De nouvelles méthodologies en catalyse asymétrique au cuivre ont été développées. D’une part, une réaction d’addition conjuguée asymétrique 1,4 du diméthylzinc sur des acylimidazoles a,b-insaturés catalysée par un complexe cuivre-NHC a été mise au point, avec une excellente énantiosélectivité. Cette réaction a été étendue à des acylimidazoles a,b,g,d-insaturés : les produits d’addition 1,4 ont été obtenus de manière hautement régio- et énantio-sélective. Cette sélectivité originale (1,4 vs 1,6) a pu être rationnalisée par des calculs DFT. La transformation de la fonction acylimidazole a ensuite ouvert l’accès à un processus itératif d’additions conjuguées. Cette stratégie a conduit à la synthèse de motifs polydéoxypropionates : la versatilité de cette méthodologie a été illustrée grâce à la synthèse de motifs syn,syn et anti,anti avec une excellente diastéréosélectivité. Différentes applications en synthèse de produits naturels et bioactifs ont permis d’illustrer le potentiel de cette méthodologie. / New methodologies in asymmetric copper catalysis have been developed. First, a reaction of 1,4-asymmetric conjugate addition of dimethylzinc on a,b-unsaturated acylimidazoles catalysed by a copper-NHC complex has been developed, with an excellent enantioselectivity. This reaction has been extended to a,b,g,d-unsaturated acylimidazoles: 1,4-addition products have been obtained with high regio- and enantio-selectivity. This original selectivity (1,4 vs 1,6) has rationalized by DFT calculations. The transformation of the acylimidazole moiety led us to an iterative process of conjugate additions. This strategy has guided us towards the synthesis of polydeoxypropionate motifs: the versatility of the methodology has been illustrated via the synthesis of syn,syn and anti,anti motifs with high diastereoselectivities. Different applications in natural and bioactive product synthesis allowed us to illustrate the potential of this methodology.

The development of new methods to make carbon-carbon bonds asymmetrically remains a challenge in organic chemistry. Indeed, the development of highly selective methods often proceeds on a trial and error basis. The way chiral information is transferred to the substrate is unclear in many reactions, limiting further development. We focus here on developing an asymmetric conjugate addition of alkylzirconium nucleophiles to Michael acceptors. The development of new phosphoramidite ligands, supported by a computer based model, allowed further development of the reaction. First, existing methods to introduce enantioselectively chirality are described. Then we discuss ligands, and modern ways to parameterise experimental data using computational methods. In chapter two, after discussing the use of alkenes as reagents, especially processes initiated by hydrometallation, we describe a new conjugate addition reaction using cyclic enones that achieves both high yields and levels of enantioselectivity. In chapter three, various applications of phosphoramidite ligands are discussed and we describe the synthesis of a variety of different phosphoramidites and identification of important structural features of these ligands. New, efficient ligands are obtained and a computer model is developed to account for the selectivity of the reaction discussed in chapter two. Chapter four describes the development of an enantioselective synthesis of quaternary centres with novel ligands used to optimise the new system. Lastly, chapter five describes the extension of the method to some linear enones, using different ligands. Overall, we have developed a variety of ligands which were used to expand the enone scope of a conjugate addition and an understanding of what factors make these ligands effective.

The development of selective SmI2-H2O-mediated mono-reductions of cyclic-1,3-diesters to the corresponding 3-hydroxy acids is described. The reaction proceeds with complete selectivity for cyclic-1,3-diesters over acyclic esters. Sequential one-pot conjugate reduction-ester reduction of alkylidene cyclic-1,3-diesters is also reported. Furthermore, we describe the exploitation of the unusual ketyl radical intermediates formed via single electron reduction of the ester carbonyl in unprecedented 5-exo-trig cyclisations providing access to highly substituted, stereo-defined, cyclopentanols and cyclopentanones. Also described is the use of a silicon control element to direct the stereochemical outcome of the SmI2-MeOH-mediated conjugate reduction-intramolecular aldol cyclisations of α,β-unsaturated lactones. These cyclisations generate two contiguous quaternary centres with complete diastereocontrol; the utility of the silicon-directing group as a synthetic handle for derivatisation of the cyclisation products has also been demonstrated. These cyclisations have been applied in a model approach to the anti-mitotic natural product pseudolaric acid B.

No description available.

The natural product 2 crotonyloxymethyl-(4R,5R,6R)-4,5,6-trihydroxy-cyclohex-2-enone (COTC) was isolated from the microorganism Streptomyces griseosporeus in 1975. It was shown to exhibit 'cytotoxic and cancerostatic activity'. The simplified synthetic analogue 2-crotonyl-oxymethyl-cyclohex-2-enone (COMC) has been shown to exhibit potent anti tumour activity against murine and human tumours in cell culture. For several years, the Whitehead research group at the University of Manchester have focused on the synthesis of COTC and COMC analogues in an attempt to produce compounds with enhanced cytotoxicity. In this thesis, the syntheses of several polyfunctionalised cyclohexenones are described. These compounds are analogues of COTC and COMC which also bear structural resemblance to the antheminone and carvotacetone natural products. Initially, the syntheses of six novel compounds from the chiral pool starting material (-)-quinic acid are described. The first four synthetic steps of each sequence were carried out by slight modification of procedures previously reported by the Whitehead research group. As part of the synthetic strategy, the diastereoselective conjugate addition of carbon nucleophiles to several polyfunctionalised cyclohexenones was investigated. The cytotoxicity of four of the synthetic analogues towards A549 non small cell lung cancer cells was investigated by use of an MTT assay. Two of the analogues were found to be more cytotoxic then COMC. The most effective synthetic analogue had an IC50 value of 2.2 μM. This analogue was more cytotoxic than similar molecules that had previously been synthesised by members of the Whitehead research group. Based on the results of the MTT assay, another two analogues were designed and their synthesis from (-)-quinic acid is described. The cytotoxicity of these analogues has yet to be assessed. In summary, the general synthetic strategies developed in this thesis will provide easy access to new analogues of the natural products, enabling the development of new cytotoxic compounds.

