to that of 12, reacted with 2 under our AT-CuAAC catenane-forming conditions (Scheme 4) 28 to give 14 with good stereocontrol (80% de, entry 1).The same reaction in CHCl 3 -EtOH gave reduced selectivity (60% de, entry 2), whereas performing the reaction at 0 °C in CH 2 Cl 2 increased the selectivity (92% de, entry 3).Lowering the temperature further (−40 °C) had no significant effect (90% de, entry 4).Thus, unsurprisingly, given the similarity of their stereogenic units, MGI-1 rotaxanes and MGI catenanes can be made with good stereocontrol using equivalent strategies.

Direct Enantioselective Synthesis of MAC Rotaxanes.
Finally, we returned to apply our findings to the stereoselective synthesis of the enantiomers of MAC rotaxanes.In our original report, 11 we separated the diastereomers of epimeric rotaxanes 4a before removing the Boc group to generate rotaxane 15 (Scheme 5), in which the MAC stereogenic unit is the only fixed source of stereochemistry.This was necessary as the AT-CuAAC reaction only proceeded in 50% de; the ultimate purpose of developing methodologies to produce stereochemically complex mechanically interlocked molecules is so that they can then be investigated in applications such as sensing 29 or catalysis, 30 for which they must be of high stereopurity.
Trivially, our optimized conditions for the diastereoselective formation of 4a (Table 1, entry 9) removes the need for the separation of the MAC epimers and so allows the synthesis of highly enantioenriched samples of rotaxane 15 in a two-step, one-pot manner (Scheme 5); AT-CuAAC coupling of (R)-1a followed by TFA-mediated removal of the Boc group gave rotaxane (R ma )-15 in good stereoselectivity (78% ee) in Scheme 4. Stereoselective Synthesis of Catenane 14 a a Reagents and conditions: 13 (2 equiv) was added over the time stated using a syringe pump to 2 (1 equiv), [Cu(CH 3 CN) 4 ]PF 6 (0.97 equiv), i Pr 2 EtN (4 equiv).agreement with that observed for 4a (80% de).The same reaction with (S)-1a gave (S ma )-5 (77% ee).
More excitingly, the high stereoselectivity observed in the AT-CuAAC reaction of azides 1 bearing a polarized NH presents the opportunity for the direct synthesis of MAC rotaxanes without the need for first forming separable coconformational diastereomers; if the N substituent is too small to trap the macrocycle in one triazole-containing compartment, the only fixed stereochemistry in the product is provided by the MAC stereogenic unit.Thus, the reaction of primary amine-containing azide (R)-1e with macrocycle 2 and alkyne 3 at rt gave MAC rotaxane 15 directly but in low stereoselectivity (16% ee, Scheme 6, entry 1), which increased when the reaction was performed at −40 °C (28% ee, entry 2) and improved further still at −78 °C (42% ee, entry 3).CSP-HPLC analysis of a sample of rotaxane (R ma )-15 produced from (R)-1a (Scheme 5) and comparison with the same product from (R)-1f confirmed that the latter also produces (R ma )-15 as the major product (Figure 4a).
When instead formamide-containing azide (R)-1g was reacted with 2 and 3, even at rt rotaxane 16 31 was obtained in reasonable stereopurity (57% ee, entry 3), which was improved further at −40 °C (67% ee, entry 4).Conducting this reaction at −78 °C reduced the observed stereoselectivity (59% ee, entry 5), suggesting that, as with azide 1d, the preequilibrium and kinetic resolution steps result in an unusual temperature dependence.CSP-HPLC analysis of a sample of rotaxane 16 produced by formylation of a sample of rotaxane (R ma )-15 of known stereopurity and comparison with the same compound produced from (R)-1g confirmed that the latter produces (R ma )-16 as the major stereoisomer.When (S)-1g was reacted instead, (S ma )-16 was produced (70% ee, entry 6).The solid-state structure of 16 obtained by SCXRD (Figure 4b) did not display the expected intermolecular NH•••O Hbond; instead, the same interaction was found to occur in an intermolecular fashion within the unit cell.
The different co-conformational behaviors of 4a, 15, and 16 are clear from the analysis of their respective 1 H NMR spectra.Diastereomers (R ma ,R co−c )-4a and (S ma ,R co−c )-4a are separable species; heating a mixture of diastereomers 4a resulted in no change in their ratio (Figure S47), confirming that the macrocycle cannot shuttle between the two compartments due to the large NHBoc unit.In contrast, the diastereotopic triazole resonances H d 32 of amine rotaxane 15 appear as two sharp singlets at 298 K, indicating that diastereomeric coconformations (R ma ,R co−c )-15 and (S ma ,R co−c )-15 are in fast exchange on the 1 H NMR timescale through rapid shuttling of the macrocycle between the two triazole-containing compartments (Figure S190).The same resonances for formamide rotaxane 16 are broad at 298 K, although once again, only two signals are observed (Figure S200).This observation is consistent with (R ma ,R co−c )-16 and (S ma ,R co−c )-16 exchanging on the 1 H NMR timescale, albeit more slowly than (R ma ,R co−c )-15 and (S ma ,R co−c )-15, in keeping with the larger steric bulk of the formamide group of 16.Accordingly, increasing the temperature resulted in the sharpening of the two resonances corresponding to protons H d (Figure S211).

