New methods for the asymmetric synthesis of α-alkylated ketones and 1,3-amino alcohols

A large number of optically active drugs and natural products contain α-functionalised ketones or simple derivatives thereof. Furthermore, chiral α-alkylated ketones are useful synthons and have found widespread use in total synthesis. The asymmetric alkylation of ketones represents one of the most powerful and longstanding procedures in organic chemistry. Surprisingly, however, only one effective methodology is available, and this involves the use of chiral auxiliaries. This is discussed in Chapter 1, which also provides a background of other key topics discussed throughout the thesis. Expanding on the existing methodology of chiral auxiliaries, Chapter 2 details the synthesis of a novel chiral auxiliary containing a pyrrolidine ring and its use in the asymmetric preparation of α-alkylated ketones with good enantioselectivity. The synthesis of racemic α-alkylated ketones as reference standards for GC chromatography is also reported in this chapter. Chapter 3 details a new approach to chiral α-alkylated ketones using an intermolecular chirality transfer methodology. This approach employs the use of simple non-chiral dimethylhydrazones and their asymmetric alkylation using the chiral diamine ligands, (+)- and (-)-sparteine. The methodology described represents the first example of an asymmetric alkylation of non-chiral azaenolates. Enantiomeric ratios up to 83 : 17 are observed. Chapter 4 introduces the first aldol-Tishchenko reaction of an imine derivative for the preparation of 1,3-aminoalcohol precursors. 1,3-Aminoalcohols can be synthesised via indirect routes involving various permutations of stepwise construction with asymmetric induction. Our approach offers an alternative highly diastereomeric route to the synthesis of this important moiety utilising N-tert-butanesulfinyl imines in an aldol-Tishchenko-type reaction. Chapter 5 details the experimental procedures for all of the above work. Chapter 6 discusses the results of a separate research project undertaken during this PhD. 2-alkyl-quinolin-4-ones and their N-substituted derivatives have several important biological functions such as the role of Pseudomonas quinolone signal (PQS) in quorum sensing. Herein, we report the synthesis of its biological precursor, 2-heptyl-4-hydroxy-quinoline (HHQ) and possible isosteres of PQS; the C-3 Cl, Br and I analogues. N-Methylation of the iodide was also feasible and the usefulness of this compound showcased in Pd-catalysed cross-coupling reactions, thus allowing access to a diverse set of biologically important molecules.

An investigation into reactivity and selectivity in cycloadditions of 1,3-dipoles with formamidines

The objective of this research was to investigate the synthesis of nitrile oxides and to study their reactivity in 1,3-dipolar cycloadditions with formamidines. Chapter one looks at the literature surrounding the 1,3-dipolar cycloaddition reaction. It explores the generation of 1,3-dipoles (mainly nitrile oxides) and dipolarophiles (predominantly amidines). It discusses the potential synthetic uses of the 1,3-dipolar cycloadducts. It examines both and inter- and intra-molecular cycloaddition reactions. It recognises the use of the 1,3-dipolar cycloadditions as a successful method in building natural products and oxadiazolines. The decomposition of oxadiazolines as a route to nitriles is also outlined in this chapter. Chapter two discusses the results of this research candidate. The preparation of nitrile oxide precursors - hydroximoyl halides - is outlined at first. The generation of nitrile oxides is then demonstrated, followed by the preparation of furoxans. Methods for preparing the reference materials (nitriles and ureas), which result from decomposition of oxadiazolines, then follow. The preparation of series of Δ2-1,2,4- oxadiazolines via the 1,3-dipolar cycloaddition reaction is illustrated in this chapter. The selectivity of the addition of nitrile oxides to dipolarophiles was tested by competition reactions, which are also described in this chapter. NMR techniques were used in the study of the kinetics of the 1,3-dipolar cycloadditions used for the preparation of a series of Δ2-1,2,4-oxadiazolines, which is addressed in this chapter. Chapter three charts the experimental procedures followed to gain results which are discussed in chapter two. It also outlines all analytical data produced during the course of this research.