Dans les chambres de combustion aéronautiques, le refroidissement par micro-percage est la technique privilégiée pour protéger les parois contre les gaz chauds. L’air frais provenant du contournement traverse des milliers de perforations inclinées et for- ment des micro-jets. Ces derniers coalescent en un film qui protège les parois du tube a flamme. Avec les moyens informatiques actuels, effectuer une simulation aux grandes échelles d’un moteur réel est impossible. En effet, le nombre de micro-trous est beaucoup trop important pour permettre une résolution détaillée de chacun. Des modèles numériques sont donc nécessaires. Le modèle homogène, développé en 2008, permet de simuler des plaques multiperforees avec des maillages dont la résolution est supérieure a celle du trou. Il ne permet cependant pas de représenter la pénétration ni le mélange des jets avec les gaz chauds. Pour remédier a cela, une approche hétérogène, appelée modèle a trou épaissi, a été développée au cours de cette thèse. La précision étant toujours relative au maillage, une méthode de maillage adaptatif augmentant automatiquement la résolution dans les zones clés a été propose afin d’obtenir de meilleurs résultats pour un faible surcoût. Predire la température des parois du tube a flamme est l’objectif final des ingénieurs. A cet effet, une méthodologie appelée Adiab2colo, permettant d’évaluer la température de paroi a partir d’un calcul adiabatique non résolu, a également été développée. Ces trois techniques sont maintenant couramment utilisées par Safran Helicopter Engine pour la conception des moteurs de demain. / Numerical simulation is progressively taking importance in the design of an aero- nautical engine. However, concerning the particular case of cooling devices, the high number of sub-millimetric cooling holes is an obstacle for computational sim- ulations. A classical approach goes through the modelling of the effusion cooling by homogenisation. It allows to simulate a full combustor but failsin representing the jet penetration and mixing. A new approach named thickened-hole model was developed during this thesis to overcome this issue. A work on improving the mesh resolution onkey areas thanks to an automatic adaptive method is also presented, leading to a clear breakthrough. In parallel, as the flame tube temperature is a cornerstone for the combustor durability,a low-cost approach is proposed to predict it. To meet the time-constraints of design, it is based on thermal modelling instead of a direct thermal resolution.

No description available.

A parallel realisation of the Conjugate Gradient Method with Schur-Complement preconditioning, based on a domain decomposition approach, is described in detail. Special kinds of solvers for the resulting interiour and coupling systems are presented. A large range of numerical results is used to demonstrate the properties and behaviour of this solvers in practical situations.

This paper concerns the solution of plate bending problems in domains composed of rectangles. Domain decomposition (DD) is the basic tool used for both the parallelization of the conjugate gradient method and the construction of efficient parallel preconditioners. A so-called Dirich- let DD preconditioner for systems of linear equations arising from the fi- nite element approximation by non-conforming Adini elements is derived. It is based on the non-overlapping DD, a multilevel preconditioner for the Schur-complement and a fast, almost direct solution method for the Dirichlet problem in rectangular domains based on fast Fourier transform. Making use of Xu's theory of the auxiliary space method we construct an optimal preconditioner for plate problems discretized by conforming Bogner-Fox-Schmidt rectangles. Results of numerical experiments carried out on a multiprocessor sys- tem are given. For the test problems considered the number of iterations is bounded independent of the mesh sizes and independent of the number of subdomains. The resulting parallel preconditioned conjugate gradient method requiresO(h^-2 ln h^-1 ln epsilon^-11) arithmetical operations per processor in order to solve the finite element equations with the relative accuracy epsilon.

This paper proposes new iterative methods for the efficient computation of the smallest eigenvalue of the symmetric nonlinear matrix eigenvalue problems of large order with a monotone dependence on the spectral parameter. Monotone nonlinear eigenvalue problems for differential equations have important applications in mechanics and physics. The discretization of these eigenvalue problems leads to ill-conditioned nonlinear eigenvalue problems with very large sparse matrices monotone depending on the spectral parameter. To compute the smallest eigenvalue of large matrix nonlinear eigenvalue problem, we suggest preconditioned iterative methods: preconditioned simple iteration method, preconditioned steepest descent method, and preconditioned conjugate gradient method. These methods use only matrix-vector multiplications, preconditioner-vector multiplications, linear operations with vectors and inner products of vectors. We investigate the convergence and derive grid-independent error estimates of these methods for computing eigenvalues. Numerical experiments demonstrate practical effectiveness of the proposed methods for a class of mechanical problems.