Structure‐Reactivity Studies of Simple 4‐Hydroxyprolinamide Organocatalysts in the Asymmetric Michael Addition Reaction of Aldehydes to Nitroolefins

Abstract

A series of simple 4-hydroxyprolinamides was synthesised and they were found to act as organocatalysts for the asymmetric conjugate addition of aldehydes to nitroolefins in excellent yields (98%), with complete diastereoselectivity (99:1, syn:anti) and enantioselectivity (98% ee for syn). Furthermore, the use of low catalyst loadings (5 mol%) and a low aldehyde molar excess (1.5 equivalents) were achieved.

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“…The authors suggested a transition state model organized by a network of hydrogen bonding interactions (Figure 2), in which the amide acts as bulky substituent and the better enantioselectivity of catalyst 3 with respect to 2 could derive from the additional stereocenter. The same asymmetric conjugate addition was investigated in 2012 by Kelleher's research group, which proposed a series of 4-hydroxyprolinamides (Scheme 2b) to examine the impact of the 4-hydroxy and the 2-methyl groups on the enantioselectivity of the prolinamide organocatalysts [32]. The synthetic route started with the α-methylation of the fully protected trans-4-hydroxyproline, followed by the diastereoisomers separation, the usual steps for the amide synthesis, and the 4-hydroxy-deprotection (Scheme 2a).…”

“…The synthetic route started with the α the fully protected trans-4-hydroxyproline, followed by the diastereoisom the usual steps for the amide synthesis, and the 4-hydroxy-deprotection ( coupling with N,α-dimethylbenzylamine provided the N-methylated low yields, due to the hindered nature of both of the coupling partners removal proved to be problematic due to the high aqueous solubility of t comparison, the analogous simple 4-hydroxy NH and N-methyl prolina pared in a similar manner. The application of all of the catalysts in the m addition showed that: (i) the cis relative position of the 4-OH was detrim methyl amide, (ii) the removal of the α-methyl group provided improved simplest hydroxyprolinamides 6c and 6d gave excellent performance, an The same asymmetric conjugate addition was investigated in 2012 by Kelleher's research group, which proposed a series of 4-hydroxyprolinamides (Scheme 2b) to examine the impact of the 4-hydroxy and the 2-methyl groups on the enantioselectivity of the prolinamide organocatalysts [32]. The synthetic route started with the α-methylation of the fully protected trans-4-hydroxyproline, followed by the diastereoisomers separation, the usual steps for the amide synthesis, and the 4-hydroxy-deprotection (Scheme 2a).…”

“…The authors suggested a transition state mode network of hydrogen bonding interactions (Figure 2), in which the ami substituent and the better enantioselectivity of catalyst 3 with respect to from the additional stereocenter. The same asymmetric conjugate addition was investigated in 2012 b search group, which proposed a series of 4-hydroxyprolinamides (Sche ine the impact of the 4-hydroxy and the 2-methyl groups on the enantios prolinamide organocatalysts [32]. The synthetic route started with the α the fully protected trans-4-hydroxyproline, followed by the diastereoisom the usual steps for the amide synthesis, and the 4-hydroxy-deprotection ( coupling with N,α-dimethylbenzylamine provided the N-methylated low yields, due to the hindered nature of both of the coupling partners removal proved to be problematic due to the high aqueous solubility of t comparison, the analogous simple 4-hydroxy NH and N-methyl prolina pared in a similar manner.…”

“…The prolinamide 29a provides an additional hydrogen bond due to the presence of the hydroxy group (A); conversely, the silylated prolinamide 29b exerts extensive steric coverage (B). Some of the 4-hydroxy-prolinamides (Figure 11) synthesized by Kelleher et al [32] in 2012 were applied by Singh in 2015 in the asymmetric aldol reaction using low catalyst loading (10 mol%) under solvent-free conditions, according to the green chemistry principles [49]. The trans-4-Hydroxy-(S)-prolinamide 6d, containing (S)-1-phenylethylamine, proved to be the best catalyst.…”