A técnica de ressonância ciclotrônica de íons permite aprisionar numa cela adequada íons produzidos por impacto de elétrons sobre um gás a baixa pressão (10-7 - 10-4 Torr) . Os íons são mantidos na cela por tempos de 3 a 10 ms e dessa maneira podem reagir com moléculas neutras do gás do qual provém ou, de algum outro gás introduzido no espectrômetro. Resultam dessas reações produtos iônicos, que frequentemente foram observados reagirem novamente com moléculas neutras, dando origem a íons terciários. Todos os íons são detectados pela potência que absorvem de um campo de rádio-frequência conveniente, podendo ser registrado um espectro, no qual cada íon é caracterizado por sua massa, sendo a intensidade do pico correspondente proporcional à corrente iônica parcial do lon na cela. Contudo, a situação é tal que íons de massa maior permanecem por tempos mais longos na cela, de modo a reagirem em maior extensão e absorverem maior potência do oscilador de rádio-frequência. Essa discriminação de massa precisa ser levada em conta ao interpretar os espectros de ressonância ciclotrônica de íons e, para esclarecer a natureza das correções necessárias, as principais equações que descrevem o movimento dos íons na cela foram deduzidas e discutidas na primeira parte deste trabalho. Tais equações sugerem urna série de experiências, que tornam a espectroscopia de ressonância ciclotrônica de íons uma técnica muito versátil. Estas experiências foram todas apresentadas na primeira parte, devendo-se salientar a experiência de ressonância dupla, que permite identificar de maneira inequívoca o precursor de algum produto iônico, a experiência de ejeção de íons, que permite remover seletivamente um íon de dada espécie da cela, além de experiências que visam a obtenção de constantes de velocidade de reações de íons com moléculas. É justamente esta última grandeza mencionada, a saber, a constante de velocidade de uma reação, a que pode ser com parada com valores calculados a partir de modelos teóricos. Esses modelos baseiam-se em sua maioria na interação do íon, considerado como carga puntiforme, com a molécula neutra de certa polarizabilidade e momento dipolar (modelo de polarização) ou, na fragmentação de um complexo intermediário (modelos estatísticos). Os aspectos teóricos das reações entre íons e moléculas em fase gasosa foram analisados e os modelos mencionados, discutidos, além de modelos chamados \"diretos\" mais apropriados para comparações com resultados de experiências de feixes iônicos. A espectroscopia de ressonância ciclotrônica de íons foi utilizada para o estudo de reações de acilação em cetonas, reações bastante gerais (foi verificado que ocorrem também em outros sistemas carbonílicos) e que podem ser representadas pela equação RCOR\'+ + RCOR\' &#8594; RCO+ (RCOR\') + R\'. Estudos de variação das correntes iônicas relativas de todos os íons das cetonas, em função da pressão de cetona neutra, possibitaram a dedução de um mecanismo de formação desses íons acilados. Os resultados estão de acordo com um esquema no qual esse produto é formado pela fragmentação de um dímero intermediário, para o qual se supõe existirem condições de estado estacionário. Esta fragmentação se dá de maneira análoga à fragmentação dos íons moleculares de cetonas em espectroscopia de massa usual, tratando-se então de uma fragmentação induzida por uma espécie neutra. A pressões elevadas, nas quais o dímero pode sofrer colisões não-reativas e relaxar o excesso de energia interna, o mesmo é estabilizado, fornecendo um pico no espectro. Cetonas de polarizabilidade maior têm uma afinidade maior para o grupo acila; isto foi concluído, quando foram observadas reações de transferência de grupos acila, como por exemplo a transferência de CH3CO+ da cetona para a butanona num sistema formado pela mistura dessas duas cetonas. Estudos de basicidade relativa de álcoois, ácidos, ésteres e cetonas revelaram que há uma relação de proporcionalidade entre a basicidade desses compostos e seu potencial de ionização. Isto havia sido mostrado anteriormente para o caso das aminas, por outros pesquisadores. O conhecimento da basicidade de álcoois, ácidos e ésteres permitiu analisar reações de esterificação e transesterificação sob o ponto de vista termoquímico. Trata-se de reações entre moléculas protonadas das espécies mencionadas, que podem ser consideradas análogas às reações catalisadas por ácidos em solução. O fato de uma reação ser exotérmica não significa que ela ocorra. Assim, foi observado que ácido fórmico não é esterificado por metanol ou etanol nas condições