Development and application of a new class of potent bifunctional organocatalysts

Thesis

This thesis describes the development and application of a new class of bifunctional organocatalysts, incorporating the novel triaryliminophosphorane organosuperbases, for asymmetric synthesis. This thesis seeks to address some of the limitations of organocatalysis, namely long reaction times, high catalyst loadings and poor atom economy was sought. Chapter 2 outlines the design and synthesis of the bifunctional iminophosphorane (BIMP) catalysts such as 1 which were synthesised on gram scale.

Chapter 3 describes the application of the BIMP catalysts to the first general organocatalytic enantioselective ketimine nitro-Mannich reaction. Twenty ketimines 2 were investigated and the β-nitroamine products 3 were formed in up to 97% yield and 95% ee. The reaction was demonstrated on a 10 gram preparative scale with 1 mol% catalyst.

Chapter 4 describes the first organocatalytic enantioselective sulfa-Michael addition of alkyl and benzylic thiols 5 to simple α-substituted α,β-unsaturated esters 6. The reaction required the development of BIMP catalysts such as 4 that incorporated an amide thiourea H-bond donor group. 31 examples were investigated with quantitative yields and up to 96% ee obtained in the formation of β-mercaptoesters 7. Catalyst loadings as low as 0.05 mol% were achieved on a 100 mmol scale.

Chapter 5 describes some structure and stability properties of the BIMP catalysts. The work disclosed in chapter 6 demonstrates the rate enhancements of the BIMP catalysts relative to tertiary amine bifunctional organocatalysts in the key steps of Dixon's total syntheses of nakadomarin A. Rate enhancements of up to 1300 times were observed in related reactions such as the Michael addition of β-amido ester 8 to nitrostyrene 7.

Chapter 7 describes a miscellany of reactions catalysed by the BIMP catalysts to demonstrate the efficacy of the new catalysts. The organocatalytic enantioselective addition of nitromethane to β-substituted α,β-unsaturated esters 10 such as methyl crotonate is disclosed with quantitative yields and enantiomeric excesses up to 73% achieved.

Authors: Farley, A; Dixon, D

• DOI: 10.5287/ora-zg1w1wjrx
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: organocatalysis