Molecular Diversity

, Volume 20, Issue 2, pp 407–419 | Cite as

Tuning the Lewis acid phenol \(\varvec{ortho}\)-prenylation as a molecular diversity tool

  • Sebastián N. Jäger
  • Exequiel O. J. Porta
  • Guillermo R. Labadie
Full-Length Paper


A diversity-oriented approach for the synthesis of various structurally different prenylated alcohols from readily accessible and common precursors was developed. With varying approaches, this article describes some successful examples of a Friedel–Crafts alkylation using methoxyphenols and different prenyl alcohols (geraniol and (E,E)-farnesol). We demonstrated that just by varying the stoichiometry of the Lewis acid used, the course of the reaction can be shifted to produce the alkylated or the cyclized product. Eighteen unique products were obtained with good isolated yields by direct alkylation with or without a consecutive \(\pi \)-cationic cyclization.


Prenylated natural products Phenols Friedel–Crafts alkylation Selective C-prenylation 



The authors wish to express their gratitude to UNR (Universidad Nacional de Rosario), Fundación Josefina Prats, CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas, PIP 2009-11/0796 and PIP 2012-14/0448), Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT—2011-0589), and Fundación Bunge y Born (FBB 31/10). This investigation also received financial support (through GRL) from the UNICEF/UNDP/WORLD BANK/WHO Special Programme for Research and Training in Tropical Diseases (TDR). GRL is member of the Research Career of the Consejo Nacional de Investigaciones Científicas y Técnicas of Argentina (CONICET). S.G.J. and E.O.J.P thank CONICET for the award of a Fellowship.

Supplementary material

11030_2015_9644_MOESM1_ESM.pdf (4.2 mb)
Supplementary material 1 (pdf 4275 KB)


