Synthesis and structure determination of kahalalide F

Kahalalide F. the only member of the family of peptides called kahalalides, isolated from the sacoglossan mollusc Elysia rufescens and the green alga Bryopsis sp., with important bioactivity, is in clinical trials for treatme nt of prostate cancer. An efficient solid-phase synthetic approach is repor ted. Kahalalide F presents several synthetic difficulties: (i) an ester bon d between two beta -branched and sterically hindered amino acids: (ii) a di dehydroamino acid: and (iii) a rather hydrophobic sequence with two fragmen ts containing several beta -branched amino acids in a row, one of them term inated with a saturated aliphatic acid. The cornerstones of our strategy we re (i) a quasiorthogonal protecting system with allyl, tert-butyl, fluoreny l, and trityl-based groups. (ii) azabenzotriazole coupling reagents, (iii) formation of the didehydroamino acid residue on the solid phase, and (iv) c yclization and final purification in solution. HPLC, high-field NMR, and bi ological activity studies showed that the correct stereochemistry of the na tural product is that proposed by Rinehart et al. whereas the stereochemist ry proposed by Scheuer et al. is that of a biologically less active diaster eoisomer.