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The symbiont dinoflagellate Amphidinium is an incredible biological manufacturing unit. According to our knowledge, 35 interesting molecules, termed Amphidinolides, have been isolated from Amphidinium sp. In 1989, Kobayashi discovered at least 10 Amphidinolides (A-J) that show cytotoxic activities against murine leukemia P388, L1210 cells and human epidermoid carcinoma KB cells. Four years later, Kobayashi isolated a new molecule, Amphidinolide K. Three total syntheses of Amphidinolide K have been reported by Williams, Lee and Vilarrasa. One of the big challenges is the exo-methylene THF pattern. We became interested in the synthesis of this molecule after discovery of a fortuitous ring contraction by the Marko group that allows ready access to exo-methylene THF moieties. Combined with the ene-IMSC sequence, this methodology represents a powerful tool to synthesize the THF ring of Amphidinolide K. Based on this idea, our approach towards this target involved a 3-fragment disconnection. The coupling of these units, based on in-situ hydroboration for Miyaura-Suzuki cross coupling and Julia-Kociensky olefination were investigated., (SC - Sciences) -- UCL, 2021

A wide variety of natural compounds contain an internal skeleton composed of bicyclic, or even polycyclic, nucleus such as hydrindanes or decalins. For sometime our laboratory has been interested in the synthesis of such compounds and hence, in the development of a short, general and efficient methodology to assemble them. We, previously, in our laboratory, established a procedure to access this type of structures using as the key cyclisation, a Stetter reaction. We are then going to try to make a library based on this method., (SC - Sciences) -- UCL, 2017

Plants modify their volatile chemical signature under pest infestation, which might directly or indirectly improve their defence against threats. These chemical signals have potential in integrated pest management strategies. Macrolophus pygmaeus (Rambur) [Heteroptera: Miridae] is a generalist predatory insect widely used to control the tomato leaf miner, Tuta absoluta (Meyrick) [Lepidoptera: Gelechiidae]. Based on a previous study demonstrating the ability of this mirid species to discriminate non-infested versus T. absoluta-infested tomato plants, our objective was to identify plant volatile chemicals (herbivore-induced plant volatiles-HIPVs) guiding the behaviour of such a generalist predator towards its prey. First, we used coupled gas chromatography-mass spectrometry-electroantennographic detection analysis to screen for active antenna components from the volatile blend released by T. absoluta-infested tomato plants. Dose responses associated with each isolated HIPV were also performed using an electroantennograph. Subsequently, behavioural assays were conducted in a double-choice olfactometer to analyse and identify the behaviourally active chemicals eliciting olfactory responses. Twenty-one total compounds induced antennal responses and six of the 21 evoked positive attractions in M. pygmaeus: (E)hex-2-enal, 2-carene, alpha-pinene, beta-phellandrene, hexanal, and linalool. A synthetic blend of active HIPVs induced olfactory responses as well as attraction in the bioassays. Our results provided evidence the generalist mirid predator M. pygmaeus uses chemical cues from infested tomato plants to identify plants infested by prey. We discussed how these results can be used to improve existing biological approaches to control the tomato leaf miner, T. absoluta.

L’halichlorine, molécule isolée d’une éponge marine, a suscité notre intérêt non seulement pour son activité biologique attrayante, mais également pour le véritable défi que représente sa synthèse. Cet alcaloïde, en inhibant l’induction des VCAM-1 (Vascular Cell Adhesion Molecule-1), pourrait être utile pour le traitement de certains cancers. Au cours de cette thèse, nous avons progressé de manière significative via une synthèse originale pour atteindre un intermédiaire clé. Dans ce but, plusieurs méthodologies développées au sein de notre laboratoire ont été utilisées, comme la formation d’orthoesters ou encore une réaction de spiroannélation. Diverses autres méthodologies intéressantes ont également fait l’objet de beaucoup d’attentions, dont un réarrangement de Beckmann et une contraction de sulfure d’Eschenmoser., (SC - Sciences) -- UCL, 2016

During this last decade, a large growth in fungal infections has been observed1, resulting, not only from the increase in immunodeficient patients but also from the capacity of the fungal microorganisms to acquire resistance towards current drugs. In 1991, the natural compounds Jerangolid A, B, D, E and H have been isolated and Jerangolid A found to display interesting antifungal properties against several fungal strains. With the aim of developing a new type of potential antifungal drug, it was decided to assemble the natural Jerangolids and some analogs. To facilitate and accelerate these syntheses, we developed various original synthetic methodologies., (SC - Sciences) -- UCL, 2016

Silicon-based cross-coupling reactions are extremely powerful tools for the introduction of new C−C bonds in complex organic frameworks. The ready availability, low cost, and high chemical stability of silylated molecules led to a rapid development of several metal-based cross-couplings. Over the past few years, our group has developed an efficient copper-catalyzed method to functionalize vinylsilanes. This cross-coupling reaction leads to the synthesis of stereodefined alkenes that remain a constant challenge in organic chemistry. Using copper(I) salts and tetrabutylammonium polyfluorides as activating agents, various cis, trans, and 1,1’-disubstituted vinylsilanes could be functionalized. Alkenyl-, allyl- and benzyl-halides could be employed to yield their corresponding cross-coupling products. Full retention of stereochemistry was observed in all cases and sensitives groups such as aldehydes were fully tolerated. This very mild method led to the stereoselective synthesis of very sensitive building blocks that are present in natural products, pharmacologically active molecules, agrochemicals, and materials for optics and electronics., (SC - Sciences) -- UCL, 2016

