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.