This thesis examines the synthesis of α-fluoro-β-amino acids, and the influence of the constituent fluorine on the conformation and biological properties of β-peptide derivatives. Chapter One discusses the unique properties of the C-F bond, and applications of fluorine substitution in organic and medicinal chemistry. This is followed by a review of fluorinated analogues of α-amino acids, and how their incorporation into α-peptides has resulted in profound modifications, such as enhanced thermal and chemical stability, increased affinity for lipid bilayers, stronger self-association and improved biological activity. Experimental and theoretical data indicate two conformational effects associated with fluoroamides: the F-C-C(O)-N(H) moiety in α-fluoroamides adopts an antiperiplanar conformation, and in N-β-fluoroethylamides a gauche conformation between the vicinal C-F and C-N(CO) bonds is favoured. Chapter Two details the synthesis of a series of fluorinated β-peptides (2.13-2.24) designed to investigate the use of these stereoelectronic effects to control the conformation of β-peptide bonds. X-ray crystal structures were obtained for seven of these compounds and revealed the compounds had the expected conformations: when fluorine was positioned β to a nitrogen a gauche conformation was observed, and when fluorine was positioned α to a C=O group the structure adopted an antiperiplanar conformation. Thus, the strategic placement of fluorine can control the conformation of β-peptide bonds, and hence could be used to direct the secondary structures of β-peptides. The chapter is prefaced by an introduction to β-amino acids and the secondary structures of β-peptides. Chapter Three outlines the stereoselective synthesis of a series of α-fluorinated-β-amino acids. The synthesis of α-fluoro-β3-amino acids was achieved via direct fluorination of β3-amino acids with LDA and NFSI. The fluorination of N-Boc-protected β3-homophenylalanine, β3-homoleucine, β3-homovaline and β3-homoalanine all proceeded with good diastereomeric excesses (> 85 % de). However, the fluorination of N-Boc-protected β3-homophenylglycine occurred with a lower diastereomeric excess of 66%. Replacement of the Boc amine protecting group of β3-homophenylglycine with Cbz and Bz groups did not alter the stereoselectivity of the fluorination reaction, and substitution with an acetyl amine protecting group reduced the diastereomeric excess to 26%. The stereoselective synthesis of an α-fluoro-β2-homophenylalanine from 3-phenylpropanoic acid is also detailed. Conversion of the acid to the Evan's oxazolidinone followed by enantioselective fluorination and alkylation in high diastereomeric excess, and subsequent amination gave the α-fluorinated β2-amino acid. Chapter Four describes the enzyme assays carried out to assess the inhibitory activity of α-fluoro-β-amino acids, and the analogous non-fluorinated β-amino acids, against α-chymotrypsin. Both fluorinated and non-fluorinated β-amino acid derivatives were found to be competitive inhibitors of α-chymotrypsin, with Ki values in the low millimolar range. The fluorinated β2-homophenylalanine and β3-homophenylglycine derivatives (2.35, 3.26a, 3.43a and 3.44) were found to be more active against α-chymotrypsin than their non-fluorinated analogues (5.27, 3.24, 3.40 and 3.41), whereas the fluorinated β3-homophenylalanine methyl ester (2S,3S)-2.49 was inactive against α-chymotrypsin although the corresponding non-fluorinated derivative (S)-3.28 was a potent inhibitor. In Chapter Five a series of N-succinyl-β-amino acids-p-nitroanilides (5.8-5.13), containing both fluorinated and non-fluorinated β-amino acids, were designed and synthesised as possible substrates of α-chymotrypsin. β-Peptides are stable towards proteolytic hydrolysis, but the introduction of fluorine at the α-position in a β-amino acid was proposed to increase the activity of the adjacent amide bond, and thus make the β-peptide more susceptible to protease cleavage. However, the incorporation of fluorine had no influence on the proteolytic stability of compounds 5.8-5.13 as they were all found to be stable towards hydrolysis by α-chymotrypsin. Compounds 5.8, 5.9 and 5.13 were established as reversible competitive inhibitors of α-chymotrypsin Chapter Six is an experimental chapter and outlines the synthesis, purification and characterisation of the compounds prepared in this thesis.

