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. 2024 Feb 7;146(5):2882-2887.
doi: 10.1021/jacs.3c11611. Epub 2024 Jan 24.

Mechanically Planar-to-Point Chirality Transmission in [2]Rotaxanes

Julio Puigcerver  1 , Marta Marin-Luna  1 , Javier Iglesias-Sigüenza  2 , Mateo Alajarin  1 , Alberto Martinez-Cuezva  1 , Jose Berna  1
Affiliations

Mechanically Planar-to-Point Chirality Transmission in [2]Rotaxanes

Julio Puigcerver et al. J Am Chem Soc. .

Abstract

Herein we describe an effective transmission of chirality, from mechanically planar chirality to point chirality, in hydrogen-bonded [2]rotaxanes. A highly selective mono-N-methylation of one (out of four) amide N atom at the macrocyclic counterpart of starting achiral rotaxanes generates mechanically planar chirality. Followed by chiral resolution, both enantiomers were subjected to a base-promoted intramolecular cyclization, where their interlocked threads were transformed into new lactam moieties. As a matter of fact, the mechanically planar chiral information was effectively transferred to the resulting stereocenters (covalent chirality) of the newly formed heterocycles. Upon removing the entwined macrocycle, the final lactams were obtained with high enantiopurity.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Transmission of Chirality from MPC-rotaxanes to Point Chiral Lactams
Our approach: (1) intramolecular cyclization; (2) removal of the macrocycle for liberating the enantioenriched lactams.
Scheme 2
Scheme 2. N-Methylation of Rotaxanes 4 for the Formation of rac-1 (Smp Enantiomers of 1 Are Shown)
Reaction carried out with NaH at 25 °C. 1c was unstable towards the competitive dethreading reaction. Reaction conditions: (i) (1) 1 (10 mg, 1 equiv), THF (1 mL), CsOH (5 equiv), 0 °C, 30 min; (2) MeI (10 equiv), 0 °C, 24 h.
Figure 1
Figure 1
(a) HPLC chromatograms of rac-1b (top), first enantiomer of 1b (middle), and second enantiomer of 1b (bottom) (Chiralpak IC-3 column, 85:13:2 CH2Cl2:MeCN:iPrOH, 0.5 mL·min–1, 254 nm) (*rotaxane 5b). (b) CD spectra of the first (blue line, 1.0 × 10–5 M in CHCl3) and second enantiomer of 1b (red line, 1.2 × 10–5 M in CHCl3). (c) X-ray structure of (Rmp, 15S,17R)-1b. Intramolecular hydrogen-bond lengths (Å) (angles [deg]): N4–H04···O1 2.06 (166); N5–H05···O2 2.07 (161). (d) X-ray structure of 5b. Intramolecular hydrogen-bond lengths [Å] (angles [deg]): N5–H05···O2 2.16 (166); N6–H06···O2 2.25 (167). Inset: Absolute configuration assignment for (Rmp, 15S,17R)-1b.
Scheme 3
Scheme 3. CsOH-Promoted Cyclization of Enantiomers of 1b To Afford the Interlocked trans-Lactams 7b, Followed by Dethreading for the Obtention of Enantioenriched trans-2b and cis-3b
Reaction conditions: (i) CsOH (3 equiv), DMF, −20 °C, 24 h; (ii) DMSO, 180 °C, 2 h, MW; (iii) DMSO:MeOH (1:1), HCl, 180 °C, 2 h, MW. Inset: X ray structure of (Rmp, 15S, 17R, 3R, 4S)-7b. Intramolecular hydrogen-bond lengths [Å] (angles [deg]): N4–H04···O1 2.12 (136); N5–H05···O2 2.26 (158); N6–H06···O2 2.36 (171).
Figure 2
Figure 2
Computed transition structures (3S, 4R)-TSRmp and (3R, 4S)-TSRmp for the cyclization step (same orientation of the thread) and their noncovalent interaction analysis. The decomposition of the energy difference between (3S,4R)-TSRmp and (3R, 4S)-TSRmp (ΔΔE⧧) into contributions from the energy difference of the macrocycles (ΔΔEmac) and threads (ΔΔEthread) and between the interaction energies of the thread with the macrocycle (ΔΔEint) is shown.
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