Palladium-Catalyzed Alkene Difunctionalization to Form Methylene Cyclobutanes, Methylene Cyclopentanes, and Tetrahydroberberines
Year: 2025
Type: dissertation
Abstract: Carbocycles and heterocycles are highly valuable synthetic building blocks, especially when they incorporate functional handles, such as amines. Palladium-catalyzed alkene difunctionalization is a mild and versatile method for the construction of these sought after motifs. This thesis will primarily describe the development of this class of reactions for the synthesis of methylene cyclopentanes, methylene cyclobutanes and tetrahydroberberine (THB) alkaloids/analogs. The first portion of this dissertation is focused on the construction of functionalized carbocycles. Therefore, Chapter 1 outlines the significance of functionalized cyclobutanes and cyclopentanes and developments towards their synthetic construction both by the Wolfe lab and other research groups. This introduction highlights the need for methodologies in which cyclization and functionalization are achieved in the same step. This need is initially addressed in Chapter 2 in which the regiodivergent methods for forming malonate functionalized cyclopentanes and cyclobutanes are summarized and my contributions in the mechanistic investigations are detailed. Chapter 3 expands upon this work by focusing on the development of a regiodivergent 4-exocyclization/functionalization for the synthesis of amine substituted methylene cyclobutanes; including the reaction optimization, substrate scope and mechanistic investigations. The second portion of the thesis targets heterocycles, specifically tetrahydroberberines (THBs). The relevance of this class of natural products and previous synthetic routes to access these molecules are discussed in Chapter 4. Within this chapter, remaining challenges in the field are highlighted; such as the lack of a method that forms the two aliphatic rings of THBs and sets the stereocenter at the same time, and the limited substrate scope due to the electronic demands of existing reactions. Chapter 5 will describe my development of intramolecular palladium catalyzed carboamination to form THB derivatives, which not only offers efficient access to biologically active heterocycles, but is also one of the first examples of carboamination reactions with aliphatic amines. Within this chapter, the development of new chiral phosphite ligands derived from a combination of a TADDOL and a cinchona alkaloid are also described. Overall, this thesis demonstrates that palladium-catalyzed alkene difunctionalization is an efficient strategy to access both carbocycles and heterocycles. As this field develops further, these and similar methods will be applied to a wider range of nucleophiles and electrophiles to access even more biologically active relevant scaffolds.
DOI: 10.7302/25518
Author: Hatt, Jessica
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W4411618753