Single-Step Enantioselective Synthesis of Mechanically Planar Chiral [2]Rotaxanes Using a Chiral Leaving Group Strategy.

We report a one-step enantioselective synthesis of mechanically planar chiral [2]rotaxanes. Previous studies of such molecules have generally involved the separation of enantiomers from racemic mixtures or the preparation and separation of diastereomeric intermediates followed by post-assembly modification to remove other sources of chirality. Here, we demonstrate a simple asymmetric metal-free active template rotaxane synthesis using a primary amine, an activated ester with a chiral leaving group, and an achiral crown ether lacking rotational symmetry. Mechanically planar chiral rotaxanes are obtained directly in up to 50% enantiomeric excess. The rotaxanes were characterized by NMR spectroscopy, high-resolution mass spectrometry, chiral HPLC, single crystal X-ray diffraction, and circular dichroism. Either rotaxane enantiomer could be prepared selectively by incorporating pseudoenantiomeric cinchona alkaloids into the chiral leaving group.


■ INTRODUCTION
Mechanical planar chirality arises in rotaxanes with achiral components when an unsymmetrical axle is threaded through a macrocycle lacking rotational symmetry ( Figure 1). 1−4 Although lacking classical elements of chirality, studies on mechanically planar chiral rotaxanes suggest their asymmetry can be well expressed for applications. 5−7 However, despite mechanically planar chiral rotaxanes being known for nearly 50 years, their enantioselective synthesis remains challenging. 1d,8 Most studies on these systems rely on the separation of enantiomers from racemic mixtures by chiral stationary phase HPLC, limiting the scale of enantioenriched material that can readily be obtained. 9 Goldup et al. have addressed this synthetic problem through a chiral auxiliary approach that forms intermediate diastereomeric rotaxanes having both point chirality and mechanically planar chirality. 10,11 Separation of these diastereomeric intermediates by flash chromatography, followed by removal of the point chirality by either substitution 10 or symmetrization, 11 afforded enantioenriched mechanically planar chiral rotaxanes. The only single-step synthesis of enantioenriched mechanically planar chiral rotaxanes to date used a chiral catalyst to resolve the interconverting enantiomers of a crown ether-ammonium pseudorotaxane by capping. 12 Despite attempts to optimize this method, it produced rotaxanes in just 4% enantiomeric excess (e.e.). Here we report a simple, single-step, enantioselective synthesis of mechanically planar chiral rotaxanes that produces either enantiomer in up to 50% e.e.
Metal-free active template reactions have recently been developed in which rotaxanes 13 are spontaneously assembled under kinetic control in a single step by combining a primary amine, electrophile, and crown ether 14 in apolar solvents. Crown ethers stabilize the transition states of various nucleophilic substitution reactions through the cavity by C− H hydrogen bonding, thereby favoring the formation of rotaxanes over the unthreaded axle. Different reactions, amines, and leaving groups result in different degrees of accelerated reaction through the ring, affording different rotaxane:thread selectivities. We chose crown ether-stabilized N-acylation for the present study (Scheme 1), as this active template reaction often results in a particularly high ratio of rotaxane:thread. 14 This suggested the reaction might be tolerant of the additional functionality necessary in the macrocycle (to break rotational symmetry) and axle building blocks (to provide a chiral leaving group).
An example of an active template N-acylation is the reaction of 24-crown-8 1, primary amine 2, and electrophile 3 in toluene at room temperature, producing amide [2]rotaxane 4 in 84% yield (Scheme 1a). 14b The rate-determining step of crown ether catalyzed N-acylation reactions is the collapse of the tetrahedral intermediate formed on addition of the amine to the activated ester. 15 The nitro-phenol ester used in the reaction of 1, 2, and 3 thus provides an opportunity for a chiral directing group to be incorporated into the leaving group that could interact with a rotationally unsymmetrical macrocycle in the transition state ( Figure 1). 16 ■ RESULTS AND DISCUSSION Development of an Enantioselective Rotaxane Synthesis. To establish that functionalized crown ethers could take part in the active template reaction, amine 2 and activated ester 3 were treated with commercially available dibenzo-24crown-8 (5) in toluene, yielding the corresponding [2]rotaxane, 6, in 73% yield (Scheme 1a). However, although the rotaxane axle is unsymmetrical, dibenzo-24-crown-8 (5) is D 2h symmetric and so rotaxane 6 is achiral. 1 Macrocycle 7, containing two different aromatic rings, lacks rotational symmetry (it has C 1h symmetry, alternatively referred to as C s ). Reaction of 7 with 2 and 3 furnished racemic mechanically planar chiral rotaxane 8 in 78% yield (Scheme 1b). The enantiomers of 8 could be separated by chiral stationary phase HPLC (see Supporting Information).
