A Stimuli-Responsive Rotaxane–Gold Catalyst: Regulation of Activity and Diastereoselectivity

A rotaxane-based Au catalyst was developed and the effect of the mechanical bond on its behavior was studied. Unlike the non-interlocked thread, the rotaxane requires a catalytically innocent cofactor, the identity of which significantly influences both the yield and diastereoselectivity of the reaction. Under optimized conditions, AuI (the catalyst), AgI (to abstract the Cl− ligand), and CuI (the cofactor) combine to produce a catalyst with excellent activity and selectivity.

Catalysts based on interlocked molecules have recently begun to receive increased attention. [1] Them ajority of the systems reported take advantage of the well-studied ability of the mechanically bonded components to undergo largeamplitude relative motion, [2] including examples in which this motion alters the reaction chemoselectivity, [3] machines inspired by DNAp olymerase that employ an interlocked catalyst-substrate architecture to produce highly processive reactions, [4] and systems where the catalytic activity of the rotaxane is controlled by reversible shielding of organocatalytic moieties in the thread. [5][6][7] In contrast to these applications of mechanical motion, comparatively little is known about the influence of the mechanical bond itself on the outcome of catalyzed reactions. [8] In 2004, Takata and co-workers reported that an achiral imidazolium organocatalyst encircled by ac hiral macrocycle mediates an enantioselective benzoin reaction, albeit with moderate ee. [9] Very recently,L eigh and coworkers reported ac hiral [2]rotaxane ligand for Ni that exhibits higher enantioselectivity than an on-interlocked model complex, although at the cost of reduced activity owing to steric hindrance. [10] These results suggest that the sterically crowded environment provided by the mechanical bond could be used to engineer novel reaction fields to alter the stereoselectivity of catalysts that are hard to control with conventional scaffolds.
Although synthetically powerful, gold(I)-mediated reactions are perhaps the quintessential example of an activation mode for which it is hard to engineer the ligand to sterically influence the reaction because of the linear coordination geometry of Au I . [11] Herein, we report ar otaxane-gold catalyst [12,13] in which the mechanical bond influences both diastereoselectivity and catalytic activity,and we demonstrate stimuli-responsive control of both of these important reaction parameters.
During the synthesis of 4 and 5,the first significant effect of the mechanical bond became apparent:a lthough phosphine rotaxane 4 does not require special handling, noninterlocked 5 is extremely susceptible to oxidation and reverts to the corresponding phosphine oxide on standing in CDCl 3 . Thus,the mechanical bond appears to stabilize the relatively electron-rich alkyl phosphine moiety. [8] Single crystals of [4AuCl] suitable for X-ray analysis were grown by slow evaporation from CDCl 3 ( Figure 1). [18] Thes pace-filling representation of [4AuCl] clearly demonstrates the sterically hindered environment around the Au center provided by the mechanical bond. In the solid state,t riazole proton H e and one of methylene protons H d participate in bifurcated CÀ H···N hydrogen bonds with the pyridine nitrogen atoms.
Despite the unusual nature of the Au coordination environment in [4AuCl],t he 31 PNMR spectra of the thread and rotaxane-AuCl complexes are similar (Figure 2) the expected shielding of thread resonances (e.g. H d ,H f and H g ), triazole proton H e resonates at 9.5 ppm in the rotaxane-Au complex, which is 1.7 ppm higher than in [5AuCl],t hus suggesting that the C À H···N hydrogen bond between H e and the bipyridine nitrogen atom observed in the solid state is at least partially maintained in solution.
