Antineoplastic agents. 428 - Synthesis of the marine sponge cycloheptapeptide phakellistatin 5

Phakellistatin 5 (1), a constituent of The Federated States of Micronesia ( Chuuk) marine sponge Phakellia costada, was synthesized by solution-phase a nd solid-phase techniques. Because the linear peptide bearing (R)-Asn resis ted cyclization, the synthesis of this peptide was repeated using the PAL r esin attachment proceeding from N-Fmoc-D-Asp-alpha-OCH2CH=CH2. After additi on of the final unit (Ala), the allyl ester was removed under neutral condi tions with Pd-o [P(C6H5)(3)](4). Removal of the final Fmoc-protecting group and cyclization with PyAOP provided (R)-Asn-phakellistatin 5 (2) in 28% ov erall yield. The same synthetic route from (S)-Asp led to natural phakellis tatin 5 (1) in 15% overall recovery. The solution-phase and solid-phase syn thetic products derived from (S)-Asp were found to be chemically but not bi ologically identical with natural phakellistatin 5 (1). This important fact suggested that a trace, albeit highly cancer-cell growth inhibitory, const ituent accompanied the natural product or that there is a subtle conformati onal difference between the synthetic and natural cyclic peptides.