The pyrrole-alkaloid family of natural products represents a wide range of biological activities, making the synthesis of these types of scaffolds a worthy endeavor. Of particular interest to our lab is the inhibitory activity of some of these natural products towards the human 20S proteasome, a validated target for the treatment of specific cancer including multiple myeloma and mantle cell lymphoma. With this in mind, the synthesis of scaffolds which bear structural similarity to these natural products was endeavored. Herein, the synthesis of pyrrole-alkaloid-like scaffolds is represented in several approaches: small molecule design of bromoindolophakellstatins, methodology development, and total synthesis. The development of a novel Rh(III)-catalyzed C-H activation/annulation between 2-imidazolones and N-pivaloyloxybenzohydroxamates is reported, which facilitates access to urea-fused tetrahydroisoquinolone scaffolds which are reminiscent of members of the pyrrole-alkaloid family. Efforts towards the syntheses of bromoindolophakellstatin small molecules is also described. Lastly, route development towards the total syntheses of nagelamide M and the ugibohlin natural products and the particular challenges associated with these approaches are discussed.
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