Oxidation, deracemization resolution

The electrochemical reduction of mono- and bis(acyl)phosphine oxides was observed to lead to the corresponding radical anions/ In the field of optically active phosphine oxides, the resolution of l-butyl-3-methyl-3-phospholene oxide with TADDOL derivatives was described/ The preparation of the enantiomers of BINAP and its derivatives was summarized in a review/ The deracemization of tert-butyl-phenylphosphine oxide using dibenzoyltartaric acid afforded one enantiomer in a configurationally stable form, in contrast to suggestions in the literature and to general opinion. The enantiomer of the secondary phosphine oxide was utilized in the preparation of a-hydroxyphosphine oxides (Scheme 64). The adducts were obtained in >95% ee and in >95% de. °... 

AAOs have also been coupled with other enzymes, like amino transferases, in order to achieve an alternate deracemization process. For example, a racemic a-AA with a bulky heterobiaryl residue was converted to the (S)-enantiomer by combination of an oxidative kinetic resolution performed by the d-AAO from Trigonopsis variabilis and an (o-TA from Burkholderia sp. (Scheme 2.31). A conversion of 85% after 22 h led to 72% isolated product yield widi an excellent stereoselectivity (>99.5% ee). 

Scheme 8. Resolution and deracemization of styrene oxide by fungal cells... 

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]. 

Fig. 20. Resolution of styrene oxide by A. niger and B. sulfurescens epoxide hydrolases. Deracemization of styrene oxide by using a mixture of these two fungi [175]...

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). 

Oxidations of C-N bonds with synthetic relevance. A kinetic resolution, deracemization and stereoinversion (Sects. 16.7.2.1 and 16.7.3.1) ... 

Simple racemate resolutions have a maximal yield of 50% for the desired compound. Furthermore, additional (potentially laborious) separation steps are necessary. As a consequence, alternative processes that involve the stereoinversion of the undesired enantiomer are gaining increasing interest 201. One approach for these so-called deracemization processes is to reconvert the oxidation product either enzymatically (Fig. 16.7-8) or chemically (Fig. 16.7-9) to the racemic substrate. 

Scheme 2.95 Microbial resolution and deracemization of styrene oxide...

In a similar dynamic kinetic resolution method, the DAAO from Rhodotorula gracilis was recently combined in a one-pot reaction with i-aspartate amino transferase (l-AAT) from Escherichia coli and used for the deracemization of racemic 2-naphthylalanine (DL-2-NAla) (Scheme 11.13b). After the oxidation of the D-amino acid catalyzed by DAAO, the formed 2-naphthyl pyruvate (2-NPA) served as a substrate of l-AAT in the presence of cysteine sulfinic acid (CSA) as an amino donor. Almost quantitative yields of the enantiomerically pure t-2-NAla were achieved by using this cascade reaction, thanks to the spontaneous degradation of the 3-keto sulfinic acid produced in the t-AAT-catalyzed transamination that drives the overall reaction equilibrium toward the desired direction [26]. 

The synthesis of chiral amines using co-TA can be performed by three different pathways (Scheme 2.2) [19] (i) kinetic resolution of amines by oxidative deamination, (ii) stereoselective synthesis via amination of prochiral ketones, and (iii) deracemization combining (i) kinetic resolution and (ii) stereoselective synthesis [19]. 

Even though the catalyhc (enz5unatic) kinetic resolution [103,104] is in general a powerful method for the separation of enantiomers, the major drawback lies in the limitation of 50% maximum yield from the outset [99]. In order to gain more than 50% product 5deld, alternative techniques based on the asymmetric transformation of a prochiral substrate, DKR [105,106] or deracemization, were established successfully [84,86,107-110]. The latter mentioned technique is either based on the combination of two enantiocomplementary enzymes or by coupling a stereoselective oxidation with a nonstereoselective reduction. This concept is rather powerful as theoretically only seven catalytic cycles are necessary to achieve a single enantiomer in >99% yield [111]. 

Aspergillus niger was the biocatalyst of choice for the biohydrolysis of para-nitro-styrene oxide. A selective kinetic resolution using a crude enzyme extract of this fungus, followed by careful acidification of the cooled crude reaction mixture, afforded the corresponding (/ )-diol in high chemical yield (94%) and good e.e. (80%) via a deracemization protocol. This key intermediate was then transformed via a four-step sequence (Scheme 21) into enantiopure (i )-nifenalol, a molecule with beta blocker activity, which was obtained in 58% overall yield [120]. 

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