Highly Diastereo‐ and Enantioselective Direct Aldol Reactions Promoted by Water‐Compatible Organocatalysts Bearing Central and Axial Chiral Elements

Abstract

Two novel bifunctional primary amine catalysts 1 (R A ,S,S) and 2 (R A ,R,R), which bear both central and axial chiral elements, have been developed to promote highly diastereoselective and enantioselective aldol reactions of arylaldehydes with cyclic and acyclic ketones in the presence of water at room temperature. The catalyst 2 (R A ,R,R) afforded the desired products with high levels of anti diastereoselectivity (up to 99:1) and enantioselectivity (up to 98%), showing that the two chiral elements of catalyst 2 (R A ,R,R) are matched, and enhance the stereochemical control. In addition, the catalyst 2 (R A ,R,R) was found to catalyze the direct aldol reaction of 4-nitrobenzaldehyde with 2-cyclohexanone under neat reaction conditions at room temperature with the high anti diastereoselectivity (98:2) and enantioselectivity (98%).

Organocatalyzed Aldol Reactions

“…Catalyst 345 (15 mol%) promoted the reaction between hydroxyacetone (58a) and aromatic aldehydes in dichloromethane at 25 • C, providing mainly syn-59 products in moderated results (48-70%, 38-80% de, and 52-91% ee) [408]. Catalyst 346 (3.5 mol%) bearing a group with an stereogenic axis, which displayed a high performance (23-96% yield, 60-99% de, and 87-98% ee) in combination with triflic acid in the aldol reaction of cyclic ketones or acetone with aromatic aldehydes in water at 25 • C [409]. Another chiral diamine catalyst (Figure 3.24) such as compound 347 (20 mol%) was used in the presence of a POM acid support (6.67% mol) in the aldol reaction of dihydroxyacetone (321a) with aromatic aldehydes in NMP as solvent at 25 • C, which gave mainly syn-aldol products in good yields and high diastereo-and enantioselectivities (59-97%, 78-99% de, and 84-99% ee).…”

Asymmetric Organocatalysis

“…Theoretical study revealed that protonated piperidine was important for the reactivity and enantiocontrol. Additionally, other primary amine derivatives have also been reported to catalyze aldol reaction with various enantioselectivity [42][43][44].…”

Acyclic Amino Acids Catalyzed Direct Asymmetric Aldol Reactions in Aqueous Media Assisted by 2,4-Dinitrophenol

“…The stereoselective transformation in water or aqueous media is a promising research topic in organic chemistry because water is an environmentally friendly, safe medium, which avoids issues of pollution that are inherent with organic solvents [13,14]. Combining the above two points, it is not surprising that a large number of organocatalysts and methods have been developed to achieve efficient adducts with high diastereo-and enantioselectivities [15][16][17][18][19]. In nature, Class I or Class II aldolases catalyze the direct aldol reaction in water.…”