The controlled translocation of submolecular units is seen as an important requirement for the future development of “machines” which function through mechanical motion at the molecular level. Mechanically-interlocked molecules, <i>i.e.</i> catenanes and rotaxanes, are ideal candidates for application as components for molecular devices due to the inherent restrictions in the degrees of freedom presented in their architectures. Hydrogen bond-directed assembly offers powerful strategies for the synthesis of such structures on a scale where practical applications become a realistic area for study. This Thesis focuses on (i) the use of hydrogen bonding interactions in the synthesis of structurally different fumaramide template-containing [2]rotaxanes, (ii) the control of the rotational and translational motion in stimuli-responsive [2]rotaxanes and (iii) the control of a physical property, such as elliptical polarization, in a stimuli-responsive two-station [2]rotaxane. The stimuli required to promote the submolecular motion are light and heat.

The first part of this thesis describes the synthesis of TBDPS protected CYB-3 125 <i>via </i>a substrate controlled acetate aldol reaction of 93. A Claisen condensation reaction of the imidazolide 157 followed by a highly diastereoselective reduction enabled a synthesis of the C(3) epimer of TBDPS protected CYB-3 159. As a further demonstration of this methodology, the Claisen condensation reaction and reduction protocol was extended to the synthesis of <i>b</i>-hydroxyl alcohol 221. The synthesis of methyl ketone 244 has been reported utilising the conditions optimised for the synthesis of 93. Preliminary investigations of the aldol reaction of 244 with a range of achiral aldehydes have been conducted. Finally studies into an interesting cyclisation using iodoxybenzoic acid (IBX) 262 are discussed.

This thesis describes the use of Pd(II) as a template in the synthesis of mechanically interlocked molecular architectures and is in three parts. Firstly, the steric and electronic parameters governing the synthesis of a [2]rotaxane utilising the preferred square planar coordination geometry of Pd(II) were investigated. Using a tridentate pyridine 2,6-dicarboxamido macrocyclic precursor and a 2,6-dimethoxypyridine unit capped with bulky terminating groups the [2]rotaxane was accessed using ring closing olefin metathesis in the crucial cyclisation step. Based on these findings the assembly of a similar [2]catenane was achieved. In this case the desired product and two of its molecular isomers were prepared selectively depending on the order in which the precursor units were cyclised. Secondly, both catenanes and rotaxanes assembled in this way were shown to contain an unusual intercomponent pyridine-amide-pyridine hydrogen bond motif following abstraction of the Pd(II) template. As a result, a range of diverse noncovalent binding interactions were observed with the [2]rotaxane and [2]catenane that are not found with similar, but not mechanically interlocked, fragments including non-native transition metal coordination and encapsulation of a sulfonic acid guest. All the neutral, anionic and cationic complexes were characterised in solution using ¹H NMR spectroscopy and in the solid state using X-ray crystallography. Thirdly, the control of large amplitude sub-molecular motion in two novel [2]catenanes was achieved. In both cases the co-conformation of the rings was confirmed in solution using ¹H NMR spectroscopy and in the solid state using X-ray crystallography.

Efficient synthetic methods have been developed for catenates and rotaxanes based on tetrahedral and trigonal bipyrimidal metal complexes using the metal-<i>bis-</i>phenanthroline synthon pioneered in Strasbourg. The aim of this project was to investigate the possibility to synthesise mechanically interlocked architecture using metals with higher oxidation states, different geometries and higher coordination motifs. Chapter Two describes the synthesis of a general ligand system for rotaxane complexes of ions that prefer octahedral coordination – the commonest ligand geometry amongst transition metals but up to now a rare coordination mode for rotaxanes. Simple mixing of the components at room temperature is sufficient to assemble a broad range of octahedrally coordinated metal-[2]rotaxanes in excellent yields. The reactions have few, if any, by products and proceed under thermodynamic control in the absence of a catalyst or any other external reagents. Chapter Three reports the template-directed synthesis of a [2]catenate and a [2]rotaxane by a clipping approach around trivalent octahedral cobalt ions. Chapter Four reports the design and investigation of the synthesis of pentacoordinate rotaxane about divalent zinc and cadmium metals and of tetracoordinate rotaxane about divalent palladium. A clipping approach as well as a threading-and-capping approach were considered for both geometries, leading to interesting results involving the kinetics and thermodynamics of each complex. Zinc was suitable for the self-assembling of the macrocycle about the metal-thread complex but failed to hold the unstoppered thread in place to undergo capping reaction; cadmium on the contrary yielded rotaxane upon threading approach but lead to the formation of more thermodynamically stable hexacoordinate catenate upon ligand self-assembly via clipping approach. Palladium did not promote any self-organization towards the assembly of the macrocycle via clipping approach about the preformed thread.

