PDF herunterladen
Synlett 2012; 23(17): 2539-2543
DOI: 10.1055/s-0031-1290461
letter
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Farnesol Analogues Containing Triazoles in Place of Isoprenes through ‘Click Chemistry’

Thangaiah Subramanian
a   Department of Cellular and Molecular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA   eMail: hps@uky.edu
,
Sean Parkin
b   Department of Chemistry, University of Kentucky, Lexington, KY, 40536, USA
,
H. Peter Spielmann*
a   Department of Cellular and Molecular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA   eMail: hps@uky.edu
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received: 12. Juli 2012

Accepted after revision: 17. August 2012

Publikationsdatum:
28. September 2012 (online)

    Lizenzen und Reprints Alle Artikel dieser Rubrik


Abstract

A solid-phase three-component Huisgen reaction has been used to generate polar farnesol and farnesyl diphosphate analogues. The Cu(I)-catalyzed 1,3-cycloadditions of various azides with solid supported (E)-3-methylhept-2-en-6-yn-1-ol provided only the 1,4-disubstituted 1,2,3-triazole regioisomers. The organic azides were generated in situ to minimize handling of potentially explosive azides. We have employed this powerful ‘click chemistry’ to make farnesol analogues where both β- and γ-isoprenes were replaced by triazole and substituted aromatic rings, respectively.

Key words

farnesol - farnesyldiphosphate - cancer - cycloaddition - triazoles - solid-phase synthesis - click chemistry

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett. Included are the detailed experimental procedure and spectroscopic data of 4a–k and 5; 1H spectra and HRMS data sheet of 4a–k; and 1H, 31P, and LRMS spectra of 5.
  • Supporting Information
 

