Total synthesis of ageladine A

Sorry for the lack of post last week but I was very busy.
In reading the ASAP of JOC, I found a very interesting paper from Weinreb (ok he has already published on this topic) describing the total synthesis of ageladine A with a 6-pi-1-aza-triene eletrocyclization for the formation of the pyridine ring as key step.




More precisely with the electrocyclization of chloromethoxyimine (synthesized in a single step from a carboxylic acid using carbontetrachloride/PPh3, Methoxyamine hydrochloride with pyridine in acetonitrile with a good yield of 87%) by heating the solution in o-xylene in 150°C to afford the chloropyridine in 84% yield. I find amazing, the first tranformation because starting from a carboxylic acid to chloromethoxyimine, it is possible to achieve different type of reactions, electrocyclization as depicted here, but also cross-coupling reeactions on the chlorine, and certainly synthesize others heterocycles.

Further substitutions, deprotection and a cross-coupling on the chloropyridine have provided the ageladine A as well as analogues for biological evaluation. Interestingly, the synthesis of the imidazole precursor has been synthesized from the tribromoimidazole by sequencial regioselective bromine lithium exchange.

Application of a 6-1-Azatriene Electrocyclization Strategy to the Total Synthesis of the Marine Sponge Metabolite Ageladine A and Biological Evaluation of Synthetic Analogues

Matthew L. Meketa, Steven M. Weinreb, Yoichi Nakao, and Nobuhiro Fusetani

JOC, 2007, ASAP