Article | Published:

Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction

Nature Chemistry volume 6, pages 484491 (2014) | Download Citation

  • An Erratum to this article was published on 20 June 2014

This article has been updated

Abstract

The inherent modularity of polypeptides, oligonucleotides and oligosaccharides has been harnessed to achieve generalized synthesis platforms. Importantly, like these other targets, most small-molecule natural products are biosynthesized via iterative coupling of bifunctional building blocks. This suggests that many small molecules also possess inherent modularity commensurate with systematic building block-based construction. Supporting this hypothesis, here we report that the polyene motifs found in >75% of all known polyene natural products can be synthesized using just 12 building blocks and one coupling reaction. Using the same general retrosynthetic algorithm and reaction conditions, this platform enabled both the synthesis of a wide range of polyene frameworks that covered all of this natural-product chemical space and the first total syntheses of the polyene natural products asnipyrone B, physarigin A and neurosporaxanthin β-D-glucopyranoside. Collectively, these results suggest the potential for a more generalized approach to making small molecules in the laboratory.

  • Compound C7H9BBrNO4

    (E)-2-(2-Bromovinyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C7H9BBrNO4

    (Z)-2-(2-Bromovinyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C8H11BBrNO4

    (Z)-2-(1-Bromoprop-1-en-2-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C8H11BBrNO4

    (E)-2-(1-Bromoprop-1-en-2-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C9H11BINO4

    2-((1E,3E)-4-Iodobuta-1,3-dien-1-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C10H13BINO4

    2-((1E,3E)-4-Iodopenta-1,3-dien-1-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C10H13BINO4

    2-((1E,3E)-4-Iodo-2-methylbuta-1,3-dien-1-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C11H13BINO4

    2-((1E,3E,5E)-6-Iodohexa-1,3,5-trien-1-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C12H15BBrNO4

    2-((1E,3E,5E)-6-Bromo-3-methylhexa-1,3,5-trien-1-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C13H17BINO4

    2-((2Z,4E,6E)-7-Iodo-6-methylhepta-2,4,6-trien-2-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C13H17BINO4

    2-((2Z,4E,6E)-7-Iodoocta-2,4,6-trien-2-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C12H15BINO4

    2-((1E,3E,5E)-6-Iodo-4-methylhexa-1,3,5-trien-1-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C15H24O

    (4E,6E,8E)-9-Cyclohexylnona-4,6,8-trien-1-ol

  • Compound C15H24O

    (4E,6Z,8E)-9-Cyclohexylnona-4,6,8-trien-1-ol

  • Compound C16H26O

    (4E,6E,8E)-9-Cyclohexyl-6-methylnona-4,6,8-trien-1-ol

  • Compound C16H26O

    (4E,6Z,8E)-9-Cyclohexyl-6-methylnona-4,6,8-trien-1-ol

  • Compound C17H26O

    (4E,6E,8E,10E)-11-Cyclohexylundeca-4,6,8,10-tetraen-1-ol

  • Compound C18H28O

    (4E,6E,8E,10E)-11-Cyclohexyl-9-methylundeca-4,6,8,10-tetraen-1-ol

  • Compound C19H28O

    (4E,6E,8E,10E,12E)-13-Cyclohexyltrideca-4,6,8,10,12-pentaen-1-ol

  • Compound C20H30O

    (4E,6E,8E,10E,12E)-13-Cyclohexyl-8-methyltrideca-4,6,8,10,12-pentaen-1-ol

  • Compound C23H34O

    (4E,6E,8E,10E,12E,14E)-15-Cyclohexyl-9,13-dimethylpentadeca-4,6,8,10,12,14-hexaen-1-ol

  • Compound C23H32O

    (4E,6E,8E,10E,12E,14E,16E)-17-Cyclohexylheptadeca-4,6,8,10,12,14,16-heptaen-1-ol

  • Compound C26H38O

    (4E,6E,8E,10E,12E,14E,16E)-17-Cyclohexyl-6,10,15-trimethylheptadeca-4,6,8,10,12,14,16-heptaen-1-ol

  • Compound C25H36O

    (4E,6E,8E,10E,12E,14E,16E)-17-Cyclohexyl-8,13-dimethylheptadeca-4,6,8,10,12,14,16-heptaen-1-ol

  • Compound C28H40O

    (4E,6E,8E,10E,12E,14E,16E,18E)-19-Cyclohexyl-6,10,15-trimethylnonadeca-4,6,8,10,12,14,16,18-octaen-1-ol

