This thesis focuses on two main areas: the synthesis of novel anti-metabolites of 1-deoxy- D-xyulose-5-phosphate (DXP) and the stereoelectronics which influence the conformation of fluoromethyl groups in organic compounds. DXP, a sugar phosphate, has recently been established as a key biosynthetic intermediate to a number of plant and bacterial co-enzymes and vitamins. Chapter 1 describes the role of DXP in three biosynthetic pathways; in the formation of the isoprenoid building block isopentenyl pyrophosphate, and the vitamins B(_1) and B(_6). A new strategy to novel antibiotics and / or herbicides is proposed by the inhibition of DXP metabolism. A description of phosphonates as hydrolytically stable phosphate mimics is presented, including fluorine phosphonates that enable fine tuning of these mimics. Synthetic targets are designed as inhibitors of the DXP reductoisomerase catalysed reaction from DXP to 2-C-methyl-D-erythritol-4-phosphate (MEP). In Chapter 2 the successful synthesis of the CH(_2) phosphonate analogues of DXP and MEP is described. The DXP analogue was initially approached via the diethyl phosphonate ester, however it proved necessary in the end to prepare the dibenzyl ester followed by hydrogenation. Synthesis towards the CF2, and the a-fluorinated ketone, phosphonate analogues of DXP were incomplete due to low yields. Further syntheses is described towards the reduced form of the CH2 phosphonate analogue of DXP, and to a compound related to fosmidomycin. Chapter 3 describes fluorine's stereoelectronic influence in determining the conformations of fluoromethyl containing organic compounds through n/π-σ* conjugation and gauche effects. Solid state evidence for the influence of these effects is presented through the first X-ray crystallographic data of fluoromethylaromatics and β-fiuoroethylamides respectively. Structures of bis-2,6-(fluoromethyl)pyridine and its N-oxide displayed fluoromethyl conformations with the C-F bond co-planar to the aromatic ring whereas benzyl fluoride and 4-bromobenzyl fluoride displayed conformafions with the C-F bond orthogonal to the aromatic ring. Structures of N-(2-fluoroethyl)-3,5-dinitrobenzamide and N-(2-fluoroethyl)-4-nitrobenzamide reveal a fluorine / amide gauche effect.

The replacement of a hydrogen or hydroxy group with a fluorine atom is a popular strategy to alter the activity of biologically important molecules, as their similar sizes mean that such a replacement has little steric impact. The effect of fluorine substitution in a number of enzyme mediated processes has been investigated. 3-Fluorocyclohex-l-enylcarbonyl-CoA has been synthesised and the reaction with cyclohexenylcarbonyl-CoA reductase investigated. The fluorinated substrate has a comparable K(_m) value to that of the natural substrate but a V(_max) that is five times greater. A change in the rate-determining step of the reduction was also observed upon fluorine incorporation. The enzyme showed a small but significant stereochemical preference for the production of the axial isomer, consistent with an Anh-Eisenstein model for the transformation. The 6а and 6β isomers of benzyl fluoropenicillanate were synthesised and their methoxide-mediated hydrolyses were investigated. Competitive hydrolysis, using (^19)F NMR spectroscopy, demonstrated that the β isomer was hydrolysed preferentially. A frill kinetic analysis was undertaken, which furnished the rate and equilibrium constants. Monofluorinated enamines were treated in situ with a range a Michael acceptors to afford a variety of novel substituted a-fluoro ketones. 2-Fluorohexanal was synthesised from methyl hexanoate and was demonstrated to be a substrate for the enzyme transketolase with hydroxypyruvate. The enzyme reaction was monitored by (^19)F NMR spectroscopy. The enzyme showed a diastereoselectivity of 9:1 in the condensation of the aldehyde and hydroxypyruvate, and a self-condensation product was also produced. The enzymatic oxidation of the mono- and di-fluoromethylenephosphonate analogues of glycerol-3-phosphate was investigated at neutral pH using a co-factor recycling protocol. The reactions allowed for the first time the identification of the products of oxidation and demonstrated the lability of fluoride via non-enzymatic elimination and stoichiometric defluorination.

