UC Berkeley

This dissertation examines the versatility of 2-pyrones as building blocks to access a variety ofring systems that can be applied to the total synthesis of natural products. Direct pericyclic annulations of 2-pyrones, such as [4+2]-cycloadditions and 4π electrocyclizations, have proven to be effective tactics for accessing synthetically versatile bicycles that have been applied, for example, in natural product total synthesis. Alternatively, our lab has been interested in novel annulation strategies enabled by the nucleophilic 1,6- and 1,2-ring openings of 2-pyrones to access myriad ring systems. Chapter 1 of this dissertation is an introduction to these known annulation reactions with 2-pyrones and highlights key areas where additional development is needed. Chapter 2 highlights the evolution of our total syntheses of cephanolides A–D and the application of this route to the total syntheses of ceforalides C, D, F, G, and H. Our synthesis features a [4+2]- cycloaddition with 2-pyrone to quickly build the core of these natural products. The cephanolides and ceforalides are members of a family of cephalotaxus diterpenoids, natural products that have shown a broad range of bioactivity including antitumor and antiviral properties, as well as plant growth inhibition. Chapter 3 highlights a novel benzenoid-to-troponoid conversion of cephanolide A, culminating in a 14-step synthesis of harringtonolide, which has anti-neoplastic and anti-viral properties. This synthesis was guided by computational analysis of the key ring expansion reaction. Chapter 4 describes a novel annulation strategy enabled by the nucleophilic 1,2-ring opening of functionalized 2-pyrones as a general strategy for synthesizing diverse N-heterocycles, including pyrido[1,2-a]indole and carbazole scaffolds. This method was applied to the formal synthesis of three natural products in the fascaplysin family, which have anti-cancer properties. Chapter 5 describes novel syntheses of substituted aromatic rings using a rhodium(I)-mediated cyclization of 1,3,5-dienyne precursors that were accessed from a 1,6-opening of alkynyl 2- pyrones with sodium cyanide. Aromatic rings are highly prevalent in medicines, materials, and bioactive molecules. Chapter 6 focuses on a modular synthesis of aryl amines from alkynyl 2-pyrones accessed via the 1,6-opening of alkynyl 2-pyrones secondary amines. This transformation occurs under mild, nometal- added conditions and this chapter discusses the computational and experimental exploration of the mechanism and scope of this transformation.