This thesis examines the synthesis of conformationally constrained β-amino acids and β- peptides, and the electron transfer properties of the latter when immobilised on gold. Additionally, cross metathesis on gold was investigated as a method for surface functionalisation. Chapter One introduces the concepts of electron transfer in nature, how it is facilitated by the secondary structure in α-peptides, and why β-peptides might be useful for studying electron transfer. This is followed by a discussion of the properties of β-peptides, including the enhanced stability and variety of helical secondary structures and the greater potential for functionalisation of the peptide backbone when compared to α-peptides. Finally, the conformational constraints of ring-systems on cyclic amino acids is discussed, with reference to the stabilising effect of these compounds on peptide secondary structures. Chapter Two describes the electrochemical analysis of β-hexapeptides immobilised on gold. The chapter is prefaced by a discussion of the important electron transfer mechanisms for peptides, the fabrication of peptide-gold self-assembled monolayer (SAM) interfaces, and the electron transfer in helical α-peptides. β-Peptides containing an electroactive ferrocene moeity were immobilised on gold and studied using cyclic voltammetry and chronoamperometry. The latter method was used to examine the dependence of the electron transfer rate on overpotential, thereby determining the likely mode of electron transfer through the β-peptides SSβ₆Fc, Fcβ₆SS and SC₁₅β₆Fc. These peptides exhibited very weak dependence on overpotential, characteristic of electron transfer behaviour of an electron hopping mechanism (which is also thought to occur in helical α-peptides). Both the dipole moment of the peptides and the structure of the sulfurlinker group were found to be important in determining the rate of electron transfer. Conversely, the equivalent α-peptide SSα₆Fc exhibited electron transfer behaviour characteristic of the less efficient tunnelling mechanism, which is thought to operate in strand-like peptides. Chapter Three examines the application of cross metathesis, using a Grubbs' second generation catalyst, as a means to functionalise olefin-terminated self-assembled monolayers on gold. Abstract iv Firstly, an introduction into the limited published research on cross metathesis on both planar surfaces and nanoparticles is given. Olefin-terminated thiol 3.18, suitable for immobilisation on gold, and solution phase olefin-terminated ferrocene 3.10 were synthesised as reactants for cross metathesis studies. An analytical methodology was developed involving the cross metathesis of surface-immobilised 3.18 with ferrocene 3.10 in dichloromethane, whereby the concentration of electroactive cross metathesis product 3.22 was monitored electrochemically as a function of time. The concentration of surface-immobilised product 3.22 was determined by integration of the oxidation peak area and found to be highly dependent on both the concentration of immobilised olefin reactant 3.18 and reaction time. Furthermore, the surface concentration of ferrocenyl model disulfide 3.21 and thiol 2.18 decayed markedly upon addition of Grubb's catalyst, as revealed by the decrease in the oxidation peak area, which suggested that catalystmediated desorption was occurring. Chapter Four details the solution-phase synthesis of ferrocene- and thiol-functionalised β- hexapeptides used in both the electron transfer studies described in chapter two, and in the determination of secondary structure using circular dichroism and NMR techniques. The synthesis of simple model compounds 4.14, 4.16 and 4.18 established the incompatibility of the deprotection of methyl and benzyl ester protecting groups with protected-thiol and disulfide linkers, leading to the use of N-hydroxysuccinmide-activated sulfur-linkers 4.20 and 4.22 in further synthesis. A number of β-hexapeptides were synthesised by amide coupling of β- tripeptides functionalised at the N- and C-termini. Structural studies of the methanol soluble β- hexapeptide 4.60 suggested that the covalent attachment of ferrocene moeity to the C-terminus of a β-peptide did not disrupt the formation of a 14-helix in solution. β-peptides containing functionality at both the C- and N-termini (such as SSβ₆Fc, SSβ₆Et and acetyl-protected SC₁₅β₆Fc) were not suitable for solution phase structural studies; however, molecular modelling suggested that helical conformations are the most stable these β-peptides in solution phase. Chapter Five outlines the synthesis of novel cyclic β-amino acids by two different general synthetic routes. The first uses an efficient conjugate addition/fluorination reaction of α,β- unsaturated esters with lithiated chiral secondary amines to prepare the novel cyclopentyl- and cyclohexyl-based fluorinated β-amino acids 2.43a and 2.43b. The high diastereoselectivity of this reaction, which introduces two stereocentres into the achiral unsaturated esters, is directed by the configuration of the attacking amine. The second methodology utilizes the versatile ringclosing metathesis reaction in the synthesis of novel cyclic β-amino acids. A stereoselective Abstract v trans-alkylation of olefinic β-amino acids gave the required β-dienes 5.62 and 5.77. Optimised cyclisation yields were achieved with a Grubb's 2nd generation catalyst for diene 5.62 and Grubb's 1st generation catalyst for diene 5.77, to give the trans-cycloheptyl- and cyclooctylbased β-amino acids 5.63 and 5.78, respectively. The attempted synthesis of cyclononyl-based β-amino acid 5.87 using both catalysts yielded only cyclic dimer products 5.88 and 5.89. The trans configuration of the 5.62 diene was confirmed by x-ray crystallography. Chapter Six is an experimental chapter and outlines the electrochemical setup and analysis, and the synthesis, purification and characterisation of compounds described in this thesis.

