Crystalline Sponge Gallery

G026 · Diterpenoid

Ingenol

C20H28O5 · 348.44 g mol−1

First crystal structure · Angewandte Chemie International Edition 2026 · compound 15 →

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INTERACTIVE 3D STRUCTURE

Explore Ingenol in its crystalline sponge

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CHONCage
2D chemical structure of Ingenol
Ingenol · 2D chemical structure
3D crystal structure of Ingenol determined by the crystalline-sponge method
Ingenol · crystalline-sponge guest structure
Ingenol inside a crystalline sponge coordination cage
Ingenol · coordination-cage host–guest structure

Ingenol resolved by the crystalline-sponge method.

A legendary molecule in natural product chemistry and total synthesis.

Molecular formula
C20H28O5
Molecular weight
348.44 g mol−1
CCDC accession
2457662 ↗
Host
Pd6L4 cage
Study
Angew. Chem. 2026
Compound in publication
15

MOLECULAR HISTORY

From isolation to the first native-form crystal structure

Ingenol challenged structural chemists for six decades. Its densely oxygenated, strained tetracyclic framework inspired repeated synthesis campaigns, while the native molecule itself resisted conventional crystallization.

  1. 1966

    Isolation from Euphorbia ingens

    The synthesis literature traces the first isolation of ingenol to Hecker and co-workers. The natural product was obtained from Euphorbia ingens, from which its name was derived.1

  2. 1970

    Structure through a crystalline derivative

    Because native ingenol did not provide a suitable crystal, its tetracyclic framework was established through X-ray analysis of ingenol triacetate. The assignment therefore depended on a derivatized form rather than the native natural product.2

  3. 1996

    The unusual in/out stereochemical problem

    The strained bicyclo[4.4.1]undecane core places the C8 bridgehead stereochemistry in the broader context of in/out isomerism—one reason an unambiguous native-form determination remained valuable.3

  4. 2003–04

    Landmark total syntheses

    Independent total syntheses by the Tanino–Kuwajima and Winkler groups demonstrated distinct solutions to the congested polycyclic skeleton and its high density of oxygenated stereocentres.4, 5

  5. 2013–14

    A concise 14-step route

    Baran and co-workers reported a 14-step synthesis of (+)-ingenol from (+)-3-carene, followed by a detailed account of the strategy and its development.6, 1

  6. 2026

    Native ingenol observed by X-ray diffraction

    The crystalline sponge organized native ingenol inside a Pd6L4 cage. The resulting structure directly verified the absolute configuration and resolved the ring junctions without converting ingenol into a crystalline derivative.7

WHY THIS STRUCTURE MATTERS

Earlier crystallographic evidence came from a chemically modified triacetate. The 2026 structure is the first X-ray observation of ingenol itself in its native molecular form, closing the gap between isolation, synthesis and direct solid-state observation.

References

  1. McKerrall, S. J.; Jørgensen, L.; Kuttruff, C. A.; Ungeheuer, F.; Baran, P. S. “Development of a Concise Synthesis of (+)-Ingenol.” J. Am. Chem. Soc. 2014, 136, 5799–5810. DOI 10.1021/ja501881p ↗
  2. Zechmeister, K.; Brandl, F.; Hoppe, W.; Hecker, E.; Opferkuch, H. J.; Adolf, W. “Structure Determination of the New Tetracyclic Diterpene Ingenol-Triacetate with Triple Product Methods.” Tetrahedron Lett. 1970, 11, 4075–4078. DOI 10.1016/S0040-4039(01)98669-1 ↗
  3. Alder, R. W.; East, S. P. “In/Out Isomerism.” Chem. Rev. 1996, 96, 2097–2112. DOI 10.1021/cr940246k ↗
  4. Tanino, K.; Onuki, K.; Asano, K.; et al. “Total Synthesis of Ingenol.” J. Am. Chem. Soc. 2003, 125, 1498–1500. DOI 10.1021/ja029226n ↗
  5. Nickel, A.; Maruyama, T.; Tang, H.; et al. “Total Synthesis of Ingenol.” J. Am. Chem. Soc. 2004, 126, 16300–16301. DOI 10.1021/ja044123l ↗
  6. Jørgensen, L.; McKerrall, S. J.; Kuttruff, C. A.; Ungeheuer, F.; Felding, J.; Baran, P. S. “14-Step Synthesis of (+)-Ingenol from (+)-3-Carene.” Science 2013, 341, 878–882. DOI 10.1126/science.1241606 ↗
  7. He, W.; Takezawa, H.; Fujita, M. “Second-Generation Crystalline Sponges Enabling Consistent Structure Analysis Under Standardized Conditions for Diverse Molecules.” Angew. Chem. Int. Ed. 2026, 65, e202524615. DOI 10.1002/anie.202524615 ↗

SOURCE PUBLICATION

Second-Generation Crystalline Sponges Enabling Consistent Structure Analysis Under Standardized Conditions for Diverse Molecules

Angewandte Chemie International Edition 2026

DOI 10.1002/anie.202524615 ↗