Exploration and extension of the n-heterocyclic carbene catalyzed anionic oxy-claisen rearrangement

2017-02-27T23:15:47Z (GMT) by Candish, Lisa
N-Heterocyclic carbene (NHC) addition into esters and acyl fluorides provides access to hemiacetal alkoxides and acyl azoliums respectively. Previously, it was demonstrated that NHC addition into an α,β unsaturated enol ester generates a diene containing tetrahedral alkoxide intermediate, which undergoes a rate accelerated anionic oxy-Claisen (AOC) rearrangement. The research detailed in this thesis extends the chemistry of this NHC catalyzed AOC rearrangement. The first chapter provides a brief overview of Lewis base catalysis of ester oxidation state carbonyls. Four common reactive intermediates, accessed via the addition or substitution of a Lewis base into an ester oxidation state carbonyl, are introduced and examples provided to highlight their reactivity. Chapter two details the application of the NHC-catalyzed AOC rearrangement in the enantioselective total synthesis of the iridoid natural product (-)-7-deoxyloganin. Members of this natural product family generally contain a cyclopenta[c]pyranone core, which was accessed via the AOC rearrangement of an enol ester derived from a formyl acetate and a cyclopentyl annulated α,β-unsaturated acyl chloride. Elaboration of the core to the natural product was achieved in four subsequent steps. The third chapter of this thesis describes discovery of the first tandem Brønsted base/Lewis base transformation catalyzed by an NHC. This was realized through the rearrangement of cyclopropyl enol esters to pyranones. Mechanistic studies suggest the reaction proceeds via an NHC-catalyzed electrocyclic ring opening followed by an AOC rearrangement of the resultant α,β-unsaturated enol ester to provide the observed pyranone product. In chapter four, the development of an NHC-catalyzed all-carbon (3+2) annulation is detailed. Rate acceleration of the Claisen rearrangement is achieved using both anionic oxygenation and Ireland-type activation of the 1,5-diene rearrangement precursor. The reaction’s facile nature enables chemoselective Claisen rearrangement in the presence of aldehydic functionality, allowing aldol cyclization of the acyl azolium enolate to provide β lactone fused cyclopentanes in good yield and excellent diastereoselectivity. Chapter five of this thesis describes the development of electron rich, chiral triazolylidene NHCs. Prior to this, NHC activation of acyl fluorides had been achieved using highly nucleophilic, achiral imidazolylidene NHCs. Replacing the N-aryl substituents of various chiral triazolylidenes with a N-tert-butyl substituent provided triazolylidenes capable of activating acyl fluorides. The efficacy of these NHCs was explored utilizing the (3+2) annulation described in Chapter 4, affording β lactone fused cyclopentanes in up to 98% ee. Finally, the sixth chapter contains experimental procedures utilized within this project and the spectroscopic data derived from the compounds introduced in the preceding chapters. 

Awards: Winner of the Mollie Holman Doctoral Medal for Excellence, Faculty of Art, Design and Architecture, [2014].