reinantes numa cela de ressonância ciclotrônica de íons, enquanto quê ácido acético o é. A ordem relativa de basicidades em fase gasosa foi determinada como sendo HCOOH < ( CH30H < C2H5OH < CH3COOH. Dessa maneira os resultados estão de acordo com um ataque nucleófilo por parte do álcool no ácido protonado; porém, se este é menos básico que o álcool, ocorre a transferência de próton e não a esterificação. Reações de transesterificação não foram observadas de maneira alguma, mas uma outra reação entre ésteres e álcoois foi encontrada e que pode ser exemplificada pela equação (CH3)2CHOH2+ + HCOOC3H7 &#8594; HCO2(C3H7) (C3H7)+ + H2O. Esta reação só se dá com álcoois capazes de produzir íons de carbônio mais estáveis que os primários; portanto metanol e etanol não reagem. O produto formado pode fragmentar novamente O que revelou que o grupo alquila proveniente do álcool retém um excesso de energia na sua ligação, pois na decomposição é esta a ligação que rompe. Em todos estes estudos, isto é, nos de acilação de cetonas e de esterificação, bem como nos estudos de basicidade, foi sempre salientada a importância de examinar essas reações em fase gasosa, pelo fato de serem reações mais simples, uma vez que se dão na ausência de solventes e portanto revelarem propriedades intrínsecas das espécies envolvidas. Finalmente foram descritas algumas modificações realizadas no espectrômetro de ressonância ciclotrônica de íons, para poder operá-lo de forma pulsada. Com isso é possível manter os íons por tempos maiores na cela (500 ms) e, o que é mais importante, esses tempos podem ser definidos com grande precisão, o que torna viável a obtenção de resultados quantitativos (constantes de velocidade de reação) melhores. / Ions can be trapped for times as long as 10 ms by the combined action of magnetic and electric fields in the cell of an ion cyclotron resonance spectrometer. Despite the low operating pressure (10-7 - 10-4 Torr), the ions experience many collisions during this time, some of which may be reactive, leading to product ions. The ion cyclotron resonance spectrum thus displays a series of peaks corresponding to the various primary, secondary, and eventually tertiary ions; the peak heights, after suitable mass correction, yield ion currents. The double resonance technique allows one to establish unambiguously the precursor ions of a given product ion, by accelerating the suspected reagent ions and examining the effect on the product ion. Ions can also be selectively ejected from the cell. These techniques, which were described in this thesis after an outline of the basic principles of ion cyclotron resonance spectroscopy, allow, one to unravel the gaseous ion chemistry in any chemical system. Rate constants of ion-molecule reactions can be determined by ion cyclotron resonance spectroscopy. The necessary equations, based on the equations relating measured peak intensities to ion currents, were derived and their limitations, as well as those of the experimental procedures for obtaining the input parameters for the expressions, were discussed. Rate constants can also be calculated theoretically and there are a few microscopic models which treat the collision of an ion with a polarizable neutral molecule (polarization model) or the unimolecular fragmentation of an intermediate complex (statistical models). Direct models, although more suitable for comparison with results from beam experiments, were presented together with the above mentioned models, and their importance for the interpretation of the basic aspects of ion-molecule chemistry was discussed. The ion cyclotron resonance spectrometer was used to study an acylation reaction in ketones, which seems to be general for carbonyl compounds. RCOR\'+ + RCOR\' &#8594; RCO+ (RCOR\') + R\'. Pressure plots of the ion currents in ketones allowed us to propose a mechanism according to which the acylated ketones are formed by the fragmentation of an excited dimer ion, in a fashion analogous to the fragmentation of ketone parent ions in ordinary mass spectroscopy. Steady state conditions prevail for the excited dimer, which can be stabilized at pressures high enough for the ion to collide with a neutral in a time short compared to his life time, thus relaxing excess energy. The acyl group can be transferred from a ketone of lower polarizability to one of higher polarizability; thus CH3CO+ is for instance transferred from acetone to butanone in a mixture of these two compounds, as detected by double resonance. Relative proton affinities of alcohols, acids, esters, and ketones were