Alternative Methylation for the Synthesis of (+)-Perophoramidine

An alternative N1-methylation strategy was reported in the late-stage of the total synthesis of (+)-perophoramidine. Preparation of (+)-perophoramidine was featured by an acid-catalyzed isomerization of amidine 5 to its C?N double bond tautomer 8, followed by two steps of N1-methylation with NaHMDS/MeOTf and oxidation with MnO2. In contrast, direct methylation of amidine 5 afforded the N23-methylation conformers 9a and 9b. Further oxidation of 9a and 9b led to N23-methylated perophoramidine.