<p>This thesis is based on ten publications (Papers I-X). The phosphodiester backbone makes DNA or RNA to behave as polyelectrolyte, the pentose sugar gives the flexibility, and the aglycones promote the self-assembly or the ligand-binding process. The hydrogen bonding, stacking, stereoelectronics and hydration are few of the important non-covalent forces dictating the self-assembly of DNA/RNA. The pH-dependent thermodynamics clearly show (Papers I and II) that a change of the electronic character of aglycone modulates the conformation of the sugar moiety by the tunable interplay of stereoelectronic anomeric and <i>gauche</i> effects, which are further transmitted to steer the sugar-phosphate backbone conformation in a cooperative manner. 3'<i>-</i>anthraniloyl<b> </b>adenosine<b> </b>(a mimic of 3'-teminal CC<u>A</u>_OH of the aminoacyl-tRNA^Phe) binds to EF-Tu*GTP in preference over 2'<i>-</i>anthraniloyl<b> </b>adenosine<b>, </b>thereby showing (Paper III) that the 2’-<i>endo</i> sugar conformation is a more suitable mimic of the transition state geometry than the 3’<i>-endo</i> conformation in discriminating between correctly and incorrectly charged aminoacyl-tRNA^Phe by EF-Tu during protein synthesis. The presence of 2'-OH in RNA distinguishesit from DNA both functionallyas well as structurally. This work (Paper IV) provides straightforward NMR evidence to show that the 2'-OH is intramolecularly hydrogen bonded with the vicinal 3'-oxygen, and the exposure of the 3'<i>-</i>phosphate of the ribonucleotides to the bulk water determines the availability of the bound water around the vicinal 2'-OH, which then can play various functional role through inter- or intramolecular interactions. The pH-dependent ¹H NMR study with nicotinamide derivatives demonstrates (Paper V) that the cascade of intramolecular cation (pyridinium)-π(phenyl)-CH(methyl) interaction in edge-to-face geometry is responsible for perturbing the p<i>K</i>_a of the pyridine-nitrogen as well as for the modulation of the aromatic character of the neighboring phenyl moiety, which is also supported by the T₁ relaxation studies and <i>ab initio</i> calculations. It has been found (Papers VI-IX) that the variable intramolecular electrostatic interaction between electronically coupled nearest neighbor nucleobases (steered by their respective microenvironments) can modulate their respective pseudoaromatic characters. The net result of this pseudoaromatic cross-modulation is the creation of a unique set of aglycones in an oligo or polynucleotide, whose physico-chemical properties are completely dependent upon the propensity and geometry of the nearest neighbor interactions (extended genetic code). The propagation of the interplay of these electrostatic interactions across the hexameric ssDNA chain is considerably less favoured (effectively up to the fourth nucleobase) compared to that of the isosequential ssRNA (up to the sixth nucleobase). The dissection of the relative strength of basepairing and stacking in a duplex shows that stability of DNA-DNA duplex weakens over the corresponding RNA-RNA duplexes with the increasing content of A-T/U base pairs, while the strength of stacking of A-T rich DNA-DNA duplex increases in comparison with A-U rich sequence in RNA-RNA duplexes (Paper X).</p>

This thesis is based on ten publications (Papers I-X). The phosphodiester backbone makes DNA or RNA to behave as polyelectrolyte, the pentose sugar gives the flexibility, and the aglycones promote the self-assembly or the ligand-binding process. The hydrogen bonding, stacking, stereoelectronics and hydration are few of the important non-covalent forces dictating the self-assembly of DNA/RNA. The pH-dependent thermodynamics clearly show (Papers I and II) that a change of the electronic character of aglycone modulates the conformation of the sugar moiety by the tunable interplay of stereoelectronic anomeric and gauche effects, which are further transmitted to steer the sugar-phosphate backbone conformation in a cooperative manner. 