Griesbeck, Axel G., Heinrich, Thomas, Oelgemoeller, Michael, Molis, Arne, and Heidtmann, Axel (2002) Synthesis of cyclic peptides by photochemical decarboxylation of N-phthaloyl peptides in aqueous solution. Helvetica Chimica Acta, 85 (12). pp. 4561-4578.

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Abstract

The synthesis of a variety of cyclic peptides from N-phthaloyl-protected di-, tri-, tetra-, and pentapeptides with different aminocarboxylic acid tethers by photodecarboxylation – initiated by intramolecular electron transfer – has been explored in aqueous media. The progress and the chemoselectivity of the follow-up processes after CO₂ extrusion were traced by the respective pH/time-profiles, as well as by the overall change in pH after completion of the reaction. The competition between cyclization and simple oxidative decarboxylation depends on spacer length and geometry, H-bonding interaction between the electron accepting phthalimide C=O groups and amide H-atoms, as well as the geometric reorganization coupled with the radical combination step and the formation of the lactam rings. With progressing reaction, hydrolysis of the phthalimide chromophore becomes an increasingly important side reaction due to the constant increase in pH. The use of phosphate-buffered aqueous media consequently improved the cyclization yields. The ground-state interactions between amide groups and the terminal COO⁻ group with the imide C=O groups were studied for the model system [N-(phthaloyl)glycyl]sarcosine (1) by NMR spectroscopy where the amide (E/Z)-equilibrium depends on the presence of carboxylate vs. free carboxylic acid, demonstrating the role of H-bonding and metal coordination.

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