2026/05/14 by Md. Nuruzzaman, Chiamaka P. Uzoewulu, Noura O. Ghader +2 · 1 voice
Biochemistry, Genetics and Molecular Biology · Chemistry · Medicine · #Chemical Synthesis and Analysis #Click Chemistry and Applications #Microbial Natural Products and Biosynthesis
paper · doi:10.1021/acs.joc.5c02882
openalex publication_date 2026/05/14 · openalex created_date 2026/05/15 · openalex updated_date 2026/07/18
Because of its chemical inertness, phenylalanine is one of the proteinogenic amino acids that does not have many chemical labeling methods for, particularly in unprotected peptide substrates. Inspired by a recently reported mechanochemical Birch reduction method, we tested a reduction-based approach as well as inverse electron-demand Diels-Alder reactions to develop a phenylalanine-targeting bioconjugation method using 1,4-cyclohexadiene as a key chemical species. Chemoselective reduction of the phenyl to cyclohexadienyl group was achieved for dipeptides and tripeptides that do not contain tryptophan residues. Through a computation- and experiment-guided approach, we also demonstrated the possibility of 1,4-cyclohexadiene-based Diels-Alder reactions on an unprotected peptide using a series of monosubstituted tetrazine reagents.