Quantum mechanical calculations aldol reactions

A detailed study of the reaction mechanism based on quantum mechanical calculations was reported very recently by Houk and List et al. [96]. In this connection, the ratio of the four stereoisomeric products in the proline-catalyzed dia-stereo- and enantioselective aldol reaction was predicted and excellent agreement... 

Based on the observations and quantum mechanical calculations for proline-catalysed asymmetric aldol reactions Li and coworkers synthesised a series of L-proline-hased dipeptides for the direct asymmetric aldol reaction between substituted aldehydes and acetone in DMSO. Dipeptide 31 was successfully employed yielding the desired adducts in excellent yield and good to excellent enantioselectivity. Additionally, PGME 5000 was used as a surfactant additive in catalytic amounts, since prior reports showed an acceleration of aldol reactions hy such additives Xheme 13.20b). 

The large number of research programs aimed at the syntheses of steroids produced a phenomenal wealth of reaction methods for organic synthesis. The development of the asymmetric proline-catalyzed Robinson annulation reaction for the preparation of the Wieland-Miescher ketone (36, Equation 3) in the early 1970s [41] is noteworthy and marks an important milestone for catalysis by small organic molecules. Asymmetric amine-catalyzed aldol reactions represent an additional variant of the stereoselective aldol addition reaction. The mechanism of the proline-catalyzed aldol addition reaction has been the subject of extensive debate, but the general consensus, based on recent mechanistic studies and quantum mechanical calculations, supports the notion of the involvement of a single amino acid molecule in the transition state structure (39, Scheme 4.4) [42]. 

Extensive molecular dynamic simulations of proline-catalysed asymmetric aldol condensation of propionaldehyde in water have revealed that the stereoselectivity can be attributed to differences in transition-state solvation pattems. " The hydrogen bond concept has been applied to design new proline-based organocatalysts. " 4-Hydroxyproline derivatives bearing hydrophobic groups in well-defined orientations have been explored as catalysts in water an advantage of aromatic substituents syn to the carboxylic acid moiety has been attributed to a stabilizing transition-state hydrophobic interaction and this is supported by quantum mechanics (QM) calculations. " Catalysts and solvents were screened for reaction between cyclohexanone andp-nitrobenzaldehyde. 

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