  • References and Notes

  • 1 Turek TC, Gaon I, Distefano MD, Strickland CL. J. Org. Chem. 2001; 66: 3253
    CrossrefPubMedSuche in Google Scholar
  • 2 Kale TA, Hsieh SJ, Rose MW, Distefano MD. Curr. Top. Med. Chem. 2003; 3: 1043
    CrossrefPubMedSuche in Google Scholar
  • 3 Gibbs BS, Zahn TJ, Mu Y, Sebolt-Leopold JS, Gibbs RA. J. Med. Chem. 1999; 42: 3800
    CrossrefPubMedSuche in Google Scholar
  • 4 Chehade KA, Andres DA, Morimoto H, Spielmann HP. J. Org. Chem. 2000; 65: 3027
    CrossrefPubMedSuche in Google Scholar
  • 5 Micali E, Chehade KA, Isaacs RJ, Andres DA, Spielmann HP. Biochemistry 2001; 40: 12254
    CrossrefPubMedSuche in Google Scholar
  • 6 Reigard SA, Zahn TJ, Haworth KB, Hicks KA, Fierke CA, Gibbs RA. Biochemistry 2005; 44: 11214
    CrossrefPubMedSuche in Google Scholar
  • 7 Zhang FL, Casey PJ. Annu. Rev. Biochem. 1996; 65: 241
    CrossrefPubMedSuche in Google Scholar
  • 8 Clarke S. Annu. Rev. Biochem. 1992; 61: 355
    CrossrefPubMedSuche in Google Scholar
  • 9 Bos JL. Cancer Res. 1989; 49: 4682
    PubMedSuche in Google Scholar
  • 10 Kloog Y, Cox AD. Semin. Cancer Biol. 2004; 14: 253
    CrossrefPubMedSuche in Google Scholar
  • 11 Gschwind A, Fischer OM, Ullrich A. Nat. Rev. Cancer 2004; 4: 361
    CrossrefPubMedSuche in Google Scholar
  • 12 Roberts MJ, Troutman JM, Chehade KA, Cha HC, Kao JP, Huang X, Zhan CG, Peterson YK, Subramanian T, Kamalakkannan S, Andres DA, Spielmann HP. Biochemistry 2006; 45: 15862
    CrossrefPubMedSuche in Google Scholar
  • 13 Troutman JM, Subramanian T, Andres DA, Spielmann HP. Biochemistry 2007; 46: 11310
    CrossrefPubMedSuche in Google Scholar
  • 14 Subramanian T, Liu S, Troutman JM, Andres DA, Spielmann HP. ChemBioChem 2008; 9: 2872
    CrossrefPubMedSuche in Google Scholar
  • 15 Subramanian T, Wang Z, Troutman JM, Andres DA, Spielmann HP. Org. Lett. 2005; 7: 2109
    CrossrefPubMedSuche in Google Scholar
  • 16 Blaney P, Grigg R, Sridharan V. Chem. Rev. 2002; 102: 2607
    CrossrefPubMedSuche in Google Scholar
  • 17 Hein JE, Fokin VV. Chem. Soc. Rev. 2010; 39: 1302
    Suche in Google Scholar
  • 18 Meldal M, Tornoe CW. Chem. Rev. 2008; 108: 2952
    Suche in Google Scholar
  • 19 Tron GC, Pirali T, Billington RA, Canonico PL, Sorba G, Genazzani AA. Med. Res. Rev. 2008; 28: 278
    CrossrefPubMedSuche in Google Scholar
  • 20 Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew. Chem. Int. Ed. Engl. 2002; 41: 2596
    CrossrefPubMedSuche in Google Scholar
  • 21 Lober S, Rodriguez-Loaiza P, Gmeiner P. Org. Lett. 2003; 5: 1753
    CrossrefPubMedSuche in Google Scholar
  • 22 Loaiza PR, Lober S, Hubner H, Gmeiner P. J. Comb. Chem. 2006; 8: 252
    CrossrefPubMedSuche in Google Scholar
  • 23 Liu Y, Wang XF, Chen Y, Zhang LH, Yang ZJ. Med. Chem. Commun. 2012; 3: 506
    CrossrefSuche in Google Scholar
  • 24 Oyelere AK, Chen PC, Yao LP, Boguslavsky N. J. Org. Chem. 2006; 71: 9791
    CrossrefPubMedSuche in Google Scholar
  • 25 Papst S, Noisier A, Brimble MA, Yang Y, Krissansen GW. Bioorg. Med. Chem. 2012; 20: 2638
    CrossrefPubMedSuche in Google Scholar
  • 26 Baccile JA, Morrell MA, Falotico RM, Milliken BT, Drew DL, Rossi FM. Tetrahedron Lett. 2012; 53: 1933
    CrossrefSuche in Google Scholar
  • 27 Bouillon C, Meyer A, Vidal S, Jochum A, Chevolot Y, Cloarec JP, Praly JP, Vasseur JJ, Morvan F. J. Org. Chem. 2006; 71: 4700
    CrossrefPubMedSuche in Google Scholar
  • 28 Bock VD, Hiemstra H, van Maarseveen JH. Eur. J. Org. Chem. 2006; 51
  • 29 Holub JM, Kirshenbaum K. Chem. Soc. Rev. 2010; 39: 1325
    CrossrefPubMedSuche in Google Scholar