determined and the results are in agreement with the assumption of constant hydrogen affinity within a homologous series, as has been shown previously for the case of amines by others. Of particular interest is the following order of proton affinities: HCOOH < ( CH30H < C2H5OH < CH3COOH. The positive ion spectra of mixtures of acetic acid with methanol or ethanol revealed that this acid reacts with the alcohols yielding a protonated ester, in a process apparently analogous to the acid catalized esterification in solution. On the other hand,formic acid was found not to behave in this way, although the reactions are all exothermic. These results could be rationalized assuming that a nucleophilic attack takes place on the protonated acid by the alcohol. If the alcohol is more basic, only proton transfer is observed. Transesterification reactions were not detected, but this failure was compensated by a reaction which all higher alcohols, namely those capable of producing a secondary or tertiary carbonium ion, undergo with the esters. This reaction can be exemplified by (CH3)2CHOH2+ + HCOOC3H7 &#8594; HCO2(C3H7) (C3H7)+ + H2O. Although in this particular reaction both alkyl groups seem equivalent, they are not so with respect to internal vibrational energy; this was demonstrated by the decomposition reactions which the ionic products like the one in the reaction above undergo: the alkyl group originally in the alcohol is always eliminated. All the reactions mentioned above, namely, acylation of ketones, proton transfer, and esterification, show the importance of ion-molecule reaction studies in the gas phase, where the intrinsic properties of the reacting species can be examined, free from solvation effects. This point has been repeatedly stressed. In a last chapter in this thesis the necessary modifications of the ion cyclotron resonance spectrometer, in order to operate it in a pulsed mode, were described. With this kind of operation a bunch of ions is formed by a pulse of the electron beam and the ions react for a known period of time, after which they are removed from the cell. Kinetic studies can be more easily carried out in this way than in the conventional one. Some preliminary results were shown.

Many mutations in superoxide dismutase 1 (SOD1) cause destabilization and misfolding of the protein and are implicated in amyotrophic lateral sclerosis. Likewise, a few post-translational modifications (PTMs) on SOD1 have been shown to cause the same phenotype. However, relatively few PTMs on SOD1 have been studied in depth and, in particular, very few studies have demonstrated how these PTMs affect SOD1's various biological roles. SOD1 is traditionally known for its role in reactive oxygen species (ROS)-scavenging but has also been found to have a few other biological roles, including transcription factor activity to promote genomic stability, preservation of cytoskeletal activity, maintaining zinc and copper homeostasis, and suppressing respiration. We have used the computational analysis tool, SAPH-ire, to find PTM 'hotspots' on SOD1 that have a high likelihood of affecting its biological functions. Interestingly, the top seven ranked PTM 'hotspots' were found in a small region of SOD1, between S98-K128. We focused our studies on one of the PTM 'hotspots' found in this region, lysine-122 (K122). K122 is found in the electrostatic loop of SOD1, a loop that is important for shuttling in superoxide radicals to be neutralized. According to our data, and other studies, this lysine is both succinylated and acetylated. We found that acetyl and succinyl-mimetics (K122Q and K122E, respectively) of this site do not affect its ROS scavenging activity but do prevent SOD1 from suppressing respiration and decrease its localization to the mitochondria. Further, when cells are depleted of SIRT5 (the desuccinylase for K122), SOD1 can no longer suppress respiration. Additionally, we found that SOD1 appears to suppress respiration at complex I, whether directly or through an indirect pathway is unknown. When HCT116 colon cancer cells were depleted of endogenous SOD1, the overexpressed succinyl K122-mimetic (K122E) could not recover growth as well as overexpressed WT SOD1. The K122E SOD1 expressing cells also exhibited increased mitochondrial ROS and unhealthier mitochondria. We propose a mechanism whereby SOD1 suppression of respiration acts as an additional regulator of oxidative stress: SOD1 suppresses the electron transport chain to decrease reactive oxygen species leakage and to promote healthier mitochondria and growth.

