Synthetic Studies of the Rubellin Natural Products

Date

2020-12-01T06:00:00.000Z

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Gartman, Jackson Andrew

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Abstract

The effective construction of complex bioactive molecules often requires the development of innovative chemical methods to push the boundaries of organic synthesis. As the utility of available reactions increases, the complexity of possible target molecules increases analogously. This manuscript includes a review of relevant recent natural product syntheses, our studies on the rubellin class of natural products, and our investigation of a rearrangement reaction of reactive iodonium ylide intermediates. First described are select syntheses of complex anthraquinone monomers and dimers within the past 20 years. The scientific community has found deep interest in the anthraquinone class of compounds due to their therapeutic properties and challenging structural elements. Various architecturally beautiful natural products have been successfully synthesized utilizing two main strategies: either an early-stage synthesis of the anthraquinone and further elongation of the system, or a late-stage introduction of the anthraquinone ring moiety. The retrosynthetic disconnections that shape the anthraquinone-installation strategy are emphasized. The second and major chapter describes our studies of the anthraquinone-based rubellin natural products through various synthetic routes and our stereoselective total synthesis of (+)-rubellin C. The synthesis of a rubellin family member represents a synthetic landmark in anthraquinone natural products, as successful total synthesis has evaded the synthetic community since their isolation almost forty years ago. Our synthesis has allowed for preliminary investigation of the reported biological activity of these compounds on the intracellular protein tau, a therapeutic target for Alzheimer's Disease and other neurodegenerative tauopathies. Thirdly, part of our foray into the selective rearrangements of allylic iodonium ylide species is described, in particular our utilization of ligand design to control the selectivity of these rearrangements. We examine the allylic iodonium ylide species, a reactive intermediate that can undergo many uncontrolled processes. In the presence of a metal catalyst and devised ligand, we can modulate the selectivity of this process to generate useful products.

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