Development of New Methods Involving Strained Heterocycles
Creators: name: Becker, Marc
Publisher: name: My University
Year: 2021
Subjects: subject: photochemistry
subject: cycloaddition reactions
subject: catalysis
subject: azetidine
subject: Lewis acid
subject: Chemistry
subject: Science

description: Four-membered heterocycles such as oxetanes and azetidines represent a unique class of small, strained rings. These scaffolds are found in a variety of biologically active natural products and also function as important structural building blocks in pharmaceutical products due to their desirable pharmacokinetic properties. However, from a synthetic standpoint, four-membered heterocycles are often considered the most difficult to access in comparison to their smaller, three-membered, as well as their larger, five- and six-membered analogs. Thus, there is a strong demand for the development of new synthetic methods that allow for the synthesis of four-membered heterocycles in an efficient and practical fashion. The synthetic challenges in accessing four-membered rings are commonly associated with their high ring-strain, yet this inherent property provides these scaffolds with unique reactivity that can also be harvested in catalytic transformations. This dissertation discusses the development of new methods for the synthesis of azetidines relying on visible light photocatalysis, as well as investigations into the Lewis acid-catalyzed carbonyl–olefin metathesis reaction that utilizes oxetanes as reactive intermediates. The first chapter of this dissertation studies the divergent reactivity in Lewis acid-mediated transformations between carbonyls and olefins. Herein, it is demonstrated that relatively simple metal salts can achieve remarkable selectivity, resulting in either carbonyl–olefin metathesis or carbonyl–ene reaction products. Furthermore, parametrization of relevant reaction intermediates through DFT calculations allowed for the development of predictive statistical models that provide important insights into the observed divergent reactivity. The second and third chapter of this dissertation discuss the development of new methods for the synthesis of azetidines via visible light-mediated [2+2] cycloadditions. This strategy is advantageous over traditional approaches as it utilizes readily available oxime and alkene precursors that are reacted in a single, highly atom-economic transformation. A method for the synthesis of azetidines via an intramolecular [2+2] cycloaddition is reported herein that proceeds via triplet energy transfer from a commercially available iridium photocatalyst. This reaction utilizes substrates containing styrenes, which possess low triplet energies and are amenable to activation via energy transfer. This intramolecular strategy readily affords highly functionalized azetidine products, yet it cannot be translated into an intermolecular variant due to the limited excited state lifetime of styrenes. Therefore, a new method is presented that relies on 2-isoxazoline-3-carboxylates as a previously unexplored imine reagent. This class of compound can be activated via triplet energy transfer from an iridium photocatalyst to react with unactivated alkenes with high efficiency. This new intermolecular strategy complements the limitations of previous methods for the synthesis of azetidines, and provides facile access to previously inaccessible azetidine scaffolds.