C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies

Abstract

To obtain key sugar derivatives for making homooligomeric foldamers or α/β-chimera peptides, economic and multigram scale synthetic methods were to be developed. Though described in the literature, the cost-effective making of both 3-amino-3-deoxy-ribofuranuronic acid (H–t X–OH) and its C-3 epimeric stereoisomer, the 3-amino-3-deoxy-xylofuranuronic acid (H–c X–OH) from d-glucose is described here. The present synthetic route elaborated is (1) appropriate for large-scale synthesis; (2) reagent costs reduced (e.g. by a factor of 400); (3) yields optimized are ~80% or higher for all six consecutive steps concluding –t X– or –c X– and (4) reaction times shortened. Thus, a new synthetic route step-by-step optimized for yield, cost, time and purification is given both for d-xylo and d-ribo-amino-furanuronic acids using sustainable chemistry (e.g. less chromatography with organic solvents; using continuous-flow reactor). Our study encompasses necessary building blocks (e.g. –X–OMe, –X–OiPr, –X–NHMe, Fmoc–X–OH) and key coupling reactions making –Aaa–t X–Aaa– or –Aaa–t Xt X–Aaa– type “inserts”. Completed for both stereoisomers of X, including the newly synthesized Fmoc–c X–OH, producing longer oligomers for drug design and discovery is more of a reality than a wish.

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Abbreviations

H-RibAFU(ip)-OH or tX:

1,2-O-Isopropylidene-3-amino-3-deoxy-α-d-ribofuranuronic acid

H-XylAFU(ip)-OH or cX:

1,2-O-Isopropylidene-3-amino-3-deoxy-α-d-xylofuranuronic acid

N3-RibAFU(ip)-OH:

1,2-O-Isopropylidene-3-azido-3-deoxy-α-d-ribofuranuronic acid

N3-XylAFU(ip)-OH:

1,2-O-Isopropylidene-3-azido-3-deoxy-α-d-xylofuranuronic acid

H-XylAFU(ip)-NHMe:

N-Methyl-1,2-O-isopropylidene-3-amino-3-deoxy-α-d-xylofuranuronamide

H-RibAFU(ip)-NHMe:

N-Methyl-1,2-O-isopropylidene-3-amino-3-deoxy-α-d-ribofuranuronamide

Ac-RibAFU(ip)-NHMe:

N-Methyl-1,2-O-isopropylidene-3-acetamido-3-deoxy-α-d-ribofuranuronamide

Ac-XylAFU(ip)-NHMe:

N-Methyl-1,2-O-isopropylidene-3-acetamido-3-deoxy-α-d-xylofuranuronamide

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Acknowledgements

The authors gratefully acknowledge Szebasztián Szaniszló for his contribution to the preparative work and Prof. Imre G Csizmadia for helpful discussion. The authors wish to thank László Kocsis and Gábor Szirbik from ThalesNano Inc. (Budapest, Hungary) for their help and advice in hydrogenation reaction and for their support with the equipment, and Anita Kapros for her help in MS measurements. This work was supported by Grants from the Hungarian Scientific Research Fund (OTKA NK101072).

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Correspondence to András Perczel.

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Nagy, A., Csordás, B., Zsoldos-Mády, V. et al. C-3 epimers of sugar amino acids as foldameric building blocks: improved synthesis, useful derivatives, coupling strategies. Amino Acids 49, 223–240 (2017). https://doi.org/10.1007/s00726-016-2346-5

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Keywords

  • Sugar amino acids
  • Azido sugars
  • Nucleophilic substitution
  • Foldamers