title: Harnessing C-H Activation of Benzhydroxamates as a Macrocyclization Strategy: Synthesis of Structurally Diverse Macrocyclic Isoquinolones.
abstract: Macrocycles are arising considerable interest in medicinal chemistry. With the goal of harnessing C-H activation reactions for the development of efficient macrocyclization processes, the ruthenium(II)-catalyzed cyclization of O-methyl benzhydroxamates possessing an ω-acetylenic chain was investigated to access new structurally diverse macrocyclic isoquinolones. A slow addition of the substrate and the presence of Cu(OAc)2 ⋅H2 O as an additive were crucial for the success of the macrocyclization that features an excellent functional-group compatibility, as illustrated by the successful synthesis of a library of 21 macrocyclic isoquinolones of different ring sizes and substitution patterns. These results contribute to significantly highlight the synthetic interest of C-H activation-mediated processes for the synthesis of new macrocyles incorporating heterocyclic scaffolds of potential interest in medicinal chemistry.
authors.affiliation: Laboratory of Organic Chemistry, Institute of Chemistry, Biology and Innovation (CBI), ESPCI Paris, CNRS (UMR8231), PSL Research University, 10 rue Vauquelin, 75231, Paris Cedex 05, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Krieger
authors.affiliation: Sanofi Process Development, 45 chemin de Mételine BP15, 04210, Sisteron Cedex, France.
authors.forename: Gino
authors.initials: G
authors.lastname: Ricci
authors.affiliation: R&D Sanofi, 1 avenue Pierre Brossolette, 91385, Chilly-Mazarin Cedex, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Lesuisse
authors.affiliation: Laboratory of Organic Chemistry, Institute of Chemistry, Biology and Innovation (CBI), ESPCI Paris, CNRS (UMR8231), PSL Research University, 10 rue Vauquelin, 75231, Paris Cedex 05, France. christophe.meyer@espci.fr.
authors.forename: Christophe
authors.initials: C
authors.lastname: Meyer
authors.affiliation: Laboratory of Organic Chemistry, Institute of Chemistry, Biology and Innovation (CBI), ESPCI Paris, CNRS (UMR8231), PSL Research University, 10 rue Vauquelin, 75231, Paris Cedex 05, France. janine.cossy@espci.fr.
authors.forename: Janine
authors.initials: J
authors.lastname: Cossy
keywords: C−H activation; isoquinolones; macrocycles; macrocyclization; ruthenium