Introducing the Petasis Reaction for the Late‐Stage Multicomponent Diversification, Labeling and Stapling of Peptides

For the first time, the Petasis – borono‐Mannich – reaction is employed for the multicomponent labeling and stapling of peptides. The report includes the solid‐phase derivatization of peptides at the N‐terminus, Lys and Nε‐MeLys side chains by on‐resin Petasis reaction with variation of the carbonyl and boronic acid components. Peptides were simultaneously functionalized with aryl/vinyl substituents bearing fluorescent/affinity tags and oxo‐components such as dihydroxyacetone, glyceraldehyde, glyoxylic acid and aldoses, thus encompassing a powerful complexi‐ty‐generating approach without changing the peptides charge. The multicomponent stapling was conducted in solution by linking Nε‐MeLys or Orn side chains – positioned at i, i+7 and i, i+4 – with aryl tethers, while hydroxyl‐carbonyl moieties were introduced as exocyclic fragments. The good efficiency and diversity oriented character of these methods show prospects for peptide drug discovery and chemical biology.

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