Total Synthesis of the Cytostatic Marine Natural Product Dibromophakellstatin Via Three-component Imidazolidinone Anellation

The tetracyclic pyrrole-imidazole alkaloid dibromophakellstatin from the marine sponge Phakellia mauritiana has been synthesized within seven steps from pyrrole in an 18% overall yield. The key step is a three-component assembly of a tricyclic enamide, a nitrene, and a carbamoyl building block, affording the imidazolidinone ring of dibromophakellstatin in one step. Notably, it is possible to employ the reagent EtO2CNHOTs in a double function as a source of the electrophilic nitrene and of a dipolar carbamoyl component. Use of debrominated precursor dipyrrolopyrazinones leads to much higher anellation yields and allowed us to develop a second generation synthesis. The cytostatic activity of dibromophakellstatin is confirmed.