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

A concise, highly efficient total synthesis of (−)-salicylihalamide A (), 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 , the latter derived from the corresponding α,β-unsaturated carboxylic acid via acyl azide formation and thermal Curtius rearrangement. Two structurally simplified analogs ( and ) were also prepared which displayed significant, but attenuated cell growth inhibitory activity against several human tumor cell lines.