The first part of the thesis shows how nuclear magnetic resonance can he used to determine the energy difference between the two conformers of mono-substituted cyclohexanes or tetrahydropyrans. Proton magnetic resonance and 13Carbon magnetic resonance were used and the recently introduced Fourier transform Carbon magnetic resonance was assessed to see if it was suitable for this kind of work. It was found that the halogeno tetrahydropyran molecules studied have similar free energy differences to those of their cyclohexane analogues. Force field refinement work was carried out using biphenyl and fluorinated and deuterated derivatives including a new compound, 4-4' difluoro biphenyl d8. The restriction that all ring C-C stretch force constants should be the same was lifted and the geometry used in the calculations was improved. The dihedral angle of 4-4' difluorobiphenyl d8 in solution was estimated. Finally variable temperature studies were carried out on the infrared band shape of the YCH mode of p'difluorobenzene in cyclohexane and acetonitrile. The band was found to be broader in acetonitrile and to show a much smaller temperature dependence in the polar solvent. This is interpreted as due to vibrational relaxation governing the band width in the polar situation.

Chirality, familiar to all chemists, is usually applied to molecules or assemblies of molecules and plays an important role in both animate and inanimate systems. It is commonly the case that chirality of a system arises from a chiral building block yet chiral systems can also emerge from achiral units. The objective of this research was to investigate the origin and recognition of chirality at the nanoscale level. To do this, self assembled monolayers made of chirally and achirally tailed molecules were used because such structures are known to form uniform surfaces, which can act as either a source of nucleation or the probing surfaces in chiral recognition. The strategy adopted in the first part of this study was to use chirally modified self assembled monolayers as a source of nucleation for crystallization of achiral compounds that can form either left or right tended forms in chiral crystallization. Such compounds, widely reviewed by Matsura, form chiral crystals even though their building blocks lack a chiral centre. This study presents experiments of induction of chirality in sodium chlorate, hippuric acid and 2,6-ditertbutyl-4-methylphenol crystals. Chiral crystallization of chosen compounds was conducted on D and L cysteine surfaces assembled on gold. The chirality of crystals grown on these surfaces was determined using polarised light microscopy, circular dichroism spectroscopy and NSOM. The small enantiomeric excess achieved in experiments was explained by the limits of chirality determination methods. It was found that crystals formed in enantiomeric excess were of opposite chirality to the SAM they were grown on. This confirms previous results presented by Mastai on crystallization of histidine on cysteine surfaces. The second part of this study presents studies of chiral recognition use of AFM technique-Force Distance Spectroscopy. Chirally and achirally modified SAMs were formed via the Cu-AAC reaction commonly called 'click Chemistry'. This project investigated how the surface preparation influences chiral recognition and if the presence of the second chiral centre affects probing ability. For surface preparation, three types of linkers were used. To functionalize them two complementary compounds equipped with AlaAlaDL and AlaAlaLL dipeptide tail were used. Additional studies were carried out with hippuric acid and glutamic acid-modified SAMs. These studies showed that the way the surface is prepared plays an important role in chiral recognition. In the final recognition experiments it was found that use of molecules possessing either peptide groups or amino acid groups generates additional forces between interacting surfaces, which can be equilibrated by conducting measurements in pH close to their isoelectric point. An influence of the second chiral centre was found for the loosely packed surfaces where the molecules can freely coil.

The efficient synthesis of all-C quaternary centres as part of an acyclic contiguous stereoarray is a highly challenging synthetic operation. Investigations have been carried out into using non-enolisable 1,3-dialdehydes, under MgBr2•OEt2 chelation control, as small building blocks for the synthesis of all-C quaternary centre as part of a stereoarray. Initial investigations focussed on developing controlled monoadditions to non-enolisable dialdehydes with allylation, hydroxyallylation and aldol reactions to give products containing two or three contiguous stereocentres, including an all-C quaternary stereocentre, with good stereocontrol. Interestingly it was found that the diastereoselection of monoaddition was different when the dialdehyde contained a pendant benzyloxy group in contrast to a pendant trityl or TBDPS ether group. The diastereoselection of additions to dialdehydes has been rationalised by considering the reactive conformations involved to form the observed diastereoisomer products of these addition reactions. A double addition process to the non-enolisable 1,3-dialdehyde with a benzyloxy group has been described. It has been found that the second addition is highly diastereoselective and is effective with a range of nucleophiles to give products containing four or five contiguous stereocentres, including an all-C quaternary stereocentre, as part of a stereoarray. The high level of diastereoselectivity of this second addition has again been rationalised by considering the reactive conformation involved. Finally, attempts have been made toward the formation of enantioenriched stereoarrays containing an all-C quaternary stereocentre. Investigations focussed on using Evans’ BOX ligands and chiral reagents in reactions with non-enolisable 1,3-dialdehydes

