Halohydrin dehydrogenase

Numerous biocatalytic routes to this challenging intermediate have been reported. " For example. Fox et al. have recently developed an efficient regioselective cyanation starting from low-cost epichlorohydrin (Scheme 1.26). Initial experiments found that halohydrin dehydrogenase from Agrobacterium radiobacter expressed in E. coli produced the desired product, but inefficiently. To meet the projected cost requirements for economic viability, the product needed to be produced at 100 g L with complete conversion and a 4000-fold increase in volumetric productivity. The biocatalyst needed to function under neutral conditions to avoid by-product formation, which causes downstream processing issues. 

Scheme 1.52) that is subsequently fed into the halohydrin-dehydrogenase-catalysed cyanation process shown in Scheme 1.26. Reaction workup using wild-type enzymes gave an emulsion that settled slowly, thus wasting valuable plant time. Modification of both ADH and GDH enzymes allowed improved separation as well as increased reaction rate and catalyst stability. 

The crystal structure of the halohydrin dehalogenase from the soil bacterium Agrobacterium radiobacter ADI, HheC, has been solved [129]. HheC is structurally related to the family of NAD(P)H-dependent short-chain dehydrogenases/reduc-... 

Figure 6.2 Overview of biocatalytic routes to vastatin side chains. PLE pig-liver esterase, ADH alcohol dehydrogenase, HHDH halohydrin dehalogenase, DERA 2-deoxy-D-ribose 5-phosphate aldolase.

Fig. 40 Concept for the two-step synthesis of enantiomerically pure (S)-epoxides out of aliphatic 1-halogenated 2-ketones. The ketone was reduced by a recombinant whole-cell catalyst bearing alcohol dehydrogenase from Lactobacillus kefir (LKADH) and glucose dehydrogenase (GDH) for regeneration of NADPH. Base-induced cyclization of the enantiomerically pure (5)-(3-halohydrin intermediate gave the desired (S)-epoxides in high yield and enantiomeric purity (>99% ee)...

Scheme 4.22 Enzymatic sequential synthesis of an atorvastatin precursor using two dehydrogenases and a halohydrin dehalogenase.

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