Diazonamide 3- indoles

The indole bis-oxazole 120, a potential intermediate for the synthesis of the marine natural product diazonamide A, has been synthesised starting from valinamide 116 and... 

Stille couplings also have been exploited in the synthesis of the aromatic macrocyclic core of diazonamide A (2) [5, 20]. Pattenden s group utilized the Pd-catalyzed coupling between the 3-stannyl substituted indole 23 and the 3-bromooxazole 24 to provide a particularly expeditious route to the ring system 25 [20]. In addition, Harran s group secured the connection between bromooxazole 12 and vinylstannane 26 also using a Stille coupling [5]. 

This oxazole synthesis has been used to prepare some important biologically active compounds such as 3-[2-R-l,3-oxazol-5-yl)indoles (370) (R = Me pimpri-nine R = Et pimprinethine R = Pr WS-30581A] and l-Boc-2-chloro-3-(2-methyl-l,3-oxazol-5-yl)indole, a structural fragment of the cytotoxic marine peptide diazonamide A (371). 

One of the more interesting and structurally complex indole-containing peptides is the previously described diazonamide (A and B) from the ascidian Diazona... 

An elegant photochemical formation of an aryl-carbon bond through a PET mechanism was recently reported in the total synthesis of the potent antimitotic polycycle (-)-diazonamide A. The reaction was initiated by intramolecular electron transfer between the indole chromophore and the adjacent bromoarene (Scheme 2.10). Thus, compound 21 was treated with an aqueous-acetonitrile solution of LiOH and the resulting lithium phenoxide solution was degassed and photolyzed (Rayonet, 300 nm) to yield biaryl 22 (as a single atropodiastereomer) in a good yield. A radical-radical anion pair (23) was formed upon excitation, and... 

Moody and co-workers adapted their rhodium-carbene methodology to prepare 3-(oxazol-5-yl)indoles 154 as model compounds in their approach to diazonamide. In this case, 152 (Ri = Boc) was readily converted to the iV-Boc-diazoacetylindole... 

With intermediate 60 in hand, a key photoinduced HBr elimination furnished the second 12-membered ring and provided intermediate 61. After reductive removal of the spectator phenol through its triflate, selective acylation, indole C-2 chlorination, and treatment with tris(dimethylamino)sulfur trimethyldifluorosilicate, afforded the desbromo diazonamide B (62). Finally, phosphoryl cyanide-mediated condensation with commercial (5)-ot-hydroxyisovaleric acid delivered (-)-diazona-mide A (47) (Scheme 9). 

A new modification of the Chan rearrangement proved to be the basis of a versatile and direct strategy for iterative polyoxazole synthesis suitably exploited for the preparation of the indole-bisoxazole fragment of the complex natural product diazonamide A. Indolyloxazole... 

The species Diazona chinensis, harvested in the Philippines in the upper part of an underwater cave, yielded diazonamides A and B, which are original bicyclic pep-tides with two isoxazoles, a chloroindole, and a fused indole/benzofuran system. X-ray analysis of diazonamide B p-bromobenzamide led to the exact structures, which were confirmed by total synthesis a decade later (Lindquist et al, 1991b Li et al, 2001). Diazonamide A is strongly cytotoxic in vitro to HCT-116 human colon cancer cells with an IC50 of 15 ngml . Diazonamide B is less active. Subsequently, diazonamides C-E were characterized in an imdetermined species of Diazona from Indonesia (Fernandez et al, 2008). 

Bagley, M.C., Hind, S.L., and Moody C.J. (2000) Studies towards the synthesis of diazonamide A. Synthesis of the indole bis-oxazole fragment. Tetrahedron Lett., 41, 6897-6900. 

Magnus, P. and Mclver, E.G. (2000) Synthesis of the dichlorobisoxazole-indole portion of the antitumor agent diazonamide by a putative biogenetic strategy. Tetrahedron Lett., 41, 831-834. 

Lachia, M. and Moody, C.J. (2008) The synthetic challenge of diazonamide A, a macrocyclic indole bis-oxazole marine natural product. Nat. Prod. Rep., 25, 227-253. 

Sperry, J. and Moody, C.J. (2010) Diazonamide studies. A direct synthesis of the indole bis-oxazole fragment from tri- and tetra-peptides using biomimetic oxidative cydizations. Tetrahedron, 66, 6483-6495. 

---