Total synthesis of (-)-salicylihalamide A and related congeners

A concise, highly efficient total synthesis of (-)-salicylihalamide A (1), a novel marine sponge metabolite, has been achieved. Key features of the synthetic strategy include a highly E-selective ring-closing metathesis to construct the 12-membered salicylihalamide A macrocycle and a practical method for installation of the labile ene-hepta-(Z,Z)-dienamide side chain involving N-acylation of enecabarmate, 5, the latter derived from the corresponding a, P-unsaturated carboxylic acid 28 via acyl azide formation and thermal Curtius rearrangement. Two structurally simplified analogs (3 and 4) were also prepared which displayed significant, but attenuated cell growth inhibitory activity against several human tumor cell lines. (C) 2002 Published by Elsevier Science Ltd.