Amino acid derivatives enantioselective organocatalytic

An important issue is the right choice of substrate 1 which functions as an anion precursor. Successful organocatalytic conversions have been reported with indanones and benzophenone imines of glycine derivatives. The latter compounds are, in particular, useful for the synthesis of optically active a-amino acids. Excellent enantioselectivity has been reported for these conversions. In the following text the main achievements in this field of asymmetric organocatalytic nucleophilic substitutions are summarized [1, 2], The related addition of the anions 2 to Michael-acceptors is covered by chapter 4. 

The use of benzophenone imines of glycine derivatives [19] as substrates in enantioselective organocatalytic alkylation has been developed toward an excellent method for preparation of a wide range of optically active a-amino acids with high enantioselectivity [1, 20],... 

Apart form a great number of chiral NHC carbenes that have been used as ligands in enantioselective transition-metal catalysis (Gade and Bellemin-Laponnanz 2007), some less usual heterazolium salts have been tested in organocatalytic transformations. A planar-chiral thia-zolium salt (Pesch et al. 2004) and a rotaxane-derived precatalyst were reported (Tachibana et al. 2004), as well as catalytically active peptides containing an unnatural thiazolium-substituted alanine amino acid (Fig. 3 Mennen et al. 2005a,b). 

Other successful asymmetric organocatalytic cycloadditions were developed in the last year, such as a three-component asymmetric 1,3-dipolar cycloaddition between aldehydes, amino esters and dipolarophiles, which was catalysed by a new biphosphoric acid derived from (i ,/ )-linked BINOL, furnishing multiply substituted pyrrolidines in high yields and with exeellent enantioselectivities of up to 99% ee. In addition, a new class of chiral bifunctional thiourea catalysts derived from traTO-2-amino-l-(diphenylphosphino)cyclohexane was applied to a highly enantioselective synthesis of a wide range of 2-aryl-2,5-dihydropyrrole derivatives on the basis of a [3 -b 2] cycloaddition between an A-phosphinoyl imine and an allene, providing high yields combined with excellent enantioselectivities of up to 98%. 

The 3 + 2-cycloaddition reaction of azomethine ylides with c-deficient alkenes produced polysubstituted l- and D-unnatural prolines. Also, phosphoramidite-(7u(OTf)2 complexes catalyse the 1,3-dipolar cycloaddition reactions of azomethine ylides with nitroalkenes to yield exo-tetrasubstituted proline esters." The 1,3-dipolar cycloaddition of non-stabilized azomethine ylides, from iV-alkyl-a-amino acids and aldehydes, with 3-substituted coumarins provides l-benzopyrano[3,4-c]pyrrolidines in good yields and high regio- and stereo-selectivity." The organocatalytic 1,3-dipolar cycloaddition of azomethine ylides, derived from azlactones, with methyleneindolinones produced spirooxindoles with high yields (up to 95%) and high diastereo- (93 7 dr) and enantioselectivity (98% ee). ... 

Efficient and versatile organocatalytic, asymmetric reactions of a-isothiocyanato phosphonate (595) with aromatic and cinnamyl aldehydes or AT-tosylimines have been successfully applied in synthesis of p-hydroxy-a-amino phosphonates (596) and a,p-diamino phosphonates (587) (Scheme 173). The described strategy provided a new route for highly enantioselective (up to >99% ee) functionalisation of a-phosphonic acid derivatives (595). ° ... 

Although natural amino acids are readily available, there is a continuing need for unnatural amino acids. Jon C. AntiUa of the University of South Florida has described J. Am. Chem. Soc. 2007,129, 5830) a promising approach, based on the enantioselective organocatalytic reduction of imines such as 1 derived from a-keto esters. The aryl group is easily removed to give the primary amine. 

During the study on enantioselective organocatalytic reductive amination, MacMillan et al. found that the pyruvic acid-derived cyclic imino ester could be efficiently reduced to yield the corresponding alanine amino ester with 97% ee and 82% yield... 

Two years later, Terada and coworkers described an asymmetric organocatalytic aza-ene-type reaction (Scheme 28) [50], BINOL phosphate (7 )-3m (0.1 mol%, R = 9-anthryl) bearing 9-anthryl substituents mediated the reaction of A-benzoylated aldimines 32 with enecarbamate 76 derived from acetophenone. Subsequent hydrolysis led to the formation of P-amino ketones 77 in good yields (53-97%) and excellent enantioselectivities (92-98% ee). A substrate/catalyst ratio of 1,000 1 has rarely been achieved in asymmetric Brpnsted acid catalysis before. 

A similar scenario has been demonstrated by Najera et al. to support the bifunc-tional Br0nsted acid-base organocatalytic character and the origin of the observed enantioselectivity achieved by protonated 2-aminobenzimidazol-derived catalyst 163 in the conjugate addition of malonates and 1,3-diketones to nitroolefins [251]. DFT calculations have shown that the lowest energy transition state corresponds to the addition of the malonate or diketone to the electrophile with activation of the nucleophile by formation of two hydrogen bonds with the amino-benzimidazole moiety and activation of the nitroolefin better achieved by the protonated tertiary amine (C, Fig. 2.19). 

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