An ion-binding approach to asymmetric allylation reactions

Ion-binding organocatalysis is an emerging field that has the potential to control the stereochemical outcome of any transformation that goes via charged intermediates. The aim of this project was to explore how this concept could be applied to an asymmetric allylation reaction. Chapter 2 of this thesis discusses anion-binding catalysis and investigates a chiral cooperative thiourea catalyst that could bind to fluoride to control allylation using an allylsilane. Optimization using a non-chiral thiourea (Schreiner’s catalyst) demonstrated that the reaction proceeded in high yield with TBAT onto an N-benzoylhydrazone. A chiral cooperative thiourea catalyst library was then synthesized but unfortunately, although the allylation using these catalysts proceeded in excellent yield, the product was isolated as the racemate (Scheme 1). Scheme 1: Anion-binding catalysis gave allylated products in high yields but gave no stereocontrol. Chapter 3 examines a chiral quaternary ammonium fluoride as an example of chiral cation-directed catalysis. We hypothesized that an allylsilane activated by fluoride would generate an allyl anion species that would associate with the chiral quaternary ammonium cation through electrostatic interactions. Extensive optimization found that the allylation reaction proceeded in good yield in chloroform at reflux with N-benzoylhydrazones. Different fluoride catalysts were prepared using an ion-exchange resin, and cinchonidine-derived catalysts performed the best. This methodology was extended to a phase-transfer catalyzed process, where solid cesium fluoride exchanged with chloride in situ, removing the need to synthesize and isolate ammonium fluoride catalysts (Scheme 2). Scheme 2: Cation-directed asymmetric allylation. In Chapter 4 cation-directed asymmetric catalysis was extended to an intramolecular allylation reaction. Substrate synthesis was attempted by cross metathesis but the reaction was capricious and yields were low. Intramolecular allylation with these materials gave promising results (Scheme 3) but a lack of material prevented optimization. Scheme 3: Intramolecular allylation results.