RESUMO
Asymmetric transfer hydrogenation was applied to a wide range of racemic aryl α-alkoxy-ß-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-ß-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-ß-hydroxyesters with excellent enantiocontrol (up to 99 %â 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.
RESUMO
A general asymmetric hydrogenation of a wide range of 2-alkyl- and 2-aryl-substituted quinoxaline derivatives catalyzed by an iridium-difluorphos complex has been developed. Under mild reaction conditions, the corresponding biologically relevant 2-substituted-1,2,3,4-tetrahydroquinoxaline units were obtained in high yields and good to excellent enantioselectivities up to 95%. With a catalyst ratio of S/C = 1000 and on a gram scale, the catalytic activity of the Ir-difluorphos complex was maintained showing its potential value. Finally, we demonstrated the application of our process in the synthesis of compound (S)-9, which is an inhibitor of cholesteryl ester transfer protein (CETP).
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/química , Hidrocarbonetos Fluorados/síntese química , Irídio/química , Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Quinoxalinas/química , Quinoxalinas/síntese química , Catálise , Hidrocarbonetos Fluorados/química , Hidrogenação , Estrutura Molecular , EstereoisomerismoRESUMO
The first enantio- and diastereoselective approach to alpha-alkoxy-substituted syn-beta-hydroxyesters through highly efficient catalytic asymmetric transfer hydrogenation via dynamic kinetic resolution reactions from the corresponding racemic beta-ketoesters is described. In this atom-economical process, two contiguous stereogenic centers are generated simultaneously with an excellent diastereoselectivity (up to 99/1) and enantioselectivity (up to 99%), allowing a rapid access to a wide variety of aromatic and heteroaromatic monodifferentiated syn-1,2-diols.