Mechanism Guided Development of Group 10 Mediated Reactions for the Synthesis of Bioactive Scaffolds

Abstract

This dissertation contains several projects that utilize a mechanism-driven approach to developing group 10-catalyzed reactions for the construction of biologically relevant scaffolds. Chapter 1 introduces the mechanism-guided development of two known catalytic reactions at group 10 metals: decarbonylative cross-coupling and directed C–H functionalization. An overview of these two catalytic transformations, previously employed methods for the creation of novel reactions within these spaces, and how these concepts are used in the following chapters are discussed.

Chapter 2 focuses on the discovery, mechanism, and substrate scope of palladium-catalyzed decarbonylative difluorobenzylation of (hetero)aryl boronate esters. Tuning the identity of the organoboron transmetallating reagent and ligand enables a decarbonylative cross-coupling of difluorobenzyl glutarimide electrophiles instead of a known fluoroacylation pathway. Specifically, a neopentyl boronate ester transmetallating reagent, alongside the use of PAd2nBu as the ligand, were found to be optimal for the target transformation. The scope of both nucleophile and fluoroalkyl glutarimide electrophile are investigated. Overall, this transformation provides access to valuable fluoroalkylated arene products from readily available fluoroalkyl carboxylic acids.

Chapter 3 centers around efforts towards four novel decarbonylative cross-coupling methods. In part 1, three transformations are explored for the decarbonylative couplings of C(sp3) carboxylic acid derivatives, which represent an underdeveloped substrate class within the field. These studies reveal that ligand choice and carboxylic acid derivatization play a critical role in enabling intramolecular thioetherification, intermolecular iodination, and intermolecular cyanation of alkyl carboxylic acids. In part 2, a decarbonylative cyanation of bioactive molecules is developed, with a focus on introducing labeled cyanide (13CN and 11CN). Key variables such as reaction time, stoichiometry, and air-stability are carefully manipulated to yield an air-tolerant method for the 13CN labeling of a wide variety of bioactive molecules. Preliminary results show that this method can also be applied to radioactive 11CN labeling for applications in positron emission tomography (PET) imaging.

Chapter 4 examines the C(sp3)–H activation and functionalization of bicyclo[1.1.1]pentanes (BCPs). These are valuable motifs in medicinal chemistry, serving as benzene bioisosteres. However, these compounds have previously failed to undergo C–H activation and subsequent functionalization under otherwise typical C–H functionalization conditions. By breaking down the proposed catalytic cycle into its C–H activation step and C–H functionalization step, unprecedented C(2)-functionalization via this manifold is uncovered. Isolation and investigation of discrete BCP palladacycle intermediates unveil differences between these and other alkyl palladacycles, which provide insight as to why previous attempts at this reaction have failed. These principles are applied to other bicycloalkanes, and preliminary C–H activation and functionalization studies of bicyclo[2.2.2]octane, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, and bicyclo[2.1.1]hexane are conducted and discussed within.

Lastly, chapter 5 summarizes the key findings from chapters 2, 3, and 4. Potential avenues for future work pertaining to the previous chapters are also outlined and discussed within.