Article | Published:

Assembly-line synthesis of organic molecules with tailored shapes

Nature volume 513, pages 183188 (11 September 2014) | Download Citation

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

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).

References

  1. 1.

    & Polyketide biosynthesis: a millennium review. Nat. Prod. Rep. 18, 380–416 (2001)

  2. 2.

    Flexible molecules with defined shape: conformational design. Angew. Chem. Int. Edn Engl. 31, 1124–1134 (1992)

  3. 3.

    Conformation design of open-chain compounds. Angew. Chem. Int. Edn Engl. 39, 2054–2070 (2000)

  4. 4.

    & The effect of substitution and stereochemistry on ion binding in the polyether ionophore monensin. J. Am. Chem. Soc. 110, 7917–7919 (1988)

  5. 5.

    , , & Enantioselective complexation of organic ammonium ions by simple tetracyclic podand ionophores. J. Am. Chem. Soc. 114, 4128–4137 (1992)

  6. 6.

    , & Biological evaluation of rationally modified analogs of the H-type II blood group trisaccharide. A correlation between solution conformation and binding affinity. J. Am. Chem. Soc. 117, 9432–9436 (1995)

  7. 7.

    , , , & Definition of the effect and role of the bleomycin A2 valerate substituents: preorganization of a rigid, compact conformation implicated in sequence-selective DNA cleavage. J. Am. Chem. Soc. 120, 9149–9158 (1998)

  8. 8.

    , , & Conformational and configurational analysis in the study and synthesis of chlorinated natural products. J. Am. Chem. Soc. 131, 15866–15876 (2009)

  9. 9.

    , & The iterative synthesis of acyclic deoxypropionate units and their implication in polyketide-derived natural products. Synthesis 7, 1057–1076 (2006)

  10. 10.

    , & Iterative strategies for the synthesis of deoxypropionates. Chem. Commun. 46, 2535–2547 (2010)

  11. 11.

    & The protein-folding problem, 50 years on. Science 338, 1042–1046 (2012)

  12. 12.

    & Directed chiral synthesis with pinanediol boronic esters. J. Am. Chem. Soc. 102, 7590–7591 (1980)

  13. 13.

    Boronic esters in asymmetric synthesis. J. Org. Chem. 78, 10009–10023 (2013)

  14. 14.

    , , & Lithiated carbamates: chiral carbenoids for iterative homologation of boranes and boronic esters. Angew. Chem. Int. Ed. 46, 7491–7494 (2007)

  15. 15.

    , , , & Synthesis of (S)-(−)-N-acetylcolchinol using intramolecular biaryl oxidative coupling. Org. Biomol. Chem. 4, 2193–2207 (2006)

  16. 16.

    , & Reagent controlled asymmetric homologation of boronic esters by enantioenriched main-group chiral carbenoids. Org. Lett. 8, 773–776 (2006)

  17. 17.

    & Iterative stereospecific reagent-controlled homologation of pinacol boronates by enantioenriched α-chloroalkyllithium reagents. J. Am. Chem. Soc. 129, 3068–3069 (2007)

  18. 18.

    , & Investigation of functionalized α-chloroalkyllithiums for a stereospecific reagent-controlled approach to the analgesic alkaloid (–)-epibatidine. Chemistry 19, 16342–16356 (2013)

  19. 19.

    , & Chiral lithium-1-oxyalkanides by asymmetric deprotonation; enantioselective synthesis of 2-hydroxyalkanoic acids and secondary alkanols. Angew. Chem. Int. Edn Engl. 29, 1422–1424 (1990)

  20. 20.

    & Enantioselective synthesis with lithium/(−)-sparteine carbanion pairs. Angew. Chem. Int. Edn Engl. 36, 2282–2316 (1997)

  21. 21.

    , & Stereospecific reaction of α-carbamoyloxy-2-alkenylboronates and α-carbamoyloxy-alkylboronates with Grignard reagents - synthesis of highly enantioenriched secondary alcohols. Synlett 13, 2275–2280 (2004)

  22. 22.

    , , & Stereocontrolled synthesis of carbon chains bearing contiguous methyl groups by iterative boronic ester homologations: application to the total synthesis of (+)-faranal. Angew. Chem. Int. Ed. 48, 6317–6319 (2009)

  23. 23.

    & Asymmetric total synthesis of solandelactone E: stereocontrolled synthesis of the 1,4-diol-2-ene core via lithiation-borylation-allylation sequence. Angew. Chem. Int. Ed. 49, 6673–6675 (2010)

  24. 24.

    & Synthesis of enantioenriched tertiary boronic esters from secondary allylic carbamates. Application to the synthesis of C30 botryococcene. J. Am. Chem. Soc. 134, 7570–7574 (2012)

  25. 25.

    , & Stereoselective total synthesis of (+)-giganin and its C10 epimer by using late-stage lithiation–borylation methodology. Angew. Chem. Int. Ed. 52, 2503–2506 (2013)

  26. 26.

    , , & Stereocontrolled synthesis of adjacent acyclic quaternary-tertiary motifs: application to a concise total synthesis of (–)-filiformin. Angew. Chem. Int. Ed. 53, 5552–5555 (2014)

  27. 27.

