Asymmetric Strecker amino acid synthesis

Asymmetric Strecker amino acid synthesis Addition of cyanotrimethylsilane catalyzed by ZnCl2 to optically active aldimines formed from 2,3,4,6-tetrapivaloyl-3-D-galactopyranosylamine as the chiral auxiliary can result in either (R)- or (S)-a-aminonitriles, depending on the solvent. THF or isopropanol favors (R)-dia-stereomers, whereas CHC13 favors the (S)-diastereomers. 

The Strecker amino acid synthesis, which involves treatment of aldehydes with ammonia and hydrogen cyanide (or equivalents) followed by hydrolysis of the intermediate a-amino nitriles to provide a-amino acids (Scheme 1), was first reported in 1850 [1], This method has been applied on an industrial scale toward the synthesis of racemic a-amino acids, but more recently interest in nonproteinogenic a-amino acids in a variety of scientific disciplines has prompted intense activity in the asymmetric syntheses of a-amino acids [2]. The catalytic asymmetric Strecker-type reaction offers one of the most direct and viable methods for the asymmetric synthesis of a-amino acid derivatives. It is the purpose of this Highlight to disclose recent developments in this emerging field of importance. 

Iyer, M. S., Gigstad, K. M., Namdev, N. D., Lipton, M. Asymmetric catalysis of the Strecker amino acid synthesis by a cyclic dipeptide. Amino Acids 1996, 11, 259-268. 

Scheme 5. Asymmetric variants of the amino acid synthesis according to Strecker (Bn = Benzyl).

Wang, H., Zhao, X., Li, Y. and Lu, L. (2006) Solvent-controlled asymmetric Strecker reaction stereoselective synthesis of a-trifluoromethylated a-amino acids. Org. Lett., 8, 1379-1381. 

Asymmetric synthesis of a,a-disubstituted a-amino acids via an intramolecular Strecker synthesis using l,4-oxazin-3-one derivatives as key intermediates 97YGK982. 

The importance of chemical syntheses of a-amino acids on industrial scale is limited by the fact that the standard procedure always yields the racemic mixture (except for the achiral glycine H2N-CH2-COOH and the corresponding amino acid from symmetrical ketones R-CO-R). A subsequent separation of the enantiomers then is a major cost factor. Various methods for the asymmetric synthesis of a-amino acids on laboratory scale have been developed, and among these are asymmetric Strecker syntheses as well. ... 

The asymmetric Strecker synthesis of a-amino nitriles from Schiff bases of a-methylbenzyl-aminc is improved by the use of trimethylsilyl cyanide, instead of hydrogen cyanide and by promotion of the transformation with a Lewis acid, preferably zinc chloride43. Thus, from the butyraldimine 2, the amino nitrile is synthesized with a yield of 98.5% and an ee of 68.5%. 

In asymmetric Strecker synthesis ( + )-(45,55 )-5-amino-2,2-dimethyl-4-phenyl-l,3-dioxane has been introduced as an alternative chiral auxiliary47. The compound is readily accessible from (lS,25)-2-amino-l-phcnyl-l,3-propancdioI, an intermediate in the industrial production of chloramphenicol, by acctalization with acetone. This chiral amine reacts smoothly with methyl ketones of the arylalkyl47 or alkyl series48 and sodium cyanide, after addition of acetic acid, to afford a-methyl-a-amino nitriles in high yield and in diastereomerically pure form. 

For a review of asymmetric Strecker syntheses, see Williams, R.M. Synthesis of Optically Active d-Amino Acids, Pergamon Elmsford, NY, 1989, p. 208. 

The addition of cyanide to imines, the Strecker reaction, constitutes an interesting strategy for the asymmetric synthesis of a-amino acid derivatives. Sigman and Jacobsen150 reported the first example of a metal-catalyzed enan-tioselective Strecker reaction using chiral salen Al(III) complexes 143 as the catalyst (see Scheme 2-59). 

Asymmetric Strecker Synthesis of a-Amino Acids via a Crystallization-Induced Asymmetric Transformation Using (/Q-Phenylglycine Amide as Chiral Auxiliary... 

Pll The asymmetric synthesis of a-amino acids and derivatives is an important topic as a result of their extensive use in pharmaceuticals and agrochemicals and as chiral ligands. Many highly enantioselective approaches have been reported. Industrial production of a-amino acids via the Strecker reaction is historically one of the most versatile methods to obtain these compounds in a cost-effective manner, making use of inexpensive and easily accessible starting materials. (From Boesten et al., 2001)... 

As the last example, we present a poster Methods section based on Boesten et al. (2001) concerning the asymmetric Strecker synthesis of an a-amino acid (excerpt 9D and at the end of chapter 2). The poster Methods section presents only... 

Most commonly, a-phenylethylamine is used as chiral amine in the asymmetric Strecker synthesis. Amino acid derivatives have also been used quite successfully as chiral amines. Especially (S)-tert.-butylglycine tert.-butyl ester was proven to be a powerful chiral inductor iM>). The optical yields were as high as 96.5%. The best results were obtained in nonpolar solvents such as n-hexane 140>. 

The asymmetric Strecker synthesis was also applied in the preparation of other chiral products. In these reactions japanese chemists 141> always used amino acid derivatives as the chiral amine component which is responsible for the induction of asymmetry. 

As indicated in Scheme 14, introduction of the rp[CH(CN)NH] peptide bond surrogate into pseudopeptides 28 is carried out via a modified asymmetric Strecker synthesis by the Lewis acid catalyzed reaction of N -protected a-amino aldehydes 26 with a-amino esters 27.11791... 

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