Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Stereodivergent synthesis with a programmable molecular machine

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Programmable operation of a molecular machine, 1, that synthesizes different products by moving a substrate between different activating sites.
Figure 2: Programmable stereodivergent synthesis of all possible stereoisomers of 4 from a one-pot tandem iminium–enamine-promoted reaction sequence by molecular machine 1.
Figure 3: Monitoring of program D at distinctive stages of operation by 1H NMR spectroscopy (600 MHz, 295 K, CD2Cl2).
Figure 4: Proposed mechanism of operation of molecular machine 1 during program D (stages I–VII).

References

  1. 1

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

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

    Jones, R. A. L. Soft Machines: Nanotechnology and Life (Oxford Univ. Press, 2004)

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

    Maier, T., Leibundgut, M. & Ban, N. The crystal structure of a mammalian fatty acid synthase. Science 321, 1315–1322 (2008)

    CAS  ADS  Article  Google Scholar 

  6. 6

    Brignole, E. J., Smith, S. & Asturias, F. J. Conformational flexibility of metazoan fatty acid synthase enables catalysis. Nat. Struct. Mol. Biol. 16, 190–197 (2009)

    CAS  Article  Google Scholar 

  7. 7

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

    CAS  Article  Google Scholar 

  8. 8

    Erbas-Cakmak, S., Leigh, D. A., McTernan, C. T. & Nussbaumer, A. L. Artificial molecular machines. Chem. Rev. 115, 10081–10206 (2015)

    CAS  Article  Google Scholar 

  9. 9

    Abendroth, J. M., Bushuyev, O. S., Weiss, P. S. & Barrett, C. J. Controlling motion at the nanoscale: rise of the molecular machines. ACS Nano 9, 7746–7768 (2015)

    CAS  Article  Google Scholar 

  10. 10

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

    CAS  Article  Google Scholar 

  11. 11

    Cheng, C. & Stoddart, J. F. Wholly synthetic molecular machines. ChemPhysChem 17, 1780–1793 (2016)

    CAS  Article  Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  13. 13

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

    CAS  ADS  Article  Google Scholar 

  14. 14

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

    Article  Google Scholar 

  15. 15

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

    CAS  Article  Google Scholar 

  16. 16

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

    CAS  ADS  Article  Google Scholar 

  17. 17

    Mortezaei, S., Catarineu, N. R. & Canary, J. W. A redox-reconfigurable, ambidextrous asymmetric catalyst. J. Am. Chem. Soc. 134, 8054–8057 (2012)

    CAS  Article  Google Scholar 

  18. 18

    Zhao, D., Neubauer, T. M. & Feringa, B. L. Dynamic control of chirality in phosphine ligands for enantioselective catalysis. Nat. Commun. 6, 6652 (2015)

    CAS  ADS  Article  Google Scholar 

  19. 19

    Mortezaei, S., Catarineu, N. R. & Canary, J. W. 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)

    CAS  Article  Google Scholar 

  20. 20

    Muraoka, T., Kinbara, K. & Aida, T. Mechanical twisting of a guest by a photoresponsive host. Nature 440, 512–515 (2006)

    CAS  ADS  Article  Google Scholar 

  21. 21

    Kassem, S., Lee, A. T. L., Leigh, D. A., Markevicius, A. & Solà, J. Pick-up, transport and release of a molecular cargo using a small-molecule robotic arm. Nat. Chem. 8, 138–143 (2016)

    CAS  Article  Google Scholar 

  22. 22

    Krautwald, S. & Carreira, E. M. Stereodivergence in asymmetric catalysis. J. Am. Chem. Soc. 139, 5627–5639 (2017)

    CAS  Article  Google Scholar 

  23. 23

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

    CAS  Article  Google Scholar 

  24. 24

    Jensen, K. L., Dickmeiss, G., Jiang, H., Albrecht, L. & Jørgensen, K. A. The diarylprolinol silyl ether system: a general organocatalyst. Acc. Chem. Res. 45, 248–264 (2012)

    CAS  Article  Google Scholar 

  25. 25

    Marigo, M., Schulte, T., Franzén, J. & Jørgensen, K. A. Asymmetric multicomponent domino reactions and highly enantioselective conjugated addition of thiols to α,β-unsaturated aldehydes. J. Am. Chem. Soc. 127, 15710–15711 (2005)

    CAS  Article  Google Scholar 

  26. 26

    Zhao, G.-L., Rios, R., Vesely, J., Eriksson, L. & Córdova, A. Organocatalytic enantioselective aminosulfenylation of α,β-unsaturated aldehydes. Angew. Chem. Int. Ed. 47, 8468–8472 (2008)

    CAS  Article  Google Scholar 

  27. 27

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

    CAS  Article  Google Scholar 

  28. 28

    Ray, D., Foy, J. T., Hughes, R. P. & Aprahamian, I. A switching cascade of hydrazone-based rotary switches through coordination-coupled proton relays. Nat. Chem. 4, 757–762 (2012)

    CAS  Article  Google Scholar 

  29. 29

    Kay, E. R. & Leigh, D. A. Rise of the molecular machines. Angew. Chem. Int. Ed. 54, 10080–10088 (2015)

    CAS  Article  Google Scholar 

  30. 30

    Drexler, K. E. Engines of Creation: The Coming Era of Nanotechnology (Anchor Books, 1986)

Download references

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

Authors

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.

Corresponding author

Correspondence to David A. Leigh.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Additional information

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.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

This file contains detailed synthetic procedures, operation methods and full characterisation data – see contents page for details. (PDF 14443 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kassem, S., Lee, A., Leigh, D. et al. Stereodivergent synthesis with a programmable molecular machine. Nature 549, 374–378 (2017). https://doi.org/10.1038/nature23677

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing