Site‐Selective Itaconation of Complex Peptides by Photoredox Catalysis

Abstract

Site-selective peptide functionalization provides astraightforwardand cost-effective access to diversify peptides for biological studies.A mong many existing non-invasive peptide conjugations methodologies,p hotoredoxc atalysis has emerged as one of the powerfula pproaches for site-specific manipulation on native peptides.Herein, we report ahighly Ntermini-specific method to rapidly access itaconated peptides and their derivatives through acombination of transamination and photoredox conditions.T his strategy exploits the facile reactivity of peptidyl-dihydropyridine in the complex peptide settings,c omplementing existing approaches for bioconjugations with excellent selectivity under mild conditions.D istinct from conventional methods,t his method utilizes the highly reactive carbamoyl radical derived from ap eptidyl-dihydropyridine.I na ddition, this itaconated peptide can be further functionalizedasaMichael acceptor to access the corresponding peptide-protein conjugate.

Nonenzymatic Asparagine Motif Synthesis by Photoredox-Catalyzed Carbamoylation of Dehydroalanine

“…To elucidate the mechanism of this reaction, Stern–Volmer experiments of 4CzIPN in relation to carbamoyl-DHP 2a (Scheme a) were examined, which indicated that carbamoyl-DHP 2a effectively quenched the luminescence property of 4CzIPN. This result suggested that the process was involved in a radical pathway, which was consistent with previous works. ,, As shown in Scheme b, we propose that this reaction proceeds possibly via a radical mechanism. First, photoexcitation of the 4CzIPN (E 1/2 (4CzIPN*/4CzIPNC •– ) = +1.43 V versus SCE in MeCN) forms an oxidant strong enough to take an electron from the dihydropyridine radical precursor 2 , generating an excited RNHCO-DHP radical cation A .…”

“…This result suggested that the process was involved in a radical pathway, which was consistent with previous works. 20,25,26 As shown in Scheme 4b, we propose that this reaction proceeds possibly via a radical mechanism. First, photoexcitation of the 4CzIPN (E 1/2 (4CzIPN*/4CzIPNC •− ) = +1.43 V versus SCE in MeCN) 27 forms an oxidant strong enough to take an electron from the dihydropyridine radical precursor 2, generating an excited RNHCO-DHP radical cation A.…”

“…We envisioned that the addition of a readily available carbamoyl radical to the Dha residue would create an Asn mutation. Developing this protocol required a suitable carbamoyl radical precursor and existing methods for the generation of carbamoyl radicals are four strategies: the C–X bond homolysis, reductive decarboxylation of N -hydroxyphthalimido oxamides, and SET of dihydropyridines adorned with a carbamoyl moiety. − Inspired by the work of Melchiorre and Wang about dihydropyridines adorned with a carbamoyl moiety, here we report a chemical mutation of Dha to Asn by installing a carbamoyl radical on Dha using 2 as the radical precursor (Scheme b).…”

Photoinduced carbamoylation reactions: unlocking new reactivities towards amide synthesis

“…Very recently, Wang and co-workers, inspired by the noteworthy importance of itaconate and its derivatives in the immune metabolism of inflammation and tumor via cysteine–protein conjugation via Michael reactions, developed a site-selective synthesis of N-terminal itaconated peptides 31 through the photocatalytic coupling of 2-(bromomethyl)acrylate 30 with peptidic carbamoyl-radicals (Scheme 17). 80 Throughout the optimization studies, it was found that Iridium catalyst PC5 showed the best performance, and CFL irradiation afforded better yields than blue LED irradiation, in a very short reaction time (30 min). Regarding the scope, a set of peptide-carbamoyl-DHPs 29 , synthesized using SPPS (Solid Phase Peptide Synthesis), bearing photolabile residues (such as Trp and Met), could be selectively coupled to 30 , affording a family of peptide itaconamides 31 in good to excellent yields.…”

carba‐Nucleopeptides (cNPs): A Biopharmaceutical Modality Formed through Aqueous Rhodamine B Photoredox Catalysis

“…(Our lab and others have found that some peptides are readily degraded with higher energy <450 nm light) [18] . By operating through SET reduction, organic dyes are also less likely to cause undesirable side reactions on peptides, which generally have amino acids that can be oxidatively modified, including Tyr, [19] Trp, [20] Met, [21, 22] His, [23, 24] N‐termini, [25] and C‐termini [26] . The discovery of an organic dye that can facilitate c NP synthesis would not only provide ready access to a novel biopharmaceutical modality but bolster the utility of fluorescent organic dyes for biomolecular synthesis.…”