A Switchable [2]Rotaxane Asymmetric Organocatalyst That Utilizes an Acyclic Chiral Secondary Amine

A rotaxane-based switchable asymmetric organocatalyst has been synthesized in which the change of the position of the macrocycle reveals or conceals an acyclic, yet still highly effective, chiral organocatalytic group. This allows control over both the rate and stereochemical outcome of a catalyzed asymmetric Michael addition. N controls the rate of enzymatic synthesis through a variety of trigger-induced effects. Such processes are inspiring the development of synthetic systems where a stimulus can be used to turn a catalyst’s activity ‘on’ or ‘off’. However, enzyme-catalyzed reactions also often proceed with exquisite stereochemical control. The Feringa group has described a molecular-machine-based organocatalyst that can be switched to bias catalysis of a conjugate addition in favor of either enantiomer (3:1 to 1:3 enantiomeric ratio (er)). Here we report on a [2]rotaxane that acts as an effective asymmetric organocatalyst in one state (>9:1 er) but is switched ‘off’ in the other state, by exploiting well-defined positional changes of the components to conceal or reveal a simple chiral organocatalytically active functional group. The design of the rotaxane-based switchable asymmetric organocatalyst (R)-1·PF6 consists of a dibenzo-24-crown-8 macrocycle and an axle bearing a triazolium ring and a chiral acyclic secondary amine derived from D-phenylalanine (Figure 1). Secondary amines employed as organocatalysts are usually cyclic, but we had previously found that pyrrolidine rings form perch, rather than threaded, complexes with crown ethers of this size which is not conducive for rotaxane formation. We were delighted, therefore, when model studies (see Tables 1 and 2 and the Supporting Information) showed that simple acyclic secondary amine derivatives of amino acids could very effectively catalyze asymmetric conjugated additions via iminium ion activation, often giving stereoselectivities as high as those obtained with commercial cyclic organocatalysts, albeit requiring longer reaction times. Such acyclic chiral moieties can be readily incorporated into a rotaxane thread. The switching mechanism of the rotaxane relies on the macrocycle preferentially encapsulating the chiral secondary ammonium group, a better binding site for the macrocycle than the triazolium ring, in the protonated form ((R)-1-H·2PF6 −; Figure 1a). The macrocycle blocks access of reactants to the catalytic site. When the secondary amine of the rotaxane is not protonated ((R)-1·PF6; Figure 1a), the triazolium group is the preferred binding site for the macrocycle and the chiral organocatalyst on the axle is exposed and available to participate in asymmetric catalysis. The synthetic route toward rotaxane (R)-1 relies on a CuAAC ‘click’ reaction to covalently capture a threaded complex of dibenzo-24-crown-8 and an alkyne-functionalized ammonium axle with an azide-functionalized bulky 3,5-di-tertbutylphenyl derivative (see Supporting Information). Switching of the preferred position of the macrocycle between the two binding sites is triggered by protonation/ deprotonation of the amine/ammonium group (Figure 1a). A comparison of the H NMR spectrum of (R)-1-H·2PF6 − (Figure 2b) to that of the protonated noninterlocked thread Received: February 19, 2014 Published: March 20, 2014 Figure 1. (a) Acid−base switching of the position of the macrocycle in chiral rotaxane (R)-1-H·2PF6 − (catalysis ‘off’)/(R)-1·PF6 (catalysis ‘on’). (b) Structure of threads (R)-2·PF6 and (R)-2-H ·2PF6 −. Communication

N ature controls the rate of enzymatic synthesis through a variety of trigger-induced effects. 1 Such processes are inspiring the development of synthetic systems where a stimulus can be used to turn a catalyst's activity 'on' or 'off'. 2−4 However, enzyme-catalyzed reactions also often proceed with exquisite stereochemical control. 5 The Feringa group has described 3a a molecular-machine-based organocatalyst that can be switched to bias catalysis of a conjugate addition in favor of either enantiomer (3:1 to 1:3 enantiomeric ratio (er)). Here we report on a [2]rotaxane 6 that acts as an effective asymmetric organocatalyst 7 in one state (>9:1 er) but is switched 'off' in the other state, by exploiting well-defined positional changes of the components to conceal or reveal a simple chiral organocatalytically active functional group.
