Solid-Phase Total Synthesis of Oscillamide Y and Analogues

• Published in: Journal of organic chemistry Vol. 62; no. 18; pp. 6199 - 6203
• Main Authors: Marsh, Ian R, Bradley, Mark, Teague, Simon J
• Format: Journal Article
• Language: English
• Published: American Chemical Society 05-09-1997
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo970671o

We report an efficient solid phase synthesis of oscillamide Y and three analogues. The cyclic peptide was prepared using a combination of Fmoc and allyl chemistries and an acid labile Wang type linker. The urea functionality was smoothly incorporated using N α-(4-nitrophenyloxycarbonyl)-N ε-(9-fluorenylmethoxycarbonyl)-d-lysine allyl ester. Coupling to the N-methyl amino 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. The cyclized materials were cleaved by acidolysis and purified by RP HPLC. In all cases the material isolated was the major product and gave the expected molecular ion information. HPLC comparison with an authentic sample of oscillamide Y showed that the isomer containing l-N-methylalanine and l-homotyrosine was the natural product. 1H NMR and 1H−1H COSY NMR experiments further confirmed this identification. The four compounds were tested as competitive and slow-tight binding inhibitors of chymotrypsin but showed, contrary to literature expectations, no inhibitory activity.