Preparation of Cyclobutene Acetals and Tricyclic Oxetanes through Photochemical Tandem and Cascade Reactions

We describe a photochemical reaction using two starting materials, a cyclopent-2-enone and an alkene, which are transformed in a controlled manner via the initial [2+2]-photocycloaddition adducts into cyclobutene aldehydes (conveniently trapped as stable acetals) or unprecedented angular tricyclic 4:4:4 oxetane-containing skeletons. These compounds are formed through tandem or triple cascade photochemical reaction processes, respectively. Small libraries of each compound class were prepared, thus suggesting that this photochemistry approach opens new opportunities for synthesis design and for widening molecular diversity

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Nouvelles réactions de couplage catalysées par des sels de cuivre ou de manganèse

Trois thèmes ont été abordés au cours de ce travail de thèse. Nous avons tout d abord mis au point une nouvelle réaction de couplage oxydatif entre des composés organomagnésiens aromatiques, acétyléniques et éthyléniques en présence de sels de manganèse et d oxygène comme oxydant. La réaction est chimio- et stéréosélective, et permet d accéder à une vaste gamme de produits conjugués polyinsaturés. Nous avons également développé une réaction de couplage entre des halogénures acétyléniques et des composés organomagnésiens aliphatiques et aromatiques en présence de sels de cuivre. La réaction est chimiosélective et permet d accéder à de nombreux alcynes simples ou fonctionnalisés avec d excellents rendements. A notre connaissance, cette méthode est la première à permettre l emploi de composés organomagnésiens secondaires, tertiaires ou aromatiques pour ce type de couplage. Par ailleurs, nous avons mis au point des réactions simples d alkylation de composés organomagnésiens aliphatiques et aromatiques par des bromures d alkyles primaires en présence de sels de cuivre. Nous avons également découvert que la substitution d halogénures d alkyles catalysée par des sels de cuivre peut être réalisée avec des composés organolithiens aliphatiques, aromatiques et vinyliques. Il faut souligner que jusqu à ce jour, les composés organolithiens n avaient jamais été utilisés pour effectuer ce type de réaction. Enfin, nous avons développé une nouvelle méthode de préparation de composés organozinciques symétriques "sans sel" en deux étapes. Cette méthode permet d accéder très simplement à divers dialkyl- et diarylzincs avec de bons rendements.Three topics were studied during this Ph.D. thesis. We first reported a new manganese-catalyzed oxidative cross-coupling reaction of alkynyl, alkenyl and aryl magnesium halides with oxygen as an oxidant. The reaction is chemo- and stereoselective, and allows obtaining a vast array of conjugated unsaturated products. We also developed a copper-catalyzed cross-coupling reaction between alkynyl halides and alkyl or aryl Grignard reagents. The reaction is chemoselective, and allows obtaining a wide range of simple or functionalized alkynes in excellent yields. To the best of our knowledge, this is the first report concerning the use of secondary and tertiary alkyl, as well as aryl Grignard reagents for this type of coupling. On the other hand, we disclosed simple procedures for the copper-catalyzed alkylation of alkyl and aryl magnesium halides with alkyl bromides. We also discovered that the copper-catalyzed substitution of alkyl halides can be performed using alkyl, aryl and vinyl lithium compounds. It should be noted that, to the best of our knowledge, organolithium compounds have never been used to perform alkylation reactions in the presence of a catalytic amount of copper. Finally, we disclosed a new method for the preparation of "salt free" diorganozinc compounds in two steps. This procedure allows a very simple access to various dialkyl and diarylzinc compounds ingoodyields.PARIS13-BU Sciences (930792102) / SudocSudocFranceF

New Insights into the Copper-Catalyzed Alkylation of Grignard and Organolithium Reagents

1 - ArticleUntil now, it was considered that the copper-catalyzed alkylation of Grignard reagents gave good yields only in the presence of ligands, such as NMP or 1-phenylpropyne. We show herein that a slow and regular addition of the Grignard reagent provides similar results. With secondary and tertiary alkyl Grignard reagents, we disclosed that the presence of benzonitrile (10 mol%), a very simple ligand, is very efficient. The copper-catalyzed alkylation of organolithium compounds was also studied

Copper-Catalyzed Cross-Coupling of Alkyl and Aryl Grignard Reagents with Alkynyl Halides

1 - ArticleGood old copper! A new general procedure to couple aliphatic and aromatic Grignard reagents with alkynyl halides under copper catalysis is described (see scheme; NMP=N-methylpyrrolidinone). The reaction is chemoselective and allows preparation of a vast array of simple and functionalized internal alkynes in high yields

Transition-Metal-Free Synthesis of Oxindoles by Potassium <i>tert</i>-Butoxide-Promoted Intramolecular α-Arylation

Potassium <i>tert</i>-butoxide-mediated intramolecular α-arylations of fluoro- and chloro-substituted anilides provide oxindoles in DMF at 80 °C. In this manner, diversely substituted products have been obtained in moderate to high yields