title: Assembly of four diverse heterocyclic libraries enabled by Prins cyclization, Au-catalyzed enyne cycloisomerization, and automated amide synthesis.
abstract: 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.
authors.affiliation: Chicago Tri-Institutional Center for Chemical Methods and Library Development, Department of Chemistry, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Jiayue
authors.initials: J
authors.lastname: Cui
authors.forename: David I
authors.initials: DI
authors.lastname: Chai
authors.forename: Christopher
authors.initials: C
authors.lastname: Miller
authors.forename: Jason
authors.initials: J
authors.lastname: Hao
authors.forename: Christopher
authors.initials: C
authors.lastname: Thomas
authors.forename: JingQi
authors.initials: J
authors.lastname: Wang
authors.forename: Karl A
authors.initials: KA
authors.lastname: Scheidt
authors.forename: Sergey A
authors.initials: SA
authors.lastname: Kozmin
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D003500:Cyclization; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D050607:Organogold Compounds / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000577:Amides; D006571:Heterocyclic Compounds; D050607:Organogold Compounds; D054852:Small Molecule Libraries