Umpolung strategies for the functionalization of peptides and proteins

Abstract

This perspective highlights the growing body of literature that leverages polarity reversal (umpolung reactivity) for the selective modification of proteinogenic functionalities and identifies opportunities for further innovation.

DFT‐Guided Discovery of Ethynyl‐Triazolyl‐Phosphinates as Modular Electrophiles for Chemoselective Cysteine Bioconjugation and Profiling

“…[22,23] Alternatively, a nucleophilic amino acid can be chemically converted into an electrophile as exemplified by the umpolung of cysteine, tyrosine, and histidine. [24][25][26][27] Another attractive application of electrophiles is in the area of chemoproteomics [28] to label a specific proteome for convenient separation and profiling. For optimal results, the labelling reagents should offer a high target coverage, a uniform modification, excellent amino acid selectivity, and stability of the formed conjugate.…”

Umpolung AlaB Reagents for the Synthesis of Non‐Proteogenic Amino Acids, Peptides and Proteins**

“…Access to unnatural surrogates through any of these strategies complements studies on selective modifications of biologics that can be achieved through various handles that can enable downstream functionalizations (Scheme 1A). One promising approach that can avoid competing reactions with innate groups are transformations based on umpolung of reactivity [11] . We recently reported the synthesis and applications of Ala Sn reagents in the form of carbastannatrane 1 , [12] a member of a larger group of reagents where alanine's β‐carbon is substituted with a metal or metalloid (Scheme 1B).…”

“…One promising approach that can avoid competing reactions with innate groups are transformations based on umpolung of reactivity. [11] We recently reported the synthesis and applications of Ala Sn reagents in the form of carbastannatrane 1, [12] a member of a larger group of reagents where alanine's β-carbon is substituted with a metal or metalloid (Scheme 1B). Ala M reagents represent a novel type of synthons that can be engaged in cross-coupling reactions through a reversal of polarity at the β-carbon.From a conceptual standpoint, these reagents can give rise to native as well as unnatural amino acids based on a formal alanine derivatization.…”

DFT‐basierte Entdeckung von Ethynyl‐Triazolyl‐Phosphinaten als modulare Elektrophile für die chemoselektive Cystein‐Biokonjugation und Profilierung

“…Jedoch werden häufig unerwünschte intramolekulare Reaktionen [21] und Dimerisierungen beobachtet [22, 23] . Alternativ kann eine nukleophile Aminosäure chemisch in ein Elektrophil umgewandelt werden, wie es beispielsweise bei der Umpolung von Cystein, Tyrosin und Histidin demonstriert wurde [24–27] …”