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, jsmiller@hws.edu. 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.