Going green: The synthetically very important aldol reaction can proceed in water without a metal catalyst with excellent enantioselectivity. The key to the reaction is a small, synthetic organic catalyst based on trans‐hydroxyproline with a siloxy group. Thus, this method is an environmentally friendly process for the synthesis of chiral molecules.

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Proline-based organocatalysts have been developed for a highly enantioselective, direct aldol reaction of aldehydes and ketones in the presence of water. While several surfactant-proline combined catalysts have proved effective, proline derivatives with a hydrophobic moiety such as trans-siloxy-L-proline and cis-siloxy-D-proline, both of which are easily prepared from the same commercially available 4-hydroxy-L-proline, have been found to be the most effective organocatalysts examined in this study, affording the aldol product with excellent diastereo- and enantioselectivities, these two catalysts generating opposite enantiomers. Water affects the selectivity, and poor results are obtained under neat reaction conditions or in dry organic solvents. More than three equivalents of water are required for the best diastereo- and enantioselectivities, while three equivalents is the recommended amount from a synthetic point of view. The reaction proceeds in the organic phase, and also proceeds in the presence of a large amount of water. The large-scale preparation of aldols with the minimal use of an organic solvent, including in the purification step, is described.

trans-4-tert-Butyldimethylsiloxy-l-proline displays a greater catalytic activity than the parent proline without compromising the enantioselectivity, which widens the substrate scope in the a-aminoxylation of carbonyl compounds, as well as O-nitrosoaldol/Michael, and Mannich reactions.Keywords: asymmetric synthesis; Mannich reaction; organic catalysis; oxidation; proline Organic catalyst-mediated asymmetric reactions [1] represent a rapidly developing field of research and numerous impressive results have appeared recently following the discovery of the proline-catalyzed aldol reaction, which is the intermolecular variant of the Hajos-Parrish À Eder-Sauer À Wiechert reaction, [2] reported by List, Lerner and Barbas in 2000.[3] Among several organic catalysts developed for asymmetric reactions, proline has occupied a central role. It has been successfully employed not only in the aldol, [3,4] but also in Mannich, [5] Michael, [6] a-amination, [7] and a-aminoxylation [8] reactions. Several modifications of proline catalyst such as the substitution of the carboxylic acid moiety of proline with an amide or tetrazole function have been performed to improve the enantioselectivity and reactivity. Substituted proline amides have been employed in the aldol reaction to improve the enantioselectivity, [9] while 5-pyrrolidin-2-yltetrazole was found to be a more reactive organic catalyst than proline in aldol, [10] a-aminoxylation [11] and O-nitroso-aldol/Michael [12] reactions as reported by Yamamoto et al. and in the Mannich reaction by Ley et al. [13] During our study of proline-catalyzed a-aminoxylations of aldehydes, [8 g] the reproducibility of the reaction was poor, especially at low catalyst loading, owing to the poor solubility of proline in the organic solvent. After intensive investigations, reproducible results were obtained using ultrasound irradiation of a DMF suspension of proline.[8g] This solubility problem prompted us to find a more soluble catalyst, which led us to try trans-4-tert-butyldimethylsiloxy-l-proline (1), easily prepared from commercially available trans-4-hydroxy-l-proline in large quantities [14] (Figure 1). The proline catalyst 1 not only provides reproducible results, but also accelerates the reaction dramatically with a reduced amount of the catalyst, promoting reactions that cannot be catalyzed by proline itself. As the catalyst 1 possesses a higher reactivity than the parent proline, its superiority to proline will be discussed in this paper.First of all, the reactivity of the catalyst 1 was investigated in the a-aminoxylation of cyclohexanone in the presence of 30 mol % of the catalyst [Eq. (1)]. The increase in the solubility of 1 in organic solvents greatly widens the choice of possible reaction medium (Table 1). For instance, the reaction scarcely proceeded in CH 2 Cl 2 and THF in the presence of proline owing to its poor solubility, while these solvents can be employed in the reaction with 1, affording the product in moderate yield (entries 1 and 2), although DMF is the ...

Grüne Chemie: Aldolreaktionen, die in vielen Synthesen eine wichtige Rolle spielen, verlaufen auch in Wasser und ohne Metallkatalysator mit ausgezeichneten Enantioselektivitäten. Entscheidend für diese umweltverträgliche Synthese chiraler Verbindungen ist ein synthetischer Organokatalysator mit trans‐Hydroxyprolin‐Gerüst und einer Siloxygruppe (siehe Bild; TBDPS=tert‐Butyldiphenylsilyl).

Optically active a-hydroxy carbonyl compounds, important building blocks in organic synthesis, can be prepared by several methods such as the electrophilic a-hydroxylation of enolates using chiral oxaziridines as the oxidizing agent.[1] As for methods based on asymmetric catalytic reactions, there are several, including the asymmetric dihydroxylation of enol ethers developed by Sharpless et al., [2] the asymmetric epoxidation of silyl enol ethers with a chiral dioxirane, [3] and the asymmetric epoxidation of enol ether with a chiral Mn-salen catalyst.[4] Recently Yamamoto et al. have developed an excellent asymmetric, catalytic nitroso-aldol reaction:[5] a catalytic amount of a binap-AgOTf complex promotes the reaction of tin enolate and nitrosobenzene, affording an a-aminoxy ketone, which is easily converted into the a-hydroxy ketone. In most of these reactions, however, the ketones must be converted into isolable enolate or enol derivatives, and there is as yet no direct catalytic method for the synthesis of chiral a-hydroxy ketones from the corresponding ketones. In this communication, we disclose the direct catalytic enantioselective a-aminoxylation of ketones, which is complementary to the recent asymmetric a-aminoxylation of aldehydes. [6] Proline [7] has been found to be an excellent catalyst of asymmetric aldol [8] and Mannich reactions [9] and of the asymmetric a-amination of carbonyl compounds.[10] In our continuing research on asymmetric reactions catalyzed by proline, [6c, 9c, 11] we have found the asymmetric a-aminoxylation of a ketone: The reaction of cyclohexanone and nitrosobenzene was conducted in dimethyl sulfoxide (DMSO) at room temperature in the presence of a catalytic amount of lproline. The desired a-aminoxylated cyclohexanone 1 was obtained in 31 % yield, along with the a,a'-diaminoxylated product 2 in 11 % yield [Eq. (1)

The direct proline-catalyzed asymmetric alpha-aminoxylation of aldehydes and ketones has been developed using nitrosobenzene as an oxygen source, affording alpha-anilinoxy-aldehydes and -ketones with excellent enantioselectivity. Reaction conditions have been optimized, and low temperature (-20 degrees C) was found to be a key for the successful alpha-aminoxylation of aldehydes, while slow addition of nitrosobenzene is essential for that of ketones. The scope of the reaction is presented.

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.