This thesis examines the synthesis of conformationally constrained β-amino acids and β- peptides, and the electron transfer properties of the latter when immobilised on gold. Additionally, cross metathesis on gold was investigated as a method for surface functionalisation. Chapter One introduces the concepts of electron transfer in nature, how it is facilitated by the secondary structure in α-peptides, and why β-peptides might be useful for studying electron transfer. This is followed by a discussion of the properties of β-peptides, including the enhanced stability and variety of helical secondary structures and the greater potential for functionalisation of the peptide backbone when compared to α-peptides. Finally, the conformational constraints of ring-systems on cyclic amino acids is discussed, with reference to the stabilising effect of these compounds on peptide secondary structures. Chapter Two describes the electrochemical analysis of β-hexapeptides immobilised on gold. The chapter is prefaced by a discussion of the important electron transfer mechanisms for peptides, the fabrication of peptide-gold self-assembled monolayer (SAM) interfaces, and the electron transfer in helical α-peptides. β-Peptides containing an electroactive ferrocene moeity were immobilised on gold and studied using cyclic voltammetry and chronoamperometry. The latter method was used to examine the dependence of the electron transfer rate on overpotential, thereby determining the likely mode of electron transfer through the β-peptides SSβ₆Fc, Fcβ₆SS and SC₁₅β₆Fc. These peptides exhibited very weak dependence on overpotential, characteristic of electron transfer behaviour of an electron hopping mechanism (which is also thought to occur in helical α-peptides). Both the dipole moment of the peptides and the structure of the sulfurlinker group were found to be important in determining the rate of electron transfer. Conversely, the equivalent α-peptide SSα₆Fc exhibited electron transfer behaviour characteristic of the less efficient tunnelling mechanism, which is thought to operate in strand-like peptides. Chapter Three examines the application of cross metathesis, using a Grubbs' second generation catalyst, as a means to functionalise olefin-terminated self-assembled monolayers on gold. Abstract iv Firstly, an introduction into the limited published research on cross metathesis on both planar surfaces and nanoparticles is given. Olefin-terminated thiol 3.18, suitable for immobilisation on gold, and solution phase olefin-terminated ferrocene 3.10 were synthesised as reactants for cross metathesis studies. An analytical methodology was developed involving the cross metathesis of surface-immobilised 3.18 with ferrocene 3.10 in dichloromethane, whereby the concentration of electroactive cross metathesis product 3.22 was monitored electrochemically as a function of time. The concentration of surface-immobilised product 3.22 was determined by integration of the oxidation peak area and found to be highly dependent on both the concentration of immobilised olefin reactant 3.18 and reaction time. Furthermore, the surface concentration of ferrocenyl model disulfide 3.21 and thiol 2.18 decayed markedly upon addition of Grubb's catalyst, as revealed by the decrease in the oxidation peak area, which suggested that catalystmediated desorption was occurring. Chapter Four details the solution-phase synthesis of ferrocene- and thiol-functionalised β- hexapeptides used in both the electron transfer studies described in chapter two, and in the determination of secondary structure using circular dichroism and NMR techniques. The synthesis of simple model compounds 4.14, 4.16 and 4.18 established the incompatibility of the deprotection of methyl and benzyl ester protecting groups with protected-thiol and disulfide linkers, leading to the use of N-hydroxysuccinmide-activated sulfur-linkers 4.20 and 4.22 in further synthesis. A number of β-hexapeptides were synthesised by amide coupling of β- tripeptides functionalised at the N- and C-termini. Structural studies of the methanol soluble β- hexapeptide 4.60 suggested that the