Neolamellarin A, a metabolite isolated from the sponge Dendrilla nigra, was found to inhibit hypoxia-inducible factor-1 (HIF-1) activation by 26% at 10 microM concentration and inhibition of HIF-1 has become a major antitumor molecular target. Herein the first synthesis of neolamellarin A is described. The synthetic strategy features the condensation of vinylogous amide with aminomalonate to construct the 3,4-bis(4-methoxyphenyl)-1H-pyrrole core and the subsequent acylation and deprotection rendered the target compound in 18% over all yield.