Dynamic Enantioconvergent Desaturation of 4,5-Disubstituted γ-Lactones in Whole Cells of Rhodococcus erythropolis

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High Resolution Image Download MS PowerPoint Slide The α,β-desaturation of esters is one of the most challenging transformations in organic synthesis. While transition-metal-catalyzed methods have significantly advanced in the last decades, they often require high catalyst loading and nongreen solvents and rarely enable stereoselective transformations. Here we show that whole cells of Rhodococcus erythropolis enable a dynamic enantioconvergent desaturation of 4,5-disubstituted γ-butyrolactones ( Quercus -like lactones), funneling all four initial stereoisomers into a single ( R )-configured product with excellent enantioselectivity (up to ee 99%). Mechanistic investigations with deuterium-labeled substrates reveal a highly complex pathway involving multiple transformations catalyzed by a network of enzymes. The process includes lactone ring-opening by esterases, stereoselective oxidation of secondary alcohols by alcohol dehydrogenases (ADHs), desaturation of carboxylates by ene-reductases (ERs), and stereoselective reductive steps mediated by ERs and ketoreductases (KRs). The final stereochemical outcome arises from the combination of two stereoediting transformations: ( i ) a site-selective de-epimerization catalyzed by ADH/KR, and ( ii ) an ER-mediated E → Z isomerization coupled to the irreversible lactonization (thermodynamic sink). Finally, this dynamic enantioconvergent biocatalytic desaturation was applied to the preparation of a key intermediate used in the total synthesis of forskolin, showcasing the potential of biocatalytic desaturations as a greener and more stereoselective alternative to traditional chemical methods with broad implications for asymmetric synthesis and sustainable chemistry.

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