Solid-Phase Total Syntheses of Trunkamide A and Kahalalide F, Cyclic Peptides from Marine Origin

Abstract

The sea is a great source of biodiversity, because life conditions there create unique mechanisms of chemical defense. Herein, the solid-phase total synthesis of Trunk-amide A [1] and Kahalalide F [2] (Figure 1), two cyclic peptides from marine origin which are currently in preclinical and clinical phase I trials respectively, are discussed. Trunkamide A contains a thiazoline heterocycle and Ser and Thr with the hydroxy function modified as reverse prenyl (rPr). Kahalalide F contains: (i) an ester bond between two sterically hindered amino acids (Val and D-allo-Thr); (ii) the didehydro-amino butyric acid (Dhb); and (iii) a rather hydrophobic sequences with two fragments containing several β-branched amino acids in a row, one of them terminated with an aliphatic acid. Common features of both syntheses are: (i) solid-phase peptide chain elongation using a quasi orthogonal protecting scheme with allyl, t-butyl, fluorenyl based groups, on a chlorotrityl resin; (ii) concourse of HOAt based coupling reagents; and (iii) cyclizations in solution.