  • Compound C31H44O

    (4E,6E,8E,10E,12E,14E,16E,18E,20E)-21-Cyclohexyl-6,10,15,19-tetramethylhenicosa-4,6,8,10,12,14,16,18,20-nonaen-1-ol

  • Compound C33H46O

    (4E,6E,8E,10E,12E,14E,16E,18E,20E,22E)-23-Cyclohexyl-8,12,17,21-tetramethyltricosa-4,6,8,10,12,14,16,18,20,22-decaen-1-ol

  • Compound C13H20BNO4

    (E)-2-(2-Cyclohexylvinyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C5H9IO

    (E)-5-Iodopent-4-en-1-ol

  • Compound C14H16BNO4

    (Z)-6-Methyl-2-(1-phenylprop-1-en-2-yl)-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C17H20BNO4

    6-Methyl-2-((2Z,4E)-4-methyl-5-phenylpenta-2,4-dien-2-yl)-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C8H7BrO3

    (E)-6-(2-Bromovinyl)-4-methoxy-2H-pyran-2-one

  • Compound C16H19BN2O6

    (E)-N-(2-Methoxy-6-(2-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)vinyl)phenyl)acetamide

  • Compound C6H8BrNO3

    (E)-3-(3-Bromoacrylamido)propanoic acid

  • Compound C20H23BN2O6

    N-(2-Methoxy-6-((1E,3E,5E)-6-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)hexa-1,3,5-trien-1-yl)phenyl)acetamide

  • Compound C24H27BN2O6

    N-(2-Methoxy-6-((1E,3E,5E,7E,9E)-10-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)deca-1,3,5,7,9-pentaen-1-yl)phenyl)acetamide

  • Compound C16H24BNO4

    (E)-6-Methyl-2-(2-(2,6,6-trimethylcyclohex-1-en-1-yl)vinyl)-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C21H30BNO4

    6-Methyl-2-((1E,3E,5E)-4-methyl-6-(2,6,6-trimethylcyclohex-1-en-1-yl)hexa-1,3,5-trien-1-yl)-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C34H71BrO7Si4

    (2R,3S,4R,5S,6S)-3,4,5-Tris((triethylsilyl)oxy)-6-(((triethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-yl (E)-3-bromo-2-methylacrylate

  • Compound C29H40BNO4

    2-((2Z,4E,6E,8E,10E,12E)-7,11-Dimethyl-13-(2,6,6-trimethylcyclohex-1-en-1-yl)trideca-2,4,6,8,10,12-hexaen-2-yl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C36H48BNO4

    6-Methyl-2-((1E,3E,5E,7E,9E,11E,13E,15E,17E)-3,7,12,16-tetramethyl-18-(2,6,6-trimethylcyclohex-1-en-1-yl)octadeca-1,3,5,7,9,11,13,15,17-nonaen-1-yl)-1,3,6,2-dioxazaborocane-4,8-dione

  • Compound C65H112O7Si4

    (2R,3S,4R,5S,6S)-3,4,5-Tris((triethylsilyl)oxy)-6-(((triethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-yl (2E,4E,6E,8E,10E,12E,14E,16E,18E,20E)-2,6,10,15,19-pentamethyl-21-(2,6,6-trimethylcyclohex-1-en-1-yl)henicosa-2,4,6,8,10,12,14,16,18,20-decaenoate

  • Compound C21H22O3

    Asnipyrone B

  • Compound C25H28N2O5

    Physarigin A

  • Compound C41H56O7

    Neurosporaxanthin β-D-glucopyranoside

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Change history

  • 18 May 2014

    In the version of this Article originally published, the Competing Financial Interest statement provided by the authors at submission was inadvertently removed during the production process. It should read "The University of Illinois has filed patents on MIDA boronate chemistry." This has been corrected in the online versions of the Article.

References

  1. 1.

    & Biochemistry (Saunders College Publishing, 1995).

  2. 2.

    Solid phase synthesis (Nobel Lecture). Angew. Chem. Int. Ed. Engl. 24, 799–810 (1985).

  3. 3.

    Gene synthesis machines: DNA chemistry and its uses. Science 230, 281–285 (1985).

  4. 4.

    & Solid-phase oligosaccharide synthesis and combinatorial carbohydrate libraries. Chem. Rev. 100, 4349–4393 (2000).

  5. 5.

    in Glyco-Bioinformatics: Bits ‘n’ Bytes of Sugars (eds Hicks, M. G. & Kettner, C.) 25–36 (Beilstein Institut zur Förderung der Chemischen Wissenschaften, 2009).

  6. 6.

