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

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

• 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.