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Over the past two decades, chiral synthesis and separation have grown in importance, particularly in pharmaceuticals, where gross differences in pharmacological behaviour can occur between the enantiomers of a compound. The most tragic example is that of the racemic sedative, thalidomide. Widely used by pregnant women in the 1960's, it was the cause of deformity in many of their children. Under certain circumstances, only the S-(-)-enantiomer produces the teratogenic effect. The search for specific information on the effects of different enantiomers and increasing attempts to prepare enantiomerically enriched compounds has led to a large demand for enantioselective analytical methods. The two most widely employed techniques are NMR spectroscopy and chromatography. My research at the Open University focused on reagents based on silicon which could be used for derivatisation with the facility of the ubiquitous trimethylsilyl (TMS) reagents. I have investigated chiral chiorosilanes, in racemic form, to derivatise nucleophilic analytes. Because of the symmetry properties of some of the chiral silicon reagents prepared, the stereochemistry of the products is not dependent on the mechanism of reaction between an analyte and the reagent. The reagents were assessed by derivatising three chiral alcohols, which were used as model analytes: (1R, 2S, 5R)-menthol, 2-octanol and 1-phenylethanol. Chloromethylphenylsilane produced derivatives that were well resolved by GC, but was considered a poor choice of reagent on the grounds of its instability to racemisation and the instability of the diastereoisomeric products. 1 -Phenylethylchlorodimethylsilane gave derivatives that were well distinguished by NMR, while only partial separation by HPLC was obtained from the 2-octanol and 1-phenylethanol derivatives. No GC separations were achieved from this reagent. Two reagents possessing pseudo-C 2 symmetry, bis(1-phenylethyl)chloromethylsilane and 1 -chloro-1-methyl-2,5-diphenylsilacyclopentane were also unsuccessful in GC analysis, but the latter provided some promise for NMR analysis, with the derivatives of menthol being particularly well resolved.

The task of creating an all carbon quaternary centre, bearing an alkyl moiety with differentiated functionalities and substituents is a desired key step in organic synthesis. A variety of endeavours by research groups have lead to the construction of stereogenic quaternary centres, albeit with narrow scope of substrate. Despite the repertoire of transition metals/ligand, chiral auxiliaries and reagents available at hand, efficient enantioselective and organocatalytic methodologies for the construction of all carbon quaternary centres still remains a daunting challenge for synthetic chemists. One of the most popular methods to install a quaternary centre is via a conjugate addition, the addition of a chiral tertiary enolate to an electron deficient alkene or carbonyl compound has led to high levels of synthetic accomplishment over generations. Our strategy to assemble such quaternary centres focused on an organocatalytic tandem. Michael-aldol reaction, as an efficient one-pot strategy to install vicinal quaternary centres with good levels of enantioselective induction. Initial 1, 4-conjugate addition of the nucleophile with <i>a</i>-acrolein type Michael acceptors generates the enolate, which is now set up to undergo an intramolecular aldol reaction providing the desired molecules. Molecular complexes of this class are also amenable to further catalytic transformations and synthetic elaborations. This thesis presents our investigations towards organocatalytic enantioselective strategies for the assembly of fully substituted quaternary centres.

Chapter 1 presents the most relevant literature in the fields of borane, carborane and metallacarborane chemistry, providing the reader with an overview of these topics. The area of supraicosahedral (hetero)carborane chemistry is covered in detail, focusing on the instability of reduced carborane dianions towards re-oxidation. Chapter 2 reports the attempted stabilisation of reduced carborane dianions by control of the cage carbon atom movement. The design and preparation of a rigid tether and its attachment to meta-carborane are presented, accompanied by a detailed study of the reduction chemistry of the unprecedented tethered carborane formed. Chapter 3 introduces the concept of reduced carborane stabilisation by inductive effects. A series of novel carboranes bearing electron withdrawing fluorinated aryl groups is reported. The influence of these substituents is investigated in detail by computational, structural, spectroscopic and electrochemical studies in order to select the best carborane precursor for polyhedral expansion chemistry. Chapter 4 describes the polyhedral expansion of selected carboranes. The synthesis and characterisation of a series of novel supraicosahedral species are presented, together with an exhaustive discussion of the effect of fluorinated aryl groups in polyhedral expansion chemistry. Chapter 5 gives full details of the experimental procedures undertaken and also provides spectroscopic and analytical data for all the new compounds reported herein. Appendix 1 provides details of the crystal structure determinations of compounds synthesised. Appendix 2 (provided on compact disc) gives the appropriate crystallographic files in RTF and CIF format.

