Aspartic Acid Forming α‑Ketoacid–Hydroxylamine (KAHA) Ligations with (S)‑4,4-Difluoro-5-oxaproline

The α-ketoacid-hydroxylamine (KAHA) ligation allows the coupling of unprotected peptide segments. Currently, the most applied hydroxylamine is the 5-membered cyclic hydroxylamine (S)-5-oxaproline, which forms a homoserine ester as the primary ligation product. In order to access native aspartic acid...

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Bibliographic Details
Published in:Journal of organic chemistry 2020-02, Vol.85 (3), p.1352-1364
Main Authors: Baldauf, Simon, Ogunkoya, Ayodele O, Boross, Gábor N, Bode, Jeffrey W
Format: Article
Language:English
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Summary:The α-ketoacid-hydroxylamine (KAHA) ligation allows the coupling of unprotected peptide segments. Currently, the most applied hydroxylamine is the 5-membered cyclic hydroxylamine (S)-5-oxaproline, which forms a homoserine ester as the primary ligation product. In order to access native aspartic acid residues at the ligation site, we synthesized a 4,4-difluoro version of this monomer. Upon KAHA ligation, the resulting difluoro alcohol hydrolyzes to an aspartic acid residue with little or no formation of aspartamide. We applied this monomer for the synthesis of the hormone peptides glucagon and an insulin variant, and as well for segment ligation of the peptides UbcH5a and SUMO3.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.9b02271