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A chiral interlocking auxiliary strategy for the synthesis of mechanically planar chiral rotaxanes

Nature Chemistry volume 14, pages 179–187 (2022)Cite this article

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An Author Correction to this article was published on 17 December 2021

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Abstract

Rotaxanes can display molecular chirality solely due to the mechanical bond between the axle and encircling macrocycle without the presence of covalent stereogenic units. However, the synthesis of such molecules remains challenging. We have discovered a combination of reaction partners that function as a chiral interlocking auxiliary to both orientate a macrocycle and, effectively, load it onto a new axle. Here we use these substrates to demonstrate the potential of a chiral interlocking auxiliary strategy for the synthesis of mechanically planar chiral rotaxanes by producing a range of examples with high enantiopurity (93–99% e.e.), including so-called ‘impossible’ rotaxanes whose axles lack any functional groups that would allow their direct synthesis by other means. Intriguingly, by varying the order of bond-forming steps, we can effectively choose which end of an axle the macrocycle is loaded onto, enabling the synthesis of both hands of a single target using the same reactions and building blocks.

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Fig. 1: The chiral interlocking auxiliary concept for the synthesis of MPC rotaxanes.
Fig. 2: The stereoselective synthesis of rotaxanes 4, their analysis by 1H NMR and single-crystal X-ray diffraction and the analysis of their co-conformational properties.
Fig. 3: Demonstration of the chiral interlocking auxiliary strategy for the synthesis of MPC rotaxanes with high stereopurity (determined by CSP-HPLC throughout).
Fig. 4: Synthesis of ‘impossible’ MPC rotaxanes in high stereopurity (determined by CSP-HPLC) using the chiral interlocking auxiliary strategy.
Fig. 5: Combining the chiral interlocking auxiliary approach with a grafting strategy and application of this methodology to the stereodivergent synthesis of rotaxane 28 from a single set of building blocks.
Fig. 6: Stereochemical analysis of rotaxane 28 demonstrating that the two different routes (as shown in Fig. 5) yield opposite enantiomers in high stereopurity.

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Data availability

Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2069804 (rac-4b(1)) and 2093365 (rac-4b(2)). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

Characterization data (NMR, mass spectrometry, circular dichroism spectroscopy, HPLC) for all novel compounds reported here are available from the University of Southampton repository at https://doi.org/10.5258/SOTON/D1935

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Acknowledgements

S.M.G. thanks the European Research Council (Consolidator Grant Agreement number 724987), the EPSRC (EP/L016621/1) and the Leverhulme Trust (ORPG-2733) for funding and the Royal Society for a Wolfson Research Fellowship (RSWF\FT\180010). J.M.S. thanks the Royal Society for a Newton International Fellowship (NIF\R1\181686). A.W.H. thanks the University of Southampton for a Presidential Scholarship.

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Author notes

  1. These authors contributed equally: A. de Juan, D. Lozano.

Authors and Affiliations

  1. Chemistry, University of Southampton, Southampton, UK

    Alberto de Juan, David Lozano, Andrew W. Heard, Michael A. Jinks, Jorge Meijide Suarez, Graham J. Tizzard & Stephen M. Goldup

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Contributions

M.A.J. synthesized rotaxane 4b. M.A.J. and A.d.J. developed the chiral interlocking auxiliary concept in collaboration with S.M.G. A.d.J. synthesized rotaxanes 8, 13–15, 23 and 28 with support from M.A.J. who provided synthetic intermediates. D.L. performed the stereochemical characterization of rotaxanes 4, 8, 13–15, 23 and 28. D.L. carried out the co-conformational analysis of rotaxane 4 and associated experiments. A.W.H. and J.M.S. developed the cross-coupling concept and collaborated to synthesize rotaxane 10. J.M.S. synthesized and characterized rotaxanes 18–20 and demonstrated the importance of the o-Me group using alkyne S87. A.W.H. synthesized and characterized rotaxane 12. G.J.T. collected the single-crystal X-ray diffraction data of rac-4b and solved and refined the structures. D.L. and A.W.H. managed the preparation of the Supplementary Information. S.M.G. directed the research. All authors contributed to the analysis of the results and the writing of the manuscript.

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Correspondence to Stephen M. Goldup.

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Peer review information Nature Chemistry thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Experimental data, procedural details, synthesis and characterization data, NMR spectra, circular dichroism spectra, HPLC chromatograms, X-ray crystallographic data, discussions, Figs. 1–418 and Tables 1–6.

Supplementary Data 1

Crystallographic data for compound rac-4b(1). CCDC reference 2069804.

Supplementary Data 1

Crystallographic data for compound rac-4b(2). CCDC reference 2093365.

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de Juan, A., Lozano, D., Heard, A.W. et al. A chiral interlocking auxiliary strategy for the synthesis of mechanically planar chiral rotaxanes. Nat. Chem. 14, 179–187 (2022). https://doi.org/10.1038/s41557-021-00825-9

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