  1. 1.
    Botta B, Vitali A, Menendez P, Misiti D, Delle Monache G (2005) Prenylated flavonoids: pharmacology and biotechnology. Curr Med Chem 12:717–739. doi: 10.2174/0929867053202241 CrossRefPubMedGoogle Scholar
  2. 2.
    Hakim E, Achmad S, Juliawaty L, Makmur L, Syah Y, Aimi N, Kitajima M, Takayama H, Ghisalberti E (2006) Prenylated flavonoids and related compounds of the Indonesian Artocarpus (Moraceae). J Nat Med 60:161–184. doi: 10.1007/s11418-006-0048-0 Google Scholar
  3. 3.
    Steffan N, Grundmann A, Yin WB, Kremer A, Li SM (2009) Indole prenyltransferases from fungi: a new enzyme group with high potential for the production of prenylated indole derivatives. Curr Med Chem 16:218–231. doi: 10.2174/092986709787002772 CrossRefPubMedGoogle Scholar
  4. 4.
    Audoin C, Sanchez JA, Genta-Jouve G, Alfonso A, Rios L, Vale C, Thomas OP, Botana LM (2014) Autumnalamide, a prenylated cyclic peptide from the cyanobacterium Phormidium autumnale, acts on SH-SY5Y cells at the mitochondrial level. J Nat Prod 77:2196–2205. doi: 10.1021/np500374a CrossRefPubMedGoogle Scholar
  5. 5.
    Bertanha CS, Januário AH, Alvarenga TA, Pimenta LP, Cunha WR, Pauletti PM (2014) Quinone and hydroquinone metabolites from the ascidians of the genus Aplidium. Mar Drugs 12:3608–3633. doi: 10.3390/md12063608 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Sunassee SN, Davies-Coleman MT (2012) Cytotoxic and antioxidant marine prenylated quinones and hydroquinones. Nat Prod Rep 29:513–535. doi: 10.1039/C2NP00086E CrossRefPubMedGoogle Scholar
  7. 7.
    Epifano F, Genovese S, Menghini L, Curini M (2007) Chemistry and pharmacology of oxyprenylated secondary plant metabolites. Phytochemistry 68:939–953. doi: 10.1016/j.phytochem.2007.01.019 CrossRefPubMedGoogle Scholar
  8. 8.
    Brandt U (1999) Proton translocation in the respiratory chain involving ubiquinone—a hypothetical semiquinone switch mechanism for complex I. Biofactors 9:95–101. doi: 10.1002/biof.5520090203 CrossRefPubMedGoogle Scholar
  9. 9.
    Fournet A, Ferreira ME, Rojas de Arias A, Fuentes S, Torres S, Inchausti A, Yaluff G, Nakayama H, Mahiou V, Hocquemiller R, Cavé A (1996) In vitro and in vivo leishmanicidal studies of Peperomia galioides (Piperaceae). Phytomedicine 3:271–275. doi: 10.1016/S0944-7113(96)80065-1 CrossRefPubMedGoogle Scholar
  10. 10.
    Mahiou V, Roblot F, Hocquemiller R, Cavé A, Rojas De Arias A, Inchausti A, Yaluff G, Fournet A (1996) New prenylated quinones from Peperomia galioides. J Nat Prod 59:694–697. doi: 10.1021/np960148p CrossRefPubMedGoogle Scholar
  11. 11.
    Jeong J-H, Kang S-S, Park K-K, Chang H-W, Magae J, Chang Y-C (2010) p53-Independent induction of G1 arrest and p21WAF1/CIP1 expression by ascofuranone, an isoprenoid antibiotic, through downregulation of c-Myc. Mol Cancer Ther 9:2102–2113. doi: 10.1158/1535-7163.mct-09-1159 CrossRefPubMedGoogle Scholar
  12. 12.
    Yabu Y, Yoshida A, Suzuki T, C-i Nihei, Kawai K, Minagawa N, Hosokawa T, Nagai K, Kita K, Ohta N (2003) The efficacy of ascofuranone in a consecutive treatment on Trypanosoma brucei brucei in mice. Parasitol Int 52:155–164. doi: 10.1016/S1383-5769(03)00012-6 CrossRefPubMedGoogle Scholar
  13. 13.
    Kido Y, Sakamoto K, Nakamura K, Harada M, Suzuki T, Yabu Y, Saimoto H, Yamakura F, Ohmori D, Moore A, Harada S, Kita K (2010) Purification and kinetic characterization of recombinant alternative oxidase from Trypanosoma brucei brucei. BBA Bioenergetics 1797:443–450. doi: 10.1016/j.bbabio.2009.12.021 CrossRefPubMedGoogle Scholar
  14. 14.
    Wachter GA, Hoffmann JJ, Furbacher T, Blake ME, Timmermann BN (1999) Antibacterial and antifungal flavanones from Eysenhardtia texana. Phytochemistry 52:1469–1471. doi: 10.1016/S0031-9422(99)00221-6 CrossRefPubMedGoogle Scholar
  15. 15.
    Han QB, Qiao CF, Song JZ, Yang NY, Cao XW, Peng Y, Yang DJ, Chen SL, Xu HX (2007) Cytotoxic prenylated phenolic compounds from the twig bark of Garcinia xanthochymus. Chem Biodivers 4:940–946. doi: 10.1002/cbdv.200790083 CrossRefPubMedGoogle Scholar
  16. 16.
    Meragelman KM, McKee TC, Boyd MR (2001) Anti-HIV prenylated flavonoids from Monotes africanus. J Nat Prod 64:546–548. doi: 10.1021/np0005457 CrossRefPubMedGoogle Scholar
  17. 17.
    Osorio M, Aravena J, Vergara A, Taborga L, Baeza E, Catalan K, Gonzalez C, Carvajal M, Carrasco H, Espinoza L (2012) Synthesis and DPPH radical scavenging activity of prenylated phenol derivatives. Molecules 17:556–570. doi: 10.3390/molecules17010556 CrossRefPubMedGoogle Scholar
  18. 18.
    Kang SY, Lee KY, Sung SH, Park MJ, Kim YC (2001) Coumarins isolated from Angelica gigas inhibit acetylcholinesterase? Structure–activity relationships. J Nat Prod 64:683–685. doi: 10.1021/np000441w CrossRefPubMedGoogle Scholar
  19. 19.
    Verotta L, Appendino G, Belloro E, Bianchi F, Sterner O, Lovati M, Bombardelli E (2002) Synthesis and biological evaluation of hyperforin analogues. Part I. Modification of the enolized cyclohexanedione moiety. J Nat Prod 65:433–438. doi: 10.1021/np0105681 CrossRefPubMedGoogle Scholar
  20. 20.
    Nicolaou K, Pfefferkorn J, Schuler F, Roecker A, Cao G, Casida J (2000) Combinatorial synthesis of novel and potent inhibitors of NADH:ubiquinone oxidoreductase. Chem Biol 7:979–992. doi: 10.1016/S1074-5521(00)00047-8 CrossRefPubMedGoogle Scholar
  21. 21.
    Tanaka S, Tajima M, Tsukada M, Tabata M (1986) A comparative study on anti-inflammatory activities of the enantiomers, shikonin and alkannin. J Nat Prod 49:466–469. doi: 10.1021/np50045a014 CrossRefPubMedGoogle Scholar
  22. 22.
    Yao XS, Ebizuka Y, Noguchi H, Kiuchi F, Shibuya M, Iitaka Y, Seto H, Sankawa U (1991) Biologically active constituents of Arnebia euchroma: structure of arnebinol, an ANSA-type monoterpenylbenzenoid with inhibitory activity on prostaglandin biosynthesis. Chem Pharm Bull (Tokyo) 39:2956–2961CrossRefGoogle Scholar
  23. 23. Accessed 1 Oct 2015
  24. 24.
    Anantachoke N, Tuchinda P, Kuhakarn C, Pohmakotr M, Reutrakul V (2012) Prenylated caged xanthones: chemistry and biology. Pharm Biol 50:78–91. doi: 10.3109/13880209.2011.636176 CrossRefPubMedGoogle Scholar
  25. 25.
    Zhang S, Marshall D, Liebeskind LS (1999) Efficient Pd-catalyzed heterobenzylic cross-coupling using sulfonium salts as substrates and (PhO)(3)P as a supporting ligand. J Org Chem 64:2796–2804. doi: 10.1021/jo982250s CrossRefPubMedGoogle Scholar
  26. 26.
    Pettus TRR, Inoue M, Chen X-T, Danishefsky SJ (2000) A fully synthetic route to the neurotrophic illicinones? Syntheses of tricycloillicinone and bicycloillicinone aldehyde. J Am Chem Soc 122:6160–6168. doi: 10.1021/ja000521m CrossRefGoogle Scholar
  27. 27.
    Depew KM, Danishefsky SJ, Rosen N, Sepp-Lorenzino L (1996) Total synthesis of tryprostatin B? Generation of a nucleophilic prenylating species from a prenylstannane. J Am Chem Soc 118:12463–12464. doi: 10.1021/ja962954o CrossRefGoogle Scholar
  28. 28.
    Mulzer M, Lamb JR, Nelson Z, Coates GW (2014) Carbonylative enantioselective meso-desymmetrization of cis-epoxides to trans-beta-lactones: effect of salen-ligand electronic variation on enantioselectivity. Chem Commun (Camb) 50:9842–9845. doi: 10.1039/c4cc04397a CrossRefGoogle Scholar
  29. 29.
    Guanti G, Banfi L, Riva R (1994) Enzymatic asymmetrization of some prochiral and meso diols through monoacetylation with pig pancreatic lipase (PPL). Tetrahedron 5:9–12. doi: 10.1016/S0957-4166(00)80471-1 CrossRefGoogle Scholar
  30. 30.
    Ishibashi H, Ishihara K, Yamamoto H (2004) A new artificial cyclase for polyprenoids: enantioselective total synthesis of \((-)\)-chromazonarol, (+)-8-epi-puupehedione, and (-)-11’-deoxytaondiol methyl ether. J Am Chem Soc 126:11122–11123. doi: 10.1021/ja0472026
  31. 31.
    Jain AC, Prasad AK (1990) Synthesis of amorilin (euchrenone a3) and 5,7-dihydroxy-6\(^{\prime \prime }\),6\(^{\prime \prime }\)-dimethyl-6,8-di-C-prenylpyrano[2\(^{\prime \prime }\),3\(^{\prime \prime }\),4\(^{\prime }\),3\(^{\prime }\)]flavanone. Indian J Chem Sect B 29:525–528Google Scholar
  32. 32.
    Cheralathan KK, Kumar IS, Palanichamy M, Murugesan V (2003) Liquid phase alkylation of phenol with 4-hydroxybutan-2-one in the presence of modified zeolite HBEA. Appl Catal A Gen 241:247–260. doi: 10.1016/S0926-860X(02)00472-6
  33. 33.
    Hamaguchi F, Tsutsui T (2000) Assessment of genotoxicity of dental antiseptics: ability of phenol, guaiacol, p-phenolsulfonic acid, sodium hypochlorite, p-chlorophenol, m-cresol or formaldehyde to induce unscheduled DNA synthesis in cultured Syrian hamster embryo cells. Jpn J Pharmacol 83:273–276. doi: 10.1254/jjp.83.273 CrossRefPubMedGoogle Scholar
  34. 34.
    Brouwer GJ (1985) Use of guaiacol glycerine ether in clinical anaesthesia in the horse. Equine Vet J 17:133–136. doi: 10.1111/j.2042-3306.1985.tb02067.x CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Sebastián N. Jäger
    • 1
  • Exequiel O. J. Porta
    • 1
  • Guillermo R. Labadie
    • 1
  1. 1.Instituto de Química Rosario (IQUIR-CONICET), Facultad de Ciencias Bioquímicas y FarmacéuticasUniversidad Nacional de RosarioRosarioArgentina

Personalised recommendations