Solid-phase total synthesis of trunkamide A(1).
Marine organisms are a rich source of novel, biologically active compounds. Herein, the solid-phase total synthesis of trunkamide A, currently in preclinical trials, is presented. Trunkamide A contains a thiazoline heterocycle and two residues of Ser and Thr with the hydroxy function modified as reverse prenyl (rPr). Cornerstones of the synthesis are as follows: (i) solid-phase peptide chain elongation using a quasi-orthogonal protecting scheme with tert-butyl and fluorenyl based groups, on a chlorotrityl resin; (ii) concourse of HOAt-based coupling reagents; and (iii) cyclizations in solution. Furthermore, the following synthetic steps are discussed: (i) preparation of the reverse prenyl derivatives of Ser and Thr; (ii) introduction of precursor of thiazoline as a protected amino thionoacid derivative; and (iii) formation of the thiazoline ring with DAST. All these features make this strategy particularly suitable for the large-scale synthesis of trunkamide A and other peptides containing the same motifs.
Caba
J M
JM
The Department of Organic Chemistry, University of Barcelona, 08028 Barcelona, Spain.
Rodriguez
I M
IM
Manzanares
I
I
Giralt
E
E
Albericio
F
F
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis; D010456:Peptides, Cyclic / Q000138:chemical synthesis*; D014561:Urochordata / Q000737:chemistry
D000970:Antineoplastic Agents; D010456:Peptides, Cyclic; C414110:trunkamide A