Dry and wet prolines for asymmetric organic solvent-free aldehyde–aldehyde and aldehyde–ketone aldol reactions

Abstract

Dry and wet prolines were found to catalyze the direct aldol reactions of aldehyde-aldehyde and aldehyde-ketone, respectively, to afford aldols with excellent diastereo- and enantioselectivities, and an organic solvent-free reaction was realized in some cases.

Highly Diastereo‐ and Enantioselective Direct Aldol Reactions of Aldehydes and Ketones Catalyzed by Siloxyproline in the Presence of Water

“…2,2-Dimethyl-1,3-dioxan-5-one [37] can be successfully employed as the nucleophilic ketone, affording a polyoxy compound with excellent selectivity. Here, the recommended amount of catalyst is 10 mol % because the reaction is slow with just 1 mol % ( Table 6, entries [25][26][27]. A water-soluble aldehyde such as formaldehyde may be successfully employed, though the use of NaCl as an additive in order to aid extraction of formaldehyde into the organic phase and of five equivalents of ketone are recommended (Table 6, entries [28][29][30].…”

“…[24] Recently, we also reported that proline itself promotes the enantioselective aldol reaction without any organic solvent under neat conditions, and in the presence of three equivalents of water for aldehyde-aldehyde and aldehyde-ketone aldol reactions, respectively, when the reaction proceeds efficiently by virtue of reactive electrophilic aldehydes. [25] We also found that proline could catalyze the enantioselective aldol reaction even in the presence of a large amount of water, though the enantioselectivities were moderate. [25] Just recently, we found that proline amide acts effectively "in water", rather than "in the presence of water".…”

“…[25] We also found that proline could catalyze the enantioselective aldol reaction even in the presence of a large amount of water, though the enantioselectivities were moderate. [25] Just recently, we found that proline amide acts effectively "in water", rather than "in the presence of water". [26] Since our first publication, a couple of asymmetric aldol reactions catalyzed by an organocatalyst and proceeding in the presence of water have appeared.…”

Asymmetric Organocatalysis: From Infancy to Adolescence

“…[32] Only a single study documenting a direct enantioselective aldol reaction "in water" has been disclosed so far. After screening 19 amino acids and some dipeptides, Hayashi and co-workers discovered that l-prolinamide 10 was capable of promoting the homoaldolization of water-soluble propanal at room temperature in 40 % yield (within 2.5 h) and with good enantioselectivity (Scheme 13).…”

“…The cross-aldol reaction of various ketones (including cyclic ketones) and diethyl formyl phosphonate hydrate (32) was also investigated (Scheme 27 b).…”