The design of the rotaxane-based switchable asymmetric organocatalyst (R)-1·PF 6 consists of a dibenzo-24-crown-8 macrocycle and an axle bearing a triazolium ring and a chiral acyclic secondary amine derived from D-phenylalanine ( Figure  1). Secondary amines employed as organocatalysts are usually cyclic, 8−10 but we had previously found 4 that pyrrolidine rings form perch, rather than threaded, complexes with crown ethers of this size which is not conducive for rotaxane formation. We were delighted, therefore, when model studies (see Tables 1 and 2 and the Supporting Information) showed that simple acyclic secondary amine derivatives of amino acids could very effectively catalyze asymmetric conjugated additions via iminium ion activation, often giving stereoselectivities as high as those obtained with commercial cyclic organocatalysts, albeit requiring longer reaction times. Such acyclic chiral moieties can be readily incorporated into a rotaxane thread.
The switching mechanism of the rotaxane relies on the macrocycle preferentially encapsulating the chiral secondary ammonium group, a better binding site for the macrocycle than the triazolium ring, 11 in the protonated form ((R)-1-H + ·2PF 6 − ; Figure 1a). The macrocycle blocks access of reactants to the catalytic site. When the secondary amine of the rotaxane is not protonated ((R)-1·PF 6 ; Figure 1a), the triazolium group is the preferred binding site for the macrocycle 11 and the chiral organocatalyst on the axle is exposed and available to participate in asymmetric catalysis.
Switching of the preferred position of the macrocycle between the two binding sites is triggered by protonation/ deprotonation of the amine/ammonium group (Figure 1a  Deprotonation of rotaxane (R)-1-H + ·2PF 6 − with aqueous NaOH smoothly afforded (R)-1·PF 6 , giving rise to significant changes in the 1 H NMR spectrum ( Figure 2c). The benzylic protons of the benzylamine motif are shifted upfield (ΔδH n = −1.17 and −1.28 ppm; ΔδH p = −0.45 ppm), indicating that the amine group is not hydrogen bonding with the dibenzo-24crown-8, and the amide methyl protons appear at the same chemical shift they do in the thread (R)-2-H + ·2PF 6 − . In contrast, the protons of the triazole ring and one of the CH 2 groups adjacent to the triazolium group are shifted downfield (ΔδH g = 0.57 ppm; ΔδH f = 0.43 ppm), indicating that they are now interacting with the crown ether, and the protons of the triazolium methyl group are shifted upfield (ΔδH dd = −0.67 ppm) due to shielding by the macrocycle. The chemical shifts confirm the position of the macrocycle is around the triazolium unit, the preferred binding site now that the amine unit is no longer protonated. Upon reprotonation of the secondary amine group with a 1 M solution of HCl in Et 2 O, the 1 H NMR spectrum of the rotaxane confirms that the original state, with the macrocycle residing over the ammonium unit, is restored ( Figure 2d).
Having demonstrated that it is possible to control the position of the crown ether macrocycle on the axle in (R)-1 by protonation/deprotonation of the secondary amine group, we investigated the efficacy of the rotaxane as an asymmetric organocatalyst. We chose as a reaction the Michael addition of 1,3-diphenyl-1,3-propanedione (4) to E-crotonaldehyde (3a), which can be catalyzed via iminium ion activation. 13 Initially, screening to optimize the reaction conditions was performed  Table  2) is known 13 to produce (S)-5a as the major enantiomer. d No reaction was observed during 24 h.   (1:4:2)). The lettering and color coding of the signals correspond to those shown in Figure 1.
