Threonine Mannich reaction

Acyclic chiral a-amino acids or derivatives are also effleient eatalysts for the asymmetric two- or three-components Mannich reaction. Protected or free 2-hydroxyketones reacted with 16 in the presence of L-tiyptophan, O-protected-L-threonine or L-serine and generally led to the a ft-adduct 17, explained by the formation of a (Z)-enamine stabilised by an intramolecular hydrogen bond (Scheme 12.5). Threonine surfactant 14 was equally effective for the three-component reaction with hydro gracetone, benzalde-hyde derivatives and anilines. ... 

As additional examples, we can first note the use of silylated serine or threonine for the addition of 2-phenylpropanal to vinylsulfone, giving the corresponding adduct in good yields (85-90%) but low ee (44-45%). As a second example, an aza-Michael reaction has been described with the ethyl methyl imidazolium salt of glycine as a catalyst. As a last example, the interest in tert-leucine can be noticed as it could act as a cocatalyst with a pyrrolidine bearing a thiopyridine. The ion-pair catalyst catalysed the domino oxa-Michael-Mannich reaction of salicylic aldehydes with cyclohex-2-enones. ... 

C. Wu, X. Fu, X. Ma, S. Li, C. Li, Tetrahedron Lett. 2010, 51, 5115—5111. Threonine-surfactant organocatalysis for the highly diastereo- and enantioselective direct anti-Mannich reactions of hydroxyacetone. 

Scheme 3.14 Mannich reactions catalysed by L-threonine derivative.

In 2008, Barbas et al. reported the first primary amine-containing amino acid-catalysed indirect a n -Mannich reactions of dihydroxyacetone and acyclic protected dihydroxyacetone derivatives with a variety of imines derived from both aliphatic and aromatic aldehydes.In spite of moderate diastereoselec-tivities, good to high yields and enantioselectivities were obtained by using an L-threonine derivative as the organocatalyst in A -methylpyrrolidinone as the solvent and 5-methyl-l-7/-tetrazole as an additive, as shown in Scheme 3.14. 

L-Threonine-derived catalysts were also found to be useful in direct asymmetric Mannich reactions. Lu and coworkers [43] demonstrated that O-silylated threonine... 

Scheme 3.11 0-Bu -L-threonine-catalyzed direct three-component Mannich reaction.

Although the number of successful applications of primary amino acids in stereoselective organocatalysis is far fewer than for the secondary amine, a few interesting examples are worth pointing out. The diversity of primary amino acids in aldol and Mannich reactions has been reviewed recently [48]. Several primary amino acids, such as alanine, valine, tryptophan, and threonine have been used as orga-nocatalysts. For instance, Barbas and coworkers have demonstrated the use of a L-threonine catalyzed protocol towards the synthesis of syn-l,2-diols through direct aldol reaction between a-hydroxyketones and para-nitrobenzaldehyde (Figure 17.13) [49]. 

A three-component Mannich reaction of O-benzyl hydroxyacetone with p-anisidine and aldehydes was carried out using the TBDPS-protected L-threonine catalyst 118 (Figure 24.37), which gave the best results among a series of catalysts... 

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