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

Angewandte Chemie (International ed. in English) 2019

["Ricardo, Manuel G", "Llanes, Dayma", "Wessjohann, Ludger A", "Rivera, Daniel G"]

Abstract

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.

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