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

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 α-amidosilane or α-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 α-amidosilane or α-amidocarboxylate
centers and (2) the nature of the penultimate cation radical α-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.