Article

The total synthesis of hyperpapuanone, hyperibone L, epi-clusianone and oblongifolin A

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Abstract

Polyprenylated polycyclic acylphloroglucines (PPAPs) are a family of natural products that possess a wide range of different important biological activities because of the relative position and configuration of four substituents that decorate one common central bicyclo[3.3.1]nonane-2,4,9-trione core. The rigid bicyclic framework with its lipophilic side chains and its hydrophilic trione moiety represents a nature-derived lead structure that arranges the substituents (R1 to R4) into a defined topographical orientation. As the substituents are responsible for the biological activities, the seven-step synthetic approach presented here sets the stage for an iterative introduction of R1 to R4 and thus generates structurally diverse trans-type B PPAPs. Four natural and one non-natural trans-type B PPAPs were prepared starting from acetylacetone with overall yields that ranged from 6 to 22%. The concept of separating framework construction from decorating transformations plus the minimization of protecting-group operations are the key issues for the realization of our synthetic approach.

  • Compound C38H50O6

    Oblongifolin A

  • Compound C33H42O4

    epi-Cusianone

  • Compound C29H36O4

    Hyperibone L

  • Compound C26H38O4

    Hyperpapuanone

  • Compound C26H38O4

    regio-Hyperpapuanone

  • Compound C14H22O

    (E)-6,10-Dimethyl-3-methyleneundeca-5,9-dien-2-one

  • Compound C9H14O

    6-Methyl-3-methylenehept-5-en-2-one

  • Compound C21H30O5

    (E)-Dimethyl 5-(3,7-dimethylocta-2,6-dienyl)-4-methyl-2-oxocyclohex-3-ene-1,3-dicarboxylate

  • Compound C16H22O5

    Dimethyl 4-methyl-5-(3-methylbut-2-enyl)-2-oxocyclohex-3-ene-1,3-dicarboxylate

  • Compound C26H38O4

    (1S*,5R*)-Methyl 3-acetyl-5-((E)-3,7-dimethylocta-2,6-dien-1-yl)-4-methyl-1-(3-methylbut-2-en-1-yl)-2-oxocyclohex-3-enecarboxylate

  • Compound C17H24O4

    (1S*,5R*)-Methyl 3-acetyl-1,4-dimethyl-5-(3-methylbut-2-en-1-yl)-2-oxocyclohex-3-enecarboxylate

  • Compound C21H30O4

    (1S*,5R*)-Methyl 3-acetyl-4-methyl-1,5-bis(3-methylbut-2-en-1-yl)-2-oxocyclohex-3-enecarboxylate

  • Compound C27H42O4

    (1S*,5R*)-Methyl 3-acetyl-5-((E)-3,7-dimethylocta-2,6-dien-1-yl)-4,4-dimethyl-1-(3-methylbut-2-en-1-yl)-2-oxocyclohexanecarboxylate

  • Compound C18H28O4

    (1S*,5R*)-Methyl 3-acetyl-1,4,4-trimethyl-5-(3-methylbut-2-en-1-yl)-2-oxocyclohexanecarboxylate

  • Compound C22H34O4

    (1S*,5R*)-Methyl 3-acetyl-4,4-dimethyl-1,5-bis(3-methylbut-2-en-1-yl)-2-oxocyclohexanecarboxylate

  • Compound C32H50O4

    (1S*,3S*,5R*)-Methyl 3-acetyl-5-((E)-3,7-dimethylocta-2,6-dien-1-yl)-4,4-dimethyl-1,3-bis(3-methylbut-2-en-1-yl)-2-oxocyclohexanecarboxylate

  • Compound C32H50O4

    (1S*,5R*)-Methyl 3-acetyl-5-((E)-3,7-dimethylocta-2,6-dien-1-yl)-4,4-dimethyl-1-(3-methylbut-2-en-1-yl)-2-((3-methylbut-2-en-1-yl)oxy)cyclohex-2-enecarboxylate

  • Compound C32H50O4

    (1S*,3R*,5R*)-Methyl 3-acetyl-5-((E)-3,7-dimethylocta-2,6-dien-1-yl)-4,4-dimethyl-1,3-bis(3-methylbut-2-en-1-yl)-2-oxocyclohexanecarboxylate

  • Compound C23H36O4

    (1S*,3S*,5R*)-Methyl 3-acetyl-1,4,4-trimethyl-3,5-bis(3-methylbut-2-en-1-yl)-2-oxocyclohexanecarboxylate

  • Compound C23H36O4

    (1S*,5R*)-Methyl 3-acetyl-1,4,4-trimethyl-5-(3-methylbut-2-en-1-yl)-2-((3-methylbut-2-en-1-yl)oxy)cyclohex-2-enecarboxylate

  • Compound C27H42O4

    (1S*,3S*,5R*)-Methyl 3-acetyl-4,4-dimethyl-1,3,5-tris(3-methylbut-2-en-1-yl)-2-oxocyclohexanecarboxylate

  • Compound C27H42O4

    (1S*,5R*)-Methyl 3-acetyl-4,4-dimethyl-1,5-bis(3-methylbut-2-en-1-yl)-2-((3-methylbut-2-en-1-yl)oxy)cyclohex-2-enecarboxylate

  • Compound C27H42O4

    (1S*,3R*,5R*)-Methyl 3-acetyl-4,4-dimethyl-1,3,5-tris(3-methylbut-2-en-1-yl)-2-oxocyclohexanecarboxylate

  • Compound C23H36O4

    (1S*,3S*,5R*)-Methyl 3-acetyl-3,4,4-trimethyl-1,5-bis(3-methylbut-2-en-1-yl)-2-oxocyclohexanecarboxylate

  • Compound C23H36O4

    (1S*,5R*)-Methyl 3-acetyl-2-methoxy-4,4-dimethyl-1,5-bis(3-methylbut-2-en-1-yl)cyclohex-2-enecarboxylate

  • Compound C23H36O4

    (1S*,3R*,5R*)-Methyl 3-acetyl-3,4,4-trimethyl-1,5-bis(3-methylbut-2-en-1-yl)-2-oxocyclohexanecarboxylate

  • Compound C30H38O4

    (1R*,5S*,7R*)-3-Benzoyl-4-methoxy-1,8,8-trimethyl-5,7-bis(3-methylbut-2-en-1-yl)bicyclo[3.3.1]non-3-ene-2,9-dione

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Acknowledgements

Dedicated to Barry M. Trost on the occasion of his 70th birthday. The authors thank the Deutsche Forschungsgemeinschaft, the Deutsche Krebshilfe e.V., the Landesgraduiertenstiftung Baden-Württemberg (PhD grant for N.B.) and the Studienstiftung des deutschen Volkes (PhD grant for K.M.) for financial support.

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Affiliations

  1. Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany

    • Nicole Biber
    • , Katrin Möws
    •  & Bernd Plietker

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Contributions

N.B. prepared the natural products 1–5. K.M. was involved in model studies towards the synthesis of O-methyl hyperibone and crystallized this compound (see Supplementary Information). B.P. designed the study, analysed the data and wrote the paper. All the authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Bernd Plietker.

Supplementary information

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    Supplementary information

Crystallographic information files

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    Supplementary information

    Crystallographic data for compound 21