title: Efficient Synthesis of Differentiated syn-1,2-Diol Derivatives by Asymmetric Transfer Hydrogenation-Dynamic Kinetic Resolution of α-Alkoxy-Substituted β-Ketoesters.
abstract: Asymmetric transfer hydrogenation was applied to a wide range of racemic aryl α-alkoxy-β-ketoesters in the presence of well-defined, commercially available, chiral catalyst Ru(II) -(N-p-toluenesulfonyl-1,2-diphenylethylenediamine) and a 5:2 mixture of formic acid and triethylamine as the hydrogen source. Under these conditions, dynamic kinetic resolution was efficiently promoted to provide the corresponding syn α-alkoxy-β-hydroxyesters derived from substituted aromatic and heteroaromatic aldehydes with a high level of diastereoselectivity (diastereomeric ratio (d.r.)>99:1) and an almost perfect enantioselectivity (enantiomeric excess (ee)>99 %). Additionally, after extensive screening of the reaction conditions, the use of Ru(II) - and Rh(III) -tethered precatalysts extended this process to more-challenging substrates that bore alkenyl-, alkynyl-, and alkyl substituents to provide the corresponding syn α-alkoxy-β-hydroxyesters with excellent enantiocontrol (up to 99 % ee) and good to perfect diastereocontrol (d.r.>99:1). Lastly, the synthetic utility of the present protocol was demonstrated by application to the asymmetric synthesis of chiral ester ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)-propanoate, which is an important pharmacophore in a number of peroxisome proliferator-activated receptor α/γ dual agonist advanced drug candidates used for the treatment of type-II diabetes.
authors.affiliation: PSL Research University, Chimie ParisTech - CNRS, Institut de Recherche de Chimie Paris, 75005 Paris (France), Fax: (+33) 144-071-062.
authors.forename: Laure
authors.initials: L
authors.lastname: Monnereau
authors.affiliation: PSL Research University, Chimie ParisTech - CNRS, Institut de Recherche de Chimie Paris, 75005 Paris (France), Fax: (+33) 144-071-062.
authors.forename: Damien
authors.initials: D
authors.lastname: Cartigny
authors.affiliation: Process Research & Development, F. Hoffmann-La Roche AG, Bldg. 62/413, 4070 Basel (Switzerland).
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Scalone
authors.affiliation: PSL Research University, Chimie ParisTech - CNRS, Institut de Recherche de Chimie Paris, 75005 Paris (France), Fax: (+33) 144-071-062. tahar.Ayad@chimie-paristech.fr.
authors.forename: Tahar
authors.initials: T
authors.lastname: Ayad
authors.affiliation: PSL Research University, Chimie ParisTech - CNRS, Institut de Recherche de Chimie Paris, 75005 Paris (France), Fax: (+33) 144-071-062. virginie.vidal@chimie-paristech.fr.
authors.forename: Virginie
authors.initials: V
authors.lastname: Ratovelomanana-Vidal
keywords: alpha-alkoxy-beta-ketoesters; asymmetric catalysis; asymmetric transfer hydrogenation; dynamic kinetic resolution; ruthenium