Next, we investigated the structure and location for an effective chiral leaving group in the electrophile. Preliminary screening studies identified nitrophenol ester 9, in which the chiral information stems from an O-alkylated cinchonidine unit adjacent to the nitro-group (Scheme 1b). This electrophile was reactive under the rotaxane-forming conditions despite the introduction of the deactivating electron-donating ether linkage. Combining 2, 7, and 9 in a 1:1:1 stoichiometry in toluene at room temperature afforded rotaxane 8 in 43% yield (Scheme 1b). Under similar conditions, electrophiles based on alkyl (thio)esters or with the cinchonidine unit positioned at the ortho position of the nitrophenol ring were either unreactive or generated less rotaxane (see Supporting Information). HPLC analysis of rotaxane 8 (isolated by flash chromatography) obtained from electrophile 9 revealed that the (+)-enantiomer (determined by polarimetry) had been formed in 12% e.e., confirming that a point-chiral leaving group was able to induce enantioselectivity of a mechanically planar rotaxane product.  Increasing the electronic difference between the two aromatic substituents within the macrocycle improved the enantioselectivity of the active template reaction. Macrocycle 10, with a nitro group on the catechol unit (see Supporting Information for its synthesis), afforded rotaxane (+)-11 in 23% e.e. at room temperature, which increased to 40% e.e. (55% yield) when the rotaxane-forming reaction was performed at −40°C (Figure 2a). Lowering the reaction temperature beyond −40°C did not result in further improvements in enantioselectivity. 17 The opposite enantiomer of the rotaxane, (−)-11, could be selectively accessed using electrophile 12, derived from (+)-cinchonine, a pseudoenantiomer of cinchonidine (see Supporting Information for synthesis). 18 Combining 2, 10, and 12 at −40°C gave rotaxane (−)-11 in 50% e.e. and 51% yield ( Figure 2a). The difference in enantioenrichment is a consequence of electrophiles 9 and 12 being diastereomers rather than true enantiomers. Enantioenriched samples of rotaxane 11 (40% e.e. for the (+) enantiomer and 50% e.e. for the (−) enantiomer) were compared by circular dichroism (Figure 3a). The CD spectra Although we were unable to obtain high quality single crystals of 11, single crystals of a racemic sample of 13 suitable for analysis by X-ray diffraction were grown by slow evaporation of an isopropanol/hexane solution of 13 ( Figure  3b). Rotaxane 13 contains the same macrocycle as 11 and an axle derived from amine 2 and a different acyl stopper. The Xray crystal structure of 13 (Figure 3c), containing both rotaxane enantiomers in the unit cell, shows similar intercomponent interactions to those observed by 1 H NMR for 11 in solution (Figure 2b). Hydrogen bonds are present between an oxygen of the macrocycle glycol chain and the amide hydrogen atom of the axle and between the amide oxygen and a macrocycle C−H hydrogen atom (analogous to H D in 11). 14 The di(alkoxyl)naphthalene ring of the macrocycle and bis(trifluoromethyl)benzene unit of the axle π-stack (Figure 3d, closest centroid-centroid distance = 3.67 Å), 19 with the nitro-catechol moiety positioned so as to cover one face of the amide group. A similar arrangement in the transition state of the active template reaction would orient the macrocycle with respect to the axle building blocks such that one mechanically planar chiral enantiomer would be favored over the other.
Origin of Enantioselectivity. A preliminary indication of the origin of chiral transduction in these systems comes from the relative energies of the tetrahedral intermediates preceding (+)-and (−)-11, calculated at the PM6 level 20 using the Gaussian 09 software package 21 (Supporting Information and Figure 4). The collapse of similar tetrahedral intermediates has previously been shown 15a to be the rate-determining step for the glyme catalysis of ester aminolysis. Following the Hammond postulate, the differences between the diastereomeric tetrahedral intermediates to (+)-and (−)-11 from 9 and 12 may resemble those between the transition states. The lowest energy intermediate calculated for both pseudoenantiomeric leaving groups featured an (S) stereocenter adjacent to the ammonium unit, but with the macrocycle orientation inverted for the two pseudoenantiomers (Figure 4), meaning changing between the leaving groups of 9 and 12 favors the formation of a different enantiomer of 11, as observed experimentally. The somewhat surprising indication that the two chiral leaving groups both favor an (S)-tetrahedral intermediate may reflect why the pseudoenantiomers do not generate equal and opposite e.e.'s in the active template reaction. The noncovalent interactions in the intermediate (e.g., the stacking of the electron-rich naphthalene unit with the electron-poor aryl group of the nucleophile, and the hydrogen bonding of the glycol oxygens to the H−N atoms) are reminiscent of those present in the X-ray crystal structure of rotaxane 13.  Journal of the American Chemical Society pubs.acs.org/JACS Article Also consistent with the stacking of the electron-rich naphthalene unit with the electron-poor aryl group of the nucleophile providing the driving force for organization of the transition state is the experimental evidence that decreasing the electron density of the other aromatic ring of the macrocycle increases the enantioselectivity of rotaxane formation (i.e., 12% e.e. for (+)-8; 40% e.e. for (+)-11). The less electron-rich the catechol ring is, the less it competes with the naphthalene group for π-stacking with the bis(trifluoromethyl)benzylamine and so the greater the enantiodiscrimination in the transition state.

■ CONCLUSIONS
The examples presented demonstrate that mechanically planar chiral rotaxanes can be directly accessed in up to 50% e.e. in a single synthetic step. The chirality of the point-chiral leaving group is transferred into mechanically planar chirality in the rotaxane through metal-free active template N-acylation. Pseudoenantiomeric cinchona alkaloids allow either rotaxane enantiomer to be accessed. X-ray crystallography and molecular modeling suggest that the origin of the enantioselectivity lies in π-stacking of an electron-rich aromatic ring on the macrocycle with an electron-poor aryl group originating from the nucleophilic axle building block. This positions the second aromatic ring of the macrocycle in an orientation that blocks one face of the electrophile. Simple methods for accessing enantioenriched mechanically planar chiral rotaxanes should improve their availability for investigation in applications such as asymmetric catalysis, 7 chiral (bio)molecule sensing, 1,6,22 and novel designs 23 of molecular machinery.