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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
› Author Affiliations
Further Information

Publication History

Received: 12 July 2012

Accepted after revision: 17 August 2012

Publication Date:
28 September 2012 (online)

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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

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  • 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.