Chapter 1 outlines the development of a catalytic electrocyclic process and its exploitation in asymmetric synthesis. Since Woodward and Hoffmann delineated a rationale for the mechanism and stereochemistry of these reactions they have become powerful synthetic tools. The aim of this project was to investigate catalytic asymmetric 6π electrocyclizations that will enable the rapid synthesis of highly functionalized molecules. We have demonstrated that the transient hexatriene precursors for [1,6]-electrocyclization are difficult to synthesize. When possible the central cis-alkene prefers to exist in a trans-configured geometry, while the free ketone undergoes an essentially irreversible oxo-electrocyclization. However the precursors for [1,5]-electrocyclization could be assembled via the Suzuki or Stille reactions. We have established a methodology for [1,5]-electrocyclization using chiral phase-transfer catalysis. These reactions afford the electrocyclized products in excellent yield and diastereoselectivity with enantiomeric excess up to 68%. These transformations offer a glimpse of the potential of electrocyclic reactions. In chapter 2, the effects of cyclic backbones on the secondary structures of γ-peptides were evaluated. Two series of abiotic γ-peptides were synthesized with five and six-membered cyclic backbones. We have demonstrated that intra-residue nearest-neighbour hydrogen bonds may be favoured when the flexibility of the ring constraint can permit their formation. These cyclic backbone containing γ-peptides have been shown to populate a bend-ribbon conformation in the solution and solid phase by NMR and X-ray crystallography respectively.

Atropisomerism is a property exhibited by molecules where rotation about one or more bonds is restricted. Along with biaryls, which are widely utilised in asymmetric catalysis, several other classes of compounds display atropisomerism. These molecules have applications in enantioselective synthesis, asymmetric catalysis and have been used to relay stereochemical information. There are, however, a number of challenges associated with their asymmetric synthesis (Chapter 1). This thesis describes research carried out on the synthesis and asymmetric synthesis of atropisomeric diaryl ethers. Chapter 2.1 explains how these ethers are synthesised in multi-gram quantities and to allow the incorporation of large ortho substituents. Having a number of diaryl ethers with suitable substitution patterns to achieve atropisomerism, Chapter 2.2 goes on to report two novel and complimentary biocatalytic approaches to the enantioselective synthesis of diaryl ethers by desymmetrisation. This chapter also describes a possible route towards the synthesis of a diaryl ether based ligand. Chapter 2.3 reports the lateral lithiation of meso diaryl ethers to yield diastereomeric atropisomers stereoselectively. Our attempts to use (-)-sparteine in lateral lithiations to desymmetrise a diaryl ether enantioselectively is also described. We go on to determine the configurational integrity of our organolithiums and the reaction pathway that exists in lithium substitution. Finally, the diastereoselective synthesis of both a diaryl ether (via a stereoselective reduction of a pro-chiral ketone) and a diaryl sulfide (via an addition reaction) is described in chapter 2.4. This chapter also reports the conformational behaviour of a diaryl amide in solution.

