A new photochemical method for the preparation of amino acid-α-phenylthioesters and peptide-α-phenylthioesters
We describe the development of a novel resin with a photoreactive N-acylnitroindoline linker, that allows for the synthesis of amino acid- (in solution) or peptide-α-thioesters using standard Fmoc/t-Bu standard solid phase peptide synthesis (SPPS). Recent advances have shown that the yields of this thioesterification reaction have dramatically increased due to a simple change in the order of addition of reagents. Upon illumination with UV-light, in the presence of N-hydroxybenzotriazole (HOBt), the amino acid-α- or peptide-α-OBt ester is generated by direct photo-release from the nitroindoline linker with minimal epimerization, followed by reaction with thiophenol in the dark to produce amino acid-α-phenylthioesters or peptide-α-phenylthioesters. Nine amino acid-α-phenylthioesters of the twenty proteinogenic amino acids were prepared in high yield and high purity (75-83). Eight photoreactive tripeptides were prepared on Rink Amide resin following Fmoc-based SPPS strategies and cleaved to give their corresponding photoreactive tripeptide amides (67-74). Seven tripepide-α-phenylthioesters were prepared in high yield and high purity (84-90). Three tripeptide-α-phenylthioesters were prepared in good yield by direct photo-release from the solid support (86, 87, 90). Five photoreactive glycopeptides based on sequences found in human erythropoietin (98 and 99) and the GP-120 HIV-1 envelope protein (100, 101, and 102) were synthesized and cleaved from Rink Amide resin for future conversion to their corresponding thioesters.
Hogenauer, Tyrone Justin, "A new photochemical method for the preparation of amino acid-α-phenylthioesters and peptide-α-phenylthioesters" (2010). ETD Collection for University of Texas, El Paso. AAI3426848.