covalent attachment of ferrocene moeity to the C-terminus of a β-peptide did not disrupt the formation of a 14-helix in solution. β-peptides containing functionality at both the C- and N-termini (such as SSβ₆Fc, SSβ₆Et and acetyl-protected SC₁₅β₆Fc) were not suitable for solution phase structural studies; however, molecular modelling suggested that helical conformations are the most stable these β-peptides in solution phase. Chapter Five outlines the synthesis of novel cyclic β-amino acids by two different general synthetic routes. The first uses an efficient conjugate addition/fluorination reaction of α,β- unsaturated esters with lithiated chiral secondary amines to prepare the novel cyclopentyl- and cyclohexyl-based fluorinated β-amino acids 2.43a and 2.43b. The high diastereoselectivity of this reaction, which introduces two stereocentres into the achiral unsaturated esters, is directed by the configuration of the attacking amine. The second methodology utilizes the versatile ringclosing metathesis reaction in the synthesis of novel cyclic β-amino acids. A stereoselective Abstract v trans-alkylation of olefinic β-amino acids gave the required β-dienes 5.62 and 5.77. Optimised cyclisation yields were achieved with a Grubb's 2nd generation catalyst for diene 5.62 and Grubb's 1st generation catalyst for diene 5.77, to give the trans-cycloheptyl- and cyclooctylbased β-amino acids 5.63 and 5.78, respectively. The attempted synthesis of cyclononyl-based β-amino acid 5.87 using both catalysts yielded only cyclic dimer products 5.88 and 5.89. The trans configuration of the 5.62 diene was confirmed by x-ray crystallography. Chapter Six is an experimental chapter and outlines the electrochemical setup and analysis, and the synthesis, purification and characterisation of compounds described in this thesis.

Les transformations photochimiques sont des outils puissants pour créer de la diversité moléculaires à partir de substrats facilement accessibles; elles requièrent le réactif le plus simple : un photon. Les réactions de cycloaddition [2+2] photochimiques de composés carbonylés ou carboxylés α,β-insaturés avec des oléfines sont les réactions photochimiques les plus largement utilisées en synthèse organique. Les photoadduits cyclobutaniques sont très appliqués en synthèse multi-étapes de produits naturels ou dérivés et sont également prisés comme intermédiaires de synthèse du fait de la grande réactivité intrinsèque liée à leur tension de cycle. Dans la première partie de cette thèse, nous nous sommes intéressés à une approche photochimique pour la synthèse de β-acides aminés cyclobutaniques substitués. Notre objectif était de mettre en place une synthèse robuste et efficace sur l’échelle du gramme des acides cis- et trans-2-aminocyclobutane-1-carboxyliques (cis- et trans-ACBC) diversement substitués en position 3 ou 4. La construction du cycle à quatre chaînons a été réalisée via une réaction de cycloaddition [2+2] photochimique entre le tert-butoxyéthène et le maléimide ou l’anhydride maléique. Les fonctions amine et acide carboxylique ont ensuite été générées par des processus consécutifs ou “one-pot” impliquant un réarrangement de Hofmann. Les mélanges racémiques des 3- et 4-cis-syn-hydroxy-ACBCs ont été dédoublés via l’utilisation d’une oxazolidinone chirale, donnant accès aux β-acides aminés énantiopures ciblés sur grande échelle, sous la forme déprotégée ou protégée orthogonalement. Le contrôle d’une procédure d’épimérisation cis-trans a permis l’accès aux composés trans-syn-3-hydroxy-ACBC à partir des substrats cis-syn-3-hydroxy-ACBC. Enfin, les composés ACBCs diversement substitués en position 3 et de configuration cis-anti ou trans-anti ont pu être préparés grâce à une réaction de Mitsunobu ou d’autres transformations de type SN2, à partir des réactifs cis-syn- ou trans-syn-3-hydroxy-ACBC correspondants. Dans la seconde partie de cette thèse, nous avons étudié des processus photochimiques tandem et cascade initiés par une réaction de cycloaddition [2+2] photochimique. En collaboration avec un chercheur post-doctorant, nous avons réalisé la synthèse contrôlée d’une librairie