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Large-scale and chromatography-free synthesis of an octameric quinoline-based aromatic amide helical foldamer

Nature Protocols volume 8, pages 693–708 (2013)Cite this article

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Abstract

The synthesis of helical aromatic oligoamide foldamers derived from 8-amino-2-quinolinecarboxylic acid is described. The precursors are commercially available and products up to and including the octamer are obtained. The procedure covers the synthesis of the monomer, reduction of N-terminal nitro groups into amines, saponification of C-terminal methyl esters to form carboxylic acids, and coupling of amines and acids to form amides via acid chloride activation. Emphasis is given to how these reactions can be scaled up and how purification can be greatly simplified using recrystallization methods, thus providing considerable improvements over previously described procedures. As an illustration of the improvement, 8.4 g of an octamer can now reliably be prepared from a nitro-ester monomer in a matter of 8 (working) weeks without any chromatography.

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Figure 1
Figure 2
Figure 3: Preparation of the monomer.
Figure 4: Preparation of the monomer acid chloride.
Figure 5: Preparation of the dimer amine.
Figure 6: Preparation of the dimer acid chloride.
Figure 7: Preparation of the tetramer amine.
Figure 8: Preparation of the hexamer amine.
Figure 9: Products of coupling reactions.
Figure 10
Figure 11: Part of the 1H-NMR spectra (25 °C, CDCl3, 300 MHz) showing the amide and aromatic proton resonances of tetramer amine 10.

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Acknowledgements

This work was supported by Agence Nationale de la Recherche (ANR) contract ANR-07-PCVI-0037, by Marie Curie Contract IIF-2009-254156 (postdoctoral fellowship to T.Q.) and by Association pour la Recherche Contre le Cancer (ARC) (postdoctoral fellowship to T.D.).

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Authors and Affiliations

  1. Université de Bordeaux, Centre National de la Recherche Scientifique (CNRS) UMR5248, Institut Européen de Chimie et Biologie, Pessac, France

    Ting Qi, Tiny Deschrijver & Ivan Huc

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  1. Ting Qi
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Contributions

T.D. and T.Q. contributed equally to this work. They carried out and optimized experiments, interpreted the results and wrote the manuscript. I.H. interpreted the results and wrote the manuscript.

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Correspondence to Ivan Huc.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Data

Analytical data for compounds 1–15 (PDF 3282 kb)

Supplementary Figure 1

1H NMR spectrum for compound 1 (PDF 927 kb)

Supplementary Figure 2

1H NMR spectrum for compound 2 (PDF 834 kb)

Supplementary Figure 3

1H NMR spectrum for compound 3 (PDF 926 kb)

Supplementary Figure 4

1H NMR spectrum for compound 4 (PDF 916 kb)

Supplementary Figure 5

1H NMR spectrum for compound 5 (PDF 1068 kb)

Supplementary Figure 6

1H NMR spectrum for compound 6 (PDF 1005 kb)

Supplementary Figure 7

1H NMR spectrum for compound 7 (PDF 1082 kb)

Supplementary Figure 8

1H NMR spectrum for compound 8 (PDF 1121 kb)

Supplementary Figure 9

1H NMR spectrum for compound 9 (PDF 1413 kb)

Supplementary Figure 10

1H NMR spectrum for compound 10 (PDF 1304 kb)

Supplementary Figure 11

1H NMR spectrum for compound 11 (PDF 1400 kb)

Supplementary Figure 12

1H NMR spectrum for compound 12 (PDF 1418 kb)

Supplementary Figure 13

1H NMR spectrum for compound 13 (PDF 1502 kb)

Supplementary Figure 14

1H NMR spectrum for compound 14 (PDF 988 kb)

Supplementary Figure 15

1H NMR spectrum for compound 15 (PDF 892 kb)

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Qi, T., Deschrijver, T. & Huc, I. Large-scale and chromatography-free synthesis of an octameric quinoline-based aromatic amide helical foldamer. Nat Protoc 8, 693–708 (2013). https://doi.org/10.1038/nprot.2013.029

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