Diazonamides A is an unusual novel halogenated cyclic peptide isolated form the marine ascidian Diazona chinensis possessing potent in vitro activity against HCT-116 human colon carcinoma and B-16 murine melanoma cancer cell lines (IC/50 <15ng/mL). Many biologically active cyclopeptides display encouraging therapeutic potential in vitro and are promising lead structures wherein the absence of ionized C- and N-termini leads to improved bioavailability, more facile membrane permeability, and greater resistance to in vivo enzymatic degradation. However, as with many marine natural products, the amount of material available from natural sources is usually scare making broad spectrum biological screening an advanced testing impossible. Therefore, total synthesis plays an essential role in understanding the effect thee compounds have on cancer cells by proving quantities of material otherwise not available. An original approach to the synthesis of diazonamide A will be described herein. Key features presented in the approach include the rapid functionalization of the tyrosine core by Claisen Rearrangement and a subsequent catalytic asymmetric cyclopropanation to produce the critical quaternary carbon center (C10). Finally, a novel macrocyclic ring-contractive oxazole formation protocol and its potential application to other oxazole containing macrocycles will be described. The striking array of complex structural features present in diazonamide A creates a formidable challenge for synthesis; however, the proposed strategy delivers the natural material in a concise enantioselective fashion (19 steps, best case).
