Metathesis and radical reactions : application to the synthesis of molecules of biological interest

La formation de liaisons carbone-carbone est primordiale dans le domaine de la chimie organique. Parmi les nombreuses méthodes existantes, les réactions de métathèse des oléf ines et de chimie radicalaire constituent deux techniques de choix mais n'ont été que très rarement utilisées de façon concomitante en synthèse organique. Cette constatation a été le point de départ de ces travaux de thèse dont le but a alors été d'appliquer ces deux réactions à la synthèse de molécules aux possibles propriétés biologiques. Une première étude combinant les réactions de métathèse qu'elles soient croisées ou d'énynes, et de cyclisation de type radicalaire ou de Heck, a été menée et a permis l'obtention de molécules à forte valeur ajoutée : des sultames à six chaînons et une nouvelle famille de spiro-sultames. Une seconde étude a quant à elle utilisé pour la première fois de façon séquentielle et en un seul pot les réactions de photodéconjugaison et de métathèse cyclisante permettant d'aboutir à la synthèse de composés intéressants mais difficiles à préparer, à savoir des lactones α,β-insaturées possédant un groupement alkyle en position α. Un troisième sujet utilisant à la fois les réactions d'addition de Michael asymétrique organocatalysée et de cyclisation radicalaire induite par le diiodure de samarium a permis de synthétiser des cyclopentanols trisubstitués comportant trois stéréocentres contigus. Enfin, une approche synthétique vers la nhatrangine A, molécule naturelle possédant six centres stéréogènes, et la synthèse totale du (+)-guaymasol ont été réaliséesCarbon-carbon bond formation constitutes a crucial research field in organic chemistry. Among all existing methods, olefin metathesis and radical reactions are particularly attractive ones but were rarely used in a concomitant way. That was the starting point of this PhD work, whose aim was to apply these two reactions to the synthesis of molecules having a potential biological interest. The first topic which was taken up was the use of cross- or enyne metathesis combined with a radical or an Heck cyclization for the synthesis of very valuable compounds : sultams and their spirocyclic derivatives. The second subject allowed the synthesis of α,β-unsaturated lactones bearing an alkyl group at the α position by using for the first time, in a one-pot and sequential manner, photochemistry and ringclosing metathesis. The third study led to cyclopentanol derivatives bearing three contiguous stereocentres by associating organocatalysis and radical cyclization induced by the use of samarium diiodide. Last but not least, a synthetic approach to nhatrangin A, natural compound holding six stereocentres, and total synthesis of (+)-guaymasol were carried ou

Total synthesis of (+)-guaymasol

International audienceThe synthesis of (+)-guaymasol has been achieved from O-methyl chavicol by using a sequence combining a cross-metathesis and an asymmetric dihydroxylation of the newly created double bond. The first step using Grubbs type II catalyst delivered an inseparable 88:12 mixture of E and Z isomers. After treatment with AD-mix-β and deprotection of the benzyl ether by hydrogenolysis, (+)-guaymasol was finally isolated in 84% de and 90% ee

Total synthesis of (+)-guaymasol

International audienceThe synthesis of (+)-guaymasol has been achieved from O-methyl chavicol by using a sequence combining a cross-metathesis and an asymmetric dihydroxylation of the newly created double bond. The first step using Grubbs type II catalyst delivered an inseparable 88:12 mixture of E and Z isomers. After treatment with AD-mix-β and deprotection of the benzyl ether by hydrogenolysis, (+)-guaymasol was finally isolated in 84% de and 90% ee

Merging Cross-Metathesis and Radical Cyclization: A Straightforward Access to 4-Substituted Benzosultams

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Cross‐Dehydrogenative Homocoupling of 2‐Aryl‐N‐heterocycles and Application to the Synthesis of Phenylpyridine Borane Dimers

Abstract A method for the synthesis of 2‐aryl‐N‐heterocyclic dimers via a cross‐dehydrogenative homocoupling (homo‐CDC) has been developed using commercially available Ruthenium on charcoal as catalyst and iron trichloride as oxidant. A large variety of heterocyclic scaffolds and functional groups are tolerated and a complete regioselectivity resulting from the activation of the less sterically hindered C−H bonds was observed for meta ‐substituted substrates. Starting from several homocoupling products obtained, a series of pyridine‐borane complexes was synthesized and the impact of the dimerization on their photophysical properties was studied and rationalized using theoretical calculations

Formal enantioselective synthesis of nhatrangin A

International audienceA new and straightforward synthesis of the C 1 –C 7 core fragment of nhatrangin A was achieved in 14 steps from achiral 3-hydroxybenzaldehyde, without the need of chiral reagents or enzymatic resolution to introduce the chiral centers

