Proline-based catalysts Mannich reactions

Under the reaction conditions used in the one-pot Mannich reaction described above, L-proline (S)-27 was clearly found to be the preferred organocatalyst. As is apparent from Scheme 5.14, the best yield (90%) and enantioselectivity (93% ee) were obtained by use of this organocatalyst [23]. The suitability of all other organo-catalysts used in this one-pot reaction, using 3-methylbutanal as aldehyde, was poor. Remarkably lower yields and poor enantioselectivity were obtained when the thiazolidine catalyst (S)-31 and other pyrrolidine-based organocatalysts were used. 

Note that catalyst 13 was designed for anti-selective Mannich reactions based on the study of proline-catalyzed Mannich reactions. Four considerations are key for the diastereo- and enantioselectivities observed in the (S)-proline-catalyzed reactions (Scheme 2.15a) ... 

Surprisingly, little follow-up work on this idea of small molecule asymmetric catalysis appeared for the next 25 years. In the late 1980s, Agami reported the asymmetric intramolecular aldol reaction of acyclic diketones with (S)-proline as the catalyst. It was not nntil the twenty-first centnry, however, when this notion of organocatalysts became fnlly exploited. List and Barbas ° pioneered enam-ines as catalysts for aldol and Mannich and related reactions. MacMillan has developed a variety of imininm-based catalysts prodncing large asymmetric indnction for Diels-Alder chemistry, Friedel-Crafts alkylations, Mnkaiyama-Michael and cyclopropanation " reactions. 

Enders et al. also reported direct asymmetric Mannich reactions starting from the protected ketone 14 [10]. Several protected carbohydrates and amino sugars were assembled in a three-component reaction. Alongside L-proline (1) they employed the L-hydroxyproline-based catalyst 17 (Scheme 5.10). This catalyst proved to be beneficial in terms of reaction rate due to superior solubility properties. Remarkably, the addition of water had a positive effect on the stereoselectivity in case catalyst 17 was employed. 

In analogy with the above-mentioned amine-catalysed aldol reactions, our binaphthyl-based amino sulfonamide catalysts showed unique reactivity and selectivity in the asymmetric Mannich reaction of aldehydes. For instance, the Mannich reaction of propanal with an a-imino ester catalysed by (S)-3 gave the antr-Mannich adduct as a major diastereomer, while the syn-Mannich adduct was obtained in the proline-catalysed reaction first reported by the Barbas group (Scheme 17.8). ... 

Since the discovery of proline-catalyzed enantioselective aldol reactions, an extensive research program to explore chiral secondary amine catalysts has been pursued. Several polymer-supported chiral amines have been synthesized for aldol, Mannich, and related reactions. Polystyrene is a popular solid phase for use in place of silica gel in the proline-based organocatalysis. In contrast, silica gel displays a slightly acidic character and has a hydrogen-bond donor or acceptor, which may change the catalytic activity and chiral space of the organocatalyst. Flow enantioselective aldol [158-161], Mannich [162], Michael [163], and related reactions... 

Chiral 3-amino carbonyl compounds and 1,2-amino alcohols are among the most valuable building blocks for asymmetric synthesis and catalysis. Efficient enanti-oselective syntheses of these compounds were reported from 2000 to 2006 using enamine-based organocatalysts. For example, Mannich reactions employing aliphatic aldehyde as a donor with a-imino glyoxylate as an acceptor provide syn-adducts (74) as the major product with excellent enantiomeric excess in the presence of (S)-proline (13) as a catalyst (Table 28.5, entry 1) [41]. When the ketone is employed as a donor, the sy -isomer is obtained with excellent diastereo-and enantioselectivities (entry 2) [42]. 

An example of a cascade reaction combining enamine and silver catalysis for synthesis of 1,2-dihydroisoquinoline derivatives is shown in Fig. 8.26. In the first step, nucleophilic enamine formed from the ketone and proline reacts with the imine, which is generated from the aldehyde and the amine. As a result, the Mannich base is formed, which then undergoes a hydroamination reaction in the presence of silver catalyst. 

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