Amino deracemization

Figure 5.4 Deracemization of a-amino acids using D-amino acid oxidase in combination with sodium borohydride.

Recently Turner and coworkers have sought to extend the deracemization method beyond a-amino acids to encompass chiral amines. Chiral amines are increasingly important building blocks for pharmaceutical compounds that are either in clinical development or currently licensed for use as drugs (Figure 5.7). At the outset of this work, it was known that type II monoamine oxidases were able to catalyze the oxidation of simple amines to imines in an analogous fashion to amino acid oxidases. However, monoamine oxidases generally possess narrow substrate specificity and moreover have been only documented to catalyze the oxidation of simple, nonchiral... 

Figure 14.6 Enzymatic deracemization concepts for production of chiral alcohols, amines and amino acids...

Fotheringham, I., Archer, I., Carr, R. et al. (2006) Preparative deracemization of unnatural amino acids. Biochemical Society Transactions, 34 (2), 287-290. 

The use of D-AAO from the yeast Rhodotorula gracilis to deracemize naphthyl amino acids has been studied in some detail by the groups of Servi and Pollegioni, who compared the kinetic properties of the enzyme with racemic 1- and 2-naphthylalanine (1 and 2) and 1- and 2-naphthylglycine (3 and 4). 

The same group have used the enzyme combination employed in the aspartate deracemization cited above to deracemize 2-naphthylalanine, hut have made use of an interesting innovation introduced by Helaine et al to pull over the poised equilibrium of the transamination reaction. Cysteine sulphinic acid was used as the amino donor in the transamination. The oxoacid product spontaneously decomposes in to pyruvic acid and SO2 (Scheme 3). 

Chemoenzymatic processes involving oxidizing enzymes have been reported particularly for specific chemical syntheses. For example, industrially important amino acids can be deracemized by exploiting the enantioselectivity of amino acid oxidases a commercial process has recently been developed in which efficient... 

An elegant four-enzyme cascade process was described by Nakajima et al. [28] for the deracemization of an a-amino acid (Scheme 6.13). It involved amine oxidase-catalyzed, (i )-selective oxidation of the amino acid to afford the ammonium salt of the a-keto acid and the unreacted (S)-enantiomer of the substrate. The keto acid then undergoes reductive amination, catalyzed by leucine dehydrogenase, to afford the (S)-amino acid. NADH cofactor regeneration is achieved with formate/FDH. The overall process affords the (S)-enantiomer in 95% yield and 99% e.e. from racemic starting material, formate and molecular oxygen, and the help of three enzymes in concert. A fourth enzyme, catalase, is added to decompose the hydrogen peroxide formed in the first step which otherwise would have a detrimental effect on the enzymes. 

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

Scheme 5.35 Chemo-enzymatic deracemization of cyclic amino acids.

Deracemization of acyclic amino acids is more difficult than that of cyclic ones because of the higher instability of the imino acid intermediates toward hydrolysis (Scheme 5.36). 

Similarly to the case of amino acids, hydroxy acids can also be deracemized by combining an enantioselective oxidation with a non-enantioselective reduction with sodium borohydride. For example, the group of Soda has reported the transformation of DL-lactate into D-lactate in >99% (Scheme 5.38) [78]. 

Turner has applied this deracemization process to a very interesting tandem transformation where y-amino ketones are transformed into enantiopure secondary amines via intramolecular reductive animation followed by deracemization (Scheme 5.41) [80]. 

Biocatalytic deracemizations of amino acids and hydroxy acids have also been reported [83]. 

An application of the deracemization strategy has provided efficient entry to a novel amino acid substituent of the antifungal agents, polyoxins and nikkomycins, as shown in Scheme 8E.20. The versatile five-carbon building block was obtained from phthalimidation of the hydroxymethyl-substituted epoxide in 87% yield and 82% ee. Straightforward synthesis of polyoxamic acid was then accomplished by subsequent dihydroxylation and selective oxidation of the alkylation product. 

Scheme 8E.29. Deracemization of isoprene monoepoxide with a-amino ester.

Deracemization of amino-acids One-pot h2o NaCNBH3 or NaBE, Amino acid oxidase 2,7,14... 

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

Kroutil, W., and Faber, K. 1998. Deracemization of compounds possessing a sec-alcohol or -amino group through a cyclic oxidation-reduction sequence a kinetic treatment. Tetrahedron Asymm., 9(16), 2901-2913. 

In this chapter deracemization methods for the preparation of multifunctional compounds (a- and P-hydroxy acids, a-hydroxynitriles, and a-amino acids) are discussed (Scheme 13.1). 

The method is similar to the deracemization of a-amino acids (see Section... 

In a conceptually related method, the oxidation of the L-lactate is catalyzed by the commercially available L-specific lactate oxidase from Aerococcus viridans and the reduction of pyruvate to rac-lactate is performed with NaBH4 in the same solution. In repeating cycles D-lactate 5 is obtained as the sole product and in an excellent e.e. [16] (Scheme 13.6). This concept has recently been applied to the deracemization of a-amino acids [17]. 

For several reasons a-amino acids are ideal substrates for deracemization methods. They racemize easily by base catalysis under a number of conditions and they are racemized in Nature by the intervention of specific amino acid racemases. They are also recognized as substrates by oxidative enzymes to give the corresponding oxo-acids, in turn substrates for amino transferases and amino acid dehydrogenases. Several industrial preparations of L- and D-amino acids are based on processes of deracemization [26] or of separate two-steps resolution-racemization [27]. 

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