A new synthetic approach to the C-D ring portion of streptonigrin analogues

Development of an efficient synthesis of the C-D ring portion of streptonigrin is a key operation in the synthesis of this antibiotic and its analogues. A new method for the synthesis of 3-cyano-5,6-dimethyl-4-(3,4,5-trimethoxyphenyl)-2-pyridone (14), a compound having the requisite functionality for conversion into a streptonigrin analogue, has been established. It involves treatment of 3,4,5-trimethoxybenzonitrile with ethylmagnesium bromide and malononitrile to give propylenemalononitrile derivative 7, which is condensed with trimethyl orthoacetate to give a mixture of 9 and pyridine derivative 12. Demethylation of 12 then affords 14. The overall yield for this route was 50%, allowing for conversion of 9 to 12.