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

Thangaiah Subramanian; Sean Parkin; H. Peter Spielmann

doi:10.1055/s-0031-1290461

Synlett, Table of Contents

Synlett 2012; 23(17): 2539-2543
DOI: 10.1055/s-0031-1290461

letter

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

Authors

Thangaiah Subramanian

^aDepartment of Cellular and Molecular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA Email: hps@uky.edu
Sean Parkin

^bDepartment of Chemistry, University of Kentucky, Lexington, KY, 40536, USA
H. Peter Spielmann*

^aDepartment of Cellular and Molecular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA Email: hps@uky.edu

Abstract

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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

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References

References and Notes
1 Turek TC, Gaon I, Distefano MD, Strickland CL. J. Org. Chem. 2001; 66: 3253
2 Kale TA, Hsieh SJ, Rose MW, Distefano MD. Curr. Top. Med. Chem. 2003; 3: 1043
3 Gibbs BS, Zahn TJ, Mu Y, Sebolt-Leopold JS, Gibbs RA. J. Med. Chem. 1999; 42: 3800
4 Chehade KA, Andres DA, Morimoto H, Spielmann HP. J. Org. Chem. 2000; 65: 3027
5 Micali E, Chehade KA, Isaacs RJ, Andres DA, Spielmann HP. Biochemistry 2001; 40: 12254
6 Reigard SA, Zahn TJ, Haworth KB, Hicks KA, Fierke CA, Gibbs RA. Biochemistry 2005; 44: 11214
7 Zhang FL, Casey PJ. Annu. Rev. Biochem. 1996; 65: 241
8 Clarke S. Annu. Rev. Biochem. 1992; 61: 355
9 Bos JL. Cancer Res. 1989; 49: 4682
10 Kloog Y, Cox AD. Semin. Cancer Biol. 2004; 14: 253
11 Gschwind A, Fischer OM, Ullrich A. Nat. Rev. Cancer 2004; 4: 361
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
13 Troutman JM, Subramanian T, Andres DA, Spielmann HP. Biochemistry 2007; 46: 11310
14 Subramanian T, Liu S, Troutman JM, Andres DA, Spielmann HP. ChemBioChem 2008; 9: 2872
15 Subramanian T, Wang Z, Troutman JM, Andres DA, Spielmann HP. Org. Lett. 2005; 7: 2109
16 Blaney P, Grigg R, Sridharan V. Chem. Rev. 2002; 102: 2607
17 Hein JE, Fokin VV. Chem. Soc. Rev. 2010; 39: 1302
18 Meldal M, Tornoe CW. Chem. Rev. 2008; 108: 2952
19 Tron GC, Pirali T, Billington RA, Canonico PL, Sorba G, Genazzani AA. Med. Res. Rev. 2008; 28: 278
20 Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew. Chem. Int. Ed. Engl. 2002; 41: 2596
21 Lober S, Rodriguez-Loaiza P, Gmeiner P. Org. Lett. 2003; 5: 1753
22 Loaiza PR, Lober S, Hubner H, Gmeiner P. J. Comb. Chem. 2006; 8: 252
23 Liu Y, Wang XF, Chen Y, Zhang LH, Yang ZJ. Med. Chem. Commun. 2012; 3: 506
24 Oyelere AK, Chen PC, Yao LP, Boguslavsky N. J. Org. Chem. 2006; 71: 9791
25 Papst S, Noisier A, Brimble MA, Yang Y, Krissansen GW. Bioorg. Med. Chem. 2012; 20: 2638
26 Baccile JA, Morrell MA, Falotico RM, Milliken BT, Drew DL, Rossi FM. Tetrahedron Lett. 2012; 53: 1933
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
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
30 Isobe H, Fujino T, Yamazaki N, Guillot-Nieckowski M, Nakamura E. Org. Lett. 2008; 10: 3729
31 Bergman JA, Hahne K, Song J, Hrycyna CA, Gibbs RA. ACS Med. Chem. Lett. 2012; 3: 15
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
34 Cohrt AE, Jensen JF, Nielsen TE. Org. Lett. 2010; 12: 5414
35 Peet NP, Weintraub PM. Chem. Eng. News 1993; 71 (16): 4
36 Peet NP, Weintraub PM. Chem. Eng. News 1994; 72 (11): 4
37 Weisenburger GA, Vogt PF. Org. Process Res. Dev. 2006; 10: 1246
38 Conrow RE, Dean WD. Org. Process Res. Dev. 2008; 12: 1285
39 Lee BY, Park SR, Jeon HB, Kim KS. Tetrahedron Lett. 2006; 47: 5105
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.¹⁵The 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.

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