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. 2024 Apr 3;146(13):9134-9141.
doi: 10.1021/jacs.3c14329. Epub 2024 Mar 20.

Facial Selectivity in Mechanical Bond Formation: Axially Chiral Enantiomers and Geometric Isomers from a Simple Prochiral Macrocycle

Peter R Gallagher  1   2 , Andrea Savoini  1   2 , Abed Saady  1   2 , John R J Maynard  1 , Patrick W V Butler  1 , Graham J Tizzard  1 , Stephen M Goldup  1   2
Affiliations

Facial Selectivity in Mechanical Bond Formation: Axially Chiral Enantiomers and Geometric Isomers from a Simple Prochiral Macrocycle

Peter R Gallagher et al. J Am Chem Soc. .

Abstract

In 1971, Schill recognized that a prochiral macrocycle encircling an oriented axle led to geometric isomerism in rotaxanes. More recently, we identified an overlooked chiral stereogenic unit in rotaxanes that arises when a prochiral macrocycle encircles a prochiral axle. Here, we show that both stereogenic units can be accessed using equivalent strategies, with a single weak stereodifferentiating interaction sufficient for moderate to excellent stereoselectivity. Using this understanding, we demonstrated the first direct enantioselective (70% ee) synthesis of a mechanically axially chiral rotaxane.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Schematic active template retrosyntheses of the mechanical (a) type 1 geometric isomers and (b) axially chiral enantiomers of rotaxanes, highlighting the need to control facial selectivity in the mechanical bond-forming step and the potential for attractive interactions between one face of the macrocycle and one of the half-axles to provide this control.
Scheme 1
Scheme 1. Synthesis of Rotaxanes 4
Reagents and conditions (see also Table 1): (R)-1 (1.1 equiv), 2 (1 equiv), 3 (1.1 equiv), [Cu(CH3CN)4]PF6 (0.96 equiv), iPr2NEt (2 equiv). Determined by SCXRD for 1a(11) and 1d (Figure 1); 1b, c, and e are presumed. Ar = 3,5-di-tBu-C6H3.
Figure 2
Figure 2
SCXRD structure of [(Rma,Rco–c)-4d (major isomer), with key intercomponent interactions highlighted. Colors as in Scheme 1, including the sulfoxide (SO) moiety to highlight the differentiation of the macrocycle faces, except N [dark blue], O [gray], and H [white]. The majority of H was omitted.
Scheme 2
Scheme 2. Proposed AT-CuAAC Mechanism Highlighting Pre-Equilibrium and Kinetic Resolution Steps
Scheme 3
Scheme 3. AT-CuAAC Synthesis of Rotaxane Geometric Isomers of Type 1. (a) Effect of Conditions on the Formation of Rotaxanes 6. (b) Effect of the Half-Axle Structure, on the Stereoselectivity of Mechanical Bond Formation with Macrocycle 2,
Reagents and conditions: 2 (1 equiv), 3 (1.1 equiv), 5 (1.1 equiv), [Cu(CH3CN)4]PF6 (0.96 equiv), iPr2EtN (2 equiv). Synthesized in THF at rt (Scheme 3a, entry 2) unless otherwise stated. Stereochemistry of the major isomer indicated where determined. Determined by 1H NMR analysis of the crude reaction product. Synthesized in EtOH. Synthesized at –40 °C in THF. Ar = 3,5-di-tBu-C6H3.
Figure 3
Figure 3
(a) Solid-state structures of (a) (Zm)-6, (b) (Em)-6, (c) (Zm)-9, and (d) (Em)-11 with key intercomponent interactions highlighted. Colors as in Scheme 1, including the sulfoxide (SO) moiety to emphasize the macrocycle faces, except for O (gray), N (dark blue), and H (white). The majority of H was omitted for clarity.
Scheme 4
Scheme 4. Stereoselective Synthesis of Catenane 14
Reagents and conditions: 13 (2 equiv) was added over the time stated using a syringe pump to 2 (1 equiv), [Cu(CH3CN)4]PF6 (0.97 equiv), iPr2EtN (4 equiv).
Scheme 5
Scheme 5. Two-Step, One-Pot Synthesis of Enantioenriched MAC Rotaxanes 15,
Reagents and conditions: i. 1a (1.1 equiv), 2 (1 equiv), 3 (1.1 equiv), [Cu(CH3CN)]PF6 (0.96 equiv), iPr2EtN (2 equiv), CH2Cl2, 16 h; ii. TFA, CH2Cl2, –78 °C to rt, 6 h. Determined by analytical CSP-HPLC. Ar = 3,5-di-tBu-C6H3.
Figure 4
Figure 4
(a) CSP-HPLC analysis of i. (Rma)-16 (67% ee) produced from (R)-1g; ii. (Rma)-16 (21% ee) produced from (Rma)-15 (21% ee; minor impurity highlighted in gray), and iii. (Sma)-16 (70% ee) produced from (S)-1g. (b) Solid-state structure of rac-16, in which the N–H···O bond between the SO unit and the amide is intermolecular (colors as in Scheme 6, including the sulfoxide (SO) moiety to highlight the differentiation of the macrocycle faces, except N [dark blue], O [gray], and H [white]). The majority of H was omitted for clarity.
Scheme 6
Scheme 6. Direct Synthesis of Enantioenriched Mechanically Axially Chiral Rotaxanes 15 and 16
Reagents and conditions: i. 1 (1.1 equiv), 2 (1 equiv), 3 (1.1 equiv), [Cu(CH3CN)]PF6 (0.96 equiv), iPr2EtN (2 equiv), CH2Cl2, 16 h. Determined by analytical CSP-HPLC. Ar = 3,5-di-tBu-C6H3.
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