Visible-light-mediated catalyst-free synthesis of unnatural α-amino acids and peptide macrocycles

Abstract

The visible light induced, photocatalysts or photoabsorbing EDA complexes mediated cleavage of pyridinium C-N bond were reported in the past years. Here, we report an ionic compound promote homolytic cleavage of pyridinium C-N bond by exploiting the photonic energy from visible light. This finding is successfully applied in deaminative hydroalkylation of a series of alkenes including naturally occurring dehydroalanine, which provides an efficient way to prepare β-alkyl substituted unnatural amino acids under mild and photocatalyst-free conditions. Importantly, by using this protocol, the deaminative cyclization of peptide backbone N-terminals is realized. Furthermore, the use of Et3N or PPh3 as reductants and H2O as hydrogen atom source is a practical advantage. We anticipate that our protocol will be useful in peptide synthesis and modern peptide drug discovery.

Solid-Phase Photochemical Peptide Homologation Cyclization

“…1 H NMR assignments based on TOCSY spectra are consistent with literature precedents (page S47 of the Supporting Information). The high cyclization yield of 47% for Atosiban-5 is similar to the findings of both MacMillan and Xu on photochemical C–N cyclizations of peptides.…”

“…Previous reports of photochemical peptide cyclizations have required activated radical precursors, preventing the use of Asp and Glu as chiral radical sources within a peptide. − The most common photochemical cyclization strategy is thus to perform a Giese-type reaction using radicals generated by oxidative decarboxylation of a free C-terminal Gly, limiting the overall structure of the macrocycles generated. , We envisioned a direct route to a series of C­(sp 3 )–C­(sp 3 )-linked macrocycles from a common intermediate utilizing natural amino acids via tandem photochemical couplings on unactivated primary radicals. To accomplish this, electron-donor-acceptor (EDA) complexes were employed to access alaninyl and homoalaninyl radicals (Figure A).…”

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

“…However, this SET process becomes favorable when the resulting iminium ion is hydrolyzed to diisopropylamine and acetaldehyde giving a net −53 kcal mol −1 driving force (Figure 3B). We find this to be an important result considering emerging reports on the promiscuity of α‐amino radicals as halogen‐atom transfer reagents for photoredox catalysis and as bifurcated SET reductants for photolytic reactions [13b, 58, 59] . We now show that in addition to being modest reducing agents, α‐amino radicals can help drive endergonic steps in photoredox catalyzed reactions via oxidative fragmentation.…”

Solid‐Phase Peptide Modification via Deaminative Photochemical Csp3‐Csp3Bond Formation Using Katritzky Salts

“…reported the photocatalytic deaminative Minisci reaction of amino acid feedstocks in solution while the deaminative intramolecular Giese cyclisation was described by Xu et al. using ionic compound‐promoted cleavage of the Katritzky salt [11a,15d] . To demonstrate the applicability of our methodology for the Giese reaction at the N ‐terminus of resin‐bound peptide substrates, we synthesized a model tripeptide where the N ‐terminal lysine residue was replaced with glycine (to avoid diastereoisomer formation) and converted the N ‐terminus primary amine to the Katritzky salt 30 with a good yield of 74 % (Scheme 4B).…”