Studies in asymmetric synthesis: I. the asymmetric α-alkylation of N,N-dimethylhydrazones II. the asymmetric aldol-Tishchenko reaction of (S)-tert-butanesulfinyl imines for the introduction of 2, 3, 4 and 5 new chiral centres in one pot
University College Cork
This thesis is split into two sections based on two different areas of research. Part 1 The asymmetric α-alkylation of ketones is one of the most fundamental yet challenging transformations in organic chemistry. Recently a new methodology to furnish enantiomerically enriched α-alkylated ketones was developed within the McGlacken group using N,N-dimethylhydrazones as ketone synthetic equivalents and the chiral diamine sparteine. The first section of this thesis outlines efforts to further expand the scope of this methodology to include more diverse and challenging electrophiles. As a result, a number of synthetically useful ketones were prepared. Investigations were also performed in an attempt to improve the enantioselectivity of this system. This included examining a number of reaction parameters such as changing the chiral diamine, investigating different organolithium/(+)-sparteine and (+)-sparteine surrogate complexes and exploring different solvent combinations. The final section of this chapter examines the use of sub-stoichiometric amounts of chiral ligand in the asymmetric α-alkylation of hydrazones. While a number of important insights were gathered into this methodology, attempts to improve the enantioselectivity proved unsuccessful. Part 2 Part 2 of this thesis outlines the enantio- and diastereoselective synthesis of anti-1,3-amino alcohol derivatives using an aldol-Tishchenko reaction. A range of acetophenone and propiophenone derived anti-1,3 amino alcohols was synthesised using N-tert-butanesulfinyl imines. A number of potential aldol acceptors including aldimines and a formaldehyde equivalent were examined. A challenging yet successful, scale-up of an aldol-Tishchenko reaction is also reported. The final section of this thesis describes the development of a remarkable novel methodology to synthesize 3-amino-1,5-diol derivatives with the simultaneous introduction of four and five chiral centres in one pot. Cyclopentanone, cycloheptanone and 2-butanone derived 3-amino-1,5-diol products were isolated in excellent diastereoselectivity (up to >98:2 dr) via a tandem double aldol-Tishchenko reaction. A broad range of meta- and para-substituted benzaldehydes including a number of challenging aldol acceptors was examined under the reaction conditions. Mechanistic studies were also performed using DFT calculations through a collaboration and a summary of the results of these investigations are presented. Finally, derivatisation of the double aldol-Tishchenko products was investigated.
Asymmetric α-alkylation , N-dimethylhydrazones , N , Aldol-Tishchenko reaction , Anti-1 , 3-Amino alcohol derivatives , Double aldol-Tishchenko reaction , 3-Amino-1 , 5-Diol derivatives , Contiguous chiral centres , DFT , (-)-Sparteine
Mackey, P. 2020. Studies in asymmetric synthesis: I. the asymmetric α-alkylation of N,N-dimethylhydrazones II. the asymmetric aldol-Tishchenko reaction of (S)-tert-butanesulfinyl imines for the introduction of 2, 3, 4 and 5 new chiral centres in one pot. PhD Thesis, University College Cork.