Highly efficient and scalable chemoenzymatic syntheses of (R)- and (S)-lactaldehydes

Abstract

Biocatalytic asymmetric reductions have been key steps in the synthesis of 1,1-dimethoxy-2-propanone, catalyzed by suitable ketoreductases to (S)- and (R)-1,1-dimethoxy-2-propanol, obtained in ≥99.9% ee and excellent yield. Removal of the protecting group gave the (S)- and (R)-lactaldehydes in excellent yield and purity.

Horizons of Systems Biocatalysis and Renaissance of Metabolite Synthesis

“…The number and diversity of biocatalytic asymmetric reductions of carbonyl groups to their corresponding chiral alcohols has grown tremendously, due to an increasing number of suitable enantioselective ketoreductases/alcoholdehydrogenases and efficient cofactor regeneration systems . Biocatalytic reductions of carbonyl groups have enabled the preparation of the key metabolites L‐glyceraldehyde, D‐ and L‐lactaldehyde in enantiomerically pure and stable form (Figure A).…”

“…Analysing the reaction kinetics, enzyme inhibition, instable products and other process bottlenecks has been useful for selecting the most suitable reaction conditions and reactor type, as shown in the case of the synthesis of glyceraldehyde‐3‐phosphates . The common inhibition of enzymatic reactions by substrates, products or byproducts can be overcome by a number of different approaches, such as using solid adsorbents for substrate and product inhibition, protecting reactive aldehyde groups as dimethylacetals or utilizing an enzymatic reaction for removing an inhibiting byproduct . Experimental investigations of enzyme activity and stability as a function of pH, temperature, cosolvents or neat substrates can lead to optimum reaction conditions with high space‐time yields .…”

Biocatalytic Process Design and Reaction Engineering

“…Lipase-catalysed resolution of rac-2-carboxyethyl-3-cyano-5-methyl-hexanoic acid ethyl ester and subsequent decarboxylation has been a key process improvement in the synthesis of the Pregabalin precursor (S)-3-cyano-5-methylhexanoic acid ethyl ester 53 . In the case of the (S)-and (R)-lactaldehydes, the identification of the most suitable ketoreductases has been decisive for the key biocatalytic asymmetric reductions of 1,1-dimethoxy-2-propanone to enantiomerically pure (S)-and (R)-1,1-dimethoxy-2-propanols, which have been obtained in ≥99.9 % ee and excellent yield 33 . In the case of a one-step route to (R)-mevalonate-5-phosphate, prototyping the kinetic resolution of racemic mevalo-lactone required a recombinant mevalonate kinase and reaction monitoring of the biocatalytic asymmetric phosphorylation by quantitative 31 P-NMR 54 .…”

“…Even with complete conversion, the final product also needs to be recovered and purified from the reaction system with high efficiency 64 . In a systematic optimization of the biocatalytic reaction system using DoE parameter investigations for the manufacturing of the enantiomerically pure D-and L-lactaldehydes, the reaction engineering target values have been met and even surpassed with >99 % yield, >99 % ee at 250 g L -1 substrate loading and 0.05 g L -1 NADP cofactor requirement, after two phases of process development subsequent to screening 33 . In the case of the biocatalytic resolution of (+)-cis/trans limonene oxide and (-)-cis/trans-limonene oxide, the choice of the most suitable reaction parameters, like substrate loading, pH, tem-F i g .…”

“…Target product-oriented routes are routinely designed by a retrosynthetic analysis and a decision from which material to start with, as schematically shown in Figure 3. The integration of biocatalysis into classical retrosynthetic analysis is thereby important 32 and demonstrated by the cases of the target products enantiomerically pure D-and L-lactaldehydes as well as KDG [33][34] . Another key prerequisite for successful biocatalytic processes is the availability of adequate and reliable methodologies for bioprocess analysis at the start of development for the unambiguous identification and purity determination of the product.…”