Total Synthesis of Skyllamycins A-C.

The skyllamycins are a family of highly functionalized non-ribosomal cyclic depsipeptide natural products which contain the extremely rare α-OH-glycine functionality. Herein the first total synthesis of skyllamycins A-C is reported, together with the biofilm inhibitory activity of the natural products. Linear peptide precursors for each natural product were prepared through an efficient solid-phase route incorporating a number of synthetic modified amino acids. A novel macrocyclization step between a C-terminal amide and an N-terminal glyoxylamide moiety served as a key transformation to install the unique α-OH-glycine unit and generate the natural products in the final step of the synthesis.