Stereodivergent Anion Binding Catalysis with Molecular Motors

Abstract A photoresponsive chiral catalyst based on an oligotriazole‐functionalized unidirectional molecular motor has been developed for stereodivergent anion binding catalysis. The motor function controls the helical chirality of supramolecular assemblies with chloride anions, which by means of chirality transfer enables the enantioselective addition of a silyl ketene acetal nucleophile to oxocarbenium cations. Reversal of stereoselectivity (up to 142 % Δee) was achieved through rotation of the motor core induced by photochemical and thermal isomerization steps.

Abstract: Ap hotoresponsive chiral catalyst based on an oligotriazole-functionalized unidirectional molecular motor has been developed for stereodivergent anion binding catalysis. The motor function controls the helical chirality of supramolecular assemblies with chloride anions,which by means of chirality transfer enables the enantioselective addition of asilyl ketene acetal nucleophile to oxocarbenium cations.Reversal of stereoselectivity (up to 142 % Dee) was achieved through rotation of the motor core induced by photochemical and thermal isomerization steps.
Theallostericregulationofenzymesinnature [1] has served as as ource of inspiration for the development of responsive artificial catalysts whose function can be altered by the action of external stimuli, [2,3] which may translate into variations in activity, [2a,4] selectivity, [5] or reaction type [6] without reengineering the structure of the catalyst. Particularly desirable and at the same time remarkably challenging are switchable catalysts that can on-demand selectively provide all the different stereoisomers in agiven chemical transformation. [7] Our group pioneered this concept [8] through the use of socalled first generation molecular motors [9] -which can be interconverted between four different states by the action of light and heat-containing two reactive sites attached to the motor core.B ased on this approach, the stereodivergent addition of at hiolate to an a,b-unsaturated ketone was initially accomplished, [8] followed by the development of thiourea-based switchable organocatalysts for the Henry reaction [10] as well as aT rost-type ligand for ap alladiumcatalyzed asymmetric allylic substitution. [11] More recently, photoswitchable catalysts based on second generation molecular motors [12] have also been realized. [13] Asymmetric anion binding catalysis is based on the activation of an ion pair for the attack of an ucleophile through the recognition of the anion by ac hiral receptor. [14] Since the groundbreaking reports by Jacobsen and co-workers on the use of chiral thioureas as the anion binding catalysts, [15] several other classes of anion receptors have been designed and successfully applied in asymmetric catalysis. [16] Herein, we report on the use of am olecular motor-based stimuliresponsive anion receptor to illustrate the concept of adaptive stereodivergent anion binding catalysis,which is achieved by means of supramolecular transfer of chirality ( Figure 1). The precise positioning of two ion binders with respect to each other at each stage of the rotation cycle of the motor creates different chiral environments at the anion recognition site, which translates into different stereochemical outcomes in anion binding catalysis.
Tr iazoles have been recognized as amide surrogate anion binders due to their dipole moment (ca. 5D), which results in an electropositive C À Hc apable of engaging in hydrogen bonding with negatively charged species. [17] In the case of aryl triazole oligomers that cannot adopt ap lanar conformation, this interaction translates into ah elical supramolecular arrangement in the presence of,a mong others,c hloride anions. [18,19] Based on this concept, chiral oligotriazoles bearing a trans-1,2-cyclohexanediamine backbone have been developed [20] and their utility in asymmetric anion binding catalysis has been elegantly illustrated for the dearomatization of av ariety of heterocycles. [21] We anticipated that af irst generation molecular motor could serve as au nique responsive chiral scaffold for oligotriazole-based anion receptors,w hich due to the motor function could interconvert between isomeric states as aresponse to external stimuli. In our design, molecular motors 1 feature two branches,e ach of them containing two triazole moieties linked by an aryl group (Scheme 1). While the two branches would be far apart from each other in (R,R)-(P,P)-trans-1, they could come into close proximity in both (R,R)-(M,M)cis-1 and (R,R)-(P,P)-cis-1 forms,w hich would be sequentially accessed by irradiation of (R,R)-(P,P)-trans-1 and heating of the resulting photogenerated species,r espectively. These species are pseudoenantiomers,o nly differing from each other in the handedness of the helical structure.I nt he presence of chloride anions,( R,R)-(M,M)-cis-1 and (R,R)-(P,P)-cis-1 can form asupramolecular helical assembly to give rise to (R,R)-(M,M)-cis-1-Cl and (R,R)-(P,P)-cis-1-Cl,respectively,w hose configuration would be dictated by the helicity of the motor backbone. [22] We envisioned that this transfer and amplification of chiral information from the molecular to the supramolecular level could be exploited to achieve the preferential formation of different stereoisomers in the context of asymmetric anion binding catalysis depending upon the external stimulus applied.
