Diazonamide structure revision

Shortly after Harran s structure revision of diazonamide A (47), Nicolaou and coworkers reported the first total synthesis [39]. Retrosynthetically, assembly of fragments 63-67 could lead to diazonamide A through side-chain excision, chlorination, macrolactamization, aminal and oxazole formation, and bis-aryl ring realization (Scheme 10). 

Other notable oxazole-containing natural products that have received intense scrutiny include macrolide phorbox-azoles and cyclic peptide diazonamide (Figure 6). The structure of diazonamide has been revised from the original assignments as the result of an elegant total synthesis study <2003AGE4961>. 

Other issues the revised structure of diazonamide A has been synthesized. ... 

Diazonamides have evoked much interest in the synthetic community due to both their interesting architecture and potent cytotoxic properties. It took a decade to achieve the total synthesis of diazonamide A and the -bromobenzoate derivative of diazonamide B. " However, the synthetic materials turned out to be not identical to the natural products. This synthetic group then elicited the revised structures of diazonamides A and B based on verification of the spectral data. The major spectral data differences between the synthetic and... 

Diazonamide A, a marine natural product isolated from the colonial ascidian Diazona angulata. The revised structure was confirmed by total synthesis in 2002. It shows cytotoxicity against several tumor cell lines with IC50 values <15 ngmL [N. Lindquist etal.,J. Am. Chem. Soc. 1991, 113, 2303 K. C. Nicolaou et al., Angew. Chem. Int. Ed. 2002, 41, 3495]. 

The marine metabolite diazonamide A (47) (Fig. 3) was isolated from the colonial ascidian Diazona angulata, collected from the ceiUngs of caves along the northwest coast of Siquijor Island in the Phihppines [31]. The original structure of diazonamide A was suggested by an X-ray crystallographic study of the p-bromobenzoyl derivative of diazonamide B (48) (Fig. 3). Harran and coworkers completed the synthesis of the proposed diazonamide A [32], which differs from the natural diazonamide A, and thus the revised structure is 47 [33]. 

Following the synthesis of the originally proposed incorrect structure of diazonamide and its revision, Harran and coworkers reported a concise and flexible synthesis of diazonamide A (47) [38]. Retrosynthetically, 47 was realized from intermediate 49 by photoinduced electron transfer mediated HBr elimination. Intermediate 49 was derived from methyl ester 50 through oxazole formation, which in turn was accessed through an oxidative cycloaddition from phenol derivative 51 (Scheme 7). 

Although we opened this chapter by stating that total synthesis played a minimal role in modem structure elucidation, at this point it now constituted the only tool that could finally prove if the structure of diazonamide A was indeed 1. As we shall see, it took just a few months to put this problem to rest, as the Nicolaou group at The Scripps Research Institute was ultimately able to develop not one, but two, completely divergent routes to this revised structure (1) which verified its accuracy. These endeavors are the focus of the remainder of this chapter. 

Having analyzed the Nicolaou group s approaches to diazonamide A at some length on paper, it is now time to see whether or not these strategies could lead to the revised structure of diazonamide A (1) in practice, and, if so, whether it actually was the correct assignment. 

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