    & Programmed synthesis of a contiguous stereotriad motif by triple stereospecific reagent-controlled homologation. Org. Lett. 15, 4500–4503 (2013)

  28. 28.

    , , & Use of alkyl 2,4,6-triisopropylbenzoates in the asymmetric homologation of challenging boronic esters. Chem. Commun. (Camb.) 47, 12592–12594 (2011)

  29. 29.

    & α-Alkoxyorganolithium reagents. A new class of configurationally stable carbanions for organic synthesis. J. Am. Chem. Soc. 102, 1201–1202 (1980)

  30. 30.

    , & Preparation and reactions of enantiomerically pure α-functionalized Grignard reagents. J. Am. Chem. Soc. 135, 8071–8077 (2013)

  31. 31.

    A quarter of a century of explorations in organozirconium chemistry. Dalton Trans. 827–848 (2005)

  32. 32.

    , & Nouvelle methode pour porter au maximum la purete optique d’un produit partiellement dedouble sans l’aide d’aucune substance chirale. Tetrahedron 29, 1055–1059 (1973)

  33. 33.

    et al. Investigation of intramolecular interactions in n-alkanes. Cooperative energy increments associated with GG and GTG’ sequences. J. Am. Chem. Soc. 113, 4665–4671 (1991)

  34. 34.

    , & Structure and morphology of poly(propylenes): a molecular analysis. Polymer 37, 4979–4992 (1996)

  35. 35.

    , , & Synthesis and structure of stereoisomeric multivicinal hexafluoroalkanes. Angew. Chem. Int. Ed. 48, 5457–5460 (2009)

  36. 36.

    , , & Conformation design of hydrocarbon backbones: a modular approach. Chemistry 4, 559–566 (1998)

  37. 37.

    , & High precision NOEs as a probe for low level conformers – a second conformation of strychnine. Chem. Commun. 47, 1193–1195 (2011)

  38. 38.

    et al. Interproton distance determinations by NOE – surprising accuracy and precision in a rigid organic molecule. Org. Biomol. Chem. 9, 177–184 (2011)

  39. 39.

    , & Local explicitly correlated second-order perturbation theory for the accurate treatment of large molecules. J. Chem. Phys. 130, 054106 (2009)

  40. 40.

    et al. Quantitative ROE-derived interproton distances combined with quantum chemical calculations of NMR parameters in the stereochemical determination of conicasterol F, a nuclear receptor ligand from Theonella swinhoei. J. Org. Chem. 77, 1489–1496 (2012)

  41. 41.

    , , & Quantum mechanical calculation of NMR parameters in the stereostructural determination of natural products. Eur. J. Org. Chem. 2010, 1411–1434 (2010)

  42. 42.

    et al. Application of conformation design in acyclic stereoselection: total synthesis of borrelidin as the crystalline benzene solvate. J. Am. Chem. Soc. 125, 13784–13792 (2003)

  43. 43.

    , & Iterative synthesis of (oligo)deoxypropionates via zinc-catalyzed enantiospecific sp3−sp3 cross-coupling. Org. Lett. 11, 4668–4670 (2009)

  44. 44.

    , & Catalytic asymmetric synthesis of phthioceranic acid, a heptamethyl-branched acid from Mycobacterium tuberculosis. Org. Lett. 9, 3013–3015 (2007)

  45. 45.

    , , & Total synthesis of (+)-roxaticin via C−C bond forming transfer hydrogenation: a departure from stoichiometric chiral reagents, auxiliaries, and premetalated nucleophiles in polyketide construction. J. Am. Chem. Soc. 132, 15559–15561 (2010)

  46. 46.

    , , & Simple, efficient, and modular syntheses of polyene natural products via iterative cross-coupling. J. Am. Chem. Soc. 130, 466–468 (2008)

  47. 47.

    & Controlled iterative cross-coupling: on the way to the automation of organic synthesis. Angew. Chem. Int. Ed. 48, 5240–5244 (2009)

  48. 48.

    , & Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction. Nat. Chem. 6, 484–491 (2014)

  49. 49.

    , , & An efficient and general route to reduced polypropionates via Zr-catalyzed asymmetric C—C bond formation. Proc. Natl Acad. Sci. USA 101, 5782–5787 (2004)

  50. 50.

    & A triple-aldol cascade reaction for the rapid assembly of polyketides. Angew. Chem. Int. Ed. 49, 2747–2749 (2010)

Download references

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.

Author information

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

Authors

  1. Search for Matthew Burns in:

  2. Search for Stéphanie Essafi in:

  3. Search for Jessica R. Bame in:

  4. Search for Stephanie P. Bull in:

  5. Search for Matthew P. Webster in:

  6. Search for Sébastien Balieu in:

  7. Search for James W. Dale in:

  8. Search for Craig P. Butts in:

  9. Search for Jeremy N. Harvey in:

  10. Search for Varinder K. Aggarwal in:

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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

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

Supplementary information

PDF files

  1. 1.

    Supplementary information

    This file contains Supplementary Text and Data – see Supplementary Contents page for details.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature13711

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.