Total synthesis of cysteine-containing, depsipeptidic natural products in solution and on the solid phase via chemoselective macrocyclization using latent thioester solid-phase linkers

ORGN 785

Deirdre M. Wholly, Travis R. Blum, Janelle A. Walkley, Kimberly A. Hlavac, and Justin S. Miller, Department of Chemistry, Hobart and William Smith Colleges, Geneva, NY 14456
The total synthesis of Spiruchostatin A by a straightforward route is described, along with progress along similar routes adapted for the solid-phase toward the synthesis of this and other cysteine-containing, depsipeptidic natural products including the other Spiruchostatins, FK228, and FR901,375. The key step common to all of these synthetic routes involves chemoselective macrocyclization, mediated by a novel latent thioester, of an N-terminal cysteine residue with a C-terminal alanine or valine residue. The latent thioester solid-phase linker is easily prepared as a single enantiomer in three high-yielding steps from commercially available starting materials. The development of other latent thioesters for solid-phase synthesis is also described. This work is intended to facilitate the production of peptidic and depsipeptidic analogs of the natural products for SAR and pharmaceutical development.