Letter

Stereodivergent synthesis with a programmable molecular machine

Received:
Accepted:
Published online:

Abstract

It has been convincingly argued1,2,3 that molecular machines that manipulate individual atoms, or highly reactive clusters of atoms, with Ångström precision are unlikely to be realized. However, biological molecular machines routinely position rather less reactive substrates in order to direct chemical reaction sequences, from sequence-specific synthesis by the ribosome4 to polyketide synthases5,6,7, where tethered molecules are passed from active site to active site in multi-enzyme complexes. Artificial molecular machines8,9,10,11,12 have been developed for tasks that include sequence-specific oligomer synthesis13,14,15 and the switching of product chirality16,17,18,19, a photo-responsive host molecule has been described that is able to mechanically twist a bound molecular guest20, and molecular fragments have been selectively transported in either direction between sites on a molecular platform through a ratchet mechanism21. Here we detail an artificial molecular machine that moves a substrate between different activating sites to achieve different product outcomes from chemical synthesis. This molecular robot can be programmed to stereoselectively produce, in a sequential one-pot operation, an excess of any one of four possible diastereoisomers from the addition of a thiol and an alkene to an α,β-unsaturated aldehyde in a tandem reaction process. The stereodivergent synthesis includes diastereoisomers that cannot be selectively synthesized22 through conventional iminium–enamine organocatalysis. We anticipate that future generations of programmable molecular machines may have significant roles in chemical synthesis and molecular manufacturing.

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References

  1. 1.

    Of chemistry, love and nanobots. Sci. Am. 285, 76–77 (2001)

  2. 2.

    The once and future nanomachine. Sci. Am. 285, 78–83 (2001)

  3. 3.

    Soft Machines: Nanotechnology and Life (Oxford Univ. Press, 2004)

  4. 4.

    Hibernating bears, antibiotics, and the evolving ribosome (Nobel Lecture). Angew. Chem. Int. Ed. 49, 4340–4354 (2010)

  5. 5.

    , & The crystal structure of a mammalian fatty acid synthase. Science 321, 1315–1322 (2008)

  6. 6.

    , & Conformational flexibility of metazoan fatty acid synthase enables catalysis. Nat. Struct. Mol. Biol. 16, 190–197 (2009)

  7. 7.

    & Current understanding of fatty acid biosynthesis and the acyl carrier protein. Biochem. J. 430, 1–19 (2010)

  8. 8.

    , , & Artificial molecular machines. Chem. Rev. 115, 10081–10206 (2015)

  9. 9.

    , , & Controlling motion at the nanoscale: rise of the molecular machines. ACS Nano 9, 7746–7768 (2015)

  10. 10.

    & Catalysts encapsulated in molecular machines. ChemPhysChem 17, 1752–1758 (2016)

  11. 11.

    & Wholly synthetic molecular machines. ChemPhysChem 17, 1780–1793 (2016)

  12. 12.

    How molecular motors work—insights from the molecular machinist’s toolbox: the Nobel Prize in Chemistry 2016. Chem. Sci. 8, 840–845 (2017)

  13. 13.

    et al. Sequence-specific peptide synthesis by an artificial small-molecule machine. Science 339, 189–193 (2013)

  14. 14.

    et al. Efficient assembly of threaded molecular machines for sequence-specific synthesis. J. Am. Chem. Soc. 136, 5811–5814 (2014)

  15. 15.

    et al. An autonomous molecular assembler for programmable chemical synthesis. Nat. Chem. 8, 542–548 (2016)

  16. 16.

    & Dynamic control of chiral space in a catalytic asymmetric reaction using a molecular motor. Science 331, 1429–1432 (2011)

  17. 17.

    , & A redox-reconfigurable, ambidextrous asymmetric catalyst. J. Am. Chem. Soc. 134, 8054–8057 (2012)

  18. 18.

    , & Dynamic control of chirality in phosphine ligands for enantioselective catalysis. Nat. Commun. 6, 6652 (2015)

  19. 19.

    , & Dial-in selection of any of four stereochemical outcomes among two substrates by in situ stereo-reconfiguration of a single ambidextrous catalyst. Tetrahedr. Lett. 57, 459–462 (2016)

  20. 20.

    , & Mechanical twisting of a guest by a photoresponsive host. Nature 440, 512–515 (2006)

  21. 21.

    , , , & Pick-up, transport and release of a molecular cargo using a small-molecule robotic arm. Nat. Chem. 8, 138–143 (2016)

  22. 22.

    & Stereodivergence in asymmetric catalysis. J. Am. Chem. Soc. 139, 5627–5639 (2017)

  23. 23.

    & α,α-diarylprolinol ethers: new tools for functionalization of carbonyl compounds. Chem. Asian J. 3, 922–948 (2008)

  24. 24.

    , , , & The diarylprolinol silyl ether system: a general organocatalyst. Acc. Chem. Res. 45, 248–264 (2012)

  25. 25.

    , , & Asymmetric multicomponent domino reactions and highly enantioselective conjugated addition of thiols to α,β-unsaturated aldehydes. J. Am. Chem. Soc. 127, 15710–15711 (2005)

  26. 26.

    , , , & Organocatalytic enantioselective aminosulfenylation of α,β-unsaturated aldehydes. Angew. Chem. Int. Ed. 47, 8468–8472 (2008)

  27. 27.

    & Switching around two axles: controlling the configuration and conformation of a hydrazone-based switch. Org. Lett. 13, 30–33 (2011)

  28. 28.

    , , & A switching cascade of hydrazone-based rotary switches through coordination-coupled proton relays. Nat. Chem. 4, 757–762 (2012)

  29. 29.

    & Rise of the molecular machines. Angew. Chem. Int. Ed. 54, 10080–10088 (2015)

  30. 30.

    Engines of Creation: The Coming Era of Nanotechnology (Anchor Books, 1986)

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Acknowledgements

We thank the Engineering and Physical Sciences Research Council (EPSRC) (EP/H021620/1 & 2) and the European Research Council (ERC) (Advanced Grant No. 339019) for funding, and the EPSRC National Mass Spectrometry Service Centre (Swansea, UK) for high-resolution mass spectrometry. D.A.L. is a Royal Society Research Professor.

Author information

Affiliations

  1. School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK

    • Salma Kassem
    • , Alan T. L. Lee
    • , David A. Leigh
    • , Vanesa Marcos
    • , Leoni I. Palmer
    •  & Simone Pisano

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Contributions

V.M. devised the concept. S.K., V.M. and L.I.P. carried out the experimental work. S.P. and L.I.P. performed model studies. S.K., V.M. and A.T.L.L. designed the operation experiments. D.A.L. directed the research. All the authors contributed to the analysis of the results and the writing of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David A. Leigh.

Reviewer Information Nature thanks T. R. Kelly, P. Pihko and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains detailed synthetic procedures, operation methods and full characterisation data – see contents page for details.

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