Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Aug 20;136(33):11799-804.
doi: 10.1021/ja5060302. Epub 2014 Aug 7.

Rapid synthesis of polyprenylated acylphloroglucinol analogs via dearomative conjunctive allylic annulation

Alexander J Grenning  1 , Jonathan H Boyce, John A Porco Jr
Affiliations

Rapid synthesis of polyprenylated acylphloroglucinol analogs via dearomative conjunctive allylic annulation

Alexander J Grenning et al. J Am Chem Soc. .

Abstract

Polyprenylated acylphloroglucinols (PPAPs) are structurally complex natural products with promising biological activities. Herein, we present a biosynthesis-inspired, diversity-oriented synthesis approach for rapid construction of PPAP analogs via double decarboxylative allylation (DcA) of acylphloroglucinol scaffolds to access allyl-desoxyhumulones followed by dearomative conjunctive allylic alkylation (DCAA).

PubMed Disclaimer

Figures

Figure 1
Figure 1
Representative PPAP natural products.
Scheme 1
Scheme 1. Biosynthetic Hypothesis for PPAP’s
Scheme 2
Scheme 2. A Biosynthesis-Inspired DOS Approach to PPAP Analogs
Scheme 3
Scheme 3. Utility and Challenges Associated with Allyl-Desoxyhumulone 1a
Scheme 4
Scheme 4. Alternative Approaches to C-allylated phenols
Scheme 5
Scheme 5. Double DcA/Formal Claisen Rearrangement
Scheme 6
Scheme 6. Requirement of Pd(0) for [3,3]-Allyl Aryl Ether Claisen Rearrangement
Scheme 7
Scheme 7. Scope of Allyl-Desoxyhumulone Synthesis
Scheme 8
Scheme 8. Related Scaffolds for Pd-Catalyzed DcA
Scheme 9
Scheme 9. “Type A” PPAP Analogs via DCAA
Scheme 10
Scheme 10. “Type B” PPAP Analogs via DCAA
Scheme 11
Scheme 11. Importance of Alkyl Substitution at Both C4 and C6
Scheme 12
Scheme 12. Other Scaffolds That Undergo DCAA
Figure 2
Figure 2
X-ray crystal structure of analog 3h.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. For reviews on the chemistry and/or biology of PPAPs, see:

    2. Ciochina R.; Grossman R. B. Chem. Rev. 2006, 106, 3963. - PubMed
    3. Singh I. P.; Sidana J.; Bharate S. B.; Foley W. J. Nat. Prod. Rep. 2010, 27, 393. - PubMed
    4. Njardarson J. T. Tetrahedron 2011, 67, 7631. - PMC - PubMed
    5. Richard J.-A.; Pouwer R. H.; Chen D. Y.-K. Angew. Chem., Int. Ed. 2012, 51, 4536. - PubMed
    6. Richard J.-A. Eur. J. Org. Chem. 2014, 2014, 273.

    1. For selected examples of the PPAP biological activities and medicinal significance, see:

    2. Ito C.; Itoigawa M.; Miyamoto Y.; Onoda S.; Rao K. S.; Mukainaka T.; Tokuda H.; Nishino H.; Furukawa H. J. Nat. Prod. 2003, 66, 206. - PubMed
    3. Martinez-Poveda B.; Quesada A. R.; Medina M. A. Int. J. Cancer 2005, 117, 775. - PubMed
    4. Quiney C.; Billard C.; Salanoubat C.; Fourneron J. D.; Kolb J. P. Leukemia 2006, 20, 1519. - PubMed
    5. Gey C.; Kyrylenko S.; Hennig L.; Nguyen L.-H. D.; Buettner A.; Pham H. D.; Giannis A. Angew. Chem., Int. Ed. 2007, 46, 5219. - PubMed
    6. Diaz-Carballo D.; Malak S.; Freistuehler M.; Elmaagacli A.; Bardenheuer W.; Reusch H. P. Int. J. Clin. Pharmacol. Ther. 2008, 46, 428. - PubMed
    7. Diaz-Carballo D.; Ueberla K.; Kleff V.; Ergun S.; Malak S.; Freistuehler M.; Somogyi S.; Kuecherer C.; Bardenheuer W.; Strumberg D. Int. J. Clin. Pharmacol. Ther. 2010, 48, 670. - PubMed
    8. Dal Fabrizio P.; Tosco A.; Eletto D.; Piccinelli A. L.; Moltedo O.; Franceschelli S.; Sbardella G.; Remondelli P.; Rastrelli L.; Vesci L.; Pisano C.; De Nunziatina T. ChemBioChem. 2010, 11, 818. - PubMed
    9. Wolf R. J.; Hilger R. A.; Hoheisel J. D.; Werner J.; Holtrup F. PLoS One 2013, 8, e74555. - PMC - PubMed
    10. Winkelmann K.; Heilmann J.; Zerbe O.; Rali T.; Sticher O. J. Nat. Prod. 2001, 64, 701. - PubMed

    1. For select examples highlighting synthetic strategies toward PPAPs, see:

    2. Spessard S. J.; Stoltz B. M. Org. Lett. 2002, 4, 1943. - PubMed
    3. Tsukano C.; Siegel D. R.; Danishefsky S. J. Angew. Chem., Int. Ed. 2007, 46, 8840. - PubMed
    4. Qi J.; Porco J. A. Jr. J. Am. Chem. Soc. 2007, 129, 12682. - PMC - PubMed
    5. Couladouros E. A.; Dakanali M.; Demadis K. D.; Vidali V. P. Org. Lett. 2009, 11, 4430. - PubMed
    6. Mitasev B.; Porco J. A. Org. Lett. 2009, 11, 2285. - PMC - PubMed
    7. Garnsey M. R.; Lim D.; Yost J. M.; Coltart D. M. Org. Lett. 2010, 12, 5234. - PubMed
    8. Zhang Q.; Mitasev B.; Qi J.; Porco J. A. J. Am. Chem. Soc. 2010, 132, 14212. - PMC - PubMed
    9. Biber N.; Moews K.; Plietker B. Nat. Chem. 2011, 3, 938. - PubMed
    10. Richard J.-A.; Chen D. Y.-K. Eur. J. Org. Chem. 2012, 2012, 484.
    11. Richard J.-A.; Pouwer R. H.; Chen D. Y.-K. Angew. Chem., Int. Ed. 2012, 51, 4536. - PubMed
    12. Uwamori M.; Saito A.; Nakada M. J. Org. Chem. 2012, 77, 5098. - PubMed
    13. Zhang Q.; Porco J. A. Jr. Org. Lett. 2012, 14, 1796. - PMC - PubMed
    14. Sparling B. A.; Moebius D. C.; Shair M. D. J. Am. Chem. Soc. 2012, 135, 644. - PubMed
    15. Lindermayr K.; Plietker B. Angew. Chem., Int. Ed. 2013, 52, 12183. - PubMed
    16. Horeischi F.; Biber N.; Plietker B. J. Am. Chem. Soc. 2014, 136, 4026. - PubMed
    17. Boyce J. H.; Porco J. A. Jr. Angew. Chem., Int. Ed. 2014, 53, 7832. - PMC - PubMed
    18. Bellavance G.; Barriault L. Angew. Chem., Int. Ed. 2014, 53, 6701. - PubMed

    1. PPAP salts have been prepared to increase the shelf life of the natural products:

    2. Dona M.; Dell’Aica I.; Pezzato E.; Sartor L.; Calabrese F.; Della Mila B.; Donella-Deana A.; Appendino G.; Borsarini A.; Caniato R.; Garbisa S. Cancer Res. 2004, 64, 6225. - PubMed
    3. Liu J.-Y.; Liu Z.; Wang D.-M.; Li M.-M.; Wang S.-X.; Wang R.; Chen J.-P.; Wang Y.-F.; Yang D.-P. Chem.-Biol. Interact. 2011, 190, 91. - PubMed

    1. For examples of synthetic or semisynthetic PPAP analogs, see:

    2. Gartner M.; Müller T.; Simon J. C.; Giannis A.; Sleeman J. P. ChemBioChem. 2005, 6, 171. - PubMed
    3. van Klink J. W.; Larsen L.; Perry N. B.; Weavers R. T.; Cook G. M.; Bremer P. J.; MacKenzie A. D.; Kirikae T. Bioorg. Med. Chem. 2005, 13, 6651. - PubMed

Publication types