Functionally a-amino

E. J. Corey, M. C. Noe, F. Xu, Highly Enantioselective Synthesis of Cyclic Functionalized a-Amino Acids by Means of a Chiral Phase Transfer Catalyst , Tetrahedron Lett. 1998, 39, 5347-5350. 

Bienz et al. have prepared functionalized a-amino acids containing Si that are derivatives of serine and methionine.191 Saturated and unsaturated 7-trialkylsilyl-substituted a-amino acid derivatives 30-35 have been prepared stereoselectively by Reginato et a/.192 193 The synthetic approach involves a silylcupration of chiral-protected 4-ethynlyloxazolidine (Scheme 5). 

Scheme 3.17. Synthesis of functionalized a-amino acids by silylcupration [72a] or stannylcupration [81c] of chiral propargyl amines (Boc = t-butoxycarbonyl TFA = trifluoroacetic acid).

Variants of the PTC Michael reaction have been successfully applied for a variety of chemical transformations, including the synthesis of functionalized a-amino acids (Scheme jjjg addition... 

By ozonolysis and subsequent in situ acylation in the presence of base, the enantiopure 1,2-oxazine 177 (R = Bn) was converted to the highly functionalized a-amino-/ -hydroxy ester 181 along with a minor product 5-hydroxylated oxazine 182 <2005EJ0998>. Similarly, D-erythrose-derived syn- and 7 // -compounds 183 afforded the expected diastereomeric syn- and /f-oxazine esters 184 and 5-hydroxylated oxazine 185 <2005EJ0998>. The arbinose-derived anti-configured 1,2-oxazine 186 was subjected to an ozonolysis/elimination sequence which provided the desired functionalized a-amino ester 187 in 75% yield. 

An interesting extension of this Mannich reaction was reported very recently by the Barbas group [26]. An a-imino glyoxylate 33 was used as a (preformed imine) starting material. The corresponding Mannich reaction furnished directly functionalized a-amino acids of type (S)-34 (see also the selected example in Scheme 5.15) which are difficult to synthesize by other synthetic routes. 

In conclusion, this new organocatalytic direct asymmetric Mannich reaction is an efficient means of obtaining optically active //-amino carbonyl compounds. It is worthy of note that besides the enantioselective process, enantio- and diastereose-lective Mannich reactions can also be performed, which makes synthesis of products bearing one or two stereogenic centers possible. Depending on the type of acceptor or donor, a broad range of products with a completely different substitution pattern can be obtained. The range of these Mannich products comprises classic / -amino ketones and esters as well as carbonyl-functionalized a-amino acids, and -after reduction-y-amino alcohols. 

Fernandez-Megia, E. Iglesias-Pintos, J. M. Sardina, F. J. Enantiomerically pure highly functionalized a-amino ketones from the reaction of chiral cyclic N-(9-phenylfluorenyl)... 

The corresponding /i-amino aldehydes are reduced in situ and the corresponding amino alcohols are isolated in good yield with up to >99 % ee. The Mannich reactions proceed with excellent chemoselectivity and inline formation occurs with the acceptor aldehyde at a faster rate than C-C bond-formation. Moreover, the one-pot three-component direct asymmetric cross-Mannich reaction enables aliphatic aldehydes to serve as acceptors. The absolute stereochemistry of the reaction was determined by synthesis and reveled that L-proline provides syn /i-amino aldehydes with (S) stereochemistry of the amino group. In addition, the proline-catalyzed direct asymmetric Mannich-type reaction has been connected to one-pot tandem cyanation and allylation reaction in THF and aqueous media affording functional a-amino acid derivatives [39, 42]. 

Cordova, A., Nots, W., Zhong, G., et al. (2002) A highly enantioselective amino acid-catalyzed route to functionalized a-amino acids. J. Am. Chem. Soc., 124, 1842-1843. 

The method described above has been used by Corey to functionalize a-amino acid derivatives [87], iV-Phthaloyl-a-amino acid amides of 8-aminoquinoline can... 

Chinchilla, R., Najera, C. and Sanchez-Agullo, P. (1994) Enantiomerically pure guanidine-catalysed asymmetric nitroaldol reaction. Tetrahedron Asymmetry, 5, 1393-1402 Ma, D. and Cheng, K. (1999) Enatioselective synthesis of functionalized a-amino acids via a chiral guanidine-catalysed Michael addition reaction. Tetrahedron Asymmetry, 10, 713. 

Michael addition is one of the most efficient and effective routes to C-C bond formation[127]. This reaction is widely applied in organic synthesis and several new versions of it have been introduced recently. The commonly employed anionic alkyl synthons for Michael addition are those derived from nitroalkanes, ethyl cyanocarboxylates, and malonates, and their limitations have been largely overcome by newer methodologies. However, the newer approaches are by no means devoid of drawbacks such as long reaction times, modest product yields in many cases, and the requirement for excess nitroalkane. Michael addition reactions of Schiff s bases have long been known to constitute a convenient method for functionalizing a-amino esters at the a position and the ratio of Michael addition to cycloaddition product has been found to depend upon the metal ion employed to chelate the enolate produced upon deprotonation (see below). 

F. Pan, J.-M. Chen, Z. Zhuang, Y.-Z. Fang, S. X.-A. Zhang, W.-W. Liao, Org. Biomol. Chem. 2012, 10, 2214—2217. Construction of highly functional a-amino nitriles via a novel multicomponent tandem organocatalytic reaction a facile access to a-methylene y-lactams. 

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