Aldimines, asymmetric Mannich reaction

Recent efforts in the development of efficient routes to highly substituted yS-ami-no acids based on asymmetric Mannich reactions with enantiopure sulfmyl imine are worthy of mention. Following the pioneering work of Davis on p-tolu-enesulfmyl imines [116], Ellman and coworkers have recently developed a new and efficient approach to enantiomerically pure N-tert-butanesulfmyl imines and have reported their use as versatile intermediates for the asymmetric synthesis of amines [91]. Addition of titanium enolates to tert-butane sulfmyl aldimines and ketimines 31 proceeds in high yields and diastereoselectivities, thus providing general access to yS -amino acids 32 (Scheme 2.5)... 

Scheme 6.88 Asymmetric Mannich reaction of N-Boc-protected aldimines catalyzed by simplified thiourea 76.

Systematic investigations of the catalyst structure-enantioselectivity profile in the Mannich reaction [72] led to significantly simplified thiourea catalyst 76 lacking both the Schiff base unit and the chiral diaminocyclohexane backbone (figure 6.14 Scheme 6.88). Yet, catalyst 76 displayed comparable catalytic activity (99% conv.) and enantioselectivity (94% ee) to the Schiff base catalyst 48 in the asymmetric Mannich reaction of N-Boc-protected aldimines (Schemes 6.49 and 6.88) [245]. This confirmed the enantioinductive function of the amino acid-thiourea side chain unit, which also appeared responsible for high enantioselectivities obtained with catalysts 72, 73, and 74, respectively, in the cyanosilylation of ketones (Schemes 6.84 and 6.85) [240, 242]. 

Their previous screening of catalysts for of aldol reactions and Robinson annu-lations suggested the possibility that chiral amines might also be able to catalyze the Mannich reaction [30, 31]. Thus, screening of catalysts for Mannich-type reactions between N-OMP-protected aldimines and acetone revealed that chiral diamine salt 10, L-proline 11, and 5,5-dimethylthiazolidine-4-carboxylic acid (DMTC) 12 are catalysts of Mannich-type reactions affording Mannich adducts in moderate yields with 60-88 % ee. To extend the Mannich-type reactions to aliphatic imines, the DMTC 12-catalyzed reactions are performed as one-pot three-component procedures. The o-anisidine component has to be exchanged with p-anisidine for the one-pot reactions to occur. The DMTC 12-catalyzed one-pot three-component direct asymmetric Mannich reactions provide Mannich adducts in moderate yield with 50-86 % ee. 

In 2006, Hoveyda and coworkers developed an asymmetric Mannich reaction of silyloxyfurans and aldimines using a similar catalyst system (Scheme 9.18).28 The diastereo- and enantioselective reaction between silyloxyfurans and aldimines in the presence of catalyst gave y-butenolides, which are useful building blocks for organic synthesis. They also reported a mechanistic study of this reaction.2811... 

In 2004, Akiyama s and Terada s groups independently pioneered the development of chiral BINOL-derived phosphoric acids 197, which have subsequently found wide resonance as catalysts in various asymmetric transformations [33, 41, 42]. Akiyama reported that silyl ketene acetals such as 237 participate in additions to aromatic aldimines with high diastereo- and enantioselectivity in the presence of catalyst 238 (Equation 21) [146]. In parallel studies, Terada demonstrated that the chiral phosphoric acid 242 readily catalyzes direct asymmetric Mannich reactions between acetylacetone (241) and N-Boc-protected aromatic aldimines such as 240 (Equation 22) [145]. 

Saito, S. Hatanaka, K. Yamamoto, H. Asymmetric Mannich-type reactions of aldimines with a chiral acetate. Org. Lett. 2000, 2, 1891-1894. 

The enamine catalysis detailed above proceeds via activation of the Mannich donor. An alternate strategy to the catalysis of the Mannich reaction is by the use of Brensted acids that activate the acceptor imine by protonation on nitrogen. Some of the most successful asymmetric variants of this process use BINOL-based phosphoric acids as catalysts. For instance Terada and coworkers used (7.144) to effect highly enantioselective addition of acetylacetone to a range of aryl aldimines ... 

Chiral amines can react with so-called Mannich donors such as ketones or aldehydes. The resulting chiral enamines wiU then attack a Mannich acceptor, usually a prochiral aldimine, thereby introducing one or two chiral centers in the Mannich product. This usually is a P-aminoaldehyde or P-aminoketone, optionally substituted at the a-position. Inspired by their work on proline-catalyzed asymmetric aldol reactions [1], the List group envisioned that the related Mannich reactions might also be carried out with a catalytic amount of an enantiomerically pure chiral amine. This led in 2000 to the first direct catalytic asymmetric organocatalyzed Mannich reaction, catalyzed by L-proline (1, Scheme 5.1) [2],... 

Enders et al. developed an asymmetric synthesis of polyfiinctionalized pyrrolidines based on Mannich-Michael cascade strategy (Scheme 2.42). Under the promotion of 10mol% thiourea catalyst 140b, y-malonate-substituted a,P-unsaturated esters 149 and N-protected aryl aldimines 148 underwent Mannich reaction to afford chiral amine intermediates, which then underwent an intramolecular aza-Michael reaction to yield pyrrolidine derivatives 150 with moderate to good enantioselectivities [60]. 

Niobium lies directly below vanadium in Group 5 and thus is expected to have high Lewis acidity however, there are few reports on chiral niobium catalysts. This is in contrast to the various asymmetric transformations catalysed by neighbouring Group 4 metal complexes, i.e., titanium and zirconium. In 2005, Kobayashi first reported highly enantioselective niobium Lewis-acid catalysts for the Mannich-type reaction of aldimines 57 with silyl enol ethers 58. To prepare an efficient chiral pentavalent niobium(v) catalyst for the activation of aldimines 57, Kobayashi designed tridentate ligand 56 (Scheme 9.24). 

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