■ CONCLUSIONS
In conclusion, we have demonstrated that type 1 rotaxane mechanical geometric isomers and mechanically axially chiral enantiomers can be obtained by controlling facial selectivity in an AT-CuAAC synthesis.Specifically, we show that an Hbonding interaction between a prochiral macrocycle and a functional group contained in one of the two half-axles (rotaxane synthesis) or unsymmetrically disposed in the corresponding pre-macrocycle structure (catenane synthesis) appears to be sufficient to control the reaction outcome.Although the focus of our discussion has been on reaction stereoselectivities, it should be noted that, as is typically the case for AT-CuAAC reactions mediated by bipyridine macrocycles, 33 all of the interlocked structures reported were obtained in good to excellent isolated yield (50−90%, see the SI for details).The high selectivity observed with optimized substrates allowed us to design a direct enantioselective synthesis of mechanically axially chiral rotaxanes, only the second 34a example of a direct stereoselective synthesis of a mechanically chiral molecule and the first of this recently identified stereogenic unit.To date, type 1 mechanical geometric isomers of rotaxanes based on calixarenes and similar cone-shaped macrocycles, 5,8b,6d,e as well as structures expressing combinations of mechanical and covalent stereochemistry 4h have been investigated as components of molecular switches and motors.Here, we have demonstrated that such isomerism can be expressed and controlled in much simpler macrocycles, opening up new motifs for study.Similarly, mechanically planar chiral molecules, for which  Journal of the American Chemical Society stereoselective methods are known, 14,26,34 have been investigated as enantioselective sensors, 29 catalysts, 30 and chiroptical switches. 35With methodological concepts now in hand to efficiently synthesize their mechanically axially chiral cousins in high stereopurity, we eagerly anticipate the chemical applications to which molecules containing this stereogenic unit will soon be put.(18) The suffix "ma" indicates that the label refers to the mechanical axial stereogenic unit.The suffix "co-c" indicates that the stereochemical label refers to the co-conformational covalent stereogenic unit. 1119) We note that others have referred to such co-conformational covalent stereochemistry as "mechanical point chirality" ( Cakmak, Y.; Erbas-Cakmak, S.; Leigh, D. A. Asymmetric Catalysis with a Mechanically Point-Chiral Rotaxane.J. Am.Chem.Soc.2016, 138 (6), 1749−1751.).We introduced the co-conformational covalent description 12a as it is more precise and information rich; it highlights that that the stereogenic unit arises due to desymmetrization of a covalent pro-stereogenic unit and that these stereoisomers can in principle be converted by co-conformational movement.One of the reviewers of this manuscript suggested the term "co-configurational isomers" might be more useful and clearer for a nonexpert.We hesitate to adopt it here as changes in nomenclature should be properly discussed and put in the wider context of the field.However, we wanted to give credit to our anonymous reviewer for this intriguing suggestion and will consider its use in future.
(20) We note that the previously reported SCXRD structure of minor diastereomer (S ma ,R co-c )-4a 11 contains the same interaction but in this case it occurs intermolecularly between neighboring molecules in the unit cell, as observed for 4d (Figure 1).(23) We note that our results cannot rule out that either K eq or k SS / SR depends on a large negative entropy of reaction or activation respectively, which may also account for the unexpected temperature dependence of the AT-CuAAC reaction.
(24) The subscript is intended to indicate the mechanical origin of the stereochemistry.For a detailed discussion of how the mechanical stereogenic unit is assigned in such systems, see SI Section 8.

Figure 1 .
Figure 1.Schematic active template retrosyntheses of the mechanical (a) type 1 geometric isomers and (b) axially chiral enantiomers of rotaxanes, highlighting the need to control facial selectivity in the mechanical bond-forming step and the potential for attractive interactions between one face of the macrocycle and one of the half-axles to provide this control.

Figure 2 .
Figure 2. SCXRD structure of [(R ma ,R co−c )-4d (major isomer), with key intercomponent interactions highlighted.Colors as in Scheme 1, including the sulfoxide (SO) moiety to highlight the differentiation of the macrocycle faces, except N [dark blue], O [gray], and H [white].The majority of H was omitted.

Scheme 2 .
Scheme 2. Proposed AT-CuAAC Mechanism Highlighting Pre-Equilibrium and Kinetic Resolution Steps

Table 1 .
Effect of the Reaction Conditions and Substrate on the AT-CuAAC Diastereoselective Synthesis of Rotaxanes 4