Our starting point for the synthesis of the target triazolefunctionalized molecular motors was am ixture of (R, R)-(P,P)-cis-and (R, R)-(P,P)-trans-2 (e.r. > 95:5), which results from the McMurry coupling of the corresponding enantiomerically enriched indanone. [23] This mixture could be converted into pure (R, R)-(P,P)-cis-2 by heating at 180 8 8C (Scheme 2). [24] While the attempts of direct Sonogashira coupling from (R, R)-(P,P)-cis-2 turned out to be unsuccessful, the double aromatic Finkelstein reaction [25] proceeded smoothly on (R, R)-(P,P)-cis-2 to afford (R, R)-(P,P)-cis-3, which could be coupled with trimethylsilylacetylene under standard reaction conditions.S ubsequent cleavage of the trimethylsilyl groups at the alkyne termini provided (R, R)-(P,P)-cis-4,w hich was obtained in its enantiomerically pure form after recrystallization. Alternatively,t he double aromatic Finkelstein followed by double Sonogashira coupling starting from the mixture of cis-a nd trans-2 provided separable mixtures of bis-alkynylated motors,w hich after TMS cleavage afforded (R, R)-(P,P)-cis-a nd (R, R)-(P,P)trans-4.U ltimately,t he reaction of (R, R)-(P,P)-cis-4 with aromatic azides 5 and 6 in the presence of substoichiometric amounts of copper afforded tetra-and bistriazole-functionalized molecular motors (R, R)-(P,P)-cis-1a-d and (R, R)-(P,P)cis-7,r espectively.I nt he case of cis-1a-d,d ifferent electron withdrawing substituents (R) at the ring connecting the triazole moieties were selected, since they are known to have an impact on the performance of oligotriazole receptors in asymmetric catalysis. [20] Likewise,( R, R)-(P,P)-trans-4 could be used to obtain trans-configured oligotriazole-containing molecular motors 1.
With enantiomerically pure (P,P)-cis-configured triazolecontaining motors 1a-d and 7 in hand, their performance as anion binding catalysts was next examined. We selected the addition of silyl ketene acetal nucleophiles to 1-chloroisochroman as am odel reaction (Table 1), which has been studied in the presence of thiourea-based anion binders [15,26] among others. [27] We initially tested the reaction between 1-  (9)i nM TBE at À70 8 8Cf or 36 h. We found that two triazole moieties per branch are required in order to induce enantioselectivity in this transformation since (R,R)-(P,P)-cis-7 provided rac-10 ( Table 1, entry 1), which is in line with the predicted formation of as upramolecular helical structure upon chloride binding.A mong the tetratriazolemotors (R,R)-(P,P)-cis-1a-d tested (Table 1, entries 2-5), motor (R,R)-(P,P)-cis-1b bearing CF 3 substituents at the linking ring gave the highest conversion (65 %) and enantioinduction (e.r. = 86:14) in the formation of 10 a (Table 1, entry 3) and was therefore selected for further optimization studies.T he use of other solvents including Et 2 O, THF, CH 2 Cl 2 ,o rt oluene resulted in lower values of enantioselectivity (see Table S1 in the Supporting Information for details). We also examined the influence of the nucleophile,f inding lower levels of enantioinduction with the other silyl ketene acetals tested and no conversion when an enol ether was used as the nucleophile (see Table S2 in the Supporting Information for details). Therefore, 9 was the nucleophile of choice for further experimentation. Lowering the reaction temperature to À80 8 8Cl ed to an increase in e.r. (Table 1, entry 6). Finally,d ilution to an initial 0.15 m concentration of 8a provided the addition product 10 a