Abstract
The proline-catalysed asymmetric aldol reaction is usually carried out in highly dipolar aprotic solvents (dimethylsulfoxide, dimethylformamide, acetonitrile) where proline presents an acceptable solubility. Protic solvents are generally characterized by poor stereocontrol (e.g., methanol) or poor reactivity (e.g., water). Here, we report that water/methanol mixtures are exceptionally simple and effective reaction media for the intermolecular organocatalytic aldol reaction using the simple proline as the catalyst.
Highlights
The asymmetric intermolecular aldol addition catalysed by (S)-proline, proposed by List and co-workers in 2000 [1], is the prototype of enamine-based organocatalysis [2,3]
This study proves that, in the asymmetric aldol process promoted by proline, the reaction time providing the best performance strongly depends on the substrate; a careful investigation should be done before tackling a large-scale application
A further point that we evaluated to increase the sustainability of our large-scale protocol was the reduction of the ketone excess
Summary
The asymmetric intermolecular aldol addition catalysed by (S)-proline, proposed by List and co-workers in 2000 [1], is the prototype of enamine-based organocatalysis [2,3]. Proline often displays poor activity, requiring the use of high catalyst loadings and high reaction times, sometimes with unsatisfactory stereocontrol [1,28,29,30,31,32,33,34,35,36]. The new substituent, generally installed on the 4-OH group of 4-hydroxyproline, may play different roles: (i) it modifies the solubility profile of the parent amino acid, expanding the solvent choice to further classes [38]; and/or (ii) it enhances the catalyst activity and stereoselectivity, allowing a reduction of catalyst loading and reaction time; and/or (iii) it allows the catalyst immobilization on Catalysts 2020, 10, 649; doi:10.3390/catal10060649 www.mdpi.com/journal/catalysts
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