Z. Zhao, A. Felix
Jul 1, 1994
Citations
0
Influential Citations
2
Citations
Journal
Peptide research
Abstract
Conventional side-chain to side-chain cyclization between Lys/Orn and Asp/Glu side chains has the inherent shortcoming of limited variability in the ring sizes; limited by the amino acids involved in the lactamization. A novel approach to modulate the ring size has been introduced by using "spacers" (e.g., Gly, beta-Ala, gamma-Aba). General solid-phase procedures were developed that enabled the insertion of these spacers for the preparation of extended and reverse-extended lactam ring systems. Extended lactam ring systems were prepared using the Boc/Bzl strategy with Fmoc protection on the side chain of the basic residue, Lys/Orn. The spacer was introduced as the Fmoc amino acid, and chain elongation proceeded by the Boc/Bzl strategy. The acidic residue, Asp/Glu, involved in the lactam bridge was introduced with side-chain -OFm protection. Selective deprotection of the Fmoc and -OFm functions was followed by BOP cyclization, further chain elongation and HF cleavage. Reverse-extended lactam ring systems were prepared analogously using the Boc/Bzl strategy with the initial introduction of -OFm protection on the side chain of the acidic residue. In this case, amino acid alpha-fluorenylmethyl esters were used as the spacers. Amino acid alpha-fluorenylmethyl ester hydrochlorides were prepared in two steps from N-t-butyloxycarbonyl amino acids in excellent yield. These intermediates have general utility in peptide synthesis, including their specific application as "spacers" for the solid-phase synthesis of extended cyclic peptides (lactams). Using these intermediates, we prepared a model dicyclo-peptide that contains both an extended and reverse-extended lactam ring system.