d’acétals cyclobuténiques et d’oxétanes polycycliques, via des photoréactions tandem et cascade entre des cyclopent-2-énones et des partenaires alcènes. Le processus tandem résulte d’une réaction de cycloaddition [2+2] photochimique suivie d’une fragmentation de type Norrish I et d’un transfert d’hydrogène en position γ, conduisant aux aldéhydes cyclobuténiques protégés in situ sous la forme de dérivés acétals stables. La triple cascade réactionnelle a permis l’accès à de nouveaux oxétanes tricycliques angulaires par le biais d’une réaction de Paternò-Büchi intramoléculaire à partir des aldéhydes cyclobuténiques précédemment cités. La généralisation de ces deux processus domino a été étudiée à partir d’un panel de cyclopent-2-énones et de trois partenaires alcènes représentatifs. La formation de certains des composés obtenus a pu être expliqué par à une réaction supplémentaire de type SN’. Une étude préliminaire de cette transformation non-attendue a été réalisée. / Photochemical transformations are powerful tools for the creation of molecular diversity from simple and readily available starting materials; they employ the simplest of reagents, a photon. Photochemical [2+2] cycloaddition reactions of α,β-unsaturated carbonyl or carboxyl compounds with olefins are one of the most widely applied photochemical reactions in organic synthesis. The cyclobutane photoadducts have been used ubiquitously in multi-step syntheses of a wide array of natural products or related derivatives, and they have also been used as intermediates in other synthetic procedures which exploit their strained molecular skeletons and their resulting intrinsic chemical reactivity.In the first part of this thesis, we focused on a photochemical approach for the synthesis of ring-substituted cyclobutane β-amino acids. Our objective was to establish a robust, large-scale and efficient synthesis of cis- and trans-2-aminocyclobutane-1-carboxylic acids (cis- and trans-ACBC) diversely substituted at the 3- or 4-positions. The cyclobutane ring was constructed using a photochemical [2+2] cycloaddition reaction between tert-butyl vinyl ether and either maleimide or maleic anhydride. The amine and carboxylic acid functions were subsequently installed through consecutive or one-pot protocols including a Hofmann rearrangement. The protected racemates of 3- and 4-cis-syn-hydroxy-ACBCs obtained in this way were resolved using a chiral oxazolidinone auxiliary to provide a large scale access to enantiomerically pure samples of the target β-amino acids in either free or orthogonally protected form. A controlled cis-to-trans epimerization procedure from cis-syn-3-hydroxy-ACBC substrates permitted facile access to target trans-syn-3-hydroxy-ACBCs. Finally, diversely substituted 3-ACBCs with cis-anti or trans-anti relative configurations were synthesized using Mitsunobu or other SN2-type reactions, starting from corresponding cis-syn- or trans-syn-3-hydroxy-ACBC derivatives.In the second part of the thesis, we investigated photochemical tandem and cascade processes which began with a photochemical [2+2] cycloaddition reaction. In collaboration with a post-doctoral researcher, we reacted cyclopent-2-enones and alkenes to afford libraries of cyclobutene acetals and polycyclic oxetanes, in a controlled manner, via tandem and triple cascade photoreactions. The tandem process consisted of a photochemical [2+2] cycloaddition followed by Norrish I/γ-H transfer which led to cyclobutene aldehydes; these reactive photoadducts were trapped in situ as stable acetal derivatives. The triple cascade process provided access to unprecedented angular tricyclic oxetanes via an intramolecular Paternò-Büchi reaction of the above-mentioned cyclobutane aldehydes. The scope of these two domino processes was investigated using panels of 2- and 4-substituted cyclopent-2-enones and three representative alkene partners. The formation of some of the compounds obtained during this study was attributed to an additional SN’ reaction. Preliminary investigations on this unexpected transformation were performed.

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