Synthesis and Structure Determination of Kahalalide F^1,2

Abstract

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 treatment of prostate cancer. An efficient solid-phase synthetic approach is reported. Kahalalide F presents several synthetic difficulties: (i) an ester bond between two beta-branched and sterically hindered amino acids; (ii) a didehydroamino acid; and (iii) a rather hydrophobic sequence with two fragments containing several beta-branched amino acids in a row, one of them terminated with a saturated aliphatic acid. The cornerstones of our strategy were (i) a quasiorthogonal protecting system with allyl, tert-butyl, fluorenyl, and trityl-based groups, (ii) azabenzotriazole coupling reagents, (iii) formation of the didehydroamino acid residue on the solid phase, and (iv) cyclization and final purification in solution. HPLC, high-field NMR, and biological activity studies showed that the correct stereochemistry of the natural product is that proposed by Rinehart et al. whereas the stereochemistry proposed by Scheuer et al. is that of a biologically less active diastereoisomer.

The cyclization of peptides and depsipeptides

“…Equally as representative as the above syntheses would be the strategies used in making luzopeptins [164], HUN-7293 [165], kahalalide B and F [166,167], dolastatin 11 [168], AM toxin II [169] and doliculide [170]. In many of these examples the non-peptidic parts are as, or even more, demanding than the cyclodepsipeptide skeleton itself.…”

Marine Natural Products as Prototype Agrochemical Agents

“…(26). The absolute stereochemistry of kahalalide F was completely assigned in 2001 through a total synthesis (27). Halichondramide (40) was a 25-membered macrolide, which accommodates an unusual system of three contiguous oxazole rings in the macrocyclic ring (28).…”

Phase I Clinical and Pharmacokinetic Study of Kahalalide F in Patients with Advanced Androgen Refractory Prostate Cancer

“…KF is the largest and most active of the seven natural compounds isolated from E. rufescens. Six cyclic (peptides A-F) and one acyclic analogue (peptide G) are known (3).…”