This thesis is concerned primarily with the application of chiral organoborane reagents for asymmetric synthesis. A short chapter on the use of thexylborane N, N'-diethylaniline for reduction reactions is also included. The first chapter contains three main sections. The first (1.2) introduces the concepts of chirality and asymmetric synthesis, with discussions on mechanism, efficiency and importance of asymmetric synthesis. The second section (1.3), discusses the hydroboration reaction and reactions of organoboranes. The last section (1.4) reviews general developments in asymmetric synthesis followed by a detailed review of organoboron reagents in asymmetric synthesis. Chapters 2, 3 and 4 report attempts made to synthesise chiral monoalkylborane reagents from α-pinene (chapter 2), <i>trans</i>-verbenol derivatives (chapter 3) and nopol derivatives (chapter 4). The application of these chiral organoboranes for asymmetric hydroboration and, in some cases, reduction is discussed together with the enantiomeric yields achieved. The use of monoisopinocampheylborane and some chiral organoboranes derived from nopol for chiral hydroboration of trisubstituted alkenes, led to enantiomeric yields in excess of 70% . Chapter 5 reports the reducing properties of thexylborane N, N'-diethylaniline and compares the results with those from thexylborane reductions. The nature of the species present in this reagent was studied by infra-red spectrometry; the reagent was found to exist only partly in complexed form.

An introduction to lignans, including classification, occurrrence, biological activity, the role of lignans and their biosynthesis, is described in chapter 1. Chapter 2 presents a review of the conjugate addition reaction, with particular emphasis on chiral conjugate additions. This chapter also reviews the synthesis of lignans <i>via</i> conjugate additions to both chiral and achiral acceptors. Chapter 3 describes an attempt to synthesize lignans <i>via</i> tandem conjugate additions to a chiral crotonate ester. The project was, however, unsuccessful, due to problems associated with the synthesis of the chiral ester. A number of protected derivatives of ethyl 4-hydroxycrotonate were, however synthesized, as were various mono-protected derivatives of (<i>Z</i>)-1,4-dihydroxybut-2-ene. Chapter 4 describes the synthesis of lignans <i>via</i> tandem conjugate addition to chiral (-)-5-(1-menthyloxy)furan-2(5H)-one. Conjugate addition utilizing diphenyl thioacetals as acyl anion equivalents, followed by <i>in situ</i> trapping with aromatic aldehydes or acid chlorides afforded the adducts in good yields. Desulphurisation and dementhylation yielded (-)-epipodorhizol, which on oxidation afforded (-)-podorhizon. This was successfully cyclised to (-)-γ-apopicropodophyllin, thereby constituting a formal total synthesis of chiral deoxypodophyllotoxin. Chapter 5 describes the use of O-<i>tert</i>-butyldimethysilyl protected cyanohydrins as acyl anion equivalents in the conjugate addition to the chiral butenolide. It has been shown that conjugate additions proceed to afford a single isomer, while tandem conjugate additions afford the adduct as a mixture of two isomers. Ketone regeneration from the cyanohydrin causes isomerisation to occur, to afford a single isomer. A novel dementhylation reaction utilizing sodium borohydride, which occurs with concurrent stereoselective reduction of ther benzylic ketone, is discussed. This methodology has realised the chiral synthesis of a member of the retrolignan series, and the potential for the synthesis of chiral 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane lignans is discussed.

Optically active butenolides have been prepared from the reaction of chiral 1,3-dioxolans and 1,3-oxazolidines with the silyl enol ethers 2-trimethylsilyloxyfuran and 2-trimethylsilyoxy-4-methoxyfuran. Chiral 1,3-dioxolans were prepared in high yields (80-96%) by the exchange reaction of diisopropyl L-tartrate with triethyl orthoformate, triethyl orthoacetate and triethyl orthobenzoate. These were reacted with 2-trimethylsilyoxyfuran (TMSOF) under Lewis acid conditions to give optically active butenolides. The stereoselectivity and yield were not very good. (-)-(R)-Phenyl glycinol and (-)-(1R,2R)-norpseudoephedrine, as their N-tosyl derivatives were reacted with trimethyl orthobenzoate to furnish the chiral 1,3-oxazolidines in high yields (79-85%). Their reaction with TMSOF and 2-trimethylsilyoxy-4-methoxyfuran in the presence of BF<SUB>3</SUB>.Et<SUB>2</SUB>O afforded the optically active butenolides. Moderate yield, but high stereoselectivity, were obtained. Conjugate addition of lithium organocuprates and sulphur stabilized carbanions to the chiral butenolides gave γ-lactones with high stereoselectivity.

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