Palladium-mediated C-N, C-C, and C-O functionalization of azolopyrimidines: a new total synthesis of variolin B

A new total synthesis of the alkaloid variolin B is achieved by a selective and sequential palladium-mediated functionalization of a trihalo-substituted pyrido[30 ,20 :4,5]pyrrolo[1,2-c]pyrimidine. This intermediate is obtained by a new heterocyclization reaction between an appropriate bromomethyl azaindole and N-tosylmethyl dichloroformimide. The methodology may be effective for the synthesis of some analogs by substitution on the relatively unexplored C4 and C9 positions of the alkaloid.The authors acknowledge financial support from the Spanish Ministerio de Educación y Ciencia (project CTQ2005/011060/BQU), Comunidad de Madrid (CAM), and Universidad de Alcalá (UAH) (project CCG-UAH/ SAL-0660) and a grant from the Ministerio de Educación y Ciencia (A.B.)