Synthesis of a Mechanically Planar Chiral Rotaxane Ligand for Enantioselective Catalysis

Abstract

Rotaxanes are interlocked molecules in which a molecular ring is trapped on a dumbbell-shaped axle because of its inability to escape over the bulky end groups, resulting in a so-called mechanical bond. Interlocked molecules have mainly been studied as components of molecular machines, but the crowded, flexible environment created by threading one molecule through another has also been explored in catalysis and sensing. However, so far, the applications of one of the most intriguing properties of interlocked molecules, their ability to display stereogenic units that do not rely on the stereochemistry of their covalent subunits, termed "mechanical chirality," have yet to be properly explored, and prototypical demonstration of the applications of mechanically chiral rotaxanes remain scarce. Here, we describe a mechanically planar chiral rotaxane-based Au complex that mediates a cyclopropanation reaction with stereoselectivities that are comparable with the best conventional covalent catalyst reported for this reaction.

Keywords: SDG9: Industry, innovation, and infrastructure.

Graphical abstract

Figure 1

Different Forms of Chirality in Mechanically and Covalently Bonded Molecules (A) Examples of (i) co-conformational, (ii) conditional mechanical, and (iii) unconditional topological stereogenic units. (B) Examples of covalently bonded chiral acyl transfer catalysts based on (i) point, (ii) axial, (iii) planar, and (iv) helical stereogenic units.

Scheme 1

Synthesis of Mechanically Planar Chiral Rotaxane Precatalysts Reagents and conditions: (1) (i) [Cu(MeCN)₄]PF₆, ¹H-sponge, CH₂Cl₂, room temperature (RT), 8 h; (ii) KCN, MeOH-CH₂Cl₂ (1:1), RT, 30 min; (iii) H₂O₂ (35% w/w in H₂O), CH₂Cl₂, RT, 5 min. 72% combined yield over 3 steps prior to separation of diastereomers. (S,R_mp)-4: 30%, 98% ee, >99: <1 dr; (S,S_mp)-4: 24%, (S,S_mp)-4-(R,S_mp)-4-(S,R_mp)-4 = 98.4:1.0:0.6. (2) LiHMDS, tetrahydrofuran, −78°C then, BnI, −78°C to RT, 18 h. (R_mp)-5: 81% (98% ee). (S_mp)-5 63% (98% ee; data not shown, see Supplemental Information). (3) HSiCl₃, NEt₃, PhMe, CH₂Cl₂, 100°C, 3 days. (4) (Me₂S)AuCl, CH₂Cl₂, RT, 1 h. (R_mp)-5: 64% yield over two steps (98% ee). (S_mp)-6: 62% (98% ee; data not shown, see Supplemental Information).

Figure 2

Characterization of Rotaxanes 4 and 5 (A) Solid-state structure of (S,R_mp)-4 with selected intercomponent interactions highlighted (atom labels and colors [O, dark gray; N, dark blue] as in Scheme 1, selected distances [Å]: H_g•••O = 2.4, H_g•••centroid = 2.6, H_h•••N = 2.5, H_j•••centroid = 3.2, and H_E•••O = 2.5). (B) Solid-state structure of (S,S_mp)-4 with selected intercomponent interactions (atom labels and colors [O, dark gray; N, dark blue] as in Scheme 1, selected distances [Å]: H_h•••N = 2.4, H_i•••C = 2.6, H_j•••N = 2.7, and H_E•••O = 2.7). It should be noted that the asymmetric unit contains an oxidized derivative of (S,S_mp)-4 as a disordered impurity. The figure depicts the component of the unit cell that is unaffected by this disorder. (C) Partial ¹H NMR (CDCl₃, 400 MHz, 298 K) of (i) macrocycle 3, (ii) rotaxane (S,R_mp)-4, (iii) rotaxane (S,S_mp)-4, and (iv) rotaxane (R_mp)-5. Selected signals are assigned and color coded (see Scheme 1 for labels; H_k and H_o, assigned arbitrarily, are the ortho protons of the diastereotopic axle benzyl groups). Signals corresponding to macrocycle 3 are all shown in blue for clarity.

Figure 3

Cyclopropane Products Synthesized Using [Au((R_mp)−6)(Cl)] All reactions carried out under the conditions shown in Table 1, entry 8. Combined yields of cyclopropanes and de were determined by ¹H NMR analysis of the crude reaction product using C₂Cl₄H₂ as an internal standard. ee of the major cis diastereomer determined by HPLC analysis of purified samples.

Figure 4

Reaction Pathway and Modeled Transition State Structures (A) Reaction pathway presumed for the reaction of [Au(6)(Cl)] based on molecular modeling (Gaussian ‘09, CAM-B3LYP, 6-31G∗/SDD(Au)) of the reaction of 7 and 8 mediated by [Au(PPh₃)(Cl)]. R = C(Bn)₂CO₂ⁱPr. (B) Modeled (CHCl₃, CAM-B3LYP, 6-31G/SDD) structure of TS1 leading to (1R,2S)-9 for the reaction of 7 with 8 mediated by [AuCu((R_mp)-6)]²⁺ in (i) sticks representation and (ii) close-up of the transition state fragment in mixed space-filling and sticks representation. Selected intercomponent interactions and the carbene-styrene interaction associated with the reaction coordinate are highlighted in yellow and red, respectively. (C) Modeled (CHCl₃, CAM-B3LYP, 6-31G/SDD) structure of TS1 leading to (1S,2R)-9 for the reaction of 7 with 8 mediated by [AuCu((R_mp)-6)]²⁺ in (i) sticks representation and (ii) close-up of the transition state fragment in mixed space-filling and sticks representation. Selected intercomponent interactions and the carbene-styrene interaction associated with the reaction coordinate are highlighted in yellow and red, respectively.