Application of palladium-catalyzed aryl C–H alkylation in total synthesis of (−)-berkelic acid

An unprecedented palladium(II)-catalyzed ortho-alkylation of N-methoxybenzamide with epoxides has been applied to the total synthesis of the isochroman natural product (–)-berkelic acid. Combining this strategy with a well documented spiroacetalization cascade reaction, (–)-berkelic acid is obtained in 13.9% overall yield with the longest linear sequence of 11 steps. The results of preliminary biological studies on the synthesized natural product and its analogues are also reported.