A Highly Active 4‐Siloxyproline Catalyst for Asymmetric Synthesis

Abstract

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 ...

Highly Enantioselective Construction of a Quaternary Carbon Center of Dihydroquinazoline by Asymmetric Mannich Reaction and Chiral Recognition

“…However, the major product had an opposite absolute configuration (entry 5). The more soluble catalyst, 4-siloxyproline (3d), [8] gave good yield but with poor enantioselectivity (entry 6). The MacMillan chiral imidazolidinone [9] (HCl salt) (3e) could not catalyze the reaction at all (entry 7).…”

Asymmetric Multicomponent Reactions (AMCRs): The New Frontier

“…[230] The problems of reproducibility and reactivity of the above organocatalyzed reaction have been partially overcome by the use of trans-4-tert-butyldimethylsiloxy-l-proline. [231] The diastereoselective Biginelli MCR with Si(NCS) 4 and a chiral 1,3-ketoester derivative has been used in the synthesis of the bicyclic core of batzelladine alkaloids, with a 70:30 diastereomeric ratio. [232] The diastereoselective Petasis MCR, with chiral aldehydes and ammonia, has been extended to the use of allylboronate derivatives, which led to the expected primary amines with excellent diastereoselectivity.…”

Imidazolium Ion‐Tagged Proline Organocatalyst for α‐Aminoxylation of Aldehydes and Ketones in Ionic Liquids

“…Shortly after, the scope of this aminoxylation reaction was extended to ketones by the groups of Hayashi [4b] and Córdova [5] at the same time. However, there has been no progress in developing new organocatalysts [6] for this reaction up to now. Some other similar work was just focused on changing different substrates and solvents [7] and efforts were devoted to the reaction mechanism [8] and applications.…”