Catalytic enantioselective methods for challenging polar addition reactions

Thesis

Chapter 1 serves as an introduction to the fundamental principles of organocatalysis and enantioselective synthesis. Seminal contributions to the evolution of modern superbase catalysis are discussed.

Chapter 2 describes the development of a novel enantioselective direct aldol reaction catalysed by a bifunctional iminophosphorane. The ability of a BIMP catalyst to activate high-pKa aryl methyl ketone pro-nucleophiles is emphasised against the backdrop of traditional Cinchona and thiourea organocatalysis. The broad downstream utility of the β-hydroxy ketone products is demonstrated, along with an efficient scale-up protocol showcasing catalyst recyclability. Finally, mechanistic considerations are discussed based on NMR studies and reaction observations.

Chapter 3 outlines the development of an efficient aza-Michael addition/condensation strategy for the preparation of enantioenriched 2-pyrazolines. A simple one-pot protocol affords useful heterocycles from readily accessible enones. Highly reactive hydrazines are made amenable to enantioselective catalysis by in situ conversion to the corresponding hydrazone, which subsequently engages in an enantio-determining aza-Michael addition. The Cinchona alkaloid-derived catalyst is recyclable, and the large-scale utility of the method was demonstrated with the preparation of over 80 grams of a product in a single reaction.

Authors: Thomson, CJ

• DOI: 10.5287/ora-ve7m06n6q
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: enantioselective synthesis; Michael addition; organic synthesis; organocatalysis; catalysis
• Subjects: Chemistry; Enantioselective catalysis; Asymmetric synthesis