Asymmetrical synthesis of a-amino acids

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. ... 

Abelian T., Chinchilla R., Galindo N., Guillena G., Najera C., Sansano J. M. Glycine and Alanine Imines As Templates for Asymmetric Synthesis of a-Amino Acids Eur. J. Org. Chem. 2000 2689-2697... 

I. Addition of C-Radicals to Nitrones Recently (525), the addition of alkyl radicals to chiral nitrones as a new method of asymmetrical synthesis of a-amino acids has been described. Addition of ethyl radicals to glycosyl nitrone (286) using Et3B as a source of ethyl radicals appears to proceed with a high stereo-control rate. 

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). 

T. Ooi, M Kameda, K Maruoka, Molecular Design of a C2-Symmetric Chiral Phase-Transfer Catalyst for Practical Asymmetric Synthesis of a-Amino Acids , J. Am Chem Soc, 1999,121, 6519-6520. 

Asymmetric Synthesis of a-Amino Acids by the Alkylation of Pseudoephedrine Glycinamide. Preparation of L-Allylglycine and N-Boc L-Allylglycine. 

Gu, R.-L., Lee, I.S. and Sih, C.J., Chemo-enzymatic asymmetric synthesis of amino acids. Enantioselective hydrolyses of 2-phenyl-oxazolin-5-ones. Tetrahedron Lett., 1992, 33, 1953-1956 Crich, J., Brieva, R., Marquart, P., Gu, R.-L., Flemming, S. and Sih, C.J., Enzymic asymmetric synthesis of a-amino acids. Enantioselective cleavage of 4-substituted oxazolin-5-ones and thiazolin-5-ones. J. Org. Chem., 1993, 58, 3252-3258. 

The diastereofacial selective imine-ene reactions with a-imino esters prepared from (—)-8-phenylmenthyl glyoxylate have provided an efficient entry to the asymmetric synthesis of a-amino acids, and a Lewis acid-mediated intramolecular imine-ene reaction has been used for the key spirocyclization step in a recent synthesis of (—)-perhydrohistrionicotoxin. Asymmetric azo-ene reactions have been effected using the chiral azo-enophile, di-(—)-(lR,2S)-2-phenyl-l-cyclohexyldiazenedicarboxylate. ... 

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)... 

An asymmetric synthesis of a-amino acids uses the alkylation of glycine enolates by mixed sulfates, e.g., methyl 1,2 5,6-di-O-isopropylidene-a-D-glucofuranose 3-sulfate, bearing a chiral leaving group1 13-15. 

Bycroft and Lee (75CC988) developed this into a general method for the asymmetric synthesis of a-amino acids, wherein the chiral auxiliary (L-proline) could be recovered and recycled. Condensation of L-proline methyl ester with a-keto acids using DCC, followed by a treatment with anhydrous ammonia at room temperature, gave the 3-hydroxypiperazine-2,5-diones with high stereoselectivity (cf. Scheme 79). These could be... 

In 1989, O Donnell and coworkers successfully utilized cinchona alkaloid-derived chiral quaternary ammonium salts for the asymmetric synthesis of a-amino acids using tert-butyl glycinate benzophenone Schiff base 1 as a key substrate [5]. The asymmetric alkylation of 1 proceeded smoothly under mild phase-transfer... 

Figure4.9 The selected highly efficient dimeric PTCsforthe asymmetric synthesis of a-amino acids.

The facile asymmetric synthesis of a-amino acids usually inaccessible by enzymatic processes becomes feasible by employing appropriate electrophiles such as ortho-disubstituted benzyl bromides. In the reaction with simple alkyl halides such as ethyl iodide, the use of aqueous cesium hydroxide (CsOH) as a basic phase at a lower reaction temperature is generally recommended [7e]. 

Maruoka and coworkers also investigated the substantial reactivity enhancement of N-spiro chiral quaternary ammonium salt and simplification of its structure, the aim being to establish a truly practical method for the asymmetric synthesis of a-amino acids and their derivatives. As ultrasonic irradiation produces homogenization (i.e., very fine emulsions), it greatly increases the reactive interfacial area, which may in turn deliver a substantial rate acceleration in the liquid-liquid phase-transfer reactions. Indeed, sonication of the reaction mixture of 2, methyl iodide and (S,S)-lc (1 mol%) in toluene-50% KOH aqueous solution at 0 °C for 1 h gave rise to the corresponding alkylation product in 63% yield with 88% ee. Hence, the reaction was speeded up markedly, and the chemical yield and enantioselectivity were comparable with those of the reaction with simple stirring (0°C for 8h 64%, 90% ee) (Scheme 5.5) [10]. 

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. 

A novel asymmetric synthesis of a-amino acids via electrophilic amination has been demonstrated by Zheng and Armstrong and co-workers.94 No +NHBoc was observed when lithium tert-butyl-A-tosyloxycarbamate (LiBTOC) was reacted with zinc and lithium enolates of 48. Transmetallation of the lithium enolate with copper cyanide was necessary to generate a reactive amide cuprate, which then added efficiently to the electrophile. The electrophilic amination of chiral cuprates with LiBTOC provided an expedient approach to a-amino acids with predictable absolute configuration in high enantiomeric purity and good yield (Scheme 24.23). 

Serine hydroxymethyltransferase is a PLP-dependent aldolase. It catalyzes interconversion between glycine and various P-hydroxy-a-amino acids, such as serine and threonine, via formation of a quinoid intermediate derived from PLP with the amino acid substrate (Scheme 2.9). This aldolase-type reaction is of interest as an asymmetric synthesis of a-amino acids via C-C bond formation. 

An even more efficient asymmetric synthesis of a-amino acid derivatives has been described by the Monsanto group (20a-e). They have found that chiral o-anisylcyclohexylmethylphosphine (ACMP) (II), like DIOP, exerts an extra-... 

Scheme 6. Asymmetric synthesis of a-amino acids bearing a quaternary stereo-genic center...

Ooi T, Kameda M, Maruoka K (2003) Design of N-spiro C2-symmetric chiral quaternary ammonium bromides as novel chiral phase-transfer catalysts synthesis and application to practical asymmetric synthesis of a-amino acids. J Am Chem Soc 125 5139-5151... 

Agami, C. Couty, R Puchot-Kadouri, C. Asymmetric Synthesis of a-Amino Acids from a Chiral Masked Form of Glyoxal, Synlett 1998,449-456. 

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