Towards frontiers of acyl transfer reaction by nucleophilic enantioselective organocatalysis

Devant l’intérêt grandissant pour le développement de stratégies innovantes applicables à la synthèse de molécules complexes, notre groupe s’est orienté vers la construction de motifs présents dans un grand nombre de produits biologiquement actifs : les tétrahydropyranes (THP) et les polypropionates. Notre stratégie, basée sur la formation diastéréosélective de diols méso primaires, fait intervenir une étape inédite de désymétrisation organocatalysée par transfert d’acyle asymétrique. Cette approche permet la synthèse énantiosélective de THP pentasubstitués qui par la suite peuvent être valorisés par l’obtention de polypropionates fonctionnalisés, possédant quatre centres stéréogènes contigus. Par ailleurs, cette nouvelle méthodologie de désymétrisation donne accès à des motifs cycliques et acycliques comportant plusieurs centres stéréogènes quaternaires. Elle constitue, de plus, l’unique exemple de désymétrisation énantiosélective de diols méso primaires catalysée par une dialkylaminopyridine chirale. Bien que le transfert d’acyle asymétrique organocatalysé ait été très largement étudié depuis la fin des années 90, de nombreuses études sont en cours pour accéder à des catalyseurs plus sélectifs et plus nucléophiles. Inspiré des récents travaux de Steglich et Vedejs, notre deuxième objectif s’est porté sur la synthèse énantiosélective et modulaire d’une nouvelle famille d’organocatalyseurs chiraux plus polyvalents dérivés de la 1,6-naphtyridine. Leur application, en catalyse nucléophile, a pu être évaluée dans des réactions de dédoublement cinétique d’alcools et dans les réarrangements de Steglich.Alongside metallocatalysis and biocatalysis, organocatalysis has emerged as a complementary and powerful tool that can circumvent limitations associated to the use of metals or enzymes. Because of the growing interest for new innovative methodologies useful for complex molecules synthesis, we get interested in the preparation of versatile building blocks present in many bioactive molecules: tetrahydropyrans (THP) and polypropionates. Based on the diastereoselective formation of primary meso diols, our strategy involves an original organocatalyzed desymmetrization of these compounds by asymmetric acyl transfer. This approach allows the enantioselective synthesis of pentasubstituted THP which were valorized through the synthesis of polypropionates bearing four consecutive stereogenic centers. In addition, this new methodology provides cyclic and acyclic scaffolds with several all carbon quaternary stereogenic centers. It represents the first example in organocatalyzed asymmetric desymmetrization by acyl transfer using a chiral dialkylaminopyridine. Although asymmetric organocatalyzed acyl transfer has been widely studied since the late 90s, several investigations are currently underway to access to new chiral nucleophilic catalysts. Following the recent work of Steglich and Vedejs, we were interested in the development of new chiral organocatalysts derived from 1,6-naphthyridine. Their applications in nucleophilic catalysis have then been evaluated in kinetic resolutions of alcohols and in asymmetric Steglich rearrangements

Le forum de discussion en formation : un espace potentiel d’accès au rapport qu’entretient autrui avec les objets d’apprentissage

This research focuses on the discussion forum, a space for asynchronous communication at distance. Using the discussion forum as part of open and distance learning systems in vocational training, is a growing activity because it is considered as a place offering interesting pedagogical possibilities. Based on the difference between what the designers of these learning systems expect and what can be observed on these forums, we have chosen to approach this social subject from a perspective which is fairly uncommon in other works in this field. Indeed, we focus on the concept of activity and consider contributing to the forum as a situated practice. Our research goal is to identify how the forum constitutes a meditation system which generates activities likely to produce learning. We use professional didactics and mediation theories as a basis for our work. This paper addresses the forum situation, a work situation into which learners are integrated. Thus, the methodological choices are in line with the methods used to analyze situations at work; they establish a distinction between task and activity and during interviews, confront learners with the traces of their activity.In the forum we studied, the learners’ activity is only mildly consistent with the prescribed tasks. This being said, the forum does seem to be an ideal place to gain access to the way in which others relate to the learning objects. If we take this into consideration it serves as a form of mediation to build, strengthen or re-examine the relationship to learning objects and to control a mutual understanding of them

Coopérer à travers un réseau d'établissements : gouvernance, tensions et controverses

