Biomimetic approaches to diazonamide A. Direct synthesis of the indole bis-oxazole fragment by oxidation of a TyrValTrpTrp tetrapeptide

Abstract

The marine secondary metabolite diazonamide A, isolated from the colonial ascidian Diazona chinensis, was reported to have potent in vitro cytoxicity against human tumor cell lines. 1 This biological activity, 2 together with its unique and complex structure, assigned on the basis of an X-ray crystallographic study of a derivative, 1 ensured that diazonamide A immediately captured the imagination of synthetic organic chemists. Therefore in the 15 years since the structure of diazonamide A was reported in 1991, some 10 research groups have published approaches to this fascinating natural product. 3–12 The story acquired a new dimension in 2001 when Harran and co-workers completed a total synthesis of the reported structure only to discover that not only was it rather unstable, but it was also different from the natural product. 13,14 On the basis of his own studies and a re-examination of the original X-ray data, Harran proposed an alternative structure 1 for diazonamide A. Unequivocal proof that the revised structure 1 was indeed that of diazonamide A came when Nicolaou and coworkers published the first total synthesis of the natural product. 15 Subsequently, the Nicolaou group reported a second route to diazonamide A, 16 whilst Harran and co-workers completed their own total synthesis of the correct structure. 17 Despite the fact that Nicolaou’s and Harran’s efforts in total synthesis have laid to rest the structural problem of diazonamide A, such is its attraction as a target molecule that it continues to hold the attention of a number of research groups.