The Larock group at Iowa State University will prepare for high throughput screening a large number of libraries of heterocycles and carbocycles expected to exhibit a wide range of biological activity. Three very general synthetic methods primarily developed in the Larock group will be employed. (1) The Pd-catalyzed annulation of alkynes, dienes, alkenes and arynes will be employed to prepare specially diverse libraries of indoles, benzofurans, benzopyrans, coumarins, isocoumarins, phthalides, pyrones, 2-quinolones, pyridines, isoquinolin-1-ones, isoindolin-1-ones, isoquinolines, carbolines, isoindolo[2,1-a]indoles, carbazoles, dibenzofurans and various other heterocycles, plus indenones, indenes, fluoren-9-ones and 9-alkylidene-9Hfluorenes. (2) The cyclization of readily available, functionally-substituted alkynes by halogen, sulfur, selenium and organopalladium electrophiles will be utilized to prepare libraries of medicinally interesting indoles, benzofurans, coumestans, chromones, benzothiophenes, benzoselenophenes, phthalides, isocoumarins, isochromenes, isoquinolines, quinolines, furans, isoxazoles and various spirotrienones. (3) Aryne annulations will be used to prepare xanthones, thioxanthones and acridones. Halogen-containing heterocycles and carbocycles will be further elaborated to more diverse libraries by well known, Pd-catalyzed processes. This methodology is very efficient, tolerates virtually all important organic functional groups, proceeds under mild reaction conditions, affords high yields of very pure compounds, and uses readily available starting materials, reagents and catalysts. Libraries consisting of (20-100 novel, small, densely functionalized, specially diverse compounds will be prepared by this very versatile solution and solid phase chemistry already worked out in the Larock group. Racemic mixtures will be separated by the Armstrong group in Texas and molecular modeling will be carried out by the Lushington group at Kansas University. The resulting libraries will be purified to generally >95% purity using standard laboratory techniques and, if necessary, the high throughput purification techniques available to the PI through the Kansas University Center of Excellence in Chemical Methodologies and Library Development. This methodology will be widely published and the resulting libraries donated to the NIH Molecular Libraries Small-Molecule Repository and the Molecular Libraries Screening Center Network.
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