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Assembly-line synthesis of organic molecules with tailored shapes

Nature volume 513, pages 183–188 (2014)Cite this article

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Abstract

Molecular ‘assembly lines’, in which organic molecules undergo iterative processes such as chain elongation and functional group manipulation, are found in many natural systems, including polyketide biosynthesis. Here we report the creation of such an assembly line using the iterative, reagent-controlled homologation of a boronic ester. This process relies on the reactivity of α-lithioethyl tri-isopropylbenzoate, which inserts into carbon–boron bonds with exceptionally high fidelity and stereocontrol; each chain-extension step generates a new boronic ester, which is immediately ready for further homologation. We used this method to generate organic molecules that contain ten contiguous, stereochemically defined methyl groups. Several stereoisomers were synthesized and shown to adopt different shapes—helical or linear—depending on the stereochemistry of the methyl groups. This work should facilitate the rational design of molecules with predictable shapes, which could have an impact in areas of molecular sciences in which bespoke molecules are required.

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Figure 1: Iterative approaches to assembly-line synthesis.
Figure 2: Methodology used for homologation of boronic esters.
Figure 3: Iterative assembly-line synthesis.
Figure 4: The effect of syn-pentane and other intramolecular steric interactions on conformation of molecules.
Figure 5: Solution conformations of compounds 14 and 18.

Accession codes

Data deposits

X-ray crystallographic data have been deposited in the Cambridge Crystallographic Data Centre database with accession numbers CCDC 993442 (12), CCDC 993443 (15) and CCDC 993441(17).

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Acknowledgements

We thank EPSRC (EP/I038071/1) and the European Research Council (FP7/2007-2013, ERC grant no. 246785) for financial support. M.B. thanks the EPSRC-funded Bristol Chemical Synthesis Centre for Doctoral Training (EP/G036764/1) and Novartis for a PhD studentship. We wish to thank C. Woodall for assistance with X-ray analysis and E. Bozoki for assistance with preparative high-performance liquid chromatography purification.

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Authors and Affiliations

  1. School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK,

    Matthew Burns, Stéphanie Essafi, Jessica R. Bame, Stephanie P. Bull, Matthew P. Webster, Sébastien Balieu, Craig P. Butts, Jeremy N. Harvey & Varinder K. Aggarwal

  2. Novartis Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH13 5AB, UK,

    James W. Dale

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  1. Matthew Burns
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Contributions

V.K.A. designed the project. M.B. conducted and designed the experiments and analysed the data. S.E. performed computational studies and analysed the data with J.N.H. J.R.B. and S.P.B. performed the NMR experiments and analysed the data with C.P.B. M.P.W. conducted the preliminary experiments with lithiated carbamates. S.B. optimized the recrystallization conditions for stannane 5. J.W.D. supervised M.B. while working at Novartis. V.K.A., M.B., J.N.H. and C.P.B. wrote the manuscript.

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Correspondence to Craig P. Butts, Jeremy N. Harvey or Varinder K. Aggarwal.

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Burns, M., Essafi, S., Bame, J. et al. Assembly-line synthesis of organic molecules with tailored shapes. Nature 513, 183–188 (2014). https://doi.org/10.1038/nature13711

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