Tandem Azide-Alkyne 1,3-Dipolar Cycloaddition/Electrophilic Addition: A Concise Three-Component Route to 4,5-Disubstituted Triazolyl-Nucleosides

Abstract

A one-pot, three-component approach to a new family of 4,5-functionalized triazolyl-nucleosides is described. The method relies on the one-pot azide-alkyne 1,3-cycloaddition/electrophilic addition tandem reaction, which affords good yields of the corresponding 4,5-disubstituted nucleosides.

Key words

click - 3CR - tandem reaction - nucleosides

References and Notes

• 2a Simons C. Wu Q. Htar TT. Curr. Top. Med. Chem.  2005,  5:  1191 
• 2b Book review: Recent Advances in Nucleosides: Chemistry and Chemotherapy   Chu CK. Elsevier; Amsterdam: 2002. 
• 2c Wagner CR. Iyer VV. McIntee E. J. Med. Res. Rev.  2000,  417 
• 3a Kool ET. Acc. Chem. Res.  2002,  35:  936 
• 3b Guianvarc’h D. Fourrey J.-L. Maurisse R. Sun J.-S. Benhida R. Org. Lett.  2002,  4:  4209 
• 3c Guianvarc’h D. Fourrey J.-L. Sun J.-S. Maurisse R. Benhida R. Bioorg. Med. Chem.  2003,  11:  2751 
• 3d Leconte AM. Matsuda S. Hwang GT. Romesberg FE. Angew. Chem. Int. Ed.  2006,  45:  4326 
• 3e Zahn A. Leumann CJ. Chem. Eur. J.  2008,  14:  1087 
• 3f Vrábel M. Horáková P. Pivonková H. Kalachova L. Cernocká H. Cahová H. Pohl R. Sebest P. Havran L. Hocek M. Fojtzz M. Chem. Eur. J.  2009,  15:  1144 
• 3g Grigorenko NA. Leumann CJ. Chem. Eur. J.  2009,  15:  639 
• 3h Ober M. Müller H. Pieck C. Gierlich J. Carell T. J. Am. Chem. Soc.  2005,  127:  18143 
• 3i Seela F. Peng X. Li H. J. Am. Chem. Soc.  2005,  127:  7739 
• 3j Seela F. Chittepu P. J. Org. Chem.  2007,  72:  4358 
• 3k Schwögler A. Carell T. Org. Lett.  2000,  2:  1415 
• 3l Clever GH. Kaul C. Carell T. Angew. Chem. Int. Ed.  2007,  46:  6226 
• 3m Böge N. Jacobsen MI. Szombati Z. Baerns S. Di Pasquale F. Marx A. Meier C. Chem. Eur. J.  2008,  14:  11194 
• 3n Chandra M. Keller S. Gloeckner C. Bornemann B. Marx A. Chem. Eur. J.  2007,  13:  3558 
• 4a De Clercq E. Holy A. Nat. Rev. Drug Discov.  2005,  4:  928 
• 4b De Clercq E. Antivir. Res.  2005,  67:  56 
• 5a For the use of Eicar, Ribavirin and Mizoribine as Inosine Monophosphate Dehydrogenase (IMPDH) inhibitors, see: Moya J. Pizarro H. Jashés M. De Clercq E. Sandino AM. Antivir. Res.  2000,  48:  125; 
• 5b Shu Q. Nair V. Med. Res. Rev.  2008,  28:  219 
• 5c Barnard DL. Day CW. Bailey K. Heiner M. Montgomery R. Lauridsen L. Winslow S. Hoopes J. Li JK. Carson DA. Cottam HB. Sidwell RW. Antivir. Res.  2006,  71:  53 
• 6a Suwa A. Hirakata M. Kaneko Y. Sato S. Suzuki Y. Huwana M. Clin. Rheumatol.  2009,  28:  227 
• 6b Yokota S. Pediatr. Int.  2002,  44:  196 
• 7a Broggi J. Kumamoto H. Berteina-Raboin S. Nolan SP. Agrofoglio LA. Eur. J. Org. Chem.  2009,  1880 
• 7b Pradere U. Roy V. McBrayer TR. Schinazi RF. Agrofolio LA. Tetrahedron  2008,  64:  9044 
• 7c Joubert N. Shinazi RF. Agrofoglio LA. Tetrahedron  2005,  61:  11744 
• 8a Zhu R. Wang M. Xia Y. Qu F. Neyts J. Peng L. Bioorg. Med. Chem. Lett.  2008,  18:  3321 
• 8b Li W. Xia Y. Fan Z. Qu F. Wu Q. Peng L. Tetrahedron Lett.  2008,  49:  2804 
• 8c Xia Y. Li W. Qu F. Fan Z. Liu X. Berro C. Rauzy E. Peng L. Org. Biomol. Chem.  2007,  5:  1695 
• 9 Ackermann L. Potukichi HK. Landsberg D. Vicente R. Org. Lett.  2008,  10:  3081 
• 10 Li L. Zhang G. Zhu A. Zhang L. J. Org. Chem.  2008,  73:  3630 
• 11a El Akri K. Bougrin K. Balzarini J. Faraj A. Benhida R. Bioorg. Med. Chem. Lett.  2007,  17:  6656 
• 11b Guezguez R. Bougrin K. El Akri K. Benhida R. Tetrahedron Lett.  2006,  47:  4807 
• 12a Peyron C. Benhida R. Bories C. Loiseau P. Bioorg. Chem.  2005,  33:  439 
• 12b Spadafora M. Burger A. Benhida R. Synlett  2008,  1225 
• 12c Spadafora M. Mehiri M. Burger A. Benhida R. Tetrahedron Lett.  2008,  49:  3967 
• 12d Peyron C. Benhida R. Synlett  2009,  3:  472 
• 13a Tornoe CW. Christensen C. Meldal MJ. J. Org. Chem.  2002,  67:  3057 
• 13b Rostovtsev VV. Gree LG. Fokin VV. Sharpless KB. Angew. Chem. Int. Ed.  2002,  41:  2596 
• 14 For mechanistic studies on the Cu-catalyzed alkyne-azide 1,3-dipolar cycloaddition, see: Himo F. Locell T. Hilgtaf R. Rostovtsev VV. Noodleman L. Sharpless KB. Fokin VV. J. Am. Chem. Soc.  2005,  127:  210 
• 16a Benhida R. Blanchard P. Fourrey J.-L. Tetrahedron Lett.  1998,  39:  6849 
• 16b Wirth T. Hirt UH. Synthesis  1999,  1271 
• 16c Zhdankin VV. Stang PJ. Chem. Rev.  2002,  102:  2523 
• 16d Wirth T. Top. Curr. Chem.  2003,  224 
• 17 With excess of I₂ as electrophile the reaction was sluggish when only one equivalent of DIPEA was used

