Synthesis and Preliminary Evaluation of a Library of Polycyclic Small Molecules for Use in Chemical Genetic Assays

(-)-Shikimic acid, 3, was converted into both enantiomers of epoxycyclohexenol carboxylic acid, 7, which were attached to a solid support via a photocleavable linker. Tandem acylation-1,3-dipolar cycloaddition with nitrones 11a-g yielded tetracyclic templates 12a-g. After development of several efficient coupling reactions of iodobenzyl tetracycles 12b-d and completion of extensive validation protocols, a splitpool synthesis yielded a binary encoded library calculated to contain 2.18 million polycyclic compounds. These compounds are compatible with miniaturized cell-based “forward” chemical genetic assays designed to explore biological pathways and “reverse” chemical genetic assays designed to explore protein function. As a simple illustration of the potential of these compounds, several were shown to activate a TGF-â-responsive reporter gene in mammalian cells.