3'-anthraniloyl<b> </b>adenosine<b> </b>(a mimic of 3'-teminal CC<u>A</u>OH of the aminoacyl-tRNAPhe) binds to EF-Tu*GTP in preference over 2'-anthraniloyl<b> </b>adenosine<b>, </b>thereby showing (Paper III) that the 2’-endo sugar conformation is a more suitable mimic of the transition state geometry than the 3’-endo conformation in discriminating between correctly and incorrectly charged aminoacyl-tRNAPhe by EF-Tu during protein synthesis. The presence of 2'-OH in RNA distinguishes it from DNA both functionally as well as structurally. This work (Paper IV) provides straightforward NMR evidence to show that the 2'-OH is intramolecularly hydrogen bonded with the vicinal 3'-oxygen, and the exposure of the 3'-phosphate of the ribonucleotides to the bulk water determines the availability of the bound water around the vicinal 2'-OH, which then can play various functional role through inter- or intramolecular interactions. The pH-dependent 1H NMR study with nicotinamide derivatives demonstrates (Paper V) that the cascade of intramolecular cation (pyridinium)-π(phenyl)-CH(methyl) interaction in edge-to-face geometry is responsible for perturbing the pKa of the pyridine-nitrogen as well as for the modulation of the aromatic character of the neighboring phenyl moiety, which is also supported by the T1 relaxation studies and ab initio calculations. It has been found (Papers VI-IX) that the variable intramolecular electrostatic interaction between electronically coupled nearest neighbor nucleobases (steered by their respective microenvironments) can modulate their respective pseudoaromatic characters. The net result of this pseudoaromatic cross-modulation is the creation of a unique set of aglycones in an oligo or polynucleotide, whose physico-chemical properties are completely dependent upon the propensity and geometry of the nearest neighbor interactions (extended genetic code). The propagation of the interplay of these electrostatic interactions across the hexameric ssDNA chain is considerably less favoured (effectively up to the fourth nucleobase) compared to that of the isosequential ssRNA (up to the sixth nucleobase). The dissection of the relative strength of basepairing and stacking in a duplex shows that stability of DNA-DNA duplex weakens over the corresponding RNA-RNA duplexes with the increasing content of A-T/U base pairs, while the strength of stacking of A-T rich DNA-DNA duplex increases in comparison with A-U rich sequence in RNA-RNA duplexes (Paper X).

La réévaluation des impacts toxicologique et environnemental des répulsifs synthétiques conduit à reconsidérer les répulsifs d'origine naturelle pour la prévention des maladies transmises par les insectes (dengue, chikungunya, paludisme,…). Cette étude se rapporte aux structures de type bis(oxazolidine) envisagées comme prodrogues de répulsifs naturels par leur conversion avec le tris(hydroxyméthyl)aminométhane (TRIS). Différents protocoles et voies de synthèse ont été étudiés sur une série représentative d'aldéhydes pour définir l'étendue et les limites de l'approche permettant de concentrer deux unités d'un même principe actif au sein de bis(oxazolidines) symétriques et de reproduire un effet synergique avec deux unités différentes formant des bis(oxazolidines) dissymétriques. La fonctionnalisation des bis(oxazolidines) a été également envisagée pour moduler leur balance hydrophile-lipophile. L'étude de la réaction de cyclocondensation met en évidence l'influence des paramètres structuraux sur le procédé de synthèse des bis(oxazolidines), la stabilité des intermédiaires (monooxazolidines) et la stéréosélectivité de la réaction. L'interprétation des résultats est proposée sur la base des effets (stéréo)-électroniques. Cette étude démontre l'intérêt de cette approche chimique pour la production de prodrogues de répulsifs naturels qui peuvent constituer des atouts pour le développement durable. / The more sensitive human and environmental risk assessments of non natural repellents have encouraged the rehabilitation of botanical-based repellents for the prevention of insect-transmitted diseases (dengue, chikungunya, malaria…). This study is related to bis(oxazolidine) structures envisaged as prodrug derivatives of natural repellents by their conversion with tris(hydroxymethyl)aminomethane (TRIS). The scope and limitations of various procedures and pathways have been assessed with structurally diverse aldehydes to concentrate two identical units in the symmetrical structures and to reproduce a synergistic effect with two different units in the unsymmetrical ones. Subsequent functionalization of the heterocyclic derivatives has been achieved to modulate their hydrophilic-lipophilic balance. The study of the cyclocondensation reaction shows evidence for the influence of structural effects not only on the chemical process but also on the relative stability of the monocyclic intermediates and the stereochemical outcomes of the reaction. The results are discussed on the basis of (stereo)-electronic effects. Finally, this study confirms the feasibility of this chemical approach to produce prodrugs of natural repellents which could appear as a contributive effort to sustainable development.