Electrochemically-Enabled Late-Stage Peptide C-terminal Modifications

Abstract

The therapeutic relevance of C-terminally modified peptides serves as a strong impetus for the exploration of late-stage peptide C-terminal modification strategies, particularly those which enable direct functionalization of the native C-terminal carboxylate motif. Considering the discrepancy between the enormous potential of electrochemistry and the scarcity of its applications on complex peptide and protein systems, electrochemical decarboxylation stands as an attractive modification strategy. The methodologies described in this thesis explore the chemo- and regio-selectivity of direct anodic oxidation of peptide C-terminal carboxylates, leveraging electrochemically-generated N,O-acetals as valuable handles for divergent late-stage modifications.

Chapter One introduces C-terminally modified peptides as promising biochemical targets and highlights recent advances in C-terminal peptide modification, especially decarboxylation strategies. The outlined methods are principally categorized by the substrate employed for decarboxylation (e.g., peptide redox-active esters or unprotected carboxylic acids). Electrochemically-enabled peptide C-terminal modification is underlined as a key transformation investigated in this thesis.

Chapter Two details the first total synthesis of the natural products biseokeaniamides A-C, structurally distinct lipopeptides bearing a C-terminal thiazole motif. The intrinsic reactivity of peptide C-terminal carboxylates towards electrochemical decarboxylation was reinvestigated and the electrochemically-generated N,O-acetal intermediates were subjected to a variety of arylation conditions which targeted the synthesis of biseokeaniamide natural product analogues. This proof-of-principle study highlighted the feasibility of electrochemical decarboxylation in late-stage peptide C-terminal modification.

Chapter Three describes an electrochemical approach to designer peptide alpha-amides by pairing anodic decarboxylation with a tandem hydrolysis/reduction of the electrochemically-generated N,O-acetals. The electrochemical decarboxylation was demonstrated to be compatible with the vast majority of proteinogenic functional groups. Moreover, this strategy was successfully applied to complex peptide systems to accomplish the synthesis of several bioactive peptides and their associated analogues.

Chapter Four builds on the above strategy to enable access to novel peptide N-acylpyrroles. Following anodic oxidation, hydroxyproline-derived N,O-acetals are readily aromatized to N-acylpyrroles under acidic conditions, which allow concomitant peptide side-chain deprotection. The resulting peptide N-acylpyrrole is amenable to diverse late-stage modifications and represents a valuable precursor to peptide C-terminal aldehydes, forged upon treatment with NaBH4.

Chapter Five summarizes the above endeavours on electrochemical decarboxylation strategies towards C-terminally modified peptides. Future studies aimed at applying electrochemical modifications to increasingly complex peptide systems are further discussed. Show more