Asymmetric transformations of enolates and azaenolates

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Alcock, Emma
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University College Cork
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Chapter I - The asymmetric α-alkylation of a ketone represents one of the most fundamental reactions in organic chemistry. In 2014, a chiral ligand strategy to furnish enantioenriched α-alkylated ketones was published by the McGlacken group. The yields and enantioselectivities achieved for this transformation were modest. The first section of this thesis outlines efforts to further expand the scope of this methodology and improve the enantioselectivity of this chiral ligand protocol. Whilst a 10% ee was observed for the direct α-alkylation of a ketone, future optimisations focused on the use of N,N-dimethylhydrazones as ketone surrogates. A number of previously unexplored solvents, chiral ligands, hydrazones and electrophiles were examined. However, attempts to improve the enantioselectivity proved unsuccessful. The latter section of this chapter details a number of asymmetric transformations with 2-alkyl pyridines (azaenolate equivalents). Investigations were undertaken to develop new asymmetric aldol and Michael-type reactions for these substrates using chiral amines. Modest enantio- and diastereoselectivities were observed for the aldol reaction. Chapter II - Outlines efforts to develop a continuous flow chemistry protocol for the α-alkylation of a range of simple ketone substrates. Extensive optimisation studies are detailed within this chapter. Continuous flow chemistry proved to be a superior alternative to traditional batch chemistry for this transformation. Advantages of the continuous approach include: i) significantly higher yields; ii) reduced reaction times; iii) increased product purity; iv) more scalable reaction temperatures and v) an increased safety profile associated with the use of hazardous alkyl lithium and alkylating agents. Chapter III - Describes methodology for the synthesis of 3-amino-1,5-diol derivatives with concurrent introduction of up to five contiguous chiral centres in one-pot. Highly functionalised amino alcohol derivatives of challenging substrates such as butanone, 3-pentanone and cyclobutanone were synthesised via an aldol, aldol-Tishchenko reaction of (S)-tert-butanesulfinyl imine derivatives. Modest yields (up to 55%) and excellent diastereoselectivites (up to > 99:1) were achieved for this transformation. The synthetic utility of the compounds synthesised was examined by selective cleavage of the ester and sulfinyl moiety. Finally, the absolute stereochemistry of the major diastereomer was elucidated by X-ray crystallography and mechanistic insight is provided using DFT calculations, through collaboration with Prof Ken Houk.
Asymmetric synthesis , Organic chemistry
Alcock, E. 2023. Asymmetric transformations of enolates and azaenolates. PhD Thesis, University College Cork.