International audienceThe choice of a new form of a network organisation to develop cooperation between the public agricultural schools arose from the will to respond to the social demand in a context of decentralization. One must go beyond the heavy tension between what is established and what is becoming established. This contribution offers a testimony of how the means to "go beyond" are a permanent construction, through the analysis of a few founding controversies of the network “Préférence Formations", reinforced by the social sciences (sociology of translation, social psychology). The current learning of cooperation within this network of schools is a puzzle to the institution and, in parallel, interrogates the schools about their own governance.Le choix d'une nouvelle forme d'organisation en réseau pour développer la coopération entre les établissements d'enseignement agricole public est né de la volonté de mieux répondre à la demande sociale dans un contexte de décentralisation. Mais il nécessite de dépasser la tension forte entre une culture institutionnelle dominante et le caractère fondamentalement instituant du réseau. Cette contribution propose un témoignage de la construction permanente des moyens de ce dépassement à travers l'analyse de quelques controverses fondatrices du réseau Préférence Formations, éclairée par les apports des sciences sociales (sociologie de la traduction, psychologie sociale). L'apprentissage de la coopération qui se fait dans le cadre de ce réseau d'établissements intrigue l'institution et interroge parallèlement les établissements sur leur propre gouvernance

Renforcer les capacités réflexives à des fins de développement professionnel : une grille-repères pour la conception de dispositifs pédagogiques

International audienceWhile reflexivity is seen as a not-to-be-missed concept in professional training, references to design pedagogical devices to enhance actors’ reflective capacities on their professional situations and to foster their professional and personal development are scarce and embedded in a patchwork of theoretical and practical approaches. As designers of such devices in agricultural higher education, our practical experiences, theoretical background and discussions led us to build a model of reflexivity as five intertwined key dimensions. These dimensions deal with aspects of reflexivity that it is possible to work on directly with learners by using appropriate scaffolding methods, which we describe and illustrate in this paper, referring to our teaching experiences. Two dimensions of the model are particularly relevant for people who are not familiar with reflexivity, and sometimes reluctant to practice it.Alors que le concept de réflexivité se présente comme incontournable en formation professionnelle, les repères pour construire des dispositifs pédagogiques visant le renforcement des capacités réflexives d’acteurs sur leurs situations professionnelles à des fins de développement professionnel et personnel paraissent, sinon manquants, du moins noyés dans un foisonnement théorique et pratique. En tant que concepteurs de tels dispositifs dans le domaine de l’enseignement supérieur agronomique, nous présentons une grille-repères articulant cinq dimensions de la réflexivité, forgée au fil de nos expériences, de nos échanges et de nos lectures. Ces cinq dimensions renvoient à cinq aspects de la réflexivité qu’il est possible de travailler directement avec des apprenants, en mettant en place un étayage adapté que nous caractérisons et illustrons dans l’article, en puisant dans nos expériences de formateurs. Deux dimensions de la grille sont particulièrement pertinentes pour accompagner des publics non familiers avec la réflexivité, et parfois réfractaires aux exercices réflexifs

Stereocontrol of all-carbon quaternary centers through enantioselective desymmetrization of meso primary diols by organocatalyzed acyl transfer

International audienceThe symmetry breaking of meso primary diols bearing a tetrahydropyran ring was employed, using catalytic asymmetric acyl transfer, to control all-carbon quaternary stereocenters. The planar chiral Fu DMAP catalyst was used in this reaction to reach a high degree of enantioselectivity (up to 97:3 e.r.) through a synergic effect combining a desymmetrization step and a kinetic resolution. Moreover, a beneficial effect was exhibited by C6F6 solvent, yielding the first example of an organocatalyzed asymmetric acyl transfer. The desymmetrized monoesters were then used to obtain, after a straightforward ring opening sequence, complex polyketide building blocks bearing all-carbon quaternary stereocenter

Un entretien pour évaluer des capacités à partir de situations professionnelles vécues : un nouveau défi pour l’enseignement agricole français

The Ministry of Agriculture in France has recently decided to renovate its technical education diplomas with a so-called "capacity" entry and the implementation of a type of certification assessment involving an interview based on real-life professional situations. How can an interview be designed to serve the certification of skills in vocational training? On which theoretical and technical corpus should it be based ? Being in charge of councelling teachers across this renovation in agricultural education, we have tried to answer these questions by developing an interview approach, which mobilizes both explicitation as defined by Vermersch and the contributions of professional didactics. We then experimented this interview with future agricultural workers in training in order to test its relevance and feasibility. We thus propose in the end an approach composed of two distinct phases during which the type of questions, the language rules, the posture and the intentions of the assessor vary

Highly Enantioselective Acylation of Acyclic Meso 1,3-Diols through Synergistic Isothiourea-Catalyzed Desymmetrization/Chiroablative Kinetic Resolution

International audienceA general and highly efficient organocatalyzed desymmetrization of acyclic meso 1,3-diols through acyl transfer using chiral isothioureas is described. The introduction of π-systems in the acyclic substrates provided new opportunities in terms of reactivity, enantioselectivity and synthetic potential. To reach this high level of enantioselectivity (up to er >99:1), the reaction proceeds through a synergistic mechanism involving a desymmetrization reaction and a chiroablative kinetic resolution process. This methodology was used with success as the sole enantioselective catalytic step (developed on a gram scale) to achieve the total synthesis of the antiosteoporotic diarylheptanoid (−)-diospongin A (7 steps)

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old