A tandem in situ peptide cyclization through trifluoroacetic acid cleavage.
We present a new approach for peptide cyclization during solid phase synthesis under highly acidic conditions. Our approach involves simultaneous in situ deprotection, cyclization and trifluoroacetic acid (TFA) cleavage of the peptide, which is achieved by forming an amide bond between a lysine side chain and a succinic acid linker at the peptide N-terminus. The reaction proceeds via a highly active succinimide intermediate, which was isolated and characterized. The structure of a model cyclic peptide was solved by NMR spectroscopy. Theoretical calculations support the proposed mechanism of cyclization. Our new methodology is applicable for the formation of macrocycles in solid-phase synthesis of peptides and organic molecules.
Institute of Chemistry, Edmond J. Safra campus The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904 (Israel) http://chem.ch.huji.ac.il/∼assaf.
Koushik
K
Chandra
Tapta Kanchan
TK
Roy
Deborah E
DE
Shalev
Abraham
A
Loyter
Chaim
C
Gilon
R Benny
RB
Gerber
Assaf
A
Friedler
D000595:Amino Acid Sequence; D002384:Catalysis; D003500:Cyclization; D008239:Lysine / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry; D057786:Peptidomimetics / Q000138:chemical synthesis; D060327:Solid-Phase Synthesis Techniques; D014269:Trifluoroacetic Acid / Q000737:chemistry*
D010456:Peptides, Cyclic; D057786:Peptidomimetics; D014269:Trifluoroacetic Acid; D008239:Lysine
cyclic peptides; cyclization; peptide NMR spectroscopy; peptide synthesis; peptides