Development of sustainable catalytic methods for organic synthesis

Abstract

This thesis covers two separate projects, but both of which can be linked by the overall aim to develop sustainable catalytic methodology for use in organic synthesis. A concerted effort has been made to move away from procedures within organic chemistry that use non-renewable expensive and toxic materials as reagents and catalysts, particularly those containing second and third row transition metals, and instead to develop processes that utilise sustainable, abundant and inexpensive reagents, such as base-metals and main group elements. The first project was the attempted development of an oxidative ring contraction of aromatic compounds, with the goal of applying it in the biomimetic total synthesis of fatouapilosin. The second project concerned the development of the borane-catalysed enantioselective hydroboration and reduction of propargylic ketones. Chapter 1 is an introduction to the first project, giving details regarding the isolation and proposed biosynthetic route to fatouapilosin, as well as giving an overview of the area of biomimetic total synthesis. The oxidative ring contraction reaction, the use of iron and copper for oxidation of organic compounds, and the potential of phenols as a renewable source of carbon are also discussed. Chapter 2 describes the first total synthesis of the coumarin natural product brosiparin, an important precursor in the proposed synthesis of fatouapilosin, which was the planned substrate on which to develop a method of oxidative ring contraction. Brosiparin was successfully prepared in a three-step procedure from pyrogallol, with an initial double demethylation followed by an O-prenylation, then a tandem Wittig olefination/para- Claisen rearrangement/lactonisation sequence. Chapter 3 focuses on the oxidation chemistry of brosiparin, and the efforts to develop a reliable method of oxidative ring contraction. Unfortunately trials with a wide variety of oxidising agents, including iron and copper catalysts, did not result in the desired transformation. The use of phenyliododiacetate (PIDA) enabled us to access a masked ortho-quinone compound, from which further reactions were attempted, including an interesting aryl-aryl coupling reaction, but the unprotected ortho-quinone proved very unstable and difficult to work with. Chapter 4 covers the second project, and starts with a broad introduction to the area of hydroboration, followed by a more focused look at enantioselective hydroboration and reduction of ketones. The successful development of an enantioselective reduction of propargylic ketones using substoichiometric myrtanyl borane with stoichiometric HBpin is then described. The reaction was shown by 1H and 11B NMR studies to proceed via a transborylation mechanism, and was applied to other propargylic ketone substrates.