SYNTHESIS OF 11-DIHYDRODIBENZO[A,D]CYCLOHEPTEN-2-YL]OXY)VALERIC ACID (CHA) AND NYL)AMINO]DIBENZO[A,D]CYCLOHEPTEN-2-YL]OXY)VALERIC ACID (CHE) HANDLES FOR THE SOLID-PHASE SYNTHESIS OF C-TERMINAL PEPTIDE AMIDES UNDER MILD CONDITIONS

Two novel handles for peptide amide preparation under mild conditions were developed for use in highly efficient solid-phase peptide synthes is. These handles, 11-dihydrodibenzo[a,d]cyclohepten-2-yl]oxy}valeric acid (CHA) and nyl)amino]dibenzo[a,d]cyclohepten-2-yl]oxy}valeric acid (CHE), were attached to the solid support and were used for syntheses of peptides having a C-terminal amide by the fluorenylmethoxycarbonyl strategy. The cleavability of CHA and CHE was determined and compared with the that commercially available amide handles. CHA and CHE handl es can be rapidly cleaved from the polymer support without significant side reactions using lower acid concentrations than those required fo r conventional handles. As CHA can be easily synthesized in large amou nts, it is suitable for peptide amide preparation for pharmaceuticals. As CHE can be cleaved at very low concentrations of acid, it is espec ially suitable for preparing side chain-protected peptide amides: Seve ral brain-gut peptides having a C-terminal amide were synthesized in h igh yield and high purity with these novel handles.