Conformational Preferences and Absolute Configuration of Agelastatin A, a Cytotoxic Alkaloid of the Axinellid Sponge Agelas dendromorpha from the Coral Sea, via combined molecular modelling, NMR, and exciton splitting for diamide and hydroxyamide derivatives

The absolute configuration of agelastatin A ( 1 ), the major, strongly cytotoxic alkaloid of the axinellid sponge Agelas dendromorpha from the Coral Sea, is proposed here to be (5a S ,5b S ,8a S ,9a R ), as deduced from combined molecular‐mechanics calculations and a novel application of exciton splitting to the bis[4‐(dimethylamino)benzoyl] compounds (–)‐ 9 and (–)‐ 13 , derivatives of a diamide and a hydroxyamide, respectively. The position of the conformational equilibrium of A 1 could be finely tuned by slight molecular changes. The minor analogue, agelastatin B ( 3 ), was isolated as the trimethyl derivative (–)‐ 4 .