Development of TfOH-Catalyzed Spirocyclization by Intramolecular Friedel-Crafts-type 1,4-Addition: Application to the Total Synthesis of the Unusual Proaporphine Alkaloid (±)-Misrametine

An effective method was developed for TfOH-catalyzed construction of spiroindanes and spirotetralines containing an all-carbon quaternary stereocenter. Intramolecular Friedel-Crafts-type 1,4-addition of the substrates which were di- or trimethoxybenzene and 2-cyclohexenone linked by an alkyl chain proceeded smoothly in the presence of 30 mol % of TfOH. A variety of spiroindanes and spirotetralines were obtained with moderate to excellent yield by this method. The reaction was successfully applied in the first total synthesis of the unusual proaporphine alkaloid (+/-)-misrametine, which included the gram-scale spirocyclization and selective O-demethylation used KCN in DMSO condition as key steps.

Automated summary

An effective method was developed for the construction of spiroindanes and spirotetralines with an all-carbon quaternary stereocenter using TfOH as catalyst. The reaction proceeded smoothly by intramolecular Friedel-Crafts-type 1,4-addition of the substrates, di- or trimethoxybenzene and 2-cyclohexenone, linked by an alkyl chain in the presence of 30 mol% TfOH. This method provided a variety of spiroindanes and spirotetralines with moderate to excellent yields. The reaction was successfully applied in the total synthesis of the proaporphine alkaloid (+/-)-misrametine.