CONFORMATIONAL PREFERENCES AND ABSOLUTE-CONFIGURATION OF AGELASTATIN-A, A CYTOTOXIC ALKALOID OF THE AXINELLID SPONGE AGELAS-DENDROMORPHA FROM THE CORAL SEA, VIA COMBINED MOLECULAR MODELING, NMR, AND EXCITON SPLITTING FOR DIAMIDE AND HYDROXYAMIDE DERIVATIVES

The absolute configuration of agelastatin A (1), the major, strongly c ytotoxic alkaloid of the axinellid sponge Agelas dendromorpha from the Coral Sea, is proposed here to be (5aS,5bS,8aS,9aR), as deduced from combined molecular-mechanics calculations and a novel application of e xciton 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.