Expanding Peptide Stapling With S-Tetrazine

ABSTRACT EXPANDING PEPTIDE STAPLING WITH s-TETRAZINE Matthew H. Bunner Professor Amos B. Smith, III This dissertation presents efforts toward the extension of synthetic methods for the creation of peptide macrocycles via the addition of dichloro-s-tetrazine to peptide sequences containing lysine, serine, threonine, and tyrosine. Chapter one reviews the work and interest of the Smith group in the s-tetrazine chromophore and the history of stapled peptides in the chemical literature. Chapter two describes (A) the development of a synthetic protocol for the creation of peptide macrocycles from peptide sequences containing a single cysteine and a single lysine residue using dichloro-s-tetrazine including discussion on amino acid tolerance and seven successful examples, (B) efforts toward the development of a synthetic protocol for the creation of peptide macrocycles from peptide sequences containing a single cysteine residue and a single serine / threonine / tyrosine residue, and (C) efforts toward the investigation of the photochemical dissociation of the created cysteine / lysine peptide macrocycles. Chapter three describes our efforts to improve the synthesis of dichloro-s-tetrazine in a large-scale procedure.