The self-assembly of two-dimensional molecular systems is of significant interest, offering an insight into the fundamental interactions which drive the formation of complex supramolecular structures. A careful choice of the molecular 'building blocks' for such self-assembled systems potentially allows the design and production of nanoscale architectures with pre-determined geometries and specific chemical functionalities. Within this thesis the two-dimensional structures formed by the self-assembly of complex organic molecules, deposited on an Au(111) surface held in an ultrahigh vacuum (URV) environment, are studied using a combination of scanning tunnelling microscopy (STM), photoelectron spectroscopy (PES), molecular dynamics (MD), and density functional theory (DFT) techniques. A UHV electrospray deposition (URV-ESD) technique is employed to facilitate the introduction of thermally labile molecules into the URV environment. Bi-molecular networks, formed from perylene tetracarboxylic diimide (PTCDI) and melamine, have previously been observed to assemble on the Au(111) surface. Several more complex phases are reported here, as characterised by S'I'M, with the balance between isotropic and anisotropic interactions giving rise to a variety of structures. Chemical functionality may be added to these networks by incorporating functionalised derivatives of PTCDI. Alternative structures produced by altering the shape of the molecular 'building blocks' are also discussed. The URV-ESD technique is demonstrated here to be compatible with the deposition of the fullerene C60,the single molecule magnet Mn12012(02CCR3h6(H20)4 (Mn12(acetate)16), and porphyrin based oligomers (P4 and P6) and polymers (Pn). The URV-ESD of C60on the clean AU(ll1) surface, and on a surface prepatterned with a PTCDI/melamine network, results in similar structures to those previously observed to be produced by sublimation. Mn12(acetate)16 and the porphyrin oligomers and polymers represent complex molecules which are thermally labile and possess, respectively, novel magnetic and electronic properties. Mn12(acetate) 16is observed to form filamentary aggregates due to the anisotropic nature of the molecule-molecule and molecule-substrate interactions, while P4, P6 and Pn form highly ordered close-packed domains driven by the interdigitation of the alkyl chains attached to the porphyrin cores. The findings presented within this thesis demonstrate that self-assembled molecular structures can be understood in terms of intermolecular interactions, and that for systems containing complex molecules the molecule-molecule interaction potential can lead to the formation of novel structures.

Modern organic chemistry strives to achieve rapid molecular complexity from simple achiral substrates. One method by which this may be achieved is with enolate formation followed by attack on an electrophile which can generate one, two or even more new stereocentres in one step. However regioselective generation of an enolate in the presence of several enolisable sites has always proved problematical. A partial answer to this problem has been provided by the development of the reductive aldol reaction. The first part of this thesis is concerned with describing a highly diastereoselective Co(II)-catalysed reductive aldol reaction between α,β-unsaturated amides and ketones. The reaction proceeds using substoichiometric quantities of cobalt(II) in the presence of a stoichiometric quantity of the reductant diethylzinc. Using both N,Ndimethyl and morpholine amides, the reactions are tolerant of substituted aromatic ketones as well as aliphatic ketones. The reaction also proceeded well when the β-carbon was substituted with both aromatic and aliphatic groups resulting in improved diastereoselection. The racemic work is followed by the development of an asymmetric version of the reaction using oxazolidinone chiral auxiliaries that impart high levels of diastereofacial selectivity. The reaction was found to proceed with a variety of aromatic ketones and once again, substitution of the β-carbon resulted in improved diastereoselectivity. Finally work on formal homo aldol cyclisations using substoichiometric quantities of Ni(II) also in the presence of a stoichiometric quantity of diethylzinc is described. This work aims to develop methodology that involves double cyclisations with the formation of up to five contiguous stereocentres. Although unsuccessful, useful conclusions for future work were made as well as the serendipitous discovery of a apparent base catalysed alternative cyclisation pathway that successfully generated two new rings and four contiguous stereocentres.

