Total Synthesis of Dehydrodidemnin B. Use of Uronium and Phosphonium Salt Coupling Reagents in Peptide Synthesis in Solution.

Abstract

New total syntheses of didemnin A and of dehydrodidemnin B are described. The latter didemnin has the highest antiproliferative activity of all members of this family of macrocyclic depsipeptides. It was produced on coupling the side chain Pyr-Pro-OH to didemnin A, which was itself synthesized by two novel routes. One of these was based on the elaboration of a linear heptadepsipeptide incorporating the first amino acid of the didemnin side chain, (R)-N(Me)-Leu. Deprotection of the amino and carboxyl terminii of this linear precursor followed by macrocyclization gave a protected derivative of didemnin A. The second route involved synthesis of the Boc-protected didemnin macrocycle from a linear hexadepsipeptide lacking (R)-N(Me)-Leu. Removal of the Boc group from the macrocycle followed by its coupling with Boc-(R)-N(Me)-Leu-OH then gave Boc-didemnin A. The overall yield was much higher for the second strategy (27% compared to 4% for the first synthesis), but both allowed synthetic didemnin A, identical with a natural sample, to be prepared. Extensive use was made of phosphonium and uronium salt-based coupling reagents, such as BOP, PyBrOP, PyAOP, HBTU, and HATU for the formation of both the secondary and tertiary amide bonds present in these complex depsipeptides.