title: Enantioselective Three-Component Amination of Enecarbamates Enables the Synthesis of Structurally Complex Small Molecules.
abstract: The control of asymmetric synthesis tools represents a major challenge, especially when it comes to the synthesis of bioactive molecules. In this context, the asymmetric synthesis of 1,2-diamines through amination of enecarbamates has been proposed as a highly efficient and tunable approach. Indeed, reactivity of the latter species could be exploited to realize a double functionalization via an electrophilic amination followed by nucleophilic trapping. Herein, we describe a chiral phosphoric acid catalyzed electrophilic amination of enecarbamates with dibenzyl azodicarboxylate and oxygenated or thiol-containing nucleophiles affording stable precursors of α-hydrazinoimines in high yields and with almost complete enantioselectivities (up to >99%). These precursors were successfully functionalized with various silylated nucleophiles without epimerization of the stereogenic center, giving access to a wide range of 1,2-disubstituted 1,2-diamines. We also show that the thiolated precursors were successfully engaged in a Friedel-Crafts reaction against a variety of aromatic and heteroaromatic nucleophiles, leading to various 1-(hetero)aryl-1,2-diamines without loss of enantioselectivity and with complete diastereoselectivity. Reductive N-N bond cleavage provided the N,N-diprotected 1,2-diamines with no loss in diastereo- or enantioselectivity. The protocol was successfully scaled up to a multigram scale and the catalyst was successfully recovered, demonstrating the potential applications of this new methodology.
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay , 1 av. de la Terrasse, Gif-sur-Yvette 91198 Cedex, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Dumoulin
authors.affiliation: Équipe Molécules Fluorées et Chimie Thérapeutique, UMR-8076 (BioCIS), LabEx LERMIT, Faculté de Pharmacie, 5 Rue J.-B. Clément, Châtenay-Malabry92296 Cedex, France.
authors.forename: Guillaume
authors.identifier: 0000-0001-8955-0364
authors.initials: G
authors.lastname: Bernadat
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay , 1 av. de la Terrasse, Gif-sur-Yvette 91198 Cedex, France.
authors.forename: Géraldine
authors.identifier: 0000-0003-2333-7047
authors.initials: G
authors.lastname: Masson