Dans le domaine pharmaceutique, la voie orale demeure la voie d’administration de prédilection, car plus simple et mieux acceptée par les patients. Cependant, ce mode d’administration pose problème pour de nombreux principes actifs (PA) présentant une faible solubilité, une faible perméabilité et/ou une instabilité dans l’environnement gastro-intestinal. Leur micro-encapsulation dans des matrices polymériques peut permettre d’y répondre, notamment si les microparticules générées résistent aux environnements rencontrés lors du tractus gastro-intestinal et jouent alors un rôle protecteur, tant pour le principe actif que pour les muqueuses rencontrées. La recherche de nouveaux excipients, issus des agro-ressources tels que les polymères naturels, est en plein essor. Les protéines végétales, grâce à leurs propriétés fonctionnelles telles qu’une bonne solubilité, une viscosité relativement basse, et des propriétés émulsifiantes et filmogènes, représentent des candidats privilégiés. De plus, la grande diversité de leurs groupements fonctionnels permet d’envisager des modifications chimiques ou enzymatiques variées. L’objectif de ce travail était d’étudier l’intérêt de la protéine de soja en tant que matériau enrobant de principes actifs pharmaceutiques destinés à la voie orale, et plus particulièrement en tant que candidat pour l’élaboration de formes gastro-résistantes. Un isolat protéique de soja (SPI) été utilisé comme matière enrobante et l’atomisation comme procédé. L’ibuprofène, anti-inflammatoire non stéroïdien, a été choisi comme molécule modèle du fait de sa faible solubilité nécessitant une amélioration de sa biodisponibilité, et de ses effets indésirables gastriques nécessitant une mise en forme entérique. Deux modifications chimiques des protéines (l’acylation et la succinylation) ont été étudiées dans le but de modifier la solubilité de la protéine de soja. Ces modifications ont été effectuées dans le respect des principes de la Chimie Verte, notamment en absence de solvant organique. Les microcapsules obtenues par atomisation ont été caractérisées en termes de taux et efficacité d'encapsulation, morphologie et distribution de tailles des particules, état physique du PA encapsulé et capacité de libération en milieu gastrique et intestinal simulé. Les résultats obtenus ont permis de valider l’intérêt des modifications chimiques de la protéine de soja pour moduler les cinétiques de libération d’actif. Les modifications chimiques sont apparues particulièrement adaptées pour l’encapsulation de principes actifs hydrophobes, et ont permis de l’obtention de cinétiques de libération d’ibuprofène ralenties à pH acide (gastrique). La dernière partie de ce travail a permis de valider cette dernière hypothèse par la réalisation de formes gastro-résistantes sur le modèle des comprimés MUPS (multiple unit pellet system). Les résultats de ce travail exploratoire démontrent que les protéines de soja, associées à un procédé de mise en forme multi-particulaire couplé à de la compression directe, peuvent constituer une alternative biosourcée, respectueuse de l’environnement (manipulation en solvant aqueux, temps de séchage et étapes de compression réduits) et sûre à l’enrobage utilisé dans les formes gastro-résistantes traditionnelles.

