Serine asymmetric aldol reaction

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]. 

Acyl-1,3-thiazolidines-2-ones 1.123 (X = S, R = COOMe), obtained from cysteine methyl ether [261], have been introduced by Mukaiyama and coworkers for use in asymmetric aldol reactions [261, 433, 434, 435], In reactions of related //-acyl-1,3-oxazolidines-2-thiones 1.123 (X = O, R = COOMe), each enantiomer can be obtained either from L- or D-serine [434] and the auxiliaries can easily be recovered by methanolysis. Similarly, //-acyl derivatives of 1.121 (X = S) have been used in asymmetric aldol reactions [429, 436], and //-acyl- 1,3-thiazo-lidinethiones 1.123 (X = S, R = r -Pr) are useful in asymmetric acylation [437] and aldol and related reactions [437, 438], Cleavage of the chiral auxiliary is accomplished by aminolysis with O-benzylhydroxylamine or by reduction with LiAlH.,. ... 

Figure 5 Asymmetric aldol reaction catalysed by L-serine with a total ee of 1% in a solid-solution system giving rise to strong asymmetric amplification. Data...

L-Threonine-derived catalysts were demonstrated to be remarkably effective for the direct aldol reaction. Lu et al. investigated the potential of serine and threonine analogs in the direct asymmetric aldol reaction in aqueous medium [28]. While L-serine and L-threonine were found to be ineffective, sUylated threonine and serine derivatives were wonderful catalysts for the direct aldol reaction of cyclohexanone and aromatic aldehydes in the presence of water, affording the aldol adducts in excellent yields and with nearly perfect enantioselectivities. L-Serine-derived 9a was inferior to the corresponding threonine-based catalysts. The reaction could be extended to hydroxyacetone, and sy -diols were obtained with very good enantioselectivities (Scheme 3.6). Subsequently, Teo and coworkers also employed silylated serine catalysts for the same reaction [29]. Very recently, Cordova et al. [30] reported a co-catalyst system consisting of 8a and l,3-bis[3,5-bis(trifluoromethyl)phenyl]thiourea, and applied such catalytic pairs to the direct aldol reaction between ketones and aromatic aldehydes both cyclic and acycUc ketones were found to be suitable substrates. 

Amino acid-derived primary-tertiary diamine catalysts have been used extensively in aldol reactions. Lu and Jiang [34] documented a direct asymmetric aldol reaction between acetone and a-ketoesters catalyzed by an L-serine-derived diamine 17. Sels et al. [35] found that several primary amino acid-based diamines (18) were efficient catalysts for the syn-aldol reaction of linear aliphatic ketones with aromatic aldehydes. Luo and Cheng utilized L-phenylalanine-derived diamine catalyst 15a for the enantioselective syn-aldol reaction of hydroxyl ketones with aromatic aldehydes [36]. Moreover, a highly enantioselective direct cross aldol reaction of alkyl aldehydes and aromatic aldehydes was realized in the presence of 15a (Scheme 3.8) [37]. Very recently, the same group also achieved a highly enantioselective cross-aldol reaction of acetaldehyde [38]. Da and coworkers [39] discovered that catalyst 22, in combination with 2,4-dinitrophenol, provided good activation for the direct asymmetric aldol reaction (Scheme 3.9). 

In the same year, Teo and Chua reported that L-serine fert-butyldiphenylsilyl ether efficiently catalyzed an asymmetric aldol reaction between cycloalkanones and aromatic aldehydes in [bmim][BF4] [40]. The catalyst solution in the IL withstood three recovery cycles however, a progressive decrease of activity caused by the leaching of the siloxy serine catalyst from the IL medium to the ether solution used for extraction of products and a slight decHne of reaction enantioselectivity were recorded. 

Scheme 22.24 Asymmetric aldol reactions catalyzed by IL-tagged serine, threonine, or lysine derivatives.

Asymmetric Mukaiyama aldol reactions in aqueous media [EtOH-H20 (9 1)] were reported with FeCl2 and PYBOX ligands 27a [36] and 27b [37]. The latter provides product 28 with higher yield and diastereo- and enantioselectivity (Scheme 8.9). The ee values given are for the syn-diastereoisomer. Whereas ligand 27a is a derivative ofL-serine, compound 27b has four stereogenic centers, since it was prepared from... 

The similar type of generation of tin(ll) enolate provides a diastereoselective aldol reaction for the asymmetric synthesis of a-substituted serines using Sn(OTf)2/A-ethylpiperizine.243... 

Routes by asymmetric organocatalysis are available to account for the occurrence of chiral molecules on earth. L-proline and L-serine yielded relatively high values of ee in aldol condensations (Cordova et al. 2005). An epimer of a distinct amino acid, for instance, proline or serine, can serve as a catalyst in aldol reactions (Cordova et al. 2005). The percentage of the catalyzing amino acid determines the ee of the reaction product. Thus, the preferred formation of D-ribose compared to that of L-ribose can be accounted for by the intrinsic property of the reaction system with an asymmetric molecule acting as biocatalyst. L-proline has exceptional properties due to its structure, Fig. 3.3. 

The asymmetric total synthesis of the natural enantiomer (—)-nakadomarin A was completed by Nishida et al. in 2004 (Scheme 8.12) [82]. Diels-Alder reaction between siloxydiene 173 and chiral dienophile 172 (prepared from L-serine in 10 steps [83]) gave the highly functionalized key intermediate hydroisoquinoline 174, which was subjected to Luche reduction, cyclization, and HCl treatment to furnish the tricyclic intermediate 175. Compound 175 was converted to 177 via ozonolysis cleavage of ring B followed by recyclization of the unstable bisaldehyde to a five-membered ring by aldol condensation. The Z-olefin 178 was obtained from Wittig reaction of 177, and was further converted to furan 180 via peroxide 179. The... 

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