A Synthetic Strategy for the Preparation of Cyclic Peptide Mimetics Based on SET-Promoted Photocyclization Processes

Abstract

A novel method for the synthesis of cyclic peptide analogues has been developed. The general approach relies on the use of SET-promoted photocyclization reactions of peptides that contain N-terminal phthalimides as light absorbing electron acceptor moieties and C-terminal alpha-amidosilane or alpha-amidocarboxylate centers. Prototypical substrates are prepared by coupling preformed peptides with the acid chloride of N-phthalimidoglycine. Irradiation of these substrates results in the generation of cyclic peptide analogues in modest to good yields. The chemical efficiencies of these processes are not significantly affected by (1) the lengths of the peptide chains separating the phthalimide and alpha-amidosilane or alpha-amidocarboxylate centers and (2) the nature of the penultimate cation radical alpha-heterolytic fragmentation process (i.e., desilylation vs decarboxylation). An evaluation of the effects of N-alkyl substitution on the amide residues in the peptide chain showed that N-alkyl substitution does not have a major impact on the efficiencies of the photocyclization reactions but that it profoundly increases the stability of the cyclic peptide.

Formation of Six‐Membered (and Larger) Rings

“…hn (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) Interestingly, compact flow reactors have been applied to prepare hundred of grams of bicyclic azepines using this photochemical strategy [78].…”

“…N-Phthalimide-linked peptides that contain C-terminal a-amidotrimethylsilyl groups undergo macrocyclization reactions via sequential single-electron transfer processes [11,12]. Thus, electron transfer from the neighboring amide to the excited phthalimide chromophore leads to an amide radical cation.…”

Photochemical Approach to the Preparation of Lariat Crown Ethers Containing Peptide Sidearms

“…7 Synthetic approaches for the preparation of lariat crown ether have traditionally depended on ground state thermal polar cyclization reactions that require low concentrations of reactants to minimize competing polymerization processes. In previous studies aimed at the preparation of diverse types of macrocyclic poly-ethers, -thioethers, 8 and -peptides, 10 bis- 9 , and lariat 4c,4d,11a crown ethers we have developed protocols for promoting efficient single electron transfer (SET)-promoted photocylization reactions 11 of acceptor-polydonor substrates that proceed via sequential SET-desilylation mechanistic pathways (Scheme 2).…”

Single Electron Transfer Induced Photoaddition Reactions of Silyl Enol Ether to N-Methylphthalimide

“…[1][2][3][4] Numerous examples of SET-promoted excited states processes in which intermediate cation radical desilylation serves as the driving force are found in the photochemistry of phthalimides. 5,6 Mazzocchi et al reported that the photochemistry of Nmethylphthalimide (1) in presence of alkenes is characterized by the two competing processes 7 : In one of these reactions the alkene adds to the C(O)-N bond of N-methylphthalimide that ultimately leads to a ring expanded benzazepinedione (3).…”