Direct modification of tripeptides using photoinduced decarboxylative radical reactions

Decarboxylative couplings as versatile tools for late‐stage peptide modifications

“…Yoshimi and coworkers have reported a complimentary approach to direct, photoinduced decarboxylative Giese reactions by employing phenanthrene (phen) 97 and 1,4‐ or 1,3‐dicyanobenzene—1,4‐DCB 98 or 1,3‐DCB 99 , respectively—as a novel photocatalytic system (Scheme ) . Mechanistically, excitation of phen in the presence of light is followed by SET from the excited state of phen to the DCB derivative, forming a phen radical cation.…”

“…Extrusion of CO 2 forms the alkyl radical 18 , which may participate in a variety of subsequent radical transformations . The scope of peptide substrates for the Giese reaction includes the coupling of various tripeptide α‐acids with acrylonitrile 100 (products 103 ‐ 107 ), and the coupling of a dipeptide with Val‐Val acrylamide 101 to afford peptide 108 , albeit in lower yields . Finally the free radical polymerization of a tripeptide bearing a free side‐chain glutamic acid with excess methyl acrylate (100 equiv.)…”

“…In 2016, Opatz and coworkers reported a phenanthrene (phen)‐based photochemical strategy for the arylation of α‐amino acid derivatives (Scheme ) . The methodology exploits the phen/1,4‐DCB organic photocatalyst system employed by Yoshimi and coworkers for intermolecular Giese reactions (see Scheme ), taking advantage of the authors’ observation that 1,4‐DCB itself was capable of coupling to a tripeptide substrate 124 in the absence of other radical acceptors . Armed with this knowledge, Opatz and coworkers successfully coupled a variety of aromatic nitriles to α‐amino acid derivatives, including Fmoc‐protected dipeptide 122 to afford pyridine substituted peptide 123 …”

“…The Yoshimi lab has extended the versatility of the phen/DCB organic photocatalytic system (see section 3.2.1.) to include strategies for the reductive decarboxylation of peptidic acids . While conceptually similar to the venerable Barton decarboxylation reaction (see Scheme ), this variation does not require a discrete preactivation step.…”

Facile Preparation of Peptides with C-Terminal <i>N</i>-Alkylamide <i>via</i> Radical-Initiated Dethiocarboxylation

“…This protocol therefore requires preparing an alkylamino resin, followed by the coupling of the C-terminal amino acid on the less reactive secondary amine 6) (Chart 1A). To avoid the coupling of the first amino acid on the secondary amine, an alternative method employing on-resin aminolysis of an electrophilic peptide-resin linkage was reported 7,8) (Chart 1B). Compared with the on-resin protocol, the off-resin protocol is much more straightforward and involves the condensation of a C-terminal carboxylic acid of a peptide with an amine (Chart 1C).…”