Electrochemistry for the Chemoselective Modification of Peptides and Proteins

Abstract

Although electrochemical strategies for small-molecule synthesis are flourishing, this technology has yet to be fully exploited for the mild and chemo­selective modification of peptides and proteins. With the growing number of diverse peptide natural products being identified and the emergence of modified proteins as therapeutic and diagnostic agents, methods for electrochemical modification stand as alluring prospects for harnessing the reactivity of polypeptides to build molecular complexity. As a mild and inherently tunable reaction platform, electrochemistry is arguably well-suited to overcome the chemo- and regio­selectivity issues which limit existing bioconjugation strategies. This Perspective will showcase recently developed electrochemical approaches to peptide and protein modification. The article also highlights the wealth of untapped opportunities for the production of homogeneously modified biomolecules, with an eye toward realizing the enormous potential of electrochemistry for chemo­selective bioconjugation chemistry.

Synthesis of Peptide N-Acylpyrroles via Anodically Generated N,O-Acetals

“…Following removal of volatiles, the crude peptide N-acylpyrrole was purified by semipreparative RP-HPLC (35% to 75% MeCN over 20 min, 5 mL/min) to afford peptide 20 as a TFA salt (6.2 mg, 47% yield over 12 steps). 1 H NMR (700 MHz, CD 3 OD):  = 8.52 (d,J = 8.3 Hz,0.5 H,NH),8.30 (d,J = 7.7 Hz,0.2 H,NH),2 H),4 H),1 H),2 H),1 H),4.73 (dd,J = 9.9,4.9 Hz,1 H),1 H),4.47 (dd,J = 9.3,5.9 Hz,1 H),4.36 (dd,J = 10.4,7.5 Hz,1 H),3.34 (dd,J = 12.1,3.6 Hz,1 H),1 H),3.20 (dd,J = 14.2,5.0 Hz, 1 H), 2.89 (dd, J = 14.2, 9.9 Hz, 1 H), 2.46 (dd,J = 13.6,7.5 Hz,1 H),1 H),2.01 (ddd,J = 14.0,10.4,4.1 Hz,1 H),1 H),2 H), 1.00 (d,J = 6.8 Hz,3 H),0.98 (d,J = 6.7 Hz,3 H),0.92 (d,J = 6.5 Hz,3 H),…”

“…Inspired by seminal work from Seebach and co-workers 4 on the direct anodic oxidation of peptides, 5 our group has recently explored the utility and general compatibility of electrochemical C-terminal oxidations in the context of peptide substrates. 6 This process involves a Hofer–Moest electrochemical decarboxylation, in which the ensuing peptide N -acyliminium is readily trapped in situ by the alcohol-based solvent to generate a reactive N , O -acetal intermediate (e.g., 1 ; Scheme 1 ).…”

“…6b,19 Reflecting on this reactivity, we attempted to activate the hydroxyl group of N,O-acetal 15 in situ to promote the aromatization process. For this purpose, Ac 2 O and TFAA additives were screened (entries [5][6][7][8]. Noting that Ac 2 O generates a weak acid (AcOH) following acetylation of the alcohol, this activating agent was used in a combination with other acidic reagents (e.g., TFA, entries 5 and 6, or 4 M HCl in 1,4-dioxane, entry 8).…”

“…2 To this end, direct modification of the peptide Cterminal carboxylate moiety has undoubtedly provided broad opportunities for the rapid diversification of peptides and serves as a valuable tool for the development of peptide-based therapeutics. 3 Inspired by seminal work from Seebach and co-workers 4 on the direct anodic oxidation of peptides, 5 our group has recently explored the utility and general compatibility of electrochemical C-terminal oxidations in the context of peptide substrates. 6 This process involves a Hofer-Moest electrochemical decarboxylation, in which the ensuing peptide N-acyliminium is readily trapped in situ by the alcoholbased solvent to generate a reactive N,O-acetal intermedi-ate (e.g., 1; Scheme 1).…”

Umpolung strategies for the functionalization of peptides and proteins

“…Over the past several years, chemists seeking to extend the scope of peptide and protein modifications to include the site-specific, on-demand incorporation of both native and designer functionality have successfully mined the rich interface of peptide science and cutting-edge organic chemistry. Advances in transition-metal catalysis, 2 photochemistry, 3 and electrochemistry 4 are actively reshaping the toolbox of bioconjugation strategies.…”