with 90:10 e.r. (Table 1, entry 7), which was isolated in 81 %yield after extending the reaction time to 5days (Table 1, entry 8). Thee nantiomer preferentially formed in the presence of (R,R)-(P,P)-cis-1b as the catalyst was determined to be (S)-10 a by comparison to previously published data (see Supporting Information for details). [15] Having established 1bas the most efficient catalyst for the formation of 10 a,i ts photoswitching behavior was next examined by UV/Vis spectroscopy (Figure 2). Irradiation of asolution of (R,R)-(P,P)-trans-1bin THF (312 nm) promoted its isomerization to (R,R)-(M,M)-cis-1b (Figure 2a). The presence of clear isosbestic points is indicative of au nimolecular process (see Figure S1). This process could be reversed by irradiation with 365 nm light. Subsequent heating of (R,R)-(M,M)-cis-1b at 60 8 8Ci nduced thermal helix inver-sion (THI) to form (R,R)-(P,P)-cis-1b.The same process was monitored by 1 HNMR (Figure 2b). Thus,aPSS ratio of 90:10 (R,R)-(M,M)-cis-1b:(R,R)-(P,P)-trans-1b was obtained after irradiation of as olution of (P,P)-trans-1b in [D 8 ]THF (312 nm) for 2h.B oth isomers could be easily separated by preparative thin layer chromatography.A fter THI, the 1 HNMR spectrum obtained for (R,R)-(P,P)-cis-1b was identical to that of the corresponding synthetic sample. Additionally,t he effect of the presence of chloride anions was studied by CD spectroscopy (Figure 2c). Theaddition of 10 equiv of TBAClt oaTHF solution of (R,R)-(P,P)-cis-1b (black line in Figure 2c Figure 2c)s igns between 300 and 400 nm, which is indicative of the formation of supramolecular helical structures with opposite configurations upon anion binding. [22] Jobp lot analysis indicated a1:1 binding stoichiometry for the binding of chloride ions to the three isomers of 1b (see Supporting Information for details).
In summary,wehave developed aphotoresponsive chiral oligotriazole anion receptor based on amolecular motor core, which promotes the stereodivergent addition of silyl ketene acetal nucleophiles to oxocarbenium ions via anion binding catalysis.T he stereoselectivity of this transformation can be modulated through the light-and heat-driven rotation around the double bond axis of the molecular motor, which functions as am ultistage chiral switch. Products 10 were obtained as racemates in the presence of the (P,P)-trans state,and in up to 80:20 e.r. with (M,M)-cis state and 5:95 e.r. with (P,P)-cis state,p romoting each of the cis states the formation of opposite enantiomers.T he unidirectionality of molecular motors translates into ad efined sequence of isomers formed as one moves forward in the cycle.Inour particular case,the cycle (R,R)-(P,P)-trans-1b-(R,R)-(M,M)-cis-1b-(R,R)-(P,P)cis-1b gives rise to addition products in the order (R,S)racemic-R enantiomer-S enantiomer.S tarting from the (S,S)configured motor would invert the sequence resulting in (R,S)racemic-S enantiomer-R enantiomer.A lthough with lower absolute enantioselectivities than those reported for non-switchable organocatalysts,reversal of enantioselectivity with up to 142 % Dee was achieved in this work starting from asingle enantiomer of the catalyst through simple irradiation and heating steps.T hese results highlight the potential of helicates with switchable configuration for asymmetric synthesis and open up new avenues not only for future applications in the field of photoswitchable catalysis but also in the arena of responsive supramolecular assemblies.