Efficient Solvent-Free Robinson Annulation Protocols for the Highly Enantioselective Synthesis of the Wieland-Miescher Ketone and Analogues

A highly efficient (93% overall yield) and enantioselective (94% ee) synthesis of the Wieland-Miescher ketone (10-g scale) through a solvent-free Robinson annulation procedure is reported. The process involves only I mol% triethylamine as the base in the initial Michael process and the organocatalyst N-tosyl-(S-a)-binam-L-prolinamide (2 mol%) and benzoic acid (0.5 mol%) for the intramolecular aldol process. This green protocol is applied to a wide range of valuable building block analogues of the Wieland-Miescher ketone (10 examples). Among these, a noteworthy compound for terpene synthesis is the 8a-allyl derivative, which is prepared in 93% yield and 97% ee in a process allowing the recovery and reutilization of the organocatalyst. Furthermore, a one-pot, two-step process has also been developed.