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Nitrilium ion trapping as a strategy to access structurally diverse heterobiaryl-containing peptide macrocycles.

ABSTRACT: Biaryl and heterobiaryl-containing cyclic peptides represent promising scaffolds for the development of bioactive molecules. The incorporation of heterobiaryl motifs continues to pose synthetic challenges, which is partially due to the difficulties in effecting late-stage metal-catalyzed cross-couplings. We report a new strategy to form heterobiaryls that is based on trapping nitrilium ions. The sequence is exemplified using oxadiazole- and oxazole-containing biaryl linkages. NMR analysis and molecular dynamics simulations reveal structural control elements common to each member of the heterobiaryl containing peptide family in this study. Strategic substitutions on the C-terminal aminobenzoic acid moiety paired with installation of oxadiazole or oxazole heterobiaryl backbone linkages allow for the modulation of peptide backbone conformation, which should assist efforts to optimize the biophysical properties of peptide macrocycles.

SUBMITTER: Diamandas M

PROVIDER: S-EPMC10498670 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Nitrilium ion trapping as a strategy to access structurally diverse heterobiaryl-containing peptide macrocycles.

Diamandas Matthew M Heller Nicholas W NW Yudin Andrei K AK

Chemical science 20230809 35

Biaryl and heterobiaryl-containing cyclic peptides represent promising scaffolds for the development of bioactive molecules. The incorporation of heterobiaryl motifs continues to pose synthetic challenges, which is partially due to the difficulties in effecting late-stage metal-catalyzed cross-couplings. We report a new strategy to form heterobiaryls that is based on trapping nitrilium ions. The sequence is exemplified using oxadiazole- and oxazole-containing biaryl linkages. NMR analysis and mo ...[more]

PMID: 37712035

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