Solid-phase synthesis of extended lactam ring systems: preparation of amino acid alpha-fluorenylmethyl esters for the synthesis of reverse-extended lactams.
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.
Zhao
Z
Z
Hoffmann-La Roche, Nutley, NJ.
Felix
A M
AM
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000138:chemical synthesis*; D002851:Chromatography, High Pressure Liquid; D005449:Fluorenes / Q000138:chemical synthesis*; D007769:Lactams / Q000138:chemical synthesis*; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000138:chemical synthesis*
D000596:Amino Acids; D005449:Fluorenes; D007769:Lactams; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D010456:Peptides, Cyclic