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 variabilit y in the ring sizes; limited by the amino acids involved in the lactam ization. A novel approach to modulate the ring size has been introduce d by using ''spacers'' (e.g., Gly, beta-Ala, gamma-Aba). General solid -phase procedures were developed that enabled the insertion of these s pacers for the preparation of extended and reverse-extended lactam rin g systems. Extended lactam ring systems were prepared using the Boc/Bz l 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 -OF m protection. Selective deprotection of the Fmoc and -OFm functions wa s followed by BOP cyclization, further chain elongation and HF cleavag e. Reverse-extended lactam ring systems were prepared analogously usin g the Boc/Bzl strategy with the initial introduction of -OFm protectio n on the side chain of the acidic residue. In this case, amino acid al pha-fluorenylmethyl esters were used as the spacers. Amino acid alpha- fluorenylmethyl ester hydrochlorides were prepared in two steps from N -t-butyloxy-carbonyl amino acids in excellent yield. These intermediat es 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 mo del dicyclo-peptide that contains both an extended and reverse-extende d lactam ring system.