Cascade redox neutral

Resch, V., Fabian, W.M.F., and Kroutil, W. (2010) Deracemisation of mandelic acid to optically pure non-natural L-phenylglycine via a redox-neutral biocatalytic cascade. Adv. Synth. Catal., 352 (6), 993-997. 

Scheme 37 Brpnsted acid-catalyzed redox-neutral indole annulation cascades...

Scheme 4.6 Redox-neutral biocatalytic transamination cascade to transform primary (R=H) and secondary alcohols (RAH) to the corresponding primary amines. AlaDH, alanine dehydrogenase.

The feasibility of this redox-neutral cascade was initially demonstrated for various primary alkyl and aryl alcohols (50 mM substrate concentration), affording the corresponding products in moderate to excellent yield the alcohols 1-hexanol... 

Scheme 4.7 Redox-neutral biocatalytic oxidation-transamination cascade to provide primary diamines starting from the corresponding diols. AlaDH, alanine dehydrogenase.

Table 4.2 Selected results of the redox-neutral oxidation-transamination cascade using enantiopure and racemic secondary alcohols as substrate (Scheme 4.5).

Alanine dehydrogenase (AlaDH) has been coupled with lactate dehydrogenase (LDH) for the kinetic resolution of 3-fluoroalanine to the D-enantiomer and L-3-fluorolactic acid (Scheme 4.11). This approach represented the inverse counterpart to the LDH-AlaDH-cascade for the asymmetric synthesis of alanine from lactate as described above. As in the reverse system, internal cofactor regeneration was achieved, resulting in a redox-neutral process. D-3-Fluoroalanine and L-3-fluorolactic acid were obtained in 60% (ee = 88%) and 80% (ee>99%) yields, respectively. 

Recently, a cascade process for the simultaneous preparation of two enantiopure secondary alcohols by the same ADH was investigated [12]. In this work, a kinetic oxidative resolution of different secondary alcohols was coupled with the irreversible asymmetric reduction of selected prochiral activated ketones, that is, a-chloro ketones (Scheme 11.5a). The proposed strategy, named PIKAT (parallel intercoimected kinetic asymmetric transformations), represents an example of redox neutral (or self-sufficient) cascade, with no additional reducing or oxidizing reagents being required. Moreover, the reaction was catalyzed by a single enzyme in the presence of catalytic amounts of the cofactor. As the outcome of the cascade process is a mixture of two different enantioenriched products, substrates were properly selected on the basis of different physical properties. 

Scheme 11.5 Examples of redox neutral cascades, (a) The PIKAT strategy for the simultaneous production of optically pure sec-alcohols, (b) Simultaneous synthesis of (S)-3-fluoroalanine and...

Another interesting example of a redox neutral cascade has been proposed for the multienzymatic synthesis of (JJ)-3-fluorolactic acid together with the resolution of racemic 3-fluoroalanine (Scheme 11.5b) [13]. Optically enriched (S)-3-fluoroalanine (88% ee) was recovered unreacted after the enantioselective oxidative deamination of the racemic substrate catalyzed by the L-alanine dehydrogenase (i-AlaDH) from Bacillus subtilis. This oxidative reaction, which is thermodynamically unfavorable, was driven by the coupled reduction reaction of the intermediate 3-fluoropyruvate catalyzed by rabbit muscle i-lactate dehydrogenase (L-LDH). Since both enzymes are NADH dependent, this coupled... 

Recently, an interesting example of a redox neutral cascade using co-TAs for the key reductive amination step was presented [37]. This enzymatic activity, catalyzing the reductive amination of selected aldehydes, was coupled with an ADH for the... 

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