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Origin of problems related to Staudinger reduction in carbopeptoid syntheses

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Abstract

We report the solid phase synthesis of –GG-X-GG– type α/β-carbopeptoids incorporating RibAFU(ip) (1a, tX) or XylAFU(ip) (2a, cX) sugar amino acids. Though coupling efficacy is moderate, both the lengthier synthetic route using Fmoc derivative (e.g., Fmoc-RibAFU(ip)-OH) and the azido derivative (e.g., N3-RibAFU(ip)-OH) via Staudinger reaction with nBu3P can be successfully applied. Both X-ray diffraction, 1H- and 31P-NMR, and theoretical (QM) data support and explain why the application of Ph3P as Staudinger reagent is “ineffective” in the case of a cis stereoisomer, if cX is attached to the preceding residue with a peptide (–CONH–) bond. The failure of the polypeptide chain elongation with N3-cX originates from the “coincidence” of a steric crowdedness and an electronic effect disabling the mandatory nucleophilic attack during the hydrolysis of a quasi penta-coordinated triphenylphosphinimine. Nevertheless, the synthesis of the above α/β-chimera peptides as completed now by a new pathway via 1,2-O-isopropylidene-3-azido-3-deoxy-ribo- and -xylo-furanuronic acid (H-RibAFU(ip)-OH 1a and H-XylAFU(ip)-OH 2a) coupled with N-protected α-amino acids on solid phase could serve as useful examples and starting points of further synthetic efforts.

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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-RibAFU(ip)-NHMe:

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

H-XylAFU(ip)-NHMe:

N-methyl-1,2-O-isopropylidene-3-amino-3-deoxy-α-D-xylofuranuronamide

H-XylAFU(ip)-NHMe2 :

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

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Acknowledgments

The authors wish to thank László Kocsis and Gábor Szirbik from ThalesNano Inc. (Budapest, Hungary) for their help and advice in the hydrogenation reaction. The Biostruct Laboratory at the Budapest University of Technology and Economics is acknowledged for collecting X-ray diffraction data. The authors thank Petra Rovó for her help in NMR measurements. This work was supported by grants from the Hungarian Scientific Research Fund (OTKA K72973, NK101072) and TÁMOP-4.2.1. B-09/1/KMR.

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Correspondence to András Perczel.

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Csordás, B., Nagy, A., Harmat, V. et al. Origin of problems related to Staudinger reduction in carbopeptoid syntheses. Amino Acids 48, 2619–2633 (2016). https://doi.org/10.1007/s00726-016-2289-x

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Keywords

  • Carbopeptoids
  • Staudinger reaction
  • Sugar amino acids
  • Iminophosphorane