Mn-Mediated radical addition has been developed within the Friestad laboratory as a versatile method toward addition to C=N bonds. N-Acylhydrazones generated by condensation between an aldehyde and an N-acylamine serves as the substrate toward radical addition. A bulky directed group attached with the N-acyl moiety and restricted rotation around N-N bond due to a three point chelation with a Lewis acid differentiates the faces of the C=N bond of the N-acylhydrazones. Radical generation initiated by photolysis of Mn2(CO)10 causing homolysis of C-X bond in alkyl halide serves as the radical donor to the N-acylhydrazones. Radical addition thereafter occurs stereoselectively from the less hindered face of the C=N bond of the N-acylhydrazones. The product N-acylhydrazines can be effectively transformed to α-chiral amines. In this thesis, a new protocol toward generation of non-proteogenic γ-amino esters using Mn-mediated radical addition has been described. Moreover, the utility of the Mn-mediated radical addition has been demonstrated through studies toward synthesis of tubulysin U and V. Chapter 3 describes a new strategy for asymmetric synthesis of γ-amino esters starting from non-amino precursors. The α-substituted γ-amino esters are prevalent in drugs, drug candidates, and in peptidomimetics. As a part of progressing the Mn-mediated radical addition reaction, highly stereoselective reactions were devised for addition to N-acylhydrazonoesters in absence of Lewis acid. Spectroscopic investigations were carried out to decipher the Lewis acid chelation of N-acylhydrazones. Finally, a novel microwave mediated trifluoroacylation of N-acylhydrazinoesters facilitated the cleavage of N-N bond to liberate γ-aminoester. Chapter 4 describes application of Mn-mediated radical addition toward synthesis of tubulysin natural products. Tubulysins are natural products, isolated from myxobacteria, that have exhibited potent cytotoxicity toward cancer cells in the picomolar regime. The Mn-mediated radical addition was used to prepare two chiral amine subunits in highly diastereoselective fashion. The subunits were then assembled after required manipulations into the tetrapeptide structure characteristic of tubulysins. This strategy to synthesize tubulysins is the most stereoselective of all efforts toward the synthesis of this molecule. Synthesis toward tubulysin was achieved in 18 steps as the longest linear sequence with a 31% overall yield to tubulysin V in benzyl protected form. Chapter 5 describes a new strategy toward installation of N-hydroxymethyl unit into a peptide chain. N,O-Acetals are acid-base labile species that is present in some tubulysin natural analogs. This new approach exploits Fleming-Tamao oxidation and hence introduce the hydroxymethyl unit of the N,O-acetal in a masked form. Following peptide construction the masked hydroxy group is released to liberate the N-hydroxymethyl moiety. Acylation of the free hydroxy group furnishes the N,O-acetal moiety in a strategy that is potentially applicable toward synthesis of tubulysin D.

The intramolecular Friedel-Crafts acylation of aromatics with Meldrum?s acid derivatives catalyzed by metal trifluoromethanesulfonates and other Lewis acids is reported. Meldrum?s acids are easily prepared, functionalized, handled, and purified. The synthesis of polysubstituted 1-indanones from benzyl Meldrum's acids was investigated thoroughly, and it was shown that a variety of catalysts were effective, whilst accommodating a diversity of functional groups under mild conditions. The scope, limitations, and functional group tolerance (terminal alkene and alkyne, ketal, dialkyl ether, dialkyl thioether, aryl methyl ether, aryl TIPS and TBDPS ethers, nitrile- and nitro-substituted aryls, alkyl and aryl halides) for a variety of 5-benzyl (enolizable Meldrum?s acids) and 5-benzyl-5-substituted Meldrum?s acids (quaternarized Meldrum?s acids), forming 1-indanones and 2-substituted-1-indanones respectively, are delineated. <br ><br /> This method was further applied to the synthesis of 1-tetralones, 1-benzosuberones, and the potent acetylcholinesterase inhibitor donepezil. <br ><br /> Mechanistic investigations were undertaken to determine the rate-determining step in the acylation sequence using Meldrum?s acid, as well as to examine the role of the Lewis acid catalyst. Enolizable Meldrum?s acid derivatives can react via an acyl ketene intermediate under thermal conditions, while quaternarized Meldrum?s acid derivatives are thermally stable and only act as effective Friedel-Crafts acylating agents in the presence of a Lewis acid catalyst. <br ><br /> The total synthesis of (±)-Taiwaniaquinol B was completed. This natural product was the first ever isolated containing an unusual 6-5-6 fused ring system, and it also contains a hexasubstituted aromatic ring, and two all-carbon quaternary centers. This synthesis was accomplished via an intramolecular Friedel-Crafts acylation/carbonyl a-<em>tert</em>-alkylation reaction that exploits the unique chemistry of Meldrum?s acid. This novel methodology can be used to access a variety of highly substituted fused ring systems of various sizes.