An in-house <i>in silico</i> database mining programme (LIDAEUS) was used to screen a library of small molecules for binding to CypA. This approach identified dimedone 33 as a lead which mimics two of the key interactions of CsA and was found to possess a <i>K</i>_d= 22 mM (<i>cf. </i>30 nM for CsA). Several rounds of chemical derivatisation led to the synthesis of conformationally constrained ligands, the best of which 123 was found to bind CypA with a <i>K</i>_d= 15 μM, a greater than 1000-fold improvement on the original lead. (Fig. 3828) Inhibitor 123 was tested <i>in vivo</i> against the nematode <i>C. elegans </i>to screen for antiparasitic effects. High concentrations (> 500 μM) of 123 were lethal resulting in rapid death of the worms. At lower concentrations the worms suffered growth defects and displayed cuticle shedding and severe gut development disorders, similar in phenotype to those observed in organisms treated with CsA. Fluorescent tags were incorporated to investigate the uptake and localisation of the ligand within <i>C. elegans. </i>Sulfonamide 168a displayed similar effects to 123 and CsA <i>in vivo</i> and its fluorescence was detected throughout the worms’ gut lumen in areas where cyclophilins are thought to be involved in structural formation of the gut lining. These results demonstrate the potential of such ligands to act as chemical probes for elucidating the role of cyclophilins at different stages of <i>C. elegans </i>development. Such a forward chemical genetics approach could, in future, provide valuable information concerning the biological mode of action of cyclophilins in nematode parasites and help to identify new targets for antiparasitic drugs.

No description available.

A range of compounds designed around a template based upon (<I>Z</I>)-5-benzylidene thiazolidine-2,4-dione were synthesised by Knoevenagel condensation. These were screened against <I>Rhodotorula rubra</I> CBS 6469, a red yeast, using a modification of a process developed by SmithKline Beecham. This has allowed the construction of a 'map' defining the structural features of the template which are required to afford reduction of the carbon-carbon double bond. It has been shown that X<SUP>1</SUP> and X<SUP>2</SUP> must be S and O respectively whilst R<SUP>3</SUP> can be methyl or benzyl. Alkyl substitution at R<SUP>2</SUP> is not tolerated but a variety of substituents can be present at R<SUP>1</SUP>. <I>Para </I>groups can be accommodated at R<SUP>1</SUP>, but only methyl in the alkyl series, as well as the <I>meta</I> methoxy group. It has also been shown that replacement of the phenyl ring with a cyclohexyl moiety still allows reduction to take place. (Fig. 10893A). Relative reaction rates are also discussed along with the development of a process to afford reduction using <I>Rhodotorula rubra</I> CBS 6469 immobilised in calcium alginate beads. By carrying out reductions on deuterated compounds, and in deuterated media, steps have been taken towards the elucidation of the mechanism of reduction. The following scheme is proposed as a possible mechanistic pathway.

The synthesis and characterization of molecules possessing moving parts is a great area of interest: these molecules can act as “molecular machines” carrying out tasks that molecules with fixed conventional architectures cannot do. Chapter one gives a brief introduction to rotaxanes as unique and suitable systems for the construction of molecular machines. A further development of functionalized fumaramide-based molecular shuttles and a study of their properties are also described. Chapter two: Synthesis of functionalized [2]rotaxanes describes new routes for the functionalization of [2]rotaxanes, reporting the synthesis of systems which contain mono- and di-functionalized benzylic amide macrocycles; this approach opens a new frontier in the development of such compounds. Chapter three: Synthesis of Membrane Spanning rotaxanes reports the use of stimuli-responsive molecular shuttles based on long threads and their potential use in ion transport. This system has been titled a “Membrane Spanning Rotaxane”. A brief introduction to ion transport across cell membranes illustrates the ion transporters activity and mechanism which inspired the design of the Membrane Spanning Rotaxanes. Chapter four: Single Molecule Experiments on a Surface Attachable Bistable Molecular Shuttle (SABMS) is concerned with the synthesis of a Surface-Attachable stimuli-responsive molecular shuttle wherein the shuttling of the benzylic amide macrocycle along the two stations is measured through Single Molecule Force Spectroscopy. A brief introduction into Atomic Force Microscopy and Chemical Force Microscopy is given for this project.

No description available.

Anions have many important roles in biological systems, as well as in the environment and as such there is significant interest in their binding and sensing. In induced-fit anion sensing, the binding of an anion causes a shift in the equilibrium of conformers of the molecule, which in turn may lead to a change in a physical property. In this thesis four experimental chapters describe the synthesis and anion sensing properties of a series of induced-fit anion sensors derived from a hexa-substituted triethylbenzene and diphenylacetylene motif. Chapter one provides an introduction to anion recognition and sensing, whilst Chapter two describes a new synthetic method towards triethylbenzene receptors involving the solvent-drop grinding technique. Facile synthesis of known and novel anion receptors was achieved. Chapter three describes the use of the triethylbenzene motif, functionalised with quinolinium groups to sense anions. The receptor binds anions strongly, with complex binding observed, involving a host dimer, 2:1 host:guest and 1:1 host:guest stoichiometries. The receptor functions as a turn-off fluorescence sensor with selectivity for acetate. Chapter four describes the further functionalisation of the triethylbenzene core with the viologen moiety, leading to a series of tri- and tetrapodal anion receptors. These receptors show a colourimetic response to carboxylates through a charge transfer interaction. These receptors bind several different anions strongly. However a colourimetric response is only observed with carboxylates. Chapter five describes the use of diphenylacetylene derivatives functionalised with urea groups which have also been investigated as induced-fit anion sensors. The receptors show a high degree of preorganisation, except for free rotation around the acetylene bond. The receptors bind a range of anions to varying extents, with strong binding observed with basic anions. Upon the addition of anions, several different fluorescent responses are observed depending on the receptor design. A turn-on fluorescent response is observed with diphenylacetylene and diphenylbutadiyne derivates due to planarisation of the receptor. Fluorescent quenching is also observed with several receptors and can allow for the discrimination of several anions when the receptors are used as part of an array. The diphenylbutadiyne derivative can also be incorporated into a dipstick which shows a turn-off response in the presence of chloride.