To investigate the effect of the mechanical bond on the catalytic behavior of [4AuCl],w es elected Tostes Au Imediated modification of the Ohe-Uemura cyclopropanation reaction as asimple,well-understood model system. [19,20] As in many Au I -mediated reactions,the active catalyst is proposed to be an LAu + p acid, typically generated by abstraction of the Cl ligand from LAuCl by Ag I salts. [11]3 1 PNMR analysis of the product of treating [4AuCl] with AgSbF 6 (Figure 2c) revealed anew resonance at higher chemical shift (38.7 ppm), which is consistent with Cl abstraction and formation of as olvated PAu + complex. [21] However,i nt he presence of AgSbF 6 ,[ 4AuCl] failed to mediate the reaction between propargylic ester 6 and styrene (7) Comparison of the 1 HNMR spectra of [4AuCl] and [4Au] + provided aclue to the origin of the lack of activity of the rotaxane catalyst:u pon abstraction of the Cl anion, the resonance corresponding to triazole proton H e shifts from 9.5 to 7.5 ppm, thus suggesting that the C À H···N interaction present in [4AuCl] is at least partially interrupted in [4Au] + . This observation is consistent with the Au + center interacting with the Ndonor atoms of the macrocycle,thereby interrupting the weaker hydrogen-bonding interaction. Thep roposed NÀAu interaction would be expected to temper the catalytic activity of [4Au] + by reducing the p-acidity of the metal center and preventing coordination of the substrate. [22] Based on this hypothesis,asolution suggested itself:the addition of aguest that coordinates in the macrocyclic cavity and is able to effectively compete with the NÀAu interaction should remove the inhibition and switch the catalyst "on". [23] Addition of TsOH, [Cu(MeCN) 4 ]PF 6 ,Z n(OTf) 2 ,o r Cd(OTf) 2 to as olution of [4AuCl] in CDCl 3 led to dramatic changes in the 1 HNMR spectra but minimal change in the 31 P resonance (@ P = 24.5, 23.9, 27.7, and 24.4 ppm respectively; see the Supporting Information for details), thus suggesting that the PÀAu bond is unaffected by guest binding.Addition of AgSbF 6 to [4AuCl] and [Cu(MeCN) 4 ]PF 6 in CDCl 3 resulted in the formation of ac omplex with ab road 31 P resonance consistent with the desired PAu + species (Figure 2d). Furthermore,i nt he presence of 1equiv of TsOH (Table 1,     Cd(OTf) 2 (entry 6) led to ad iminished yield. In contrast to the behavior of the rotaxane,r eactions mediated by [5AuCl] were unaffected by the presence of Zn II (entry 7), while addition of Cu I (entry 8) led to partial decomposition of the catalyst and adiminished yield of 8. [24] In the absence of Au I , the additives have no intrinsic catalytic behavior (entry 9). Thee ffect of guest binding on the catalytic behavior of [4AuCl] is noteworthy on an umber of counts.F irstly,a nd most obviously,t he activity of the catalyst is strongly dependent on the presence of the guest. Building on these results,w ep erformed in situ switching experiments with [4AuCl] and the best performing guests,C u I and Zn II (Scheme 2). After 1h,n or eaction was observed in the absence of additives.A ddition of Zn(OTf) 2 or [Cu-(MeCN) 4 ]PF 6 led to rapid production of cyclopropanes 8 in comparable yield and diastereoselectivity to the reaction in which the guest was introduced prior to the substrate.
[4AuCl] thus behaves as aswitchable catalyst, with an extremely large difference in activity between the "off" and "on" states.
Secondly,t he selectivity observed in the presence of Cu I or TsOH is among the highest achieved by monodentate phosphines for these substrates. [25] Since diastereoselectivity in Tostes cyclopropanation reaction is correlated with ligand steric hindrance, [20] we examined the steric demand of the rotaxane ligand by using Nolans %b uried volume (%V bur ) parameter,agross measure of the volume around the metal center occupied by the ligand atoms. [26] Applying the calculation [27] to the solid-state structure of [4AuCl] (Figure 1) revealed a% V bur value of 44 %, which is significantly higher than that of PPh 3 (30 %) and even sterically hindered ligand PtBu 3 (38 %). [26] Finally,and perhaps most strikingly,each guest examined gives rise to ad ifferent degree of diastereoselectivity.T his variation is tentatively attributed to the modulation of the reaction field provided by the mechanical bond upon guest binding;a sw ell as disrupting the N À Au coordination, the binding of guests into the macrocycle cavity will alter the coconformation between the macrocycle and thread, thereby rigidifying the catalyst framework and modifying the space around the reaction site in am anner akin to allosteric modulation of enzymatic catalysts.
