title: Pushing the limits of catalytic C-H amination in polyoxygenated cyclobutanes.
abstract: A synthetic route to a new class of conformationally constrained iminosugars based on a 5-azaspiro[3.4]octane skeleton has been developed by way of Rh(ii)-catalyzed C(sp(3))-H amination. The pivotal stereocontrolled formation of the quaternary C-N bond by insertion into the C-H bonds of the cyclobutane ring was explored with a series of polyoxygenated substrates. In addition to anticipated regioselective issues induced by the high density of activated α-ethereal C-H bonds, this systematic study showed that cyclobutane C-H bonds were, in general, poorly reactive towards catalytic C-H amination. This was demonstrated inter alia by the unexpected formation of a oxathiazonane derivative, which constitutes a very rare example of the formation of a 9-membered ring by way of catalyzed C(sp(3))-H amination. A complete stereocontrol could be however achieved by activating the key insertion position as an allylic C-H bond in combination with reducing the electron density at the undesired C-H insertion sites by using electron-withdrawing protecting groups. Preliminary biological evaluations of the synthesized spiro-iminosugars were performed, which led to the identification of a new class of correctors of the defective F508del-CFTR gating involved in cystic fibrosis.
authors: Laboratoire de Synthèse Organique et Molécules Bioactives (SYBIO), Université de Strasbourg/CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux (ECPM), 25 rue Becquerel, 67087 Strasbourg, France. philippe.compain@unistra.fr.
authors: Pierre-Antoine
authors: PA
authors: Nocquet
authors: Laboratoire de Synthèse Organique et Molécules Bioactives (SYBIO), Université de Strasbourg/CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux (ECPM), 25 rue Becquerel, 67087 Strasbourg, France. philippe.compain@unistra.fr.
authors: Raphaël
authors: R
authors: Hensienne
authors: Laboratoire de Synthèse Organique et Molécules Bioactives (SYBIO), Université de Strasbourg/CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux (ECPM), 25 rue Becquerel, 67087 Strasbourg, France. philippe.compain@unistra.fr.
authors: Joanna
authors: J
authors: Wencel-Delord
authors: Laboratoire de Synthèse Organique et Molécules Bioactives (SYBIO), Université de Strasbourg/CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux (ECPM), 25 rue Becquerel, 67087 Strasbourg, France. philippe.compain@unistra.fr.
authors: Eugénie
authors: E
authors: Laigre
authors: Laboratoire Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers et CNRS (ERL7368), 1 rue Georges Bonnet, 86000 Poitiers, France.
authors: Khadidja
authors: K
authors: Sidelarbi
authors: Laboratoire Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers et CNRS (ERL7368), 1 rue Georges Bonnet, 86000 Poitiers, France.
authors: Frédéric
authors: F
authors: Becq
authors: Laboratoire Signalisation et Transports Ioniques Membranaires (STIM), Université de Poitiers et CNRS (ERL7368), 1 rue Georges Bonnet, 86000 Poitiers, France.
authors: Caroline
authors: C
authors: Norez
authors: Laboratoire de Synthèse Organique et Molécules Bioactives (SYBIO), Université de Strasbourg/CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux (ECPM), 25 rue Becquerel, 67087 Strasbourg, France. philippe.compain@unistra.fr.
authors: Damien
authors: D
authors: Hazelard
authors: Laboratoire de Synthèse Organique et Molécules Bioactives (SYBIO), Université de Strasbourg/CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux (ECPM), 25 rue Becquerel, 67087 Strasbourg, France. philippe.compain@unistra.fr.
authors: Philippe
authors: P
authors: Compain
mesh_terms: D000586:Amination; D002384:Catalysis; D003503:Cyclobutanes / Q000737:chemistry*; D015394:Molecular Structure; D012238:Rhodium / Q000737:chemistry*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D003503:Cyclobutanes; D013141:Spiro Compounds; D012238:Rhodium