Traditional high-throughput screening has not delivered on its promise of increasing the numbers of quality new drugs entering the market. This lack of success is due in part to poor quality and the relatively large size of compounds routinely being screened. This problem can be addressed by fragment-based drug discovery, which has proven to be an effective means of producing high quality lead-like compounds for the last ten year. But these fragments have been confined to commercially flat heteroaromatic compounds. Because of their flat nature, the current heteroaromatic fragments do not take full advantage of the chemical space, so the expansion of fragments' chemical space through the preparation of more globular compounds is needed. Diversity-oriented synthesis (DOS) is used in our lab to generate an expanded set of fragments by employing different reactions. To contribute to this collection of DOS fragments, a diastereoselective intramoleuclar oxa-Michael reaction was developed to synthesize morpholine-derived fragments. The developed methodology will be applied to the synthesis other oxa-Michael heterocyclic products. Compounds arising from this methodology possess 3D characteristics found in many naturally occurring small molecules.
PROJECT: Development of Fragments Through a Catalyst-Controlled Diastereoselective Intramolecular Oxa-Michael Reaction
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