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A series of functionalized α-chiral phosphonates was obtained by enzymatic reduction of the corresponding β-activated vinylphosphonate derivatives employing several ene-reductases of the Old Yellow Enzyme family as biocatalysts. The insufficient activation of the phosphonate group alone was compensated by introduction of an electron-withdrawing group at the β-position, which resulted in high levels of conversion (up to >99%). All active enzymes consistently furnished ( R)-configurated products with exquisite stereoselectivity, thereby providing a stereo-complementary approach to current asymmetric hydrogenation protocols on similar compounds. Preparative-scale syntheses performed in aqueous buffer using formate/formate dehydrogenase for recycling of the nicotinamide cofactor granted access to β-keto-, cyano- and ester phosphonates from the ( E)-isomers of α,β-unsaturated phosphonates in up to 72% isolated yield and >99% ee. [ABSTRACT FROM AUTHOR]

In contrast to the widely studied asymmetric bioreduction of α,β-unsaturated carboxylic acid esters catalyzed by ene-reductases, the reaction applied to lactones remains unexplored. A broad set of ene-reductases was found to reduce various α-, β- and γ-substituted α,β-unsaturated butyrolactones to yield the corresponding saturated non-racemic lactones. Substitution patterns greatly influenced activities and stereoselectivities and lactone products were obtained in moderate to excellent yields; importantly, enzyme-based stereocontrol allowed access to both enantiomers in up to >99% ee. Chiral recognition of a distant γ-center led to kinetic resolution with remarkable enantioselectivities (E values up to 49). An unprecedented case of dynamic kinetic resolution was observed with 3-methyl-5-phenylfuran-2(5 H)-one, whereby spontaneous racemization of the substrate furnished the product in up to 73% conversion and >99% ee and 96% de. [ABSTRACT FROM AUTHOR]

Asymmetric bioreduction of an ( E)-β-cyano-2,4-dienoic acid derivative by ene-reductases allowed a shortened access to a precursor of pregabalin [( S)-3-(aminomethyl)-5-methylhexanoic acid] possessing the desired configuration in up to 94% conversion and >99% ee. Deuterium labelling studies showed that the nitrile moiety was the preferred activating/anchor group in the active site of the enzyme over the carboxylic acid or the corresponding methyl ester. [ABSTRACT FROM AUTHOR]

The ene-reductase-mediated reduction of the carbon-carbon double bond of some alkyl 2-substituted butenedioates was investigated. The stereochemical outcome of the reaction was found to be influenced by steric effects. Ethyl and butyl citraconates were converted into the corresponding alkyl ( R)-2-methylsuccinates with excellent enantioselectivity, whereas ethyl and butyl mesaconates were completely unreactive. Methyl 2-substituted fumarates were reduced to enantiomerically enriched methyl ( S)-2-substituted succinates, whereas the ( Z)-stereoisomers were left unreacted by ene-reductases. Labelling experiments were performed to investigate the mechanism of these bioreductions and explain their stereochemical outcome. [ABSTRACT FROM AUTHOR]

The front cover image, provided by Piotr Kiełbasiński, Mélanie Hall and collaborators, illustrates the stereoselective bioreduction of activated vinylphosphonates catalyzed by Old Yellow Enzyme homologues, which can be easily produced through recombinant expression in E. coli cells. This stereocomplementary method to current asymmetric hydrogenation protocols provides access to α‐chiral phosphonates of high enantiomeric purity. (Picture from E. coli bacteria – NIAID; Under Creative Common license BY‐SA). Details can be found in the full paper on pages 4190–4196 (I. Janicki, P. Kiełbasiński, N. G. Turrini, K. Faber, M. Hall, Adv. Synth. Catal. 2017, 359, 4190–4196; DOI: 10.1002/adsc.201700716). [ABSTRACT FROM AUTHOR]