Stilbenoids possess a wide range of biological properties such as, anticancer, antiplatelet aggregation, antiestrogenic, antibacterial, antifungal and antiatherogenic, etc. Owing to these therapeutic values, a great deal of attention attracted in the synthesis of derivatives of stilbenes. During the course of the study, G6 a novel stilbenoid was discovered, through high throughput screening, to be a potent inhibitor of mutated JAK2-V617F. The mutated JAK2 variant has been implicated in various myeloproliferative disorders (MPDs) including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) has been targeted by therapeutics. Chapter 2 describes the synthesis of analogs of the stilbenoid G6 and N-substituted stilbenes bisoxazines by utilizing Mcmurry reaction and Mannich condensation methods. The main emphasis of this work is to develop novel stilbenoids as inhibitors of JAK2-V617F mutated Jak2 enzyme in Human erythroleukemia cells (HEL) since this mutation is discovered in the majority of patients with myeloproliferative disorders (MPDs). Using Mcmurry reaction, five novel trans-hydroxystilbenes have been synthesized from carbonyl compounds. Subsequently using Mannich coupling with five secondary amines and five primary amines, 25 novel stilbenoids and 9 novel N-substituted stilbene bisoxazines have been synthesized. In HEL cell assay, 8 stilbenoid analogues have been identified as potent inhibitors of Jak2 enzyme. Chapter 3 describes the modification of ketamine structurally for the synthesis of novel analogues to study for their agonist activity at GABAA receptors and antagonist activity at NMDA receptors. Ligand gated ion channels like GABAA and NMDA receptors are membrane-embedded proteins at synaptic cleft which controls intercommunication among neurons and plays an important role in motor control activity, learning. GABAA receptors are responsible for inhibitory action potentials while NMDA receptors are responsible for excitory action potentials. Ketamine, known as dissociative anesthetic, produces profound analgesia at low doses to a unique cardiovascular stimulation and a cataleptic state at higher doses with dose dependent side effects like vivid dreams, disruptions of cognitive functions. The main emphasis of this work is the synthesis of novel analogues of ketamine by transforming carbonyl group in ketamine to imine functionality with small to bulkier groups and to identify an analogue of ketamine which is highly potent in its activity at the both GABAA and NMDA receptors and improved clinical actions. Studies of analogues activity against GABAA subtypes α6Β2δ, α1Β2γ2 receptors and NMDA subtypes NR1/2A, NR1/2B, NR1/2D receptors have been described. Chapter 4 describes the formal synthesis of (±)-Rolipram and the chemoenzymatic synthesis of -aryl--lactone, a Rolipram analogue. The key steps, Pd catalyzed arylation of diethylmalonate and the efficient use of selective acylation of 1, 3-diol entails the formal synthesis of (±)-Rolipram. The regioselective deacylation of Β-aryl-1, 4-diacetate by lipase Pseudomonas Sepacia entails the formation of Β-aryl-γ-lactone. The efficient use of various methods including halogen exchange, Heck arylation of diethylmaleate and lactonization for the synthesis of Β-aryl-γ-lactone have been discussed. The present work provides an efficient and general route to γ-lactones.

Quercetin-3-O-glucoside (Q3G), a glycosylated derivative of quercetin, is a polyphenolic compound known to possess diverse biological activities. Its moderately hydrophilic nature is a critical factor governing the accessibility to the active sites of oxidative damages in vivo. It was hypothesized that biological activities of Q3G can be further enhanced by regioselective acylation with fatty acids which gives more lipophilicity. Q3G was acylated with six selected long chain fatty acids: stearic acid, oleic acid, linoleic acid, ?-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), using Candida antactica lipase. The derivatives were evaluated for their potential in inhibiting lipid oxidation in food systems and human low density lipoprotein (LDL), and cytoprotection and anti-inflammatory effect in cell culture model systems. The fatty acid derivatives of Q3G possessed greater effectiveness in inhibiting lipid oxidation in oil-in-water emulsions, and better cytoprotective effect against H2O2- and cigarette smoke toxicant-induced cytotoxicity when compared to Q3G.

A new method for the efficient synthesis of ferrocenylenones was developed. Acryloyl, methacryloyl, crotonyl, cinnamoyl, and &amp / #946 / -methylcrotonyl chlorides reacted with ferrocene in the presence of a Lewis acid (EtAlCl2 or EtAlCl2-Me3Al) to give the corrosponding ferrocenylenones (acryloyl, methacryloyl, crotonyl, cinnamoyl, and &amp / #946 / -methylcrotonylferrocenes) in good isolated yields. Using the Gabriel-Cromwell reaction, acryloyl and crotonoylferrocenes were converted to the novel ferrocenyl substituted aziridines with benzylamine, isopropylamine and furfurylamine. The aziridines were isolated in good to excellent yields.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv., 2006. / Härtill 4 uppsatser och 1 patent.

Les travaux présentés dans ce manuscrit s’inscrivent dans le contexte général de l’essor de la biocatalyse et de son utilisation en synthèse organique. Le thème principal porte sur l’étude et le développement de différentes voies d’accès stéréosélectives à des acides alpha-aminés bêta-hydroxylés substitués. L’utilisation d’un biocatalyseur permettant d’accéder à des acides alpha-aminés bêta-hydroxylés par une aldolisation entre la glycine et divers aldéhydes, en présence de phosphate de pyridoxal, a été étudiée. Des aldéhydes aliphatiques, aromatiques et hétéroaromatiques ont pu être impliqués avec succès comme partenaires électrophiles dans ces réactions qui permettent un excellent contrôle de la configuration du carbone asymétrique créé en alpha du groupe carbonyle mais s’effectuent généralement avec des diastéréosélectivités plus modestes. Par ailleurs, un dédoublement cinétique enzymatique d’esters alpha,bêta-dihydroxylés, précurseurs d’acides alpha-aminés bêta-hydroxylés substitués en alpha, a été étudié. La méthode développée repose sur la monoacylation d’esters alpha,bêta-dihydroxylés, acycliques ou cycliques, en présence d’une lipase et d’un donneur d’acyle. De façon indépendante, la mise au point de séquences réactionnelles monotopes faisant intervenir une étape d’oxydation biocatalytique a été étudiée pour accéder à des composés aminés hautement fonctionnalisés. / The research work presented in this manuscript pertains to the field of biocatalysis and some applications in organic synthesis. The main subject is the development of stereoselective synthetic methods allowing access to substituted alpha-amino beta-hydroxy acids. The use of a biocatalyst enabling the preparation of optically enriched alpha-amino beta-hydroxy acids in a single step from glycine by an aldol reaction, in the presence of pyridoxal phosphate, was investigated. Aliphatic, aromatic and heteroaromatic aldehydes could be successfully used as electrophilic partners in such reactions that allow an excellent control of the stereocenter created at the alpha position of the carbonyl group whereas moderate levels of diastereoselectivity were generally observed. The enzymatic kinetic resolution of acyclic or cyclic alpha,beta-dihydroxy esters, which are precursors of alpha-substituted alpha-amino beta-hydroxy acids, was also achieved by monoacylation in the presence of a lipase and an acyl donor. Independently, a one-pot sequence involving a biocatalytic oxidation was developed to access highly functionalized nitrogen containing compounds.