Synthetic Studies Toward the Skyllamycins: Total Synthesis and Generation of Simplified Analogues

Herein, we report our synthetic studies toward the skyllamycins, a highly modified class of nonribosomal peptide natural products which contain a number of interesting structural features, including the extremely rare α-OH-glycine residue. Before embarking on the synthesis of the natural products, we prepared four structurally simpler analogues. Access to both the analogues and the natural products first required the synthesis of a number of nonproteinogenic amino acids, including three β-OH amino acids that were accessed from the convenient chiral precursor Garner's aldehyde. Following the preparation of the suitably protected nonproteinogenic amino acids, the skyllamycin analogues were assembled using a solid-phase synthetic route followed by a final stage solution-phase cyclization reaction. To access the natural products (skyllamycins A-C) the synthetic route used for the analogues was modified. Specifically, linear peptide precursors containing a C-terminal amide were synthesized via solid-phase peptide synthesis. After cleavage from the resin the N-terminal serine residue was oxidatively cleaved to a glyoxyamide moiety. The target natural products, skyllamycins A-C, were successfully prepared via a final step cyclization with concomitant formation of the unusual α-OH-glycine residue. Purification and spectroscopic comparison to the authentic isolated material confirmed the identity of the synthetic natural products.