| Small molecules play important roles in biology, are a major source for biological probes, and can serve as medicines. Diversity-oriented synthesis (DOS) is now developing efficient pathways to small molecules with diverse properties for biological screenings. The aim of DOS is to find modulators for biological pathways and candidates for medicine. In this thesis, a newly developed catalyst system for asymmetric [3+2] cycloaddition of azomethine ylides is first presented which enables the stereoselective synthesis of pyrrolidine derivatives. Based on this methodology a pathway to fused pyrrolidine sublibrary was developed. This sublibrary was then further coupled to a bridged piperidine sublibrary and a spirocyclic oxindole sublibrary utilizing a convergent approach to make small molecule hybrids on the "one bead-one stock solution" platform. The fused pyrrolidine sublibrary was also coupled to other diverse building blocks, including members of the spirocyclic oxindoles, at a larger scale to make compounds for high-throughput screenings. After synthesis the library was formatted and screened in various unbiased biological assays by screeners at the screening facility at the Broad Institute of Harvard and MIT. The screening results from these assays are summarized and analyzed with ChemBank. |
