Biomimetic Orthogonal Removal of Arylacyl Protecting Groups from the C-Terminus of Substituted Amino Acids and Oligopeptides via Flavin N(5)-iminium Covalent Adducts

Abstract

Flavin co-factors and other flavin derivatives are traditionally associated with one- or two-electron redox reactions. Flavins also form covalent intermediates with a variety of substrates. While extensive attention has focused on reactions at the C(4a) position of the flavin ring, recent interest has shifted toward the dynamic potential of the N(5) atom. In our study, we demonstrate the formation of artificial flavin N(5)-iminium covalent adducts via nucleophilic attack by enolates derived from arylacyl esters at the flavin N(5) position. This interaction mimics the biosynthesis of ether phospholipids catalysed by alkyl-dihydroxyacetone phosphate synthase via an N(5)-FAD iminium adduct formation and fatty acid release. Accordingly, we developed a method for the selective removal of phenacyl and 2-naphthylacetyl protecting groups from the C-terminus of α-amino acids and di- and tripeptides using biomimetic flavin organocatalysis. Although many approaches are currently available for protection of C-terminus of peptides, their removal often requires harsh conditions, which cause racemization and the loss of optical purity, together with other side reactions. Our method is versatile, mild, orthogonal to most functional and protecting groups and maintains optical purity of α-amino acids. From general point of view, the method signifies the groundbreaking application of the non-canonical reactivity of flavins in organic synthesis.