Organocatalytic asymmetric aldol reaction in the presence of water

Abstract

Water was found to be a suitable solvent for the l-prolinethioamide catalysed aldol reaction of various cyclic ketones with aromatic aldehydes. Treatment of 4-nitrobenzaldehyde with as little as 1.2 equiv. of cyclohexanone in the presence of the protonated catalyst 1-TFA, afforded aldol products in high yields (up to 97%) with high diastereo- and enantioselectivity (up to >5 : 95 dr and 98% ee). The use of a high excess of ketone was avoided by conducting the aldol addition in the presence of water. Furthermore, different 'salting-out' and 'salting-in' salts were investigated and it was proven that the rate of acceleration and the stereochemical outcome of the reaction are affected by hydrophobic aggregation. Scope and limitation studies revealed that electron deficient aldehydes afforded aldol products with high stereoselectivity in the presence of 1-Cl(2)CHCO(2)H. It was shown that various cyclic ketones, under the conditions found, gave aldol products with fair yields, even if they are used in substoichiometric amounts (1.2 to 2.0 equiv.).

Prolinamides versus Prolinethioamides as Recyclable Catalysts in the Enantioselective Solvent‐Free Inter‐ and Intramolecular Aldol Reactions

“…On the other hand, l-prolinethioamides have been used as catalysts for the direct asymmetric aldol reaction of aromatic aldehydes with acetone or cyclic ketones in organic [10] or aqueous solvents, [11] respectively. In this communication, we report our findings in the solvent-free direct intra-and intermolecular aldol reactions catalyzed by recyclable 1-aminoindane-and 1-aminoindan-2-ol-derived prolinamides and l-prolinethioamides 3.…”

“Side‐Product Catalysis”: Substrate Autoxidation as an Overlooked Side Reaction Generating a Co‐Catalyst for Enhancing Asymmetric Aldol Reactions

“…In this way, additives enhance the reaction rate as well as the optical purity of the aldol product by outperforming the unselective side reaction. Consequently, this effect has thoroughly been used to achieve high catalyst efficiency ,,–,,,,–,. In general, screening tests for acid additives are conducted in a 1:1 catalyst/co‐catalyst molar ratio.…”

2.07 The Aldol Reaction: Organocatalysis Approach

“…On the basis of investigations of different salting-out and salting-in conditions, brine is clearly a unique aqueous media that accelerates the rate of reaction and affects the stereochemical outcome of the aldol reactions due to hydrophobic aggregation (entries 9 and 10). 152,153 As two electron-withdrawing ester groups strengthen the double hydrogen bonds and the siloxy group increases hydrophobicity, the catalyst 305 is highly reactive ( Table 3, entry 11). 154 A combination of fluorous separations with catalysis in water is achieved by the fluorous pyrrolidine sulfonamide 306, which provides the aldol product 146 in good yield with high stereoselectivity (entry 12).…”