1,4-diazepine-2,5-dione ring formation during solid phase synthesis of peptides containing aspartic acid beta-benzyl ester.
The Fmoc-based SPPS of H-Xaa-Asp(OBzl)-Yaa-Gly-NH(2) sequences results in side reactions yielding not only aspartimide peptides and piperidide derivatives, but also 1,4-diazepine-2,5-dione-peptides. Evidence is presented to show that the 1,4-diazepine-2,5-dione derivative is formed from the aspartimide peptide. The rate of this ring transformation depends primarily on the tendency to aspartimide and piperidide formation, which is influenced by the nature of the amino acid following the aspartic acid beta-benzyl ester (Xaa). However the bulkiness of the amino acid side chain preceeding the aspartic acid beta-benzyl ester (Yaa) is also important. Under certain conditions the 1,4-diazepine-2,5-dione peptide derivative may even be formed dominantly, which is a highly undesirable side reaction in peptide synthesis, but which provides a new way for the synthesis of diazepine peptide derivatives with targeted biological or pharmacological activity.
Süli-Vargha
Helga
H
Research Group for Peptide Chemistry, Hungarian Academy of Sciences, Eötvös Loránd University, Budapest, Hungary. suline@chem.elte.hu
Schlosser
Gitta
G
Ilas
Janez
J
D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000737:chemistry*; D004952:Esters / Q000737:chemistry*; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry
D004952:Esters; D010456:Peptides, Cyclic; D010880:Piperidines; D001224:Aspartic Acid; C075871:aspartimide