    , & Automated solid-phase synthesis of oligosaccharides. Science 291, 1523–1527 (2001).

  7. 7.

    , & Enantioselective aldol condensations. 2. Erythro-selective chiral aldol condensations via boron enolates. J. Am. Chem. Soc. 103, 2127–2129 (1981).

  8. 8.

    & Laboratory emulation of polyketide biosynthesis: an iterative, aldol-based, synthetic entry to polyketide libraries using (R)- and (S)-1-(benzyloxy)-2-methylpentan-3-one, and conformational aspects of extended polypropionates. J. Chem. Soc. Perkin Trans. 1 1003–1014 (1999).

  9. 9.

    , , & Asymmetric synthesis of 1,3-dialkyl-substituted carbon chains of any stereochemical configuration by an iterable process. Synlett 36, 457–459 (1997).

  10. 10.

    , , & 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).

  11. 11.

    & Polyene natural products. J. Chem. Soc. Perkin Trans 1 999–1023 (2002).

  12. 12.

    Oxo polyene macrolide antibiotics. Chem. Rev. 95, 2021–2040 (1995).

  13. 13.

    et al. Photosynthetic light harvesting by carotenoids: detection of an intermediate excited state. Science 298, 2395–2398 (2002).

  14. 14.

    , & Conjugated polyene fatty acids as membrane probes: preliminary characterization. Proc. Natl Acad. Sci. USA 72, 1649–1653 (1975).

  15. 15.

    & Beta-carotene: an unusual type of lipid antioxidant. Science 224, 569–573 (1984).

  16. 16.

    , , , & Structural changes in bacteriorhodopsin during ion transport at 2 angstrom resolution. Science 286, 255–260 (1999).

  17. 17.

    Handbook of Organopalladium Chemistry for Organic Synthesis Vol. 1 (Wiley, 2002).

  18. 18.

    , & Palladium-catalyzed cross-coupling reactions in total synthesis. Angew. Chem. Int. Ed. 44, 4442–4489 (2005).

  19. 19.

    & Palladium-catalyzed cross-coupling reactions of organoboron compounds. Chem. Rev. 95, 2457–2483 (1995).

  20. 20.

    , & New bicyclic organylboronic esters derived from iminodiacetic acids. J. Organomet. Chem. 307, 1–6 (1986).

  21. 21.

    & A simple and modular strategy for small molecule synthesis: iterative Suzuki–Miyaura coupling of B-protected haloboronic acid building blocks. J. Am. Chem. Soc. 129, 6716–6717 (2007).

  22. 22.

    & Iterative cross-coupling with MIDA boronates: towards a general strategy for small molecule synthesis. Aldrichim. Acta 42, 17–27 (2009).

  23. 23.

    & Multistep synthesis of complex boronic acids from simple MIDA boronates. J. Am. Chem. Soc. 130, 14084–14085 (2008).

  24. 24.

    Sigma-Aldrich, MIDA boronates;

  25. 25.

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

  26. 26.

    , , & Stereoretentive Suzuki–Miyaura coupling of haloallenes enables fully stereocontrolled access to (–)-peridinin. J. Am. Chem. Soc. 132, 6941–6943 (2010).

  27. 27.

    , & Total synthesis of synechoxanthin through iterative cross-coupling. Angew. Chem. Int. Ed. 50, 7862–7864 (2011).

  28. 28.

    & Total synthesis of (–)-aurantioclavine. Org. Lett. 12, 2004–2007 (2010).

  29. 29.

    , , & Total synthesis and structural reassignment of (+)-dictyosphaeric acid A: a tandem intramolecular Michael addition/alkene migration approach. Angew. Chem. Int. Ed. 49, 5574–5577 (2010).

  30. 30.

    , , & Concise total synthesis of (−)-myxalamide A. Angew. Chem. Int. Ed. 51, 7271–7274 (2012).

  31. 31.

    & Pinene-derived iminodiacetic acid (PIDA): a powerful ligand for stereoselective synthesis and iterative cross-coupling of C(sp3) boronate building blocks. J. Am. Chem. Soc. 133, 13774–13777 (2011).

  32. 32.

    , , , & Structure–activity relationship (SAR) study of ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017) and the potential of the lead against multidrug resistance in cancer treatment. J. Med. Chem. 55, 5566–5581 (2012).

  33. 33.

    , , & Synthesis of atropisomerically defined, highly substituted biaryl scaffolds through catalytic enantioselective bromination and regioselective cross-coupling. Angew. Chem. Int. Ed. 50, 5125–5129 (2011).

