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Emergence of low-symmetry foldamers from single monomers

Abstract

Self-assembly is a powerful method to obtain large discrete functional molecular architectures. When using a single building block, self-assembly generally yields symmetrical objects in which all the subunits relate similarly to their neighbours. Here we report the discovery of a family of self-constructing cyclic macromolecules with stable folded conformations of low symmetry, which include some with a prime number (13, 17 and 23) of units, despite being formed from a single component. The formation of these objects amounts to the production of polymers with a perfectly uniform length. Design rules for the spontaneous emergence of such macromolecules include endowing monomers with a strong potential for non-covalent interactions that remain frustrated in competing entropically favoured yet conformationally restrained smaller cycles. The process can also be templated by a guest molecule that itself has an asymmetrical structure, which paves the way to molecular imprinting techniques at the level of single polymer chains.

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Fig. 1: How foldamer formation depends on building block design.
Fig. 2: Spontaneous formation of large folded macrocycles.
Fig. 3: Crystal structures of low-symmetry-foldamers.

Data availability

The authors declare that all the data supporting the findings of this study are available within the article, in the source data files and in the Supplementary Information. Mass and NMR spectra are stored locally in native format and are available upon request. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 1942977 for (4b)16 and 1999456 for (4d)23, respectively. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Source data are provided with this paper.

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Acknowledgements

We thank P. van der Meulen and J. Kemmink for their assistance with the NMR experiments and analysing the data. We thank I. Melnikov (ID23-1, ERSF) and G. Pompidor (PETRA III, DESY) for assistance during data collection at the synchrotron beamlines. This research was supported by the ERC (AdG 741774), the EU (MCIF 745805−DSR), NWO (VICI grant), Zernike Dieptestrategie and the Dutch Ministry of Education, Culture and Science (Gravitation program 024.001.035).

Author information

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Authors

Contributions

S.O. and I.H. supervised the overall project. C.G.P. conceived and designed the study, synthesized the building blocks, analysed the DCL compositions by UPLC and isolated and characterized the foldamers by CD and NMR spectroscopy. B.L. performed the UPLC-MS experiments and analysed the data. P.K.M. and B.K. carried out the crystallographic studies. X.M. and K.L. performed the ITC experiments. D.K., W.H., C.M., R.C. and K.P. performed the IM-MS experiments and analysed the data. C.G.P., I.H. and S.O. co-wrote the paper. All the authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Ivan Huc or Sijbren Otto.

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The authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–126 and Tables 1–4.

Supplementary Video 1

Crystal structure of macrocycle (4b)16.

Supplementary Video 2

Crystal structure of macrocycle (4d)23.

Supplementary Data 1

Raw UPLC chromatograms, raw temperature-dependent CD spectral data and ion-mobility data.

Supplementary Data 2

Crystallographic information file including structure factor for the structure of (4b)16.

Supplementary Data 3

Crystallographic information file including structure factor for the structure of (4d)23.

Source data

Source Data Fig. 2

Raw UPLC chromatograms, raw ion-mobility and CD spectral data.

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Pappas, C.G., Mandal, P.K., Liu, B. et al. Emergence of low-symmetry foldamers from single monomers. Nat. Chem. 12, 1180–1186 (2020). https://doi.org/10.1038/s41557-020-00565-2

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