Stereoinversion, amino acids

Scheme 2.23 Stereoinversion of P-substituted a-amino acids using a combination of d-AAO and sodium borohydride.

In Section 5.3.1, chemoenzymatic cyclic deracemizations or stereoinversions are categorized according to the type of substrate, namely amino acids, hydroxy acids,... 

Maerkle W, Liitz S (2008) Electroenzymatic strategies for deracemization, stereoinversion and asymmetric synthesis of amino acids. Electrochim Acta 53 3175-3180... 

Deracemization by Stereoinversion via the Two-enzyme System D-Amino Acid Oxidase and L-Amino Transferase... 

A combination of D-amino acid oxidase and L-amino transferase is an example of a deracemization by stereoinversion. The product is an L-amino acid. The reaction catalyzed by amino transferase has an equilibrium constant close to unity, a very unpractical situation leading to uncomplete transformation and to the production of almost inseparable mixtures of amino acids (at least two, the amino acid product and the amino add used as an amino donor). For preparative purposes it is therefore mandatory to shift the equihbrium to the product side. A recent example of a deracemization procedure based on this coupled enzymatic system is the preparation of L-2-naphthyl-alanine 6 as illustrated in Scheme 13.9 [28]. The reaction occurs in one pot with initial oxidation of the D-amino acid catalyzed by D-amino acid oxidase from Rhodotonda gracilis. The hydrogen peroxide that is formed in stoichiometric amounts is decomposed by catalase. The a-keto add is the substrate for L-aspartate amino transferase (L-Asp amino transferase), which is able to use L-cysteine sulfinic acid 7 as an amino donor. 

Deracemization by Stereoinversion via the Three-enzyme System i-Amino Acid Oxidase, D-Amino Transferase and Amino Add Racemase... 

Scheme 13.11 Deracemization by stereoinversion finalized to the preparation of D-amino acids.

Enzymatic oxidations of carbon-nitrogen bonds are as diverse as the substances containing this structural element. Mainly amine and amino acid oxidases are reported for the oxidation of C-N bonds. The steroespecificity of amine-oxidizing enzymes can be exploited to perform resolutions and even deracemizations or stereoinversions (Fig. 16.7-1 A). Analogous to the oxidation of alcohols, primary amines are oxidized to the corresponding imines, which can hydrolyze and react with unreacted amines (Fig. 16.7-1 B). In contrast to ethers, internal C-N bonds are readily oxidized, yielding substituted imines. This can be exploited for the production of substituted pyridines (Fig. 16.7-1 C). Furthermore, pyridines can be oxidized not only to N-oxides but also to a-hydroxylated products (Fig. 16.7-1 D). 

The term deracemization covers reactions in which two enantiomers are inter-converted by a stereoinversion process such that a racemate can be transformed to a non-racemic mixture without any net change in the composition of the molecule. Deracemization reactions usually involve a redox process, for example, the interconversion of chiral secondary alcohols via the ketone or alternatively the interconversion of amino acids/amines via the corresponding imine (Scheme 4.37). 

Beard, T.M. and Turner, N ). (2002) Deracemisation and stereoinversion of alpha-amino acids using D-amino acid oxidase and hydride reducing agents. Chem. Commun. (Cambridge, UK), (3), 246-247. 

For example, n-p-hydroxyphenylglydne, a key intermediate in the synthesis of semisynthetic cephalosporins and penicillins, is currently manufactured on a multi-thousand ton scale. The hydantoinase-catalysed reaction is also suitable for the production of unnatural D-amino acids, although the in situ racemization of the remaining substrate via keto-enol tautomerization is generally slow. To facilitate the stereoinversion, base or hydantoin racemase of Pseudomonas and Arthrobacter strains is often used. 

Stereospecific nitrilases were used for the conversion of a-arninonitiiles to optically active L-amino acids (Fig. 4). In an early investigation, L-alanine was formed by an l-specific nitrilase from alginate-immobilized cells of Acinetobacter sp. APN [25]. A decrease of the enantioselectivity with the time was supposed to be caused by a racemase forming d- from L-alanine. The stereoinversion of racemic a-aminopropionitrile led to a conversion yield above 50%. Similar L-a-amino acid preparations showed no stereoinversion and additionally accumulated the D-amide due to the presence of a nitrile hydratase/ amidase system [26,27]. Additionally, a number of L-a-amino acids were synthesized by a 45-kDa monomeric nitrilase from R. rhodochrous PA-34 [28]. Remarkable in this case was the preferential hydrolysis of a-aminopropionitrile to D-alanine in contrast to the l-alanine formation by the Acinetobacter nitrilase (Fig. 4). 

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