Combinatorial chemistry has had a major impact on organic chemistry, enabling the synthesis of thousands of compounds in parallel, using state-of-art robotics for synthesis, purification and analysis. The benefits are most evident in the pharmaceutical industry where there is a high demand for novel compounds as drug candidates. Library synthesis relies greatly on the use of solid-supported reagents or scavenger resins which afford ease of purification and isolation of the required product. The synthesis of multifunctional cyclohexane-1,3-dione (CHD) I on polystyrene resin, using microwave irradiation in a key step is described. CHD resin I was used for the ‘capture and release’ of a library of amides where both resin acylation and amide release were also accelerated using microwave irradiation. CHD resin was also used as an allyl-cation scavenger resin in the palladium-catalysed deprotection of <i>O</i>-Alloc-alcohols. (Fig. 8497) The preparation of enantiomerically pure compounds is an ongoing challenge for organic chemistry and is especially important in the preparation of drug candidates. CHD resin underwent lipase-catalysed ‘capture and release’, demonstrating an unusual reversal of selectivity. In each case the predominant enantiomer observed was the (<i>R</i>)-(-)-3-phenylbutyryl acryl group rather than the expected (<i>S</i>)-enantiomer, despite the fact that the hydrolases under study showed exclusive selectivity for the (<i>S</i>)-enantiomer in the corresponding solution-phase hydrolysis reactions. The use of dimedone 1,3-enol esters for the screening of hydrolase activity by UV/V is detection of copper-dimedone chelates is also described.

This thesis reports on: 1) the development of two new methods to provoke the translation of the macrocycle along the thread (“shuttling”) in hydrogen bonded, fumaramide-based [2]rotaxanes and 2) the utilization of that movement to provoke a potentially useful response. The fumaramide template is perfectly preorganised to form four intercomponent hydrogen bonds with a benzylic amide macrocycle, affording [2]rotaxanes in “world record” yields. This preorganisation can be disrupted by photo-isomerisation (254 nm) of the E double bond to its Z counterpart. The newly formed maleamide template shows little affinity for the macrocycle. This has previously been exploited to synthesise a light and heat switchable molecular shuttles. A unique tristable molecular shuttle in which the macrocycle can be located in three different “stations” by means of thermal and photochemical stimuli is described in Chapter Two. In Chapter Three an alternative mechanism of shuttling for fumaramide-based molecular shuttles is reported. The reversibility of Diels-Alder chemistry is exploited to synthesise a chemically driven molecular shuttle. A chiral two-station [2]rotaxane in which translational motion of the macrocycle along the thread results in a profound change in its optical properties (CD spectrum) is described in Chapter Four. Finally, a light-switchable optically-addressable molecular shuttle is discussed. A [2]rotaxane with a thread containing a fluorophore and a macrocycle functionalised to quench its fluorescence was synthesised. Shuttling of the macrocycle along the thread switched the fluorescence “on” and “off”.

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The research programme has been concerned with the synthesis and rearrangement of 1,1-dibromocyclopropanes obtained by the addition of dibromocarbene to a number of olefins, including mono and dimethyl substituted styrenes and methyl, ethoxy and aryl substituted dihydronaphthalenes. When passed through a flow system at elevated temperatures (250-450°C) and reduced pressure (>0. 01 mmHz) the cyclopropanes underwent various unimolecuiar rearrangements.

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No description available.

Studies towards the synthesis of the two novel eight membered ring lactone natural products, the cytotoxic octalactin A 1 and octalactin B 2, will be described. (Fig. 10887A). The first part of this thesis discusses the methodology developed for the potential application to a total synthesis of 1 and 2. The key steps include; a boron mediate <I>anti</I> aldol coupling, an <I>E</I>-selective Horner Wadsworth Emmons coupling to give a tri-substituted double bond and a novel samarium-based cyclisation to produce several simple octalactin analogues containing unsubstituted rings (Chapter 2). The second part of this thesis describes an extension of the methodology developed to the stereoselective synthesis of racemic 3, a key fragment in the synthesis of the polyketide halichondramide (Chapter 3). (Fig. 10887B). Finally, the third part of the thesis outlines a synthetic route towards the octalactins based on the previously developed methodology. This includes the asymmetric synthesis of the two major aldehyde fragments 4 and 5 (Chapter 4).

No description available.