Pyrrolidine-carboxylic acid catalysi

Notwithstanding the progress in other reaction types, the main thrust in organo-catalysis research centers is on enantioselective catalysis applications [109,110], of which amine-based asymmetric catalysts form the majority [111]. Most of the reactions proceed via the enamine catalytic cycle (Figure 3.38a) or via imonium intermediates. The most common (and most successful) catalysts for such reactions are proline derivatives. Thanks to its secondary amine functionality and relatively high pKa value, proline (pyrrolidine-2-carboxylic acid) is a good... 

Simple L-alanine, L-valine, L-norvaline, L-isolecucine, L-serine and other linear amino acids [ 121 ] or chiral amino acids with a binaphthyl backbone [ 122] and peptides have also been used as asymmetric catalysts [123,124,125,126]. Solid-supported proline-terminated peptides have been used for heterogeneous catalysis of the asymmetric aldol reaction [ 127]. Apart from proline and derivatives, other cyclic compounds such as 5,5-dimethyl thiazolidinium-4-car-boxylate (DMTC) [128], 2-fert-butyl-4-benzyl imidazolidinones [129], (l/ ,25)-2-aminocy-clopentanecarboxylic acid [130], (5 -5-(pyrrolidin-2-yl)tetrazole, (5)-l,3-thiazolidine-4-car-boxylic acid, (5)-5,5-dimethyl-l,3-thiazolidine-4-carboxylic acid, and (5)-hydroxyproline are effective catalysts in asymmetric aldol reactions [126,131,132,133,134,135]. 

Extension of the enamine-mediated carbonyl a-amination strategy to the generation of quaternary stereogenic centers at the a-position of a-branched aldehydes under catalysis by prohne 1 [8, 9], pyrrolidine tetrazole 3 [10, 11], or L-azetidin-2-carboxylic acid 4 [8] has also been explored (Table 11.1). The observed enantio-selectivities ranged from essentially none to >99%. Derivatives of 2-phenylpropanal gave better enantioselectivities than a,a-dialkyl substituted aldehydes. Erase and coworkers [11] employed microwave irradiation to accelerate the rate of proline-catalyzed amination, and found that yields as well as enantioselectivity can be somewhat improved with shorter reaction times. It appears that the pyrrolidine tetrazol 3 was a more effective catalyst than L-proline 1 for the amination of 2-phenylpropanal derivatives [10,11]. Subsequent reduction of adducts and cyclization could be carried out to afford the respective a-amino alcohols or the A-amino-oxazolidinones. 

Other catalysts besides proline have also been investigated. A particularly large amount of data has been collected for the aldol reaction of acetone tvith p-nitrobenzaldehyde (Scheme 4.32). Simple primary a-amino acids and acyclic N-methylated a-amino acids are not catalytically active under standard reaction conditions. Of the simple cyclic amino acids studied, azeti-dine, pyrrolidine, and piperidine 2-carboxylate, proline is clearly the best catalyst, a-, a -, and, in particular, N-methylation reduce the efficiency and vhereas substitution of the 3- and 4-positions are tolerated vithout dramatic effects. Proline amide is essentially catalytically inactive under the standard reaction conditions (DMSO, room temperature, 2 h) but after three days, the aldol could be isolated in good yields, albeit vith very low enantiose-lectivity. Clearly, the carboxylic acid plays an important role in the catalysis and in determining enantioselectivity. That the enantioselectivity can be improved vas sho vn vith penicillamine derivative 168, proline derived diamine salt 169, and amide 170 [129-132]. 

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