Biphasic electrochemical peptide synthesis

Abstract

The large amount of waste derived from coupling reagents is a serious drawback of peptide synthesis from a green chemistry viewpoint. To overcome this issue, we report an electrochemical peptide...

Electrochemistry for the Chemoselective Modification of Peptides and Proteins

“…Moving beyond modification at amino acid side chains, the indirect electrochemical activation of small-molecule reagents has also led to the development of a peptide coupling protocol with improved atom economy and a reduced waste footprint compared to traditional methods. Building on a prior approach to electrochemical amide bond formation, Chiba and co-workers paired electrochemistry with an innovative soluble-support-assisted strategy to facilitate the high-yielding construction of backbone amides without significant epimerization . In this method, anodic oxidation of triphenyl­phosphine is used to generate a phosphine radical cation, which is captured by the carboxylic acid coupling partner to form an activated acyloxy­triphenyl­phosphonium ion (Scheme ).…”

An Iodide‐Mediated Anodic Amide Coupling

“…Among these approaches, the Brown group recently presented an electrochemical, microfluidic system using a N‐heterocyclic carbene to transform aldehydes into the respective amide via a Breslow intermediate and subsequent oxidation (see Scheme 1). [16] A recent growing interest in electrochemical transformations has led to the use of electric current as a pseudo‐reagent in such reactions, however, electrochemical methods for direct condensation of a carboxylic acid and amine remain scarce [17–22] . In 1991, the group of Ohmori reported a procedure, using anodically oxidized PPh 3 to activate carboxylic acids for ester and amide synthesis.…”

“…Although C‐ protected α‐amino acids are usually oxidized at higher potentials relative to PPh 3, the authors introduced a highly lipophilic benzylic alcohol as protecting group for the C ‐terminus to enhance its solubility in non‐polar solvents like cyclohexane. This allowed the electrochemical oxidation to be performed in a biphasic system, which not only circumvented the risk of unselective oxidation but also facilitated the recovery of the product and Ph 3 PO from the reaction mixture [21] . However, this soluble tag‐assisted electrochemical method was only demonstrated for amino acids and requires pre‐functionalization of the substrates.…”

An Iodide-mediated Anodic Amide Coupling

“…A recent growing interest in electrochemical transformations has led to the use of electric current as a pseudo-reagent in such reactions, however, electrochemical methods for direct condensation of a carboxylic acid and amine remain scarce. [16][17][18][19][20][21] In 1991, the group of Ohmori reported a procedure, using anodically oxidized PPh 3 to activate carboxylic acids for ester and amide synthesis. However, this methodology is limited to carboxylic acids and primary, aliphatic amines with oxidation potentials more positive than that of PPh 3 .…”

“…This allowed the electrochemical oxidation to be performed in a biphasic system, which not only circumvented the risk of unselective oxidation but also facilitated the recovery of the product and Ph 3 PO from the reaction mixture. [20] However, this soluble tag-assisted electrochemical method was only demonstrated for amino acids and requires pre-functionalization of the substrates. Thus, easily oxidizable amines remain challenging substrates for an anodic amide bond formation.…”