A deracemization

Relatively little attention has been paid to the conversion of racemic compounds into their enantiomerically pure versions in a single process, in other words a deracemization. For certain classes of chiral compounds such as secondary alcohols, this approach should provide many benefits, particularly to the pharmaceutical industry. Existing routes to high value intermediates in their racemic form may be modified to provide the equivalent homochiral product, thus reducing the extent of development chemistry required. In addition, the... 

The results actually showed a deracemization of the racemic hydroxyester 10 as opposed to enantioselective hydrolysis with formation of optically pure (R)-hydroxyester 10 and only 20 % loss in mass balance. Small quantities of ethyl 3-oxobutanoate 9 (<5%) were also detected throughout the reaction, leading the authors to suggest a multiple oxidation-reduction system with one dehydrogenase enzyme (DH-2) catalysing the irreversible reduction to the (R)-hydroxy-ester (Scheme 5). 

For instance, styrene oxide was resolved by whole cells of Aspergillus niger and Beauveria bassiana via two different pathways showing matching enantio- and regioselectivities with excellent results (Scheme 8). Combination of the two biocatalysts employing a deracemization process in a single reactor led to R) phenylethane-l,2-diol as the sole product in 98% ee and 85% isolated yield [58]. 

Recently, Turner et al. described the synthesis of the alkaloid (R)-(-t-)-crispine A, which shows cytotoxic activity against HeLa human cancer cell lines, using in the final step a deracemization procedure with the combination of an enantioselective amine oxidase obtained by directed evolution methods and a chemical non-selective reducing agent (Scheme 10.20) [48]. 

Chiral 2,2-disubstituted cycloalkanones.1 The imine 2 prepared from racemic 2-methylcyclohexanone and (S)-( - )-l, reacts with methyl vinyl ketone to form an adduct that is hydrolyzed to the (R)-( + )-diketone 3 in 91% ee with recovery of 1 in almost quantitative yield. The reaction is described as a deracemizing alkylation. ... 

E.3.2.1. Deracemization of Acyclic Substrates When chiral allylic substrates generate meso 71-allyl intermediates, the two allylic termini of such intermediates are enantiotopic. Thus, enantioselectivity is derived from the regiochemistry of the nucleophilic addition (a vs. b), and the alkylation process corresponds to a deracemization event (Eq. 8E,2). One of the prototypical reactions, which has been studied in extensive detail, is the 1,3-diphenylallyl system. Since its introduction as a different mechanistic motif in contrast with the 1,1,3-triphenylallyl system, this reaction has become a benchmark for design and comparison of a variety of different ligands in recent years [73]. 

The use of a chiral nucleophile in a deracemization reaction creates the issue of double stereodifferentiation. The ability of a chiral ligand to dictate the regiochemistry with respect to the Jl-allylpalladium intermediate (which corresponds to the diastereoselectivity in this case) is affected by the stereochemistry of the nucleophile either in a matched or mismatched fashion. 

Unhke a kinetic resolution process, where in principle both enantiomers of the same compound can be obtained, a deracemization process gives access to one single enantiomer. The possibihty of securing the enantiomer of opposite configuration depends on the availability of the enzymes involved frequently enzymes with complementary stereopreferences are not available. 

Microbial stereoinversion consists of a deracemization process in which a single whole cell system is applied for the two-step inversion of the configuration of one enantiomer, usually a compound containing a secondary alcohol group. Examples of a two-enzyme system is known for deracemization of mandelates where a single microorganism is used [18]. 

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. 

In enantioselecdve protonations, the final optically active product is generally chemically identical to the starting racemic material, precursor of the prochiral substrate on which the protonation is carried out. That is why the term deracemization was proposed for this type of process. In a deracemization, the protonation... 

Woodward probably conducted the most outstanding work on iminium catalysis before its rebirth in 2000. In this work. Woodward applied proUne catalysis in a triple organocascade reaction consisting of a deracemization (via aretro-Michael, Michael addition) and an intramolecular aldol reaction that determine the stereochemical outcome of the reaction (Scheme 1.5), leading to the synthesis of erythromycin [13]. 

Deracemization via Biocatalytic Stereoinversion. Racemic secondary alcohols may be converted into a single enantiomer via stereoinversion which proceeds through a two-step redox sequence (Scheme 2.130) [38, 941, 942] In a first step, one enantiomer from the racemic mixture is selectively oxidized to the corresponding ketone while the other enantiomer remains unaffected. Then, the ketone is reduced in a second subsequent step by another redox-enzyme displaying opposite stereochemical preference. Overall, this process constitutes a deracemization technique, which leads to the formation of a single enantiomer in 100% theoretical yield... 

The kinetic resolution of amines was exploited first with co-TAs since the reaction is thermodynamically favored using pyruvate as acceptor [21]. Unfortunately, the inherent maximum 50% yield limits the practical applications of this approach and, therefore, will nof be considered in fhis confribufion. Thus, the other methodologies (stereoselective synthesis and deracemization) are preferred since a theoretical yield of 100% is possible. The asymmefric amination allows fhe preparation of enantiomer-ically pure amines at the expense of an amine donor, usually an amine or an AA (Scheme 2.2b). On the other hand, the combination of two stereocomplementary co-TAs enables to establish a deracemization process (Scheme 2.2c). Deracemization strategies are recommended when amines are readily available or the corresponding carbonyl compounds lack stability. 

Turner et al. first reported engineered S-stereoselective flavin-dependent monoamine oxidase variants bom Aspergillus niger for the deracemization of racemic amines producing the S-enantiomers of primary, secondary, and tertiary amines (Figure 19.8) [35]. On the other hand, Leisch et al. showed that wild-type cyclohexy-lamine oxidase from Brevibacterium oxydans IH-35A, which had been isolated and characterized by Hasegawa et al., oxidized the S-enantiomer of amines and successfully synthesized (f )-amine through a deracemization reaction [37]. 

We described the development of a valuable l -stereoselective amine oxidase for the synthesis of (S)-amine through a deracemization reaction [38]. 

Flafner et al first reported an oxidase-catalyzed deracemization method using amino acids as the substrate and pkDAAOx or LAAOx from Crotalus adamanteus together with sodium borohydride as the chemical reductant in 1971 [42]. A procedure for the successful deracemization of amino acids was previously reported by Soda et al. [43]. They focused on proline and pipecolic acid as substrates for the production of L-enantiomer by deracemization because these substrates formed stable imines rather than unfavorable keto acids in water by DAAOx. However, the enzyme was denatured by the chemical reaction with sodium borohydride. Turner et al developed an effective production method for (R)- or (S)-amino acids and (S)-amines by a deracemization method using milder chemical reducing reagents such as sodium cyanoborohydride and artificial transfer hydrogenase [44,45]. 

A deracemization reaction, the transformation of racemic compounds into chiral forms in one pot without changing their chemical structures, has been performed using a... 

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]. 

---