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Cooperative asymmetric reactions combining photocatalysis and enzymatic catalysis


Living organisms rely on simultaneous reactions catalysed by mutually compatible and selective enzymes to synthesize complex natural products and other metabolites. To combine the advantages of these biological systems with the reactivity of artificial chemical catalysts, chemists have devised sequential, concurrent, and cooperative chemoenzymatic reactions that combine enzymatic and artificial catalysts1,2,3,4,5,6,7,8,9. Cooperative chemoenzymatic reactions consist of interconnected processes that generate products in yields and selectivities that cannot be obtained when the two reactions are carried out sequentially with their respective substrates2,7. However, such reactions are difficult to develop because chemical and enzymatic catalysts generally operate in different media at different temperatures and can deactivate each other1,2,3,4,5,6,7,8,9. Owing to these constraints, the vast majority of cooperative chemoenzymatic processes that have been reported over the past 30 years can be divided into just two categories: chemoenzymatic dynamic kinetic resolutions of racemic alcohols and amines, and enzymatic reactions requiring the simultaneous regeneration of a cofactor2,4,5. New approaches to the development of chemoenzymatic reactions are needed to enable valuable chemical transformations beyond this scope. Here we report a class of cooperative chemoenzymatic reaction that combines photocatalysts that isomerize alkenes with ene-reductases that reduce carbon–carbon double bonds to generate valuable enantioenriched products. This method enables the stereoconvergent reduction of E/Z mixtures of alkenes or reduction of the unreactive stereoisomers of alkenes in yields and enantiomeric excesses that match those obtained from the reduction of the pure, more reactive isomers. The system affords a range of enantioenriched precursors to biologically active compounds. More generally, these results show that the compatibility between photocatalysts and enzymes enables chemoenzymatic processes beyond cofactor regeneration and provides a general strategy for converting stereoselective enzymatic reactions into stereoconvergent ones.

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Fig. 1: Chemoenzymatic reactions.
Fig. 2: Simultaneous isomerization and reduction of (Z)-1a.
Fig. 3: Scope of the cooperative photoisomerization and reduction and comparison to sequential reactions.
Fig. 4: Derivatization of enantioenriched products.

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We thank K. Faber, U. Bornscheuer and N. Scrutton for the gift of plasmids pET21a-OPR1, pGaston-XenB and pET21b_TOYE respectively. We also thank the Metabolomics Center of University of Illinois at Urbana-Champaign for gas chromatography–mass spectrometry (GC–MS) facilities and A. Vladimirovich Ulanov for suggestions on GC analysis. This work was supported by the National Science Foundation under the CCI Center for Enabling New Technologies through Catalysis (CENTC, CHE-1205189 to H.Z. and J.F.H.) and Department of Energy (DE-SC0018420 to H.Z.).

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Nature thanks R. Gilmour, W. Wang and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Z.C.L., Y.W., J.F.H. and H.Z. conceived the project, designed the initial experiments and interpreted the data. Z.C.L. and Y.W. performed all of the experiments. Z.C.L., Y.W., J.F.H. and H.Z. wrote the manuscript.

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Correspondence to Huimin Zhao or John F. Hartwig.

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Litman, Z.C., Wang, Y., Zhao, H. et al. Cooperative asymmetric reactions combining photocatalysis and enzymatic catalysis. Nature 560, 355–359 (2018).

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