variolin-b and trifluoromethanesulfonic-acid

A total synthesis of the marine alkaloid variolin B has been completed in 13 steps in an overall yield of 6.5% from 3-formyl-4-methoxypyridine. Our approach is based on the sequential formation of the 7-azaindole ring, the tricyclic pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine ring system, and finally installation of the 2-aminopyrimidine ring at C5. The required 7-azaindole ring appropriately substituted is formed by a modified indole synthesis involving a nitrene insertion process (two steps). Formation of the annelated pyrimidine ring is achieved by two routes both involving a carbodiimide-mediated cyclization process, which allow incorporation of the amine functionality at C9 of the core tricyclic (six steps). Installation of the northeast 2-aminopyrimidine ring at C5 is performed using the Bredereck protocol (three steps). Ultimate, thermal decarboxylation with concomitant O-methyl deprotection and further N-benzyl deprotection by the action of triflic acid completed the synthesis of the target natural product variolin B.

Topics: Alkaloids; Antineoplastic Agents; Aza Compounds; Carbodiimides; Combinatorial Chemistry Techniques; Cyclization; Indicators and Reagents; Mesylates; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Pyrimidines; Structure-Activity Relationship