Enantioselective Synthesis of Caprolactam and Enone Precursors to the Heterocyclic DEFG Ring System of Zoanthenol

The enantioselective synthesis of both caprolactam and enone synthons for the DEFG ring system of zoanthenol are described. The evolution of this approach proceeds first through a synthesis using the chiral pool as a starting point. Challenges in protecting‐group strategy led to the modification of this approach beginning with (±)‐glycidol. Ultimately, an efficient approach was developed by employing an asymmetric hetero‐Diels–Alder reaction. The caprolactam building block can be converted by an interesting selective Grignard addition into the corresponding enone synthon. Addition of a model alkyne provides support for the late‐stage addition of a hindered alkyne to the caprolactam building block. The syntheses of two synthons for the heterocyclic core of the marine alkaloid zoanthenol are described. These fragments can be generated in a divergent manner from the product of an enantioselective hetero‐Diels–Alder reaction. Judicious selection of protecting groups allows control of a key Grignard reaction to form the enone synthon. The feasibility of the caprolactam as a synthon is validated.