An Auxiliary Approach for the Stereoselective Synthesis of Topologically Chiral Catenanes

Abstract

Catenanes, molecules in which two rings are threaded through one another like links in a chain, can form as two structures related like an object and its mirror image but otherwise identical if the individual rings lack bilateral symmetry. These structures are described as "topologically chiral" because, unlike most chiral molecules, it is not possible to convert one mirror-image form to the other under the rules of mathematical topology. Although intriguing and discussed as early as 1961, to date all methods of accessing molecules containing only this topological stereogenic element require the separation of the mirror-image forms via chiral stationary phase high-performance liquid chromatography, which has limited their investigation to date. Here, we present a simple method that uses a readily available source of chiral information to allow the stereoselective synthesis of topologically chiral catenanes.

Keywords: SDG9: Industry, innovation, and infrastructure; catenanes; chirality; mechanical bond; stereoselective; topology.

Graphical abstract

Figure 1

Schematic of Our Proposed Approach to Topologically Chiral Catenanes

Scheme 1

Synthesis of Diastereomeric Catenanes 3 Reagents and conditions: (i) slow addition (4 h) of (R)-1 to macrocycle 2, [Cu(MeCN)₄]PF₆, NⁱPr₂Et, CHCl₃-EtOH (1:1) at 60°C; (ii) KCN and CH₂Cl₂-MeOH (1:1). (R,R/S_mt)-3a: n = 2, 1:1 inseparable mixture, 72% combined isolated yield; (R,R/S_mt)-3b: n = 1, 2:1 separable mixture favoring (R,S_mt)-3b, 89% combined isolated yield; (R,R/S_mt)-3c: n = 0, 1:1 inseparable mixture: ∼23% conversion of 2c by ¹H NMR analysis of the unpurified reaction mixture.

Figure 2

Characterization of Catenanes 3b (A) Solid-state structure of major diastereomer (R,S_mt)-3b with selected intercomponent interactions highlighted (selected distances [Å]: H_u···N = 2.35, OH···N = 2.28). (B) CD spectra of (35 μM in CHCl₃) (R,S_mt)-3b and (R,R_mt)-3b. (C) Partial stacked ¹H NMR spectra (500 MHz, 298 K, CDCl₃) of (i) the corresponding non-interlocked triazole macrocycle derived from (S)-1, (ii) catenane (R,R_mt)-3b, (iii) catenane (R,S_mt)-3b, and (iv) macrocycle 2b. Selected signals are assigned and color coded (see Scheme 1). Signals corresponding to macrocycle 2b are all shown in blue for clarity.

Scheme 2

Cleavage of the Chiral Auxiliary from Catenane (R,S_mt)-3b to Give Catenane (S_mt)-6b Reagents and conditions: (i) (COCl)₂, DMSO, NEt₃, and CH₂Cl₂ at room temperature (RT); (ii) AcOH and CHCl₃ at RT. 6b was isolated in 68% yield over two steps.

Figure 3

Characterization of Catenanes 6b (A) Analytical chiral stationary phase HPLC chromatograms (RegisCell, 98:2 hexane-ⁱPrOH, 0.5 mL/min) of (R_mt)-6b (blue), (S_mt)-6b (green), and racemic 6b (orange). (B) CD spectra (35.0 μM in CHCl₃, 293 K) of (R_mt)-6b (blue), (S_mt)-6b (green), and racemic 6b (orange). (C) Partial stacked ¹H NMR spectra (500 MHz, 298 K, CDCl₃) of (i) the corresponding non-interlocked triazole macrocycle of catenane 6b, (ii) catenane (S_mt)-6b, and (iii) macrocycle 2b. Selected signals are assigned and color coded (see Schemes 1 and 2). Signals corresponding to macrocycle 2b are all shown in blue for clarity.