Reactivity of α,β-unsaturated acyl-imidazoles : Asymmetric Conjugate Borylations and Inverse Electron-Demand Hetero Diels-Alder

La forte occurrence des motifs polydésoxypropionates et polyols 1,3 dans une multitude de produits naturels a conduit les chimistes organiciens à élaborer de nombreuses stratégies de synthèse de ces derniers. Cependant, à notre connaissance, il n’existe pas de « stratégie unifiée » pratique et hautement stéréosélective pour accéder de façon itérative à l’alternance de motifs 1,3,5,…n (OH, CH3) en dépit de son abondance naturelle.Dans un premier temps, le développement d’une telle stratégie a été examiné lors de la mise au point d’une réaction de Borylation Conjuguée Asymétrique (BCA) catalysée au cuivre sur des acyl-imidazoles α,β-insaturés. La combinaison de cette transformation avec une Addition Conjuguée Asymétrique (ACA) de motifs « méthyles » nous a permis d’élaborer une stratégie itérative de synthèse de triades 1,3,5 (OH, CH3, OH/CH3) avec d’excellentes diastéréosélectivités.Dans une seconde partie, une nouvelle réactivité des acyl-imidazoles α,β-insaturés a été développée : une réaction Intramoléculaire d’Hétéro Diels-Alder à demande électronique inverse IMHDA. Une version énantiosélective, la détermination des configurations relatives et absolues des centres stéréogènes formés, la mise au point de différentes post-transformations sont décrites.Polydeoxypropionates and 1,3-polyols are prevalent units in numerous natural products and have been the subject of many stereoselective approaches. On the other hand, despite the prevalence of 1,3,5,...n (OH, Me) motifs in biologically relevant molecules, no practical and broadly applicable unified strategy has been to date developed for the synthesis of these subunits in high stereocontrol.The first part of this manuscript tackles the development of a strategy via a copper-catalyzed Asymmetric Conjuguate Borylation (ACB) to α,β-unsaturated 2-acyl-N-methylimidazoles. The consecutive ACB and methylation through an Asymmetric Conjugate Addition (ACA) led to the construction of 1,3,5 (OH, CH3, OH/CH3) triads with high diastereoselectivities.In a second part, a new reactivity of α,β-unsaturated 2-acyl-N-methylimidazoles have been unveiled: an Inverse Electron-Demand Hetero Diels-Alder (IEDDA) reaction. The development of an asymmetric version, the determination of relative and absolute configurations of the newly created stereogenic centers, the study of post-transformations are reported

Copper-Catalyzed Asymmetric Conjugate Additions of Bis(pinacolato)diboron and Dimethylzinc to Acyl- N -methylimidazole Michael Acceptors: A Highly Stereoselective Unified Strategy for 1,3,5,... n (OH, Me) Motif Synthesis

International audienceA unified strategy for the construction of prevalent 1,3,5,...n (OH, Me) motifs based on consecutive copper-catalyzed asymmetric conjugate borylation (ACB) and methylation (ACA) reactions involving α,β-unsaturated 2-acyl-N-methylimidazoles is described. Good yields and high diastereoselectivities have been obtained in ACA and ACB reactions for both matched and mismatched pairs as illustrated in the synthesis of syn/anti and anti/anti (Me, OTBS,Me) and (OH, OTBS, Me) motifs

Iron-Catalyzed Enantioselective Intramolecular Inverse Electron-Demand Hetero Diels–Alder Reactions: An Access to Bicyclic Dihydropyran Derivatives

International audienceA highly enantioselective iron-catalyzed Intramolecular Inverse Electron-Demand Hetero Diels-Alder (IIEDHDA) reaction is reported. By using a chiral semicorrin ligand in the presence of 2,6 lutidine, good isolated yields and excellent enantioselectivities were observed (up to 96% ee). Thanks to the versatile post-functionalization of the acyl-imidazole moiety, this methodology represents a unique example of the straightforward construction of highly valuable enantioenriched bicyclic dihydropyran derivatives

Catalytically Active Species in Copper/DiPPAM-Catalyzed 1,6-Asymmetric Conjugate Addition of Dialkylzinc to Dienones A Computational Overview

International audienceFour different catalytically active species are computationally examined in order to investigate the mechanism of Cu/DiPPAM-catalyzed 1,6-conjugate addition of dialkylzinc to acyclic dienones. A DiPPAM-bridged Cu(alkyl)-Zn(acetate) bimetallic complex exhibits the best catalytic activity, which can be associated with the best balance between the stability of the dienone adduct and its activation by copper. The selectivities (regio- and enantioselectivity) associated with the retained mechanism are investigated by DFT calculations and successfully compared to experimental data, including the critical influence of the substituents within the dienone on the regioselectivity and the obtained enantioselectivity for the formation of one 1,6-adduct