Hydrophobic Substituent Effects on Proline Catalysis of Aldol Reactions in Water

Abstract

Derivatives of 4-hydroxyproline with a series of hydrophobic groups in well-defined orientations have been tested as catalysts for the aldol reactions. All of the modified proline catalysts carry out the intermolecular aldol reaction in water and provide high diastereoselectivity and enantioselectivity. Modified prolines with aromatic groups syn to the carboxylic acid are better catalysts than those with small hydrophobic groups (1a is 43.5 times faster than 1f). Quantum mechanical calculations provide transition structures, TS-1awater and TS-1fwater that support the hypothesis that a stabilizing hydrophobic interaction occurs with 1a.

Preparation of Immobilized L‐Prolinamide Via Enzymatic Polymerization of Phenolic L‐Prolinamide and Evaluation of Its Catalytic Performance for Direct Asymmetric Aldol Reaction

“…Among the various catalysts for direct asymmetric aldol reaction, a series of organocatalysts derived from L‐proline are of particular significance. This is why many efforts have been made to modify the structure of L‐proline so as to improve selectivity and reusability, reduce load, and avoid the use of organic solvent . To overcome these drawbacks, researchers also have made attempts to graft organocatalysts with suitable supports .…”

“…This is why many efforts have been made to modify the structure of L-proline so as to improve selectivity and reusability, reduce load, and avoid the use of organic solvent. [9][10][11][12][13][14] To overcome these drawbacks, researchers also have made attempts to graft organocatalysts with suitable supports. [15][16][17][18] The resultant immobilized organocatalysts offer some advantages over small organic catalysts, such as recyclability, simple reaction set-up plus easy experimental procedure, and nontoxicity.…”

Organocatalysts Derived from Unnatural α‐Amino Acids: Scope and Applications

“…Following ad ifferent approach, Schafmeister and co-workers, [49] synthesized af amilyo fs pirocyclic imidazolidinones as organocatalystsf or the asymmetric aldol reactiono fc yclic ketones and aldehydes in water.O ft he tested derivatives, catalyst 83 exhibited the best results and gave products anti-37 and 63 in good yields and excellent diastereo-and enantioselectivity with 1mol %o fc atalyst (Scheme 19A). DFT calculations in water showed that the Houk-List transition structure, which leads to the formation of the major isomers, has as tabilizing edge-to-face hydrophobic interaction between the aromatic ring of the aldehyde and the benzyl group of the organocatalyst (Scheme 19B).…”

“…63 and 37 promoted by organocatalyst 83.B)Houk-List transition structure (M06-2X(SMD, solvent = H 2 O)/6-31G* level of theory) associated with the formation of the majori somer formed in the reaction between cyclohexanone and benzaldehydei nthe presence of 83.The edge-to-face hydrophobic contact between the phenyl groupo f benzaldehyde and the benzyl group of 83 is highlighted. Bond lengths are given in .C artesian coordinates taken from Ref [49]…”

Stabilization of the transition structures of organocatalytic asymmetric direct aldol reaction in wet solvent free condition by the formation of water assisted supramolecular network: A DFT study

“…Carboxylic acid moiety of L-proline, hydroxyl group of 4-hydroxy-L-proline individually or both groups simultaneously were reported to be modified in order to enhance the hydrophobicity of L-proline. Of late, Zhao et al [33] have reported their investigation on the hydrophobic substituent effects on proline catalyzed aldol reactions in water. They have synthesized a series of modified praline 2 that exhibit excellent diastereoselectivity and enantioselectivity with very low catalytic loading in an aldol reaction in water, which is also supported by DFT TS model of the corresponding aldolization reaction.…”