  • 30 Isobe H, Fujino T, Yamazaki N, Guillot-Nieckowski M, Nakamura E. Org. Lett. 2008; 10: 3729
    CrossrefPubMedSuche in Google Scholar
  • 31 Bergman JA, Hahne K, Song J, Hrycyna CA, Gibbs RA. ACS Med. Chem. Lett. 2012; 3: 15
    CrossrefPubMedSuche in Google Scholar
  • 32 Kogl M, Brecker L, Warrass R, Mulzer J. Eur. J. Org. Chem. 2008; 2714
  • 33 Presolski SI, Hong V, Cho SH, Finn MG. J. Am. Chem. Soc. 2010; 132: 14570
    CrossrefPubMedSuche in Google Scholar
  • 34 Cohrt AE, Jensen JF, Nielsen TE. Org. Lett. 2010; 12: 5414
    CrossrefPubMedSuche in Google Scholar
  • 35 Peet NP, Weintraub PM. Chem. Eng. News 1993; 71 (16): 4
    Suche in Google Scholar
  • 36 Peet NP, Weintraub PM. Chem. Eng. News 1994; 72 (11): 4
    Suche in Google Scholar
  • 37 Weisenburger GA, Vogt PF. Org. Process Res. Dev. 2006; 10: 1246
    CrossrefSuche in Google Scholar
  • 38 Conrow RE, Dean WD. Org. Process Res. Dev. 2008; 12: 1285
    CrossrefSuche in Google Scholar
  • 39 Lee BY, Park SR, Jeon HB, Kim KS. Tetrahedron Lett. 2006; 47: 5105
    CrossrefSuche in Google Scholar
  • 40 Typical Procedure for Cycloaddition Adducts 12a–k Reaction vessels were charged with resin 11 (100 mg) and NaN3 (57.6 mg, 0.99 mmol, 10 equiv) followed by DMF (5 mL) and then CuI (3 mg) and agitate was initiated. Hünig’s base (114 mg, 0.99 mmol, 10 equiv) was added, and, finally, the bromide (0.99 mmol, 10 equiv) was added. The resultant mixture was agitated for 1 d at r.t., heated to 50 °C for 3 h, then cooled. Then the resin was filtered and washed with DMF (2×), DMF–H2O (1:1, 2×), DMF (2×), CH2Cl2 (3×), Et2O (2×) and dried in vacuo. General Procedure for the Synthesis of Alcohols 4a–k Resin (100 mg) was heated at 80 °C with DCE–anhyd MeOH (1:1, 8 mL) in the presence of PPTS (5 mg) for 8 h. The liquid phase was collected, the resin was rinsed with CH2Cl2, and the washings were combined and sequentially washed with sat. aq NaHCO3, H2O, brine, dried over MgSO4, concentrated, and purified by silica gel column chromatography to give 4a–k. Compound 4a: 1H NMR (400 MHz, CDCl3): δ = 1.68 (s, 3 H), 2.35 (t, J = 8.4 Hz, 2 H), 2.81–2.85 (m, 2 H), 4.10 (d, J = 7.6 Hz, 2 H), 5.34–5.38 (m, 1 H), 5.48 (s, 2 H), 7.20 (s, 1 H), 7.21–7.27 (m, 2 H), 7.32–7.40 (m, 3 H) ppm. LRMS [M + H+]: m/z = 258.2. HRMS [M+]: m/z calcd for C15H19N3O: 257.1528; found: 257.1529. Compound 4b: 1H NMR (400 MHz, CDCl3): δ = 1.63 (s, 3 H), 2.31 (t, J = 8.0 Hz, 2 H), 2.81 (t, J = 8.0 Hz, 2 H), 4.10 (d, J = 6.8 Hz, 2 H), 5.33 (t, J = 6.8 Hz, 1 H), 5.58 (s, 2 H), 7.32–7.35 (m, 3 H), 8.14 (d, J = 10.8 Hz, 2 H) ppm. LRMS [M + H+]: m/z = 302.2. HRMS [M+]: m/z calcd for C15H18N4O3: 302.1379; found: 302.1375. Compound 4c: 1H NMR (400 MHz, CDCl3): δ = 1.29 (s, 3 H), 1.66 (s, 3 H), 2.33 (t, J = 8.0 Hz, 2 H), 2.80 (t, J = 7.6 Hz, 2 H), 4.10 (d, J = 6.8 Hz, 2 H), 5.37 (t, J = 6.8 Hz, 1 H), 5.43 (s, 2 H), 7.16–7.20 (m, 3 H), 7.36 (d, J = 8.4 Hz, 2 H) ppm. LRMS [M + H+]: m/z = 314.2. HRMS [M+]: m/z calcd for C19H27N3O: 313.2154; found: 313.2154. Compound 4d: 1H NMR (400 MHz, CDCl3): δ = 1.23 (d, J = 6.8 Hz, 6 H), 1.69 (s, 3 H), 2.35 (t, J = 8.4 Hz, 2 H), 2.83 (t, J = 8.4 Hz, 2 H), 2.87–2.94 (m, 1 H), 4.10 (d, J = 6.8 Hz, 2 H), 5.30 (t, J = 8.0 Hz, 1 H), 5.44 (s, 2 H), 7.16–7.26 (m, 4 H) ppm. LRMS [M + H+]: m/z = 300.2. HRMS [M+]: m/z calcd for C18H25N3O: 299.1998; found: 299.2002. Compound 4e: 1H NMR (400 MHz, CDCl3): δ = 1.69 (s, 3 H), 2.35 (t, J = 8.0 Hz, 2 H), 2.83 (t, J = 8.0 Hz, 2 H), 4.11 (d, J = 6.8 Hz, 2 H), 5.38 (t, J = 8.0 Hz, 1 H), 5.45 (s, 2 H), 7.02–7.09 (m, 2 H), 7.21–7.26 (m, 3 H) ppm. LRMS [M + H+]: m/z = 276.2. HRMS [M+]: m/z