Mannich reaction asymmetric reactions, research

Shibasaki and coworkers have conducted extensive research on the use of hetero-bimetallic complexes as catalysts for asymmetric synthesis [11]. The reactions are catalyzed by heterobimetallic complexes that function as both a Lewis acid and a Bronsted base. Among these, LaLi3tris(binaphthoxide) catalyst 1 (LLB) was proven to be an effective catalyst in direct asymmetric aldol reactions (Fig. 1) [12]. On the basis of this research, Shibasaki et al. reported the first report of a direct catalytic asymmetric Mannich reaction [13],... 

Addition of nucleophiles to electrophilic glycine templates has served as an excellent means of synthesis of a-amino acid derivatives [2c, 4—6]. In particular, imines derived from a-ethyl glyoxylate are excellent electrophiles for stereoselective construction of optically active molecules [32], This research and retrosyn-thetic analysis led us to believe that amine-catalyzed asymmetric Mannich-type additions of unmodified ketones to glyoxylate derived imines would be an attractive route for synthesis of y-keto-ce-amino acid derivatives [33], Initially, L-proline-catalyzed direct asymmetric Mannich reaction with acetone and N-PMP-protected a-ethyl glyoxylate was examined in different solvents. The Mannich-type reaction was effective in all solvents tested and the corresponding amino acid derivative was isolated in excellent yield and enantioselectivity (ee >95 %). Direct asymmetric Mannich-type additions with other ketones afford Mannich adducts in good yield and excellent regio-, diastereo- and enantioselectivity (Eq. 8). 

Cordova, A. (2004) The direct catalytic asymmetric Mannich reaction. Accounts of Chemical Research, 37, 102—112. 

The same research group also developed an enantioselective catalytic Mannich reaction using a phosphoglycine benzophenone imine as a Man-nich donor, promoted by the 2-picolyl N-oxide PTC catalyst 48h/ The new reaction represented an efficient method for the preparation of ot,p-diami-nophosphonic acids (94). Furthermore, they synthesised ot-alkylidene-p-amino carbonyl derivatives, usually named as aza-Morita-Baylis-Hillman (aza-MBH) adducts (95), by an asymmetric Mannich reaction using the N-(2-methoxybenzyl) quininium catalyst 48g followed by Horner olefination (Scheme 16.31). ... 

The method of Bella is a supreme example of how the organocatalytic asymmetric Mannich reaction can facilitate the synthesis of simple pyrrolidine or piperidine alkaloids starting from achiral starting materials. Therefore, in the snbsequent paragraphs, we wish to review recent efforts made by various research groups to implement an organocatalytic asymmetric Mannich reaction as key step in the total synthesis of alkaloids, predominately derived from L-Om and n-Lys. 

Surprisingly, the catalytic potential of proline (1) in asymmetric aldol reactions was not explored further until recently. List et al. reported pioneering studies in 2000 on intermolecular aldol reactions [14, 15]. For example, acetone can be added to a variety of aldehydes, affording the corresponding aldols in excellent yields and enantiomeric purity. The example of iso-butyraldehyde as acceptor is shown in Scheme 1.4. In this example, the product aldol 13 was obtained in 97% isolated yield and with 96% ee [14, 15]. The remarkable chemo- and enantioselectivity observed by List et al. triggered massive further research activity in proline-catalyzed aldol, Mannich, Michael, and related reactions. In the same year, MacMillan et al. reported that the phenylalanine-derived secondary amine 5 catalyzes the Diels-Alder reaction of a,/>-un saturated aldehydes with enantioselectivity up to 94% (Scheme 1.4) [16]. This initial report by MacMillan et al. was followed by numerous further applications of the catalyst 5 and related secondary amines. 

Nevertheless, the use of chirally modified Lewis acids as catalysts for enantioselective aminoalkylation reactions proved to be an extraordinary fertile research area [3b-d, 16]. Meanwhile, numerous publications demonstrate their exceptional potential for the activation and chiral modification of Mannich reagents (generally imino compounds). In this way, not only HCN or its synthetic equivalents but also various other nucleophiles could be ami-noalkylated asymmetrically (e.g., trimethylsilyl enol ethers derived from esters or ketones, alkenes, allyltributylstannane, allyltrimethylsilanes, and ketones). This way efficient routes for the enantioselective synthesis of a variety of valuable synthetic building blocks were created (e.g., a-amino nitriles, a- or //-amino acid derivatives, homoallylic amines or //-amino ketones) [3b-d]. 

Nota, W., Tanaka, F. and Barbas, C.F. IB (2004) Enamine-based organocatalysis with proline and diamines The development of direct catalytic asymmetric aldol, Mannich, Michael and Diels-Alder reactions. Accounts of Chemical Research, 37, 580-591. 

In 2004, Yamamoto and Arvidsson independently reported the catalytic activity of the L-proline tetrazole catalyst 30 in asymmetric aldol reactions of ketones with aldehydes [161-163]. At the same time. Ley and coworkers reached similar conclusions by applying this system to asymmetric Mannich and Michael addition reactions (Scheme 1.8) [164]. Since then, the scope of this chemistry has been expanded by several research groups [165-174]. 

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