UC Berkeley

Strategies aimed at the diversification of saturated cyclic amines are appealing due to theprevalence of such aza-cyclic scaffolds within biologically active small molecules. The following dissertation discusses the development of complementary strategies related to this endeavor, specifically those involving peripheral functionalization, topological diversification, and skeletal editing.

Chapter 1 begins with a brief introduction into heterocycle editing. In this chapter, a classificationscheme with related nomenclature is provided. From here, each molecular editing subclass is further contextualized by discussing the motivations for these respective areas of investigation. An overview of the state-of-the-art techniques utilized for these transformations is also highlighted.

Chapter 2 then describes our initial efforts toward the peripheral functionalization of cyclic aminesusing inherently strained ring systems. Under visible light irradiation, we achieve a Norrish–Yang cyclization, generating N-fused bicyclo a-hydroxy-b-lactams. The resulting strain embedded in these heterocycles is further exploited to achieve mild cross-couplings, arriving at peripherally functionalized saturated aza-cycles. Notably, this work represents the first palladium catalyzed C– C cleavage/functionalization of a-hydroxy-b-lactams.

Chapter 3 discusses our work toward the topological diversification of amine frameworks. Here,we present a general method for bridged bicyclic amine formation based on Hofmann–Loffler– Freytag reactivity. In our C–H bond amination strategy, we identified the distinct roles of light and heat activation, providing evidence that light promotes N–I bond homolysis and HAT, whereas heat promotes SN2 ring closure. The expansion of this strategy to fused and spirocyclic bicyclic amines is also reported.

Lastly, Chapter 4 details our most recent work related to the skeletal editing of heterocycles.Through the strategic application of a Norrish type II reaction, we established a versatile method for the ring contraction of piperidines as well as other saturated heterocycles. Initial computational insight also led to development of an asymmetric contraction variant using chiral phosphoric acids.