The template synthesis of rotaxanes and catenanes has allowed a detailed study of their intrinsically novel and interesting properties. A key strategy has been the deployment of transition metal ions with their well-defined coordination geometries allowing high-yielding and facile preparation of interlocked architectures. Knowledge of how to exploit the coordination sphere of metal ions and the design of ligands for the creation of intermediates that are pre-disposed to undergo ‘stoppering’ or ‘clipping’ has been a crucial requirement for this approach. This Thesis is in three parts describing the use of three dimensional, two dimensional and one dimensional coordination geometries in the synthesis of interlocked architectures. Firstly, the octahedral coordination geometry of cobalt(III) was utilized to organize dianionic pyridine-2,6-dicarboxamido ligands in a mutually orthogonal arrangement such that ring closing metathesis macrocyclizations gave access to interlocked or entwined products. A ‘figure-of-eight’ complex was obtained from a double macrocyclizations, whereas a catenate was accessed through a single macrocyclization. The topology of the isomers was proved by X-ray crystallography. An analogous [2]rotaxane was synthesized and the interlocked nature of the rotaxane demonstrated by 1H NMR spectroscopy and mass spectrometry. Secondly, an “active” metal template strategy, in which the metal ion plays a dual role – acting to both organize ligands and catalyze mechanical bond formation – allowed rotaxanes be constructed using the square planar coordination geometry and Lewis acidic nature of a palladium(II) complex. The interlocked nature of the rotaxane was proved by X-ray crystallography, demonstrating that a nitrile group present in the thread acted as a “station” for the Pd(II)-macrocycle. This observation led to the construction of a two “station” degenerate molecular shuttle in which the dynamics of translocation were controlled by reagent addition and observed by 1H NMR techniques. Lastly, the linear coordination geometry of gold(I) was successfully used as a template for construction of rotaxanes and catenanes via a ‘clipping’ strategy. The linear coordination geometry and the interlocked nature of the gold(I)-catenate was proved by X-ray crystallography, the rotaxane architecture was proved by 1H NMR spectroscopy and mass spectrometry. Chapters Two, Three and Four are in the form of articles that have been published in peer-reviewed journals, and are reproduced, in their published format, in the Appendix. No attempt has been made to rewrite the published work; as a consequence the numbering of compounds, whilst consistent within each Chapter, is not consistent throughout this Thesis. Another consequence is that the many failed synthetic routes have been left out. I hope the reader will forgive these omissions as well as the slight repetition that occurs in the introduction and bibliography of each chapter. Additionally, preceding each Chapter is a brief synopsis that places the work in context and acknowledges the contributions of my fellow researchers.

This thesis describes the development of chiral auxiliary based methodologies for the asymmetric synthesis of hydroxylated !-lactones and "-lactones containing multiple contiguous stereocentres. The first chapter introduces the concept of chirality and provides a general overview of the range of strategies available for the preparation of chiral molecules in enantiomerically pure forms. The second chapter critically reviews the range of synthetic methodology that is currently available for the asymmetric synthesis of chiral #-lactones that are either natural products or useful chiral building blocks for synthesis. The third chapter describes the development of novel methodology for the epoxidation/lactonisation of a range of $-vinyl-syn-aldols to directly afford !-lactones containing up to four contiguous stereocentres in high de. These reactions were shown to proceed via a mechanism whereby hydroxyl-directed diastereoselective epoxidation is followed by intramolecular attack of their !-acyl-oxazolidin-2- one fragment, to directly afford the desired chiral !-lactone. The ‘self-cleavage’ aspect of these reactions was exploited to enable this methodology to be transferred to polymer-support using an immobilised Evans’-oxazolidin-2-one for asymmetric synthesis. Chapter 4 describes the development of a complementary methodology for the asymmetric synthesis of this type of hydroxylated !-lactone based on a strategy involving dihydroxylation of N-acyl-oxazolidin-2-one-$-vinyl-syn-aldols using catalytic amounts of osmium tetroxide. This methodology was developed as part of a reinvestigation of previously reported dihydroxylation reactions by Dias and coworkers, where we have clearly shown that the stereochemistry of thelactones reported in their paper have been incorrectly assigned. This diastereoselective dihydroxylation methodology has been successfully applied to the asymmetric synthesis of the natural product deoxyribonolactone. Finally, Chapter 5 describes the development of methodology for the asymmetric synthesis of chiral "-lactones containing four contiguous stereocentres of use as potential chiral building blocks for the synthesis of polyketide natural products. In this approach, cyclopropanation of N-acyl-oxazolidin-2-one-$-vinyl-syn-aldols occurs under the sterodirecting effect of the $- hydroxyl group to afford cyclopropyl-aldols in very high de. These cyclopropyl-aldols are then ring opened in the presence of mercuric ions, with their N-acyl-oxazolidin-2-one fragment acting as an internal nucleophile, to afford highly functionalised alkyl-mercury species that may be subsequently reduced to afford their corresponding "-lactones in high de.