  34. 34.

    , , & Regioselective synthesis and slow-release Suzuki–Miyaura cross-coupling of MIDA boronate-functionalized isoxazoles and triazoles. J. Org. Chem. 76, 10241–10248 (2011).

  35. 35.

    et al. Quaterpyridine ligands for panchromatic Ru(II) dye sensitizers. J. Org. Chem. 77, 7945–7956 (2012).

  36. 36.

    , & Nucleophilic substitution of fluorine atoms in 2,6-difluoro-3-(pyridine-2-yl)benzonitrile leading to soluble blue-emitting cyclometalated Ir(III) complexes. J. Org. Chem. 76, 5143–5148 (2011).

  37. 37.

    , & Dansyl-containing boronate hydrogel film as fluorescent chemosensor of copper ions in water. RSC Adv. 2, 6555–6561 (2012).

  38. 38.

    Dictionary of Natural Products Version 22.1 (Taylor and Francis Group, 2013); dnp.chemnetbase.com

  39. 39.

    et al. Nigerapyrones A–H, α-pyrone derivatives from the marine mangrove-derived endophytic fungus Aspergillus niger MA-132. J. Nat. Prod. 74, 1787–1791 (2011).

  40. 40.

    et al. Physarigins A–C, three new yellow pigments from a cultured Myxomycete Physarum rigidum. Tetrahedron Lett. 44, 4479–4481 (2003).

  41. 41.

    et al. A new carotenoid glycosyl ester isolated from a marine microorganism, Fusarium strain T-1. J. Nat. Prod. 65, 1683–1684 (2002).

  42. 42.

    Boronic Acids (Wiley-VHC, 2005).

  43. 43.

    et al. Amphotericin primarily kills yeast by simply binding ergosterol. Proc. Natl Acad. Sci. USA 109, 2234–2239 (2012).

  44. 44.

    , & A new palladium precatalyst allows for the fast Suzuki–Miyaura coupling reactions of unstable polyfluorophenyl and 2-heteroaryl boronic acids. J. Am. Chem. Soc. 132, 14073–14075 (2010).

  45. 45.

    , & A general solution for unstable boronic acids: slow-release cross-coupling from air-stable MIDA boronates. J. Am. Chem. Soc. 131, 6961–6963 (2009).

  46. 46.

    & CuCl–K2CO3-catalyzed highly selective borylcupration of internal alkynes – ligand effect. Org. Biomol. Chem. 10, 7266–7268 (2012).

  47. 47.

    et al. Synthesis and biological evaluation of polyenylpyrrole derivatives as anticancer agents acting through caspases-dependent apoptosis. J. Med. Chem. 53, 7967–7978 (2010).

  48. 48.

    , & Efficient and selective syntheses of (all-E)- and (6E,10Z)-2′-O-methylmyxalamides D via Pd-catalyzed alkenylation–carbonyl olefination synergy. Org. Lett. 10, 3223–3226 (2008).

  49. 49.

    , & Ethynyl MIDA boronate: a readily accessible and highly versatile building block for small molecule synthesis. Tetrahedron 66, 4710–4718 (2010).

  50. 50.

    , , & Cross coupling reactions of chiral secondary organoboronic esters with retention of configuration. J. Am. Chem. Soc. 131, 5024–5025 (2009).

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Acknowledgements

We gratefully acknowledge A. Hill for helping to complete the synthesis of physarigin A and S. O'Hara and S. Fujii for building-block synthesis, as well as the National Institutes of Health (GM080436 and GM090153) and Howard Hughes Medical Institute (HHMI) for funding. M.D.B. is an HHMI Early Career Scientist and E.M.W. was a Natural Science Foundation Predoctoral Fellow.

Author information

Affiliations

  1. Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA

    • Eric M. Woerly
    • , Jahnabi Roy
    •  & Martin D. Burke

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Contributions

E.M.W. and M.D.B. conceived the project. E.M.W., J.R. and M.D.B. designed and executed the experiments. E.M.W. and M.D.B. wrote the paper.

Competing interests

The University of Illinois has filed patents on MIDA boronate chemistry.

Corresponding author

Correspondence to Martin D. Burke.

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Crystallographic information files

  1. 1.

    Supplementary information

    Crystallographic data for compound BB1

  2. 2.

    Supplementary information

    Crystallographic data for compound BB2

  3. 3.

    Supplementary information

    Crystallographic data for compound BB3

  4. 4.

    Supplementary information

    Crystallographic data for compound BB4

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DOI

https://doi.org/10.1038/nchem.1947

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