Proline as an Asymmetric Organocatalyst

Proline as an Asymmetric Organocatalyst Iminium-Activation of dienophile... 

Pyrrolidin-2-yltetrazole 204 has been found to be a new, catalytic, and more soluble alternative to proline in a highly selective, organocatalytic route to chiral dihydro-1,2-oxazines <05OL4189> and as an asymmetric organocatalyst for Mannich, nitro-Michael and aldol... 

In conclusion, the aldol reaction with L-proline as an enzyme mimic is a successful example for the concept of using simple organic molecules as chiral catalysts. However, this concept is not limited to selected enzymatic reactions, but opens up a general perspective for the asymmetric design of a multitude of catalytic reactions in the presence of organocatalysts [1, 3]. This has been also demonstrated by very recent publications in the field of asymmetric syntheses with amino acids and peptides as catalysts. In the following paragraphs this will be exemplified by selected excellent contributions. 

An asymmetric Mannich reaction was recently successfully achieved by means of different types of catalyst, metal- and organocatalysts [20, 21]. With the latter the reaction can be performed asymmetrically by use of L-proline and related compounds as chiral organocatalyst [22-35]. A key advantage of the proline-catalyzed route is that unmodified ketones are used as donors, which is synthetically highly attractive. In contrast, many other asymmetric catalytic methods require preformed enolate equivalents as nucleophile. 

Type I aldolases activate the aldol donor by the formation of enamines with active site amino acids and an alternate approach to the direct catalytic asymmetric aldol reaction centres on mimicking this process using proline-based organocatalysts. In fact, one of the earliest examples of asymmetric catalysis uses (S)-profine (7.66) as a catalyst for the intramolecular aldol reaction (the Hajos-Eder-Saeur-Wiechert reaction).As an example the achiral triketone (7.67) cyclises to give the aldol product (7.68) with good enantioselectivity. 

The initial spark for proline catalysis was provided independently and simultaneously by two groups in 1971. Hajos and Parrish on the one hand (Scheme 5.1), and Eder, Sauer and Wiechert (Scheme 5.2) on the other developed an asymmetric aldol cyclisation of triketones such as 1 to bicyclic allq l ketones 2. In the former report, (S)-proline was applied at 3 mol%, a low organocatalyst loading, even to date. The quantitative cyclisation reaction was completed in the reasonable time of 20 h, and provided the product in 93.4% ee. Dehydration to enone 3 completed the synthesis of a valuable building block in steroid chemistry. 

On the other hand, a number of asymmetric aldol reactions have been performed in the last year in the presence of variously substituted prolines as the organocatalysts. As an example, Zhao et al. reported excellent results for the cross-aldol reaction of cyclohexanone with p,y-unsaturated keto esters catalysed by a tra i-siloxy-L-proline (Scheme 2.3). This practical and highly efficient protocol could be extended to other ketones, albeit with lower enantioselectivities (<93% ee). 

The synthesis of a novel Merrifield resin-supported dipeptide Pro-Ala-O-P, derived from proline and alanine, was reported by Wang and Yan with the aim of being used as an organocatalyst in asymmetric aldol reactions of ketones with aldehydes. " Indeed, this supported dipeptide was found to be an efficient catalyst to promote the asymmetric aldol reaction under neat conditions between aromatic aldehydes and cyclic ketones, generating the corresponding aldol products with moderate to high yields and diastereoselectivities of up to 80% de combined with good enantioselectivities of up to 95% ee, as shown in Scheme 2.18. Moreover, this catalyst could be used for seven times with only a minor decrease in product yields, but maintained stereoselectivities. 

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