Letter | Published:

Cooperative asymmetric reactions combining photocatalysis and enzymatic catalysis

Naturevolume 560pages355359 (2018) | Download Citation

Abstract

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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References

  1. 1.

    Rudroff, F. et al. Opportunities and challenges for combining chemo- and biocatalysis. Nat. Catal. 1, 12–22 (2018).

  2. 2.

    Köhler, V. & Turner, N. J. Artificial concurrent catalytic processes involving enzymes. Chem. Commun. 51, 450–464 (2015).

  3. 3.

    Denard, C. A., Hartwig, J. F. & Zhao, H. Multistep one-pot reactions combining biocatalysts and chemical catalysts for asymmetric synthesis. ACS Catal. 3, 2856–2864 (2013).

  4. 4.

    Gröger, H. in Cooperative Catalysis: Designing Efficient Catalysts for Synthesis (ed. Peters, R.) Ch. 11, 325–350 (Wiley, Weinheim, 2015).

  5. 5.

    Verho, O. & Bäckvall, J.-E. Chemoenzymatic dynamic kinetic resolution: a powerful tool for the preparation of enantiomerically pure alcohols and amines. J. Am. Chem. Soc. 137, 3996–4009 (2015).

  6. 6.

    Wang, Y., Ren, H. & Zhao, H. Expanding the boundary of biocatalysis: design and optimization of in vitro tandem catalytic reactions for biochemical production. Crit. Rev. Biochem. Mol. Biol. 53, 115–129 (2018).

  7. 7.

    Denard, C. A. et al. Cooperative tandem catalysis by an organometallic complex and a metalloenzyme. Angew. Chem. Int. Ed. 53, 465–469 (2014).

  8. 8.

    Köhler, V. et al. Synthetic cascades are enabled by combining biocatalysts with artificial metalloenzymes. Nat. Chem. 5, 93–99 (2013).

  9. 9.

    Haak, R. M. et al. Dynamic kinetic resolution of racemic β-haloalcohols: direct access to enantioenriched epoxides. J. Am. Chem. Soc. 130, 13508–13509 (2008).

  10. 10.

    Yanto, Y. et al. Asymmetric bioreduction of alkenes using ene-reductases YersER and KYE1 and effects of organic solvents. Org. Lett. 13, 2540–2543 (2011).

  11. 11.

    Stueckler, C. et al. Stereocomplementary bioreduction of α,β-unsaturated dicarboxylic acids and dimethyl esters using enoate reductases: enzyme- and substrate-based stereocontrol. Org. Lett. 9, 5409–5411 (2007).

  12. 12.

    Gatti, F. G., Parmeggiani, F. & Sacchetti, A. in Synthetic Methods for Biologically Active Molecules 1st edn (ed. Brenna, E.) Ch. 3, 49–84 (Wiley, Weinheim, 2013).

  13. 13.

    Chaparro-Riggers, J. F. et al. Comparison of three enoate reductases and their potential use for biotransformations. Adv. Synth. Catal. 349, 1521–1531 (2007).

  14. 14.

    Brenna, E. et al. Opposite enantioselectivity in the bioreduction of (Z)-β-aryl-β-cyanoacrylates mediated by the tryptophan 116 mutants of old yellow enzyme 1: synthetic approach to (R)- and (S)-β-aryl-γ-lactams. Adv. Synth. Catal. 357, 1849–1860 (2015).

  15. 15.

    Brenna, E. et al. Old yellow enzyme-mediated reduction of β-cyano-α,β-unsaturated esters for the synthesis of chiral building blocks: Stereochemical analysis of the reaction. Catal. Sci. Technol. 3, 1136–1146 (2013).

  16. 16.

    Wang, Y. et al. Combining Rh-catalyzed diazocoupling and enzymatic reduction to efficiently synthesize enantioenriched 2-substituted succinate derivatives. ACS Catal. 7, 2548–2552 (2017).

  17. 17.

    Metternich, J. B. & Gilmour, R. A bio-inspired, catalytic EZ isomerization of activated olefins. J. Am. Chem. Soc. 137, 11254–11257 (2015).

  18. 18.

    Singh, K., Staig, S. J. & Weaver, J. D. Facile synthesis of Z-alkenes via uphill catalysis. J. Am. Chem. Soc. 136, 5275–5278 (2014).

  19. 19.

    Metternich, J. B. et al. Photocatalytic EZ isomerization of polarized alkenes inspired by the visual cycle: Mechanistic dichotomy and origin of selectivity. J. Org. Chem. 82, 9955–9977 (2017).

  20. 20.

    Metternich, J. B. & Gilmour, R. Photocatalytic EZ isomerization of alkenes. Synlett 27, 2541–2552 (2016).

  21. 21.

    Molloy, J. J. et al. Contra-thermodynamic, photocatalytic EZ isomerization of styrenyl boron species: vectors to facilitate exploration of two-dimensional chemical space. Angew. Chem. Int. Ed. 57, 3168–3172 (2018).

  22. 22.

    Bamaung, N. Y. et al. Protein kinase inhibitors. US patent 2009/US20090253723 Al (2009).

  23. 23.

    Meerpoel, L. et al. Mtp inhibiting aryl piperidines or piperazines substituted with 5-membered heterocycles. US patent 2007/US20070191383 Al (2007).

  24. 24.

    Caggiano, T. J. et al. Inhibitors of beta amyloid production. US patent 2009/US20090023801 Al (2009).

  25. 25.

    Dong, K., Li, Y., Wang, Z. & Ding, K. Catalytic asymmetric hydrogenation of α-CF3- or β-CF3-substituted acrylic acids using rhodium(i) complexes with a combination of chiral and achiral ligands. Angew. Chem. Int. Ed. 52, 14191–14195 (2013).

  26. 26.

    Chung, Y.-C., Janmanchi, D. & Wu, H.-L. Preparation of chiral 3-arylpyrrolidines via the enantioselective 1,4-addition of arylboronic acids to fumaric esters catalyzed by Rh(i)/chiral diene complexes. Org. Lett. 14, 2766–2769 (2012).

  27. 27.

    Kong, D., Li, M., Wang, R., Zi, G. & Hou, G. Highly efficient asymmetric hydrogenation of cyano-substituted acrylate esters for synthesis of chiral γ-lactams and amino acids. Org. Biomol. Chem. 14, 1216–1220 (2016).

  28. 28.

    Zhao, F. et al. Enantioselective aza-ene-type reactions of enamides with gold carbenes generated from α-diazoesters. Angew. Chem. Int. Ed. 56, 3247–3251 (2017).

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Acknowledgements

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.).

Reviewer information

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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Author notes

  1. These authors contributed equally: Zachary C. Litman, Yajie Wang

Affiliations

  1. Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA

    • Zachary C. Litman
    •  & John F. Hartwig
  2. Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    • Yajie Wang
    •  & Huimin Zhao
  3. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    • Huimin Zhao
  4. Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    • Huimin Zhao
  5. Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    • Huimin Zhao
  6. Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA

    • Huimin Zhao

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Contributions

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.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Huimin Zhao or John F. Hartwig.

Supplementary information

  1. Supplementary Information

    This file contains experimental procedures and experimental data – see contents page for details.

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DOI

https://doi.org/10.1038/s41586-018-0413-7

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