Solution Phase Synthesis of Libraries of Polycyclic Natural Product Analogues by Cascade Radical Annulation:  Synthesis of a 64-Member Library of Mappicine Analogues and a 48-Member Library of Mappicine Ketone Analogues

An improved cascade radical annulation route to (+/-)-mappicine, (S)-mappicine, and mappicine ketone is reported. The route is used to prepare libraries of mappicine and mappicine ketone analogues in a semiautomated fashion. Key diversity generating steps include the addition of an aldehyde to a Grignard reagent derived from a D-ring iodopyridine, N-propargylation of a subsequently derived iodopyridone, and cascade radical annulation with an isonitrile to form a mappicine analogue. Parallel oxidation of mappicine analogues produced mappicine ketones. The route is general and flexible and could be used to make very large libraries. It is also illustrative of how late stage cascade reactions can be employed strategically to generate libraries of polycyclic natural product analogues.