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Stereodivergent synthesis with a programmable molecular machine


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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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).


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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.

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Authors and Affiliations



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.

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Correspondence to David A. Leigh.

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The authors declare no competing financial interests.

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

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Kassem, S., Lee, A., Leigh, D. et al. Stereodivergent synthesis with a programmable molecular machine. Nature 549, 374–378 (2017).

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