Abstract
The hydroxyprolines (Hyps) 2-6 are tested as organocatalysts for aldol, Michael additions, and Mannich reactions. The results are compared with the well-known analogous L-proline ( 1).The effect of the additional hydroxyl group and chiral center was investigated in the three types of reactions. Catalyst 2 shows an enhancement in the stereoselectivity of the aldol reaction, while 3 in Michael addition and 5 in Mannich reaction give the best results. Derivatives of hydroxyprolines show diversity in the catalytic behavior like 6.
Highlights
L-Proline (1) is one of the most well-known organocatalysts.[1]. It has been used over a wide range of organic synthesis reactions to obtain enantiomerically or diastereomerically highly enriched asymmetric products.[2,3,4]. It is used as an asymmetric catalyst for the synthesis of -hydroxy ketones via aldol additions,[5,6,7,8,9,10,11] Michael addition reactions,[12,13,14,15] and -amino ketones via Mannich reactions.[16,17]
Hüttel et al studied the influence of hydroxyproline derivatives and some other non-proteinogenic amino acids on the aldol addition and on Michael and Mannich reactions
Aldol reaction A summary of the results of the reaction of 4-nitrobenzaldehyde with acetone is given in Table 1 using the hydroxyprolines 2-5 and ether 6 as catalysts
Summary
L-Proline (1) is one of the most well-known organocatalysts.[1]. It has been used over a wide range of organic synthesis reactions to obtain enantiomerically or diastereomerically highly enriched asymmetric products.[2,3,4] It is used as an asymmetric catalyst for the synthesis of -hydroxy ketones via aldol additions,[5,6,7,8,9,10,11] Michael addition reactions,[12,13,14,15] and -amino ketones via Mannich reactions.[16,17] The importance of L-proline (1) – more than all other amino acids as catalyst – derives from the fact that it is the only secondary proteinogenic amino acid, and it has a special rigidity which could control the stereochemistry through the formed imine/enamine intermediate.[16,17,18,19,20] L-proline is a natural amino acid, and it is available in very pure form and is inexpensive. Transformation of the carboxylic acid moiety (red) into an amide or peptide bond was the main idea to obtain more efficient and selective catalysts for the aldol addition.[26,27,28,29,30,31,32] The effect of chiral centers on the amide group was studied. The trans-4-isomers and some derivatives have been known for a long time and tested as catalysts for aldol additions and other reactions.[9,19,45] Very few studies are reported on cis-isomers.
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