Diversity-oriented synthesis of alkaloids for chemical genetic screening

In forward chemical genetic screens the nature of the interaction between a small molecule and its protein target cannot be foreseen. It is therefore advantageous to screen compounds that present functional groups as differently as possible. Diversity-oriented synthesis is a means of generating structurally complex small molecules for screening in biological assays. The work presented in this dissertation describes two diversity-oriented syntheses of alkaloids with an emphasis on developing rapid methods of accessing natural product-like compounds in sufficient quantity and high purity. The first strategy is based on the reactivity of dihydropyridine and dihydroisoquinoline enamines, which undergo a number of cyclization reactions to yield distinct polycylic compounds. A library of compounds was synthesized based on this method and was submitted to the Broad Institute for screening. Additionally, an enantioselective, catalytic method of adding terminal alkynes to isolated alkyl iminium ions was developed to control the absolute stereochemistry of the library products. A second diversity-oriented synthesis pathway was investigated, in which rationally-designed aziridines containing latent coupling partners are opened via nucleophilic addition to yield intermediates that undergo a variety of rigidifying cyclizations.