Scalable Synthesis of Cantharidin: Lithium Iodide as a Stereoselective and Efficient Catalyst in the Diels–Alder Reaction toward a Key Intermediate

A unique set of water- and air-tolerant conditions has been developed for the Diels–Alder cycloaddition, leading to a key intermediate in the preparation of synthetic cantharidin (CNR). Lithium iodide acts as an exceptional catalyst, enabling excellent conversion efficiency of the reaction along with the highest stereoselectivity (exo-selectivity) reported to date. The optimized reaction parameters were supported through a Design of Experiments (DoE) study. Moreover, we report here for the first time a crystallization-based isolation protocol, allowing us to obtain a pure exo-isomer key intermediate, free from byproducts and residual salt. Furthermore, the developed isolation conditions give the possibility of a dedicated recovery procedure for lithium iodide to further enhance the cost efficiency of the overall process. The entire synthesis was successfully scaled to the hundred-gram level using straightforward reactions and isolation procedures.