title: Biomimetic diversity-oriented synthesis of benzannulated medium rings via ring expansion.
abstract: Nature has exploited medium-sized 8- to 11-membered rings in a variety of natural products to address diverse and challenging biological targets. However, owing to the limitations of conventional cyclization-based approaches to medium-ring synthesis, these structures remain severely underrepresented in current probe and drug discovery efforts. To address this problem, we have established an alternative, biomimetic ring expansion approach to the diversity-oriented synthesis of medium-ring libraries. Oxidative dearomatization of bicyclic phenols affords polycyclic cyclohexadienones that undergo efficient ring expansion to form benzannulated medium-ring scaffolds found in natural products. The ring expansion reaction can be induced using three complementary reagents that avoid competing dienone-phenol rearrangements and is driven by rearomatization of a phenol ring adjacent to the scissile bond. Cheminformatic analysis of the resulting first-generation library confirms that these molecules occupy chemical space overlapping with medium-ring natural products and distinct from that of synthetic drugs and drug-like libraries.
authors.affiliation: Tri-Institutional Training Program in Chemical Biology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Renato A
authors.initials: RA
authors.lastname: Bauer
authors.forename: Todd A
authors.initials: TA
authors.lastname: Wenderski
authors.forename: Derek S
authors.initials: DS
authors.lastname: Tan
mesh_terms: D001688:Biological Products / Q000737:chemistry; D032701:Biomimetics; D003500:Cyclization
chemical_list: D001688:Biological Products