Carbodiimide-mediated preparation of the tricyclic pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine ring system and its application to the synthesis of the potent antitumoral marine alkaloid variolin B and analog.
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.
Molina
Pedro
P
Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Campus de Espinardo, Spain. pmolina@um.es
Fresneda
Pilar M
PM
Delgado
Santiago
S
D000470:Alkaloids / Q000138:chemical synthesis*; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D001372:Aza Compounds / Q000138:chemical synthesis*; D002234:Carbodiimides / Q000737:chemistry*; D020650:Combinatorial Chemistry Techniques; D003500:Cyclization; D007202:Indicators and Reagents; D008698:Mesylates / Q000737:chemistry; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D011743:Pyrimidines / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship
D000470:Alkaloids; D000970:Antineoplastic Agents; D001372:Aza Compounds; D002234:Carbodiimides; D007202:Indicators and Reagents; D008698:Mesylates; D011743:Pyrimidines; C474921:variolin B; C012077:trifluoromethanesulfonic acid