1

Present address: Laboratoire de Chimie des Plantes et de Synthèse Organique et Bioorganique, Faculté des Sciences, Université Mohamed-V Rabat-Agdal, Morocco

15

2a: ^¹H NMR (200 MHz, CDCl₃): δ = 1.36 (t, J = 7.1 Hz, 3 H, CH₃), 1.97 (s, 3 H, Ac), 2.07 (s, 6 H, Ac), 4.07 (dd, J = 12.3, 4.2 Hz, 1 H, H-5′), 4.25-4.50 (m, 4 H, H-4′, H-5′ and CH₂ ester), 5.72 (t, J = 5.5 Hz, 1 H, H-3′), 6.07 (dd, J = 5.5, 3.1 Hz, 1 H, H-2′), 6.12 (d, J = 3.1 Hz, 1 H, H-1′). ^¹³C NMR (50 MHz, CDCl₃): δ = 14.2, 20.4, 20.5, 20.6, 61.6, 62.5, 70.9, 73.9, 81.5, 90.3, 142.2, 159.9, 169.2, 169.4, 170.4. HRMS (ESI): m/z [M+H]⁺ calcd for C₁₆H₂₁N₃O₉I: 526.0322; found: 526.0317.

18

Typical procedure: To a solution of azido-sugar (1 mmol) in CH₂Cl₂ (10 mL) were successively added alkyne (1.1 equiv), electrophile (3 equiv), CuX (CuI, CuBr or CuCl, 1.1 equiv) and DIPEA (see Table  [¹] and Table  [²] ). The reaction mixture was stirred at r.t. until the reaction was complete as indicated by TLC. The mixture was filtered through Celite and the solvent was removed. The crude product was purified by flash silica gel chromatography (cyclohexane-EtOAc, 9:1→1:1) to afford the desired 1,4,5-trisubstituted triazoles.
Analytical data for selected compounds:
2d: ^¹H NMR (200 MHz, CDCl₃): δ = 1.28 (t, J = 7.1 Hz, 3 H, CH₃), 1.97 (s, 3 H, Ac), 1.98 (s, 3 H, Ac), 2.04 (s, 3 H, Ac), 4.05 (dd, J = 13.1, 5.1 Hz, 1 H, H-5′), 4.25-4.40 (m, 4 H, H-4′, H-5′ and CH₂ ester), 5.72 (t, J = 5.5 Hz, 1 H, H-3′), 5.88 (dd, J = 5.2, 3.0 Hz, 1 H, H-2′), 6.27 (d, J = 3.0 Hz, 1 H, H-1′), 7.17-7.25 (m, 3 H, H-Ar), 7.31-7.40 (m, 2 H, H-Ar). ^¹³C NMR (50 MHz, CDCl₃): δ = 14.3, 20.5, 20.6, 20.8, 61.7, 62.7, 71.0, 74.3, 81.2, 88.9, 128.3, 128.7, 129.9, 132.6, 136.8, 160.3, 169.2, 169.5, 170.7, 172.0. HRMS (ESI):
m/z [M + H]⁺ calcd for C₂₂H₂₆N₃O₉Se: 556.0834; found: 526.0829.
2e: ^¹H NMR (200 MHz, CDCl₃): δ = 0.93 (t, J = 7.1 Hz, 3 H, CH₃), 1.96 (s, 3 H, Ac), 2.02 (s, 3 H, Ac), 2.03 (s, 3 H, Ac), 2.37 (s, 3 H, CH₃Ph), 3.99 (dd, J = 12.3, 4.5 Hz, 1 H, H-5′), 4.07 (q, J = 7.1 Hz, 2 H, CH₂ ester), 4.17 (dd, J = 12.3, 3.3 Hz, 1 H, H-5′), 4.31 (dd, J = 7.9, 4.5 Hz, 1 H, H-4′), 5.59 (t, J = 4.7 Hz, 1 H, H-3′), 6.07 (m, 2 H, H-1′ and H-2′), 7.23 (d, J = 8.1 Hz, 2 H, H-Ar), 7.59 (d, J = 8.1 Hz, 2 H, H-Ar). ^¹³C NMR (50 MHz, CDCl₃): δ = 13.6, 20.3, 20.4, 20.6, 21.9, 61.6, 62.5, 70.8, 73.7, 81.7, 89.4, 129.7, 133.7, 137.6, 138.8, 146.5, 159.4, 169.1, 169.4, 170.4, 185.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₈N₃O₁₀: 518.1775; found: 518.1781.
2