Enantioselective reduction of ketoimines promoted by easily available (S)-proline derivatives

Abstract

SummaryThe behavior of readily synthesized and even commercially available (S)-proline derivatives, was studied in the trichlorosilane-mediated reduction of ketoimines. A small library of structurally and electronically modified chiral Lewis bases was considered; such compounds were shown to promote the enantioselective reduction of different substrates in good chemical yields. In the HSiCl3 addition to the model substrate N-phenylacetophenone imine, the organocatalyst of choice led to the formation of the corresponding amine with good stereoselectivity, up to 75% ee. Theoretical studies were also performed in order to elucidate the origin of the stereoselection.

Rational Design of Simple Organocatalysts for the HSiCl3 Enantioselective Reduction of (E)-N-(1-Phenylethylidene)aniline

“…The enantioselectivity was similar for carbamates Cbz (62% ee) and Boc (63% ee) and slightly better for amides (N-acetyl-L-Pro (68% ee) and Piv-L-Pro (77% ee). This observation was in line with previous studies suggesting pivaloyl (Piv) as an excellent N-substituent in related organocatalysts [42].…”

“…The integration of Equation ( 1) provides the kinetic model (Equation ( 2)). Although in one instance, nonlinear effects (NLE) have indicated the participation of two catalyst molecules in the mechanism [59], NLE data have confirmed in most instances the involvement of one single catalyst molecule in the mechanism, in particular for catalytic systems related to the ones in this study and involving a dual activation mechanism [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43].…”

“…Chang-ing the solvent from CH 2 Cl 2 to CHCl 3 in this kind of reaction often provides lower ee values and slower reaction rates [54,[56][57][58], but slower kinetics can enable more accurate NMR kinetic analyses and reduce the contribution of the uncatalyzed reaction. The rate constants were calculated considering a simultaneous contribution of the uncatalyzed and catalyzed reactions with first-order rate equations in both substrate and reagent, in agreement with most mechanistic studies (Scheme 2 and Equation ( 1)) [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. Although for axially chiral biscarboline-based alcohols, the participation of two molecules of HSiCl 3 has been included in the reaction mechanism, to consider the quantitative reaction of this reagent with alcohols to produce hydrogen, this could be discarded in our case, as this process was not observed [43].…”

“…To carry out a more rational catalyst design, better insight on the mechanisms for this process is needed to understand the effects of structural modifications. However, only a few computational or experimental systematic mechanistic studies are available, and, in most instances, tentative models are elaborated in order to understand the observed enantioselectivity at the molecular level [40][41][42][43]. In the seminal work of Schreiner and co-workers, a detailed evaluation of the possible mechanism of this reaction using density function theory calculations (B3PW91/cc-pVDZ) was reported [40].…”

The Development of Organocatalytic Asymmetric Reduction of Carbonyls and Imines Using Silicon Hydrides

“…In the following year, Benaglia and co-workers also reported L-proline derivative 24 catalyzed enantioselective reduction of ketimines (Scheme 8a). [46] In their work, the carboxylic group of proline was unprotected. The carboxylic group played an important role in the stereocontrol process.…”