The continuous growth of fungal infections, coupled with the increased resistance of many microorganisms towards antifungal compounds, is an alarming health problem and the discovery of new antifungal agents has become a particularly important area of research. Jerangolid D is a potential antifungal agent of major interest. Recently, the first total synthesis of this natural product has been reported by our group. Its structure can be divided into three subunits: a substituted dihydropyran, an unsaturated lactone and a skipped 1,4-diene middle fragment. Our purpose is to operate a series of chemical modifications on these three subunits in order to create a set of new compounds, similar to Jerangolid D, but possessing hopefully enhanced stability, increased activity and lower toxicity. In this thesis, we shall initially describe our efforts towards the synthesis of the substituted dihydropyran. In order to do so, two methodologies have been developed, based upon previous work in our laboratory. The second one gave the best results and enabled access to the desired dihydropyran in 6 operations using an intramolecular silyl modified Sakurai cyclisation (ISMS) as the key step. The same pathway was used to construct new dihydropyrans by modifying the C-C triple bond. With the natural DHP in hand, different modifications were applied to the double bond in order to reach the right-hand fragment of jerangolid B, E and H in which the stereochemistry at C14 was still unknown. Subsequently, we will describe our efforts towards the preparation of the left-hand lactone of jerangolid D as well as a set of new analogues. Finally, we will present some preliminary investigations on the synthesis of new analogues of the central part of these natural products., (SC - Sciences) -- UCL, 2015

With a view to addressing the shortcomings of traditional catalysts, a new generation of outstanding N- heterocyclic carbene platinum(0) complexes for the hydrosilylation of unsaturated carbon-carbon bonds is reported. Their discovery and application to the stereoselective addition of various silanes to silylated alkynes, terminal acetylenes, and olefins is presented. Insights into the catalytic cycle and the origin of the stereoselectivity are also discussed

Polyhydroxylated fragments are ubiquitous in natural products possessing interesting biological properties. Two patterns can be distinguished: skipped and contiguous polyols. On the subject of contiguous polyols, it was decided, at the onset of this work, to investigate possible pathways to access, at will, all four possible diastereoisomers of a 1,2,3-triol. The likelihood of obtaining amino diols was also envisioned. Therefore we examined the addition of achiral allylstannanes (type II, III) to functionalized chiral aldehydes. This approach led to the synthesis of anti-syn (type II allylstannane) and syn-anti (type III allylstannane) triols as well as syn-syn amino diols (type II allylstannane) with good diastereoselectivities. This efficient new tool was then employed in the total synthesis of natural bioactive products. The first target was (-)-cleistenolide and its synthesis was accomplished in 12 linear steps starting from D-mannitol. The formal total synthesis of a second natural compound, herbarumin I, was achieved and required 9 linear steps starting from 1-pentene. This tool was also used in the synthesis of 2,6-trans-THPs, a part of our synthetic endeavour towards the total synthesis of amphidinol 3. Our efforts in their preparation and subsequent functionalization complete this thesis., (SC - Sciences) -- UCL, 2014

Alkaloid Synthesis has always fascinated chemists both by the complexity of the structure of these natural products and by their diversity. To carry out these syntheses, ingenuity and originality were saught after to develop ever more simple, efficient and versatile methodologies. It is therefore in this very challenging context that our research project was born. For many years, our laboratory has been interested in the use of functionalized orthoesters as versatile reagents in order to build complex structures. The main objective of our work is to extend the previously developed annelation methodology by orthoesters to the pyrrole-based silyl enol to enter the field of the synthesis of polycyclic alkaloids. Starting from these condensed adducts, we embarked on a study aimed at the formation of bicyclic spirocyclic rings 1.059, fused bicycles and in their application to the synthesis of natural alkaloids such as Cephalotaxine and Tashiromine The first part of our work was dedicated to the synthesis of fused bicyclic alkaloids such as Tashiromine The second part of our work has been focused on the study of the synthesis of spirocyclic alkaloids such as Halichlorine and Cephalotaxine. Our route to to the Halichlorine was developed in collaboration with C. Mathot who, during her master thesis, was able to prepare a spirocycle quite efficiently. Alongside our study of spirocyclization, we designed a new synthetic approach to the Cephalotaxine using a highly functionalized orthoester The preparation of this orthoester has not been easy and forced us to develop a new methodology for the synthesis of orthoesters by electrochemistry. The last part of our work has been devoted to the application in medicinal chemistry of functionalized orthoesters via the preparation of heteroaromatic derivatives of interest such as benzimidazoles, benzoxazoles and benzothiazoles., La synthèse d’alcaloïdes a toujours fasciné les chimistes tant par la complexité de leur structure que par leur diversité. Pour réaliser ces synthèses, ils ont rivalisé d’ingéniosité et d’originalité afin de mettre au point des méthodologies toujours plus simples, efficaces et versatiles. C’est donc dans ce contexte très stimulant que s’inscrit notre projet de recherche. Depuis de nombreuses années, notre laboratoire s’est intéressé à l’utilisation des orthoesters fonctionnalisés comme réactifs versatiles afin de pouvoir construire des structures complexes. L’objectif principal de nos travaux sera d’étendre la méthodologie précédemment développée d’annélation par orthoesters à un éther d’énol silylé basé sur le pyrrole afin d’entrer dans le domaine de la synthèse d’alcaloïdes polycycliques. Au départ de ces adduits de condensation, nous nous sommes lancé dans l’étude de la formation de noyaux bicycliques spirocycliques, de bicycles fusionnés ainsi que dans leur application à la synthèse d’alcaloïdes naturels tels que la Céphalotaxine et la Tashiromine. La dernière partie de notre travail a été consacrée à l’application en chimie médicinale des orthoesters fonctionnalisés via la préparation de dérivés hétéroaromatiques d’intérêt tels que les benzimidazoles, benzoxazoles et benzothiazoles., (SC - Sciences) -- UCL, 2014