Thes erendipitous isolation of [4(H)(AuCl)]AuCl 2 as am inor byproduct during the synthesis of [4AuCl] provides insight into the effect of guest binding on the steric environment around the gold .I nt he solid-state structure of [4(H)(AuCl)] + (see the Supporting Information), the proton guest is located between at riazole nitrogen and one of the bipyridine nitrogens.T his binding event causes ac o-conformational rearrangement compared with [4AuCl];t he Au À Cl bond of [4(H)(AuCl)]AuCl 2 is projected towards rather than away from the bipyridine unit (compare to Figure 1), which clearly alters the three dimensional environment around the Au center.T he calculated %V bur of 42 %f or [4(H)-(AuCl)]AuCl 2 also differs from that of [4AuCl],a lbeit by only 2%.Although neither [4AuCl] or [4(H)(AuCl)]AuCl 2 is of direct catalytic relevance,t he large co-conformational change observed on protonation provides evidence for the proposed allosteric role of the guest.
To investigate the generality of these observations,w e compared the reactions of substrates with different steric properties mediated by [tBu 3 PAuCl],[ 5AuCl],o r[ 4AuCl] (Figure 3). In keeping with previous reports,alkyl-substituted cyclopropanes 9 and 12 were formed in low selectivity in the presence of [tBu 3 PAuCl],w hereas variation of the ester moiety between OAc( 10)a nd pivalate (OPiv; 11)l ed to no significant change in selectivity. [20a] This trend was repeated in the case of [5AuCl],a lthough in all cases the selectivity was inferior to that of the bulkier tBu 3 Pl igand. Reactions mediated by [4AuCl] gave the target cyclopropanew ith significantly higher selectivity than that produced with either non-interlocked catalyst, thus further demonstrating the sterically hindered environment provided by the mechanical bond. Once again, the diastereoselectivity of reactions mediated by [4AuCl] varied in ag uest-dependent manner. However,whereas [4AuCl] produced benzoate esters 8 and 9 in higher d.r. in the presence of Cu I than Zn II ,this trend was reversed in the case of alkyl ester derived products 10-12. Thus,a lthough the guest-dependent behavior of [4AuCl] is reproducible across the substrates investigated, the optimal guest appears to depend on the detailed structure of the reagents.T his suggests that, in addition to as imple steric component, specific interactions between substrate and catalyst that vary with the identity of the guest may play asignificant role.
In conclusion, we have demonstrated arotaxane-based Au catalyst and identified anew approach to the development of stimuli-responsive interlocked catalysts more generally. Although such behavior has previously been demonstrated in organocatalytic rotaxanes, [5] this is the first example of ar otaxane-based metal complex with stimuli-responsive catalytic activity.O nce switched on by guest binding, the flexible but sterically crowded [28] environment of the mechanical bond was shown to strongly influence the diastereoselectivity of an Au-mediated reaction, thus demonstrating the   Table 1.

Angewandte
Chemie potential of interlocked molecules for the design of new reaction fields for hard-to-influence transformations.T he influence of the mechanical bond is also responsive to external stimuli, depending as it does on the nature of the guest, and this is the first time that such stimuli-responsive stereoselectivity has been observed in arotaxane catalyst. The origin of this effect is tentatively proposed to be similar to allosteric modulation in enzymes,i nw hich cofactor binding subtly influences the environment of the active site.M odification of the reaction field by guest binding in such rotaxane architectures offers as upramolecular approach to the optimization of catalyst activity and selectivity,t he potential for catalytic signal application for the development of sensors, [29] and the possibility of controlling not just the stereoselectivity but also the chemoselectivity of metal-catalyzed reactions in astimuli-responsive manner.
Full crystallographic data and characterization of all novel compoundsi sg iven in the Supporting Information. CCDC 1406074-1406077 containsthe supplementary crystallographic data for this paper.T hese data are provided free of charge by The CambridgeC rystallographic Data Centre.