Transition metal-based strategies have the potential to provide nontraditional solutions to issues critical to the continuing advancement of the science of combinatorial library synthesis. The rich and unique chemistry of transition metal complexes will allow the metal to perform various roles in the process of library generation.
Subproject I focuses on the design of a recyclable, chiral palladium(0)-based linker/scaffold. Organic substrates will be attached to solid supports via two carbon-palladium bonds, generating selectively either enantiomer of a palladium-bonded stereogenic carbon from a single enantiomer of the linker. Subsequent insertion of unsaturated building blocks will afford organic products in a high enantiomeric purity, and allow for the recovery and recycle of the supported palladium(0) complex. This stereodivergent methodology will be validated by the synthesis of combinatorial libraries featuring nonracemic 1,2-dihydroquinolines, 2H-1-benzopyrans and pyrrolo[1,2-a]quinolines.
Subproject II proposes to develop solid-supported palladium(II) and platinum(II) catalysts for electrophilic activation and subsequent functional elaboration of aromatic C-H bonds. Furthermore, the long-standing problem of adapting eletrophilic aromatic substitutions to solid-phase synthesis will be addressed by screening and modification of the existing acid-stable resins and linkers. The new solid-phase methodology will be used to establish a synthetically powerful sequence of palladium(II)-palladium(0) catalyzed reactions for the generation of diverse arylated libraries.
Subproject III aims to develop a novel, highly practical and general iodocyclication protocol for the generation of an array of 1-iodo-2-aryl-substituted heterocycles. Building blocks with this motif will be further diversified by three alternative palladium-catalyzed cross-coupling and/or annulation processes that generate multiple new carbon-carbon bonds. The two-step sequence of idocyclization/palladium-catalyzed annulation will be applied to both solution and solid-phase synthesis of combinatorial libraries of diverse heterocycles.
