Assembly of Four Diverse Heterocyclic Libraries Enabled by Prins Cyclization, Au-Catalyzed Enyne Cycloisomerization, and Automated Amide Synthesis

We describe a unified synthetic strategy for efficient
assembly
of four new heterocyclic libraries. The synthesis began by creating
a range of structurally diverse pyrrolidinones or piperidinones. Such
compounds were obtained in a simple one-flask operation starting with
readily available amines, ketoesters, and unsaturated anhydrides.
The use of tetrahydropyran-containing ketoesters, which were rapidly
assembled by our Prins cyclization protocol, enabled efficient fusion
of pyran and piperidinone cores. A newly developed Au­(I)-catalyzed
cycloisomerization of alkyne-containing enamides further expanded
heterocyclic diversity by providing rapid entry into a wide range
of bicyclic and tricyclic dienamides. The final stage of the process
entailed diversification of each of the initially produced carboxylic
acids using a fully automated platform for amide synthesis, which
delivered 1872 compounds in high diastereomeric and chemical purity.