Application of Selective Palladium-Mediated Functionalization of the Pyrido[3′,2′:4,5]pyrrolo[1,2-c]pyrimidine Heterocyclic System for the Total Synthesis of Variolin B and Deoxyvariolin B

The reaction of protected 3-bromo-2-(bromomethyl)-4-methoxypyrrolo[2,3-b]pyridine and tosylmethyl isocyanide (TosMIC) afforded a pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine derivative in good yield. This compound was transformed through installation of the pyrimidine moiety in the C5 position, hydrolysis, and decarboxylation in an advanced intermediate for the total or formal synthesis of the natural alkaloid variolin B. Reaction of 3-bromo-2-(bromomethyl)-4-chloropyrrolo[2,3-b]pyridine with N-tosylmethyl dichloroformimide as a synthetic TosMIC equivalent afforded trihalo-substituted pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine. This compound was used in a new total synthesis of the alkaloid variolin B by selective and sequential C-N, C-C, and C-O palladium-mediated functionalization at the C9, C5, and C4 positions of the pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine system. A formal synthesis of deoxyvariolin B is also described by using the same synthetic strategy.