SOLID-PHASE TOTAL SYNTHESIS OF OSCILLAMIDE-Y AND ANALOGS

We report an efficient solid phase synthesis of oscillamide Y and thre e analogues. The cyclic peptide was prepared using a combination of Fm oc and allyl chemistries and an acid labile Wang type linker. The urea functionality was smoothly incorporated using l)-N-epsilon-(9-fluoren ylmethoxycarbonyl)-D-lysine allyl ester. Coupling to the N-methyl amin o acid was readily achieved using HATU, monitoring the reaction using bromophenol blue. Allyl deprotection was accomplished using Pd(PPh3)(4 ) and dimedone, and cyclization was smoothly accomplished using PyBroP . All reactions were monitored using mass spectrometry methodology. Th e cyclized materials were cleaved by acidolysis and purified by RP HPL C. In all cases the material isolated was the major product and gave t he expected molecular ion information. HPLC comparison with an authent ic sample of oscillamide Y showed that the isomer containing L-N-methy lalanine and L-homotyrosine was the natural product. H-1 NMR and H-1-H -1 COSY NMR experiments further confirmed this identification. The fou r compounds were tested as competitive and slow-tight binding inhibito rs of chymotrypsin but showed, contrary to literature expectations, no inhibitory activity.