Efficient Synthesis of Differentiated syn-1,2-Diol Derivatives by Asymmetric Transfer Hydrogenation-Dynamic Kinetic Resolution of α-Alkoxy-Substituted β-Ketoesters

Asymmetric transfer hydrogenation was applied to a wide range of racemic aryl -alkoxy--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 -alkoxy--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 -alkoxy--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 / dual agonist advanced drug candidates used for the treatment of type-II diabetes.