Continuous Flow Synthesis of Non‐Symmetrical Ureas from CO 2

International audienceWe report on a continuous flow synthetic process of non-symmetrical ureas, based on the implementation of a Staudinger/aza-Wittig reaction sequence. This flow technology allows obtaining the key urea functional group directly from the fundamental C1 building block CO2. A library of 24 derivatives, including alkyl/alkyl, alkyl/aryl and aryl/aryl ureas could be synthesised. In addition, the methods was also suitable for the synthesis of S-thiocarbamates. The potential for large-scale reaction implementation and a first application to continuous flow 13 C-isotope labeling are shown

Nanocatalyzed Hydrogen Isotope Exchange

International audienceConspectus. Recently, Hydrogen Isotope Exchange (HIE) reactions have experienced an impressive development due to the growing importance of isotope containing compounds in various fields including materials and life sciences, beside their classical use for mechanistic studies in chemistry and biology. Tritium-labelled compounds are also of crucial interest to study the in vivo fate of a bioactive substance or in radioligand binding assays. Over the past few years, deuterium-labelled drugs have been extensively studied for the improvement of ADME (Absorption, Distribution, Metabolism, Excretion) properties of existing bioactive molecules as a consequence of the primary kinetic isotope effect. Furthermore, in the emergent “omic” fields, the need for new stable isotopically labeled internal standards (SILS) for quantitative GC- or LC-MS analyses is increasing. Because of their numerous applications, the development of powerful synthetic methods to access deuterated and tritiated molecules with either high isotope incorporation and/or selectivities is of paramount importance.HIE reactions allow a late-stage incorporation of hydrogen isotopes in a single synthetic step, thus representing an advantageous alternative to conventional multistep synthesis approaches which are time- and resource-consuming. Moreover, HIE reactions can be considered as the most fundamental C–H functionalization processes and are therefore of great interest for the chemists’ community. Depending on the purpose, HIE reactions must either be highly regioselective or allow a maximal incorporation of hydrogen isotopes, sometimes both. In this context, metal-catalyzed HIE reactions are generally performed using either homogeneous or heterogeneous catalysis which may have considerable drawbacks including an insufficient isotope incorporation and a lack of chemo- and/or regioselectivity, respectively.Over the past 6 years, we have shown that nanocatalysis can be considered as a powerful tool to access complex labeled molecules (e.g., pharmaceuticals, peptides and oligonucleotides) via regio- and chemoselective or even enantiospecific labeling processes occurring at the surface of metallic nanoclusters (Ru or Ir). Numerous heterocyclic (both saturated and unsaturated) and acyclic scaffolds have been labeled with an impressive functional group tolerance, and highly deuterated compounds or high molar activity tritiated drugs have been obtained. An insight into mechanisms has also been provided by theoretical calculations to explain the regioselectivities of the isotope incorporation. Our studies have suggested that undisclosed key intermediates, including 4- and 5-membered dimetallacycles, account for the particular regioselectivities observed during the process, in contrast to the 5- or 6-membered metallacycle key intermediates usually encountered in homogeneous catalysis. These findings together with the important number of available coordination sites explain the compelling reactivity of metal nanoparticles, in between homogeneous and heterogeneous catalysis. They represent innovative tools combining the advantages of both methods for the isotopic labeling and activation of C–H bonds of complex molecules

Chemical Synthesis of [ 2 H]-Ethyl Tosylate and Exploration of Its Crypto-optically Active Character Combining Complementary Spectroscopic Tools

International audienceSmall chiral molecules are excellent candidates to push the boundaries of enantiodiscrimination analytical techniques. Here is reported the synthesis of two new deuterated chiral probes, (R)- and (S)-[2H]-ethyl tosylate, obtained with high enantiomeric excesses. Due to their crypto-optically active properties, the discrimination of each enantiomer is challenging. Whereas their enantiopurity is determined by 2H NMR in chiral anisotropic media, their identification was performed by combining quantum chemical calculations and vibrational circular dichroism analysis

Pyridine-based Strategy towards Nitrogen Isotope Exchange

Isotopic labeling is at the core of health and life science applications such as nuclear imaging, pharmacokinetics and bio-distribution studies and plays a central role in drug development. The rapid access to isotopically labeled organic molecules is a sine qua non condition to support these societally vital areas of research. Despite the relevance of pyridine as a biologically active scaffold, the nitrogen-13 labeling of this scaffold remains elusive and an almost prohibited challenge for radio-labelling (+ emitter, T1/2 9.97 min), despite its relevance in positron emission tomography. Based on a rationally driven approach, this study presents an innovative solution to access labeled pyridines by a nitrogen isotope exchange reaction based on a Zincke activation strategy. The technology conceptualizes a new opportunity in the field of nitrogen isotope labeling. 15N-labeling of pyridine and other heterocycles such as pyrimidines and isoquinolines was provided on a large set of derivatives including structurally elaborated pharmaceuticals. Using [13N]NH3 as the primary nitrogen-13 source, proof-of-concept was provided to achieve examples of 13N-labeling of pyridines. We believe this method will play a fundamental role for future developments of 13N-based PET radiotracers