Theoretical Investigations on the Stereoselectivity of the Proline Catalyzed Mannich Reaction in DMSO

Citations Over TimeTop 15% of 2008 papers

Abstract

The stereocontrol steps of the (S)-proline catalyzed Mannich reaction of cyclohexanone, formaldehyde, and aniline were theoretically investigated. The geometries of reactants, products, and transition states were optimized using density functional theory using the B3LYP functional with the 6-31++G(d,p) basis set. The energies of these compounds were then more accurately determined at the MP2 level, and the effect of DMSO as the solvent was included using a polarizable continuum model (PCM). The reaction was modeled from the previously proposed mechanism that cyclohexanone reacts with (S)-proline to generate an enamine, while formaldehyde reacts with aniline to produce an imine, and that the conformation around the C-N bond of the enamine 1 is crucial for the further enantioselective step. The formation of two conformations of the enamine via a proton transfer process was examined, revealing activation barriers for syn- and anti-enamine proton transfer of 10.2 and 17.9 kcal/mol, respectively. The transformation of syn- to anti-enamine through C-N bond rotation, however, was predicted to require only 4.2 kcal/mol, while the (S)- and (R)-intermediates could be obtained from subsequent reactions between enamine and imine with energy barriers of 8.5 and 12.4 kcal/mol, respectively. The difference between these barriers, but not the C-N rotation energy, becomes larger at the MP2 level and when DMSO as a solvent is included. This predicted enantioselective reaction, through the kinetic and thermodynamic favoring of the (S)-pathway, is in agreement with experimental results, which have reported the (S)-configuration as the major product.

Related Papers

• → Trityl Salt Catalyzed Stereoselective Glycosylation of Alcohols with 1-Hydroxyribofuranose(1996)36 cited
• → Pentafulvene-derived η3-allyltitanocenes as intermediates for the stereoselective functionalization of 5-membered carbocycles(2013)9 cited
• → UO‐Catalyzed Oligothioadenylate Synthesis with High Regio‐ and Stereoselectivity(1993)25 cited
• → Stereoselective synthesis of (±)-ancistrofuran: stereoselective reduction of a γ-hydroxyketone(1984)14 cited
• → Catalyst-Controlled Stereoselective Construction of Indole-Fused Heterocycles through Cycloadditions of Indolyl-Allenes: A Theoretical Investigation(2021)