Two novel amphiphilic L-proline derivatives bearing long alkyl chain on the 4-position via ether bonds, 1a and 1b, have been synthesized and evaluated for the asymmetric direct aldol reaction in organic solvents as well as in water. The catalytic activities with 5 mol% of 1a are better than that of 30 mol% of proline itself being used. Especially, high yields (up to 99%), excellent enantioselectivities (up to 99% ee) and anti-diastereoselectivities (up to 99:1) are achieved in the reactions of aromatic aldehydes and cyclic ketones at room temperature with 5 mol% of 1a in water.
In this work, six isosteviolÀamino acid conjugates were designed and synthesized through simple condensation on a large scale without protecting group (Scheme). These amphiphilic organocatalysts mediated asymmetric three-component Mannich reactions of cyclohexanone and anilines with aromatic aldehydes in the presence of H 2 O. Meanwhile, the isosteviolÀproline conjugate 3b has been established as a highly efficient catalyst ( Table 1), and afforded syn-Mannich products with excellent diastereoselectivities (syn/anti up to 98 : 2) and enantioselectivities (up to > 99% ee; Table 3). The transition state of the reaction in the presence of H 2 O is proposed (Fig. 2).Introduction. -The asymmetric Mannich reaction is one of the most important CÀC bond forming reactions for the production of optically enriched b-amino carbonyl motifs [1]. It has been considered as a crucial synthetic methodology in the synthesis of pharmaceutically valuable compounds and natural products [2]. The first organocatalyst-mediated direct asymmetric Mannich reaction was reported by List [3], followed by excellent contributions from several groups [4]. Then, the amino acid derivatives have been utilized as efficient catalysts. However, most of these reactions proceed in polar organic solvents [5].Water is the most friendly medium, which avoids the problems of pollution that are inherent with organic solvents [6]. There is an endeavor to develop highly enantioselective Mannich reaction in the presence of H 2 O. Ibrahem and Có rdova [7] have reported that l-proline catalyzes the three-component Mannich reaction in DMSO/H 2 O. Then, the application of amino acid derivatives in asymmetric Mannich reactions in aqueous media was further extended by excellent work by Córdova and coworkers [8], and Wang and co-workers [9]. Although these reactions proceeded in an aqueous solution, the polar organic solvents were dominant. The first finding that the direct asymmetric Mannich reaction is promoted by a primary amino acid derivative in a purely aqueous system was reported by Lu and co-workers [10]. Then, the application of l-serine and l-proline derivatives in H 2 O were reported by Teo et al. [11], and Hayashi et al. [12], respectively; however, only moderate yields were obtained using cyclohexanone as the ketone part.
Isosteviol-amino acid conjugates were synthesized and used as chiral catalysts for the asymmetric three-component Mannich reaction with hydroxyacetone as donor molecule. Good yields (up to 98%) and excellent stereoselectivities (up to 97∶3 dr and 99% ee) were achieved in a short reaction time. In addition, syn-or anti-configurations of α-hydroxy-β-amino carbonyl compounds were obtained as main products with different chiral catalysts.
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