New Simple Hydrophobic Proline Derivatives as Highly Active and Stereoselective Catalysts for the Direct Asymmetric Aldol Reaction in Aqueous Medium

Abstract

New 4-substituted acyloxyproline derivatives with different hydrophobic properties of the acyl group were easily synthesized and used as catalysts in the direct asymmetric aldol reaction between cyclic ketones (cyclohexanone and cyclopentanone) and several substituted benzaldehydes. Reactions were carried out using water, this being the best reaction medium examined. Screening of these catalysts showed that compounds bearing the most hydrophobic acyl chains [4-phenylbutanoate and 4-(pyren-1-yl)butanoate] provided better results. The latter catalysts were successfully used in only 2 mol% at room temperature without additives to give aldol products in excellent stereoselectivities. These results demonstrate that derivatization of the proline moiety with the proper simple hydrophobic substituent in the 4-position can furnish highly active and stereoselective catalysts without the need of additional chiral backbones in the molecule. Finally, an explanation of the observed stereoselectivities in the presence of water is provided.

Chirally Functionalized Hollow Nanospheres Containing L‐Prolinamide: Synthesis and Asymmetric Catalysis

“…Most probably, a hydrogen bond might be formed between the dangling hydroxyl groups of water and the amide oxygen at the interface. [41][42][43] In the transition state, the hydrogen bond made the NH of the amide group more acidic and thereby strengthened the hydrogen bond formed between the NH and the aldehyde (Scheme 2). The stronger hydrogen bond is able to improve both the catalytic efficiency and the stereoselectivity.…”

“…In transition state B, the hydrophobic aldehyde attacked the anti-enamine through the hydrophilic region to form an anti product (2S,1'R) configuration. [43] In the presence of water, the transition of state A could be greatly enhanced due to the hydrophobicity of the aldehyde acceptor. Thus the enantioselectivity of the catalyst was improved in the presence of water.…”

Diastereo‐ and Enantioselective Direct Aldol Reactions in Aqueous Medium: A New Highly Efficient Proline‐Sugar Chimeric Catalyst

“…No reversed configuration of the aldol product was observed. [15] In our opinion the presence of water increases the activity of the catalyst because the more hydrophilic medium enhances the affinity of the hydrophobic aldehyde to the hydrophobic moiety of the catalyst. When water is absent (THF), the aldehyde is well dissolved in the organic solvent and this causes a lower yield.…”

“…[2e,4d,5,10b, 15,16] The performances of the catalyst 1 can be accounted for by considering that in water (even more in brine, due to the salting-out effect [17] ) the catalyst molecules may undergo molecular aggregation, much like surfactants, creating a local hydrophobic microenvironment in which reactions can take place. In other words, in the transition state the organic non-polar reactants would be buried in the hydrophobic environment [18] whereas the entire system would be kept in water by a hydrophilic surface.…”

Direct Asymmetric Aldol Reactions in Water Catalysed by a Highly Active C2‐Symmetrical Bisprolinamide Organocatalyst

“…The spectra were consistent with data previously reported. [10] trans-4-tert-Butyldiphenylsiloxy-N-Boc-l-proline Benzyl Ester…”