We confirmed that the reaction between 3a and 4 in CH 2 Cl 2 does not proceed at room temperature in the absence of the organocatalyst (Table 1, entry 1). The use of the nonprotonated thread (R)-2·PF 6 as the catalyst afforded the Michael adduct 5a with excellent conversion and good stereoselectivity ( Table 1, entry 2). When this reaction was catalyzed by (S)-2·PF 6 , the enantiomer of the Michael adduct was obtained ((S)-5a 13 ) (Table 1, entry 3). In order to optimize the enantioselectivity of the reaction, additional screening of the conditions was carried out (for solvent effects, see Supporting Information). Temperature proved to have a significant influence on the reactivity and enantioselectivity of the reaction (Table 1, entries 4−6). The reactions carried out at lower temperatures afforded better enantiomeric ratios, but at the expense of slower rates. The best results were found when the reaction was performed at 10°C in CH 2 Cl 2 affording 5a with good conversion (60% after 24 h) and stereochemical control (92:8 er; Table 1, entry 6). When the reaction was catalyzed with the protonated thread (R)-2-H + ·2PF 6 − using these conditions, 5a was obtained with 50% conversion after 24 h in a 89:11 enantiomeric ratio (Table 1, entry 7), showing that the protonation of the catalyst does not inhibit catalysis to any significant extent.
Once the optimized set of conditions was established, we investigated the asymmetric Michael addition between 3a and 4 catalyzed by the nonprotonated and protonated rotaxanes (R)-1·PF 6 and (R)-1-H + ·2PF 6 − ( Table 2, entries 1−2). The amine form of the rotaxane, (R)-1·PF 6 , catalyzed the reaction as effectively as the amine form of the thread, (R)-2· PF 6 , affording 5a with good conversion and enantiomeric ratio ( Table 1, entry 6 and Table 2, entry 1). However, in contrast to the catalysis by the protonated thread (Table 1, entry 7), the protonated (ammonium) form of the rotaxane, (R)-1-H + · 2PF 6 − , did not afford any Michael addition product 5a (Table  2, entry 2) demonstrating that the switching 'off' of the asymmetric catalyst is extremely effective and is caused by the repositioning of the macrocycle to cover the catalytic site. Other alkyl-substituted α,β-unsaturated aldehydes (3b,c) with longer aliphatic chains also afforded the corresponding Michael adducts (5b,c) with good conversions and enantiomeric ratios ( Table 2, entries 3 and 4). However, no reaction was observed using the aromatic α,β-unsaturated aldehyde 3d (Table 2, entry 5).
Finally, the progress of the asymmetric Michael addition could also be controlled through in situ switching of the rotaxane catalyst (Scheme 1). After 48 h of stirring 3a and 4 in the presence of 20 mol % rotaxane in its inactive, protonated, state ((R)-1-H + ·2PF 6 − ) no conversion to product 5a was observed (Scheme 1, part 1). Upon brief washing with 1 M aqueous NaOH, the rotaxane catalyst was switched 'on' affording 5a in 70% yield and 94:6 er within 48 h (Scheme 1, part 2). The rotaxane catalyst could also be switched 'off' in situ: addition of 20 mol % of HCl (1 M) immediately stopped further formation of (R)-5a from 3a and 4 (Scheme 1, part 3).
In conclusion, rotaxane (R)-1·PF 6 is a switchable asymmetric organocatalytic system based on a simple acyclic secondary amine housed within a rotaxane architecture. The acyclic chiral secondary amine promotes an asymmetric Michael addition with stereochemical control comparable to, or better than, commercial cyclic amine organocatalysts at the expense of a slower rate of conversion. Biology uses molecular machines to control many aspects of chemical synthesis. Simultaneously employing different types of artificial switchable asymmetric catalysts may enable different products to be prepared from common pools of achiral building blocks, simply by switching the different catalysts 'on' and 'off'.

* S Supporting Information
Experimental procedures and spectral data for all compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

■ AUTHOR INFORMATION Corresponding Author
David.Leigh@manchester.ac.uk.