calcd for C15H18FN3O: 275.1434; found: 275.1431. Compound 4f: 1H NMR (400 MHz, CDCl3): δ = 1.69 (s, 3 H), 2.36 (t, J = 8.0 Hz, 2 H), 2.84 (t, J = 8.0 Hz, 2 H), 4.11 (d, J = 6.8 Hz, 2 H), 5.38 (t, J = 8.0 Hz, 1 H), 5.48 (s, 3 H), 6.91 (d, J = 9.2 Hz, 1 H), 7.02–7.05 (m, 2 H), 7.30–7.35 (m, 1 H) ppm. LRMS [M + H+]: m/z = 276.2. HRMS [M+]: m/z calcd for C15H18FN3O: 275.1434; found: 275.1437. Compound 4g: 1H NMR (400 MHz, CDCl3): δ = 1.69 (s, 3 H), 2.36 (t, J = 8.0 Hz, 2 H), 2.83 (t, J = 8.0 Hz, 2 H), 4.11 (d, J = 6.8 Hz, 2 H), 5.38 (t, J = 8.0 Hz, 1 H), 5.54 (s, 2 H), 7.08–7.37 (m, 4 H) ppm. LRMS [M + H+]: m/z = 276.2. HRMS [M+]: m/z calcd for C15H18FN3O: 275.1434; found: 275.1429. Compound 4h: 1H NMR (400 MHz, CDCl3): δ = 1.71 (s, 3 H), 2.38 (t, J = 8.0 Hz, 2 H), 2.86 (t, J = 8.0 Hz, 2 H), 4.12 (t, J = 6.8 Hz, 2 H), 5.39 (t, J = 8.0 Hz, 1 H), 5.52 (s, 2 H), 7.10–7.25 (m, 4 H), 7.40 (t, J = 8.0 Hz, 1 H) ppm. LRMS [M + H+]: m/z = 341.2. HRMS [M+]: m/z calcd for C16H18F3N3O2: 341.1350; found: 341.1359. Compound 4i: 1H NMR (400 MHz, CDCl3): δ = 1.67 (s, 3 H), 2.35 (t, J = 8.0 Hz, 2 H), 2.83 (t, J = 8.0 Hz, 2 H), 4.11 (d, J = 6.8 Hz, 2 H), 5.39 (t, J = 8.0 Hz, 1 H), 5.52 (s, 2 H), 7.18–7.27 (m, 4 H) ppm. LRMS [M + H+]: m/z = 341.2. HRMS [M+]: m/z calcd for C16H18F3N3O2: 341.1350; found: 341.1357. Compound 4j: 1H NMR (400 MHz, CDCl3) δ = 1.69 (s, 3H), 2.36 (t, J = 8.0Hz, 2H), 2.85 (t, J = 8.0Hz, 2H), 4.11 (d, J = 6.8 Hz, 2 H), 5.38 (t, J = 8.0 Hz, 1 H), 5.53 (s, 2 H), 7.29 (s, 1 H), 7.47–7.50 (m, 2 H), 7.61–7.63 (m, 1 H) ppm. LRMS [M + H+]: m/z = 283.2. HRMS [M+]: m/z calcd for C16H18N4O: 282.1480; found: 282.1482. Compound 4k: 1H NMR (400 MHz, CDCl3): δ = 1.70 (s, 3 H), 2.38 (t, J = 8.0 Hz, 2 H), 2.87 (t, J = 8.0 Hz, 2 H), 4.12 (d, J = 6.8 Hz, 2 H), 5.38 (t, J = 8.0 Hz, 1 H), 5.56 (s, 2 H), 5.56 (s, 2 H), 7.26 (s, 1 H), 7.31 (d, J = 12.0 Hz, 2 H), 7.65 (d, J = 12.0 Hz, 2 H) ppm. LRMS [M + H+]: m/z = 283.2. HRMS [M+]: m/z calcd for C16H18N4O: 282.1480; found: 282.1487. Procedure for the Synthesis of (E)-5-(1-Benzyl-1H-1,2,3-triazol-4-yl)-3-methylpent-2-en-1-yl Diphosphate (5) The vacuum-dried resin 12a (100 mg, 0.09 mmol) was suspended in CH2Cl2 (2 mL), Ph3PBr2 (84 mg, 0.19 mmol) was added, and the slurry was stirred at r.t. under N2 for 4 h. Tris[tetra(n-butyl)ammonium]hydrogen diphosphate (388 mg, 0.39 mmol) in anhyd MeCN (3 mL) was added and the reaction mixture was stirred at r.t. for 4 h under N2. The heterogeneous filtrate was concentrated, and the residue was suspended in 25 mM NH4HCO3 (4 mL) and extracted with Et2O (5 mL, 3×). The aqueous phase was applied to an NH4 + form DOWEX-AW-50 ion-exchange column (50 mL of resin) and eluted with four-column volume 25 mM NH4HCO3 buffer. The aqueous phase was lyophilized to obtain the crude diphosphate 5 as a white solid, which was dissolved in a minimum volume of 25 mM NH5CO3 buffer and purified by RP-HPLC (Varian Dynamax, 10 μm, 300 Å, C-4 (10 mm × 250 mm) column with a gradient mobile phase: 25 mM NH5AcO and MeCN.15 The product collected between 5.2–5.6 min was lyophilized to obtain compound 5 (9.0 mg, 19% in 2 steps). 1H NMR (400 MHz, D2O): δ = 1.44 (s, 3 H), 2.10 (t, J = 7.6 Hz, 2 H), 2.57 (t, J = 7.6 Hz, 2 H), 4.15 (t, J = 6.8 Hz, 2 H), 5.11 (t, 6.4 Hz, 1 H), 5.28 (s, 2 H), 7.03–7.05 (m, 1 H), 7.14–7.20 (m, 2 H), 7.50 (s, 1 H) ppm. 31P NMR (D2O, 161.8 MHz): δ = –6.80 (d, J = 21.36 Hz, 1 P), –10.40 (d, J = 21.36 Hz, 1 P). LRMS [M + H+]: m/z = 418.0.
  • 41 X-ray crystal data of the structure 4l have been deposited at the Cambridge Crystallographic Data Center with the deposition number CCDC 871186.