Design And Synthesis Of The Primary Amine Organocataysts And Their Applications For The Direct Asymmetric Aldol Reaction

The asymmetric Aldol reaction is one of the most popular carbon-carbon bond-forming reactions, the corresponding Aldol productβ-hydroxyl carbonyl compounds make up a large family of chiral intermediates for drugs and natural products. Water is an ideal reaction medium for organic reactions due to the low cost, safety and environmentally benign nature. Water as reaction medium can reduce the impact on environmental and the production costs. With the enhanced awareness of environmental protection, development of organocatalysts for the direct asymmetric Aldol reactions in aqueous medium become an attractive research field. However, reports about primary amine catalyzed asymmetric Aldol reaction in aqueous medium are limited.In this paper, we designed and synthesised two kinds of new chiral primary amine organocatalysts, and applied them to the direct asymmetric Aldol reaction in aqueous medium. When brine was used as reaction medium, good results were obtained.In this paper, we first designed and synthesized a series of primary amine organocatalysts 3a-3i from acyclic amino acids and cinchona alkaloids. We optimized the reaction conditions in the presence of 3a. Solvents,reaction temperatures, catalysts loading and additives were screened. Then, the catalytic activities of 3a-3i were evaluated in the model reaction between cyclohexanone an 4-nitrobenzaldehyde under optimized condition (3 mol% catalyst loading, -5 oC, in brine). Catalyst 3e was found to be the best one and the Aldol product was obtained in good yield (92%) with high enantioselectivity (92% ee) and diastereoselectivity (dr >99:1). Next, the direct asymmetric Aldol reactions of various aldehydes and cyclohexanone in the presence of 3e were examined. The Aldol reactions of cyclohexanone and benzaldehyde which bearing nitro and canyo group afforded the corresponding Aldol products with moderate to high enantioselectivites and excellent diastereoselectivities. Benzaldehydes which bearing fluoro and chloro groups were converted to Aldol products with low enantioselectivites. The reaction of 4-nitrobenzaldehyde and acetone cyclopentanone afforded the Aldol product with low enantioselectivity.After that, we designed and synthesized a series of L-Valine dipeptide organocatslysts 2a-2d which bearing a primary amine group and two amide units. Organocatalysts were obtained from N-Boc-Valine and arylamines through two steps of condensation and two steps of deprotection. The catalytic activities of 2a-2d were evaluated in the model reaction between cyclohexanone and 4-nitrobenzaldehyde under optimized condition (10 mol% catalyst loading, rt, 2.4-dinitrophenol as an acidic additive, in brine). Catalyst 2c was identified as the best catalyst, and the Aldol product was obtained in good yield with high enantioselectivity (ee, 95%) and diastereoselectivity (dr, 98:2). Then, the direct asymmetric Aldol reactions of various aldehydes and cyclohexanone in the presence of 2c were examined, benzaldehyde which bearing electron-withdrawing group were converted to the corresponding Aldol products in moderate yields with moderate to high enantioselectivites (from 68% ee to 95% ee) and diastereoselectivities (from 92:8 to >99:1 dr). Aldol reactions of cyclopentanone with 4-nitrobenzaldehyde and 3-nitrobenzaldehyde gave the corresponding Aldol product in high yield but with low enantioselectivity and diastereoselectivity. The reaction of acetone and 4-nitrobenzaldehyde afforded the Aldol product with low enantioselectivity.Via the researching work of this dissertation, we hope that we can provide reference for the development of water compatible organocatalysts.