Introducing the Petasis Reaction for 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 an 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 complexity‐generating approach without changing the charge of the peptides. 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 hydroxy 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. Staple reaction: A multicomponent method allows the late‐stage derivatization of peptides with the incorporation of sugars, fluorescent and affinity labels, PEGs, steroids, and lipids at both the peptide N‐terminus and Lys side‐chains. Stapled peptides with rigid aromatic linkages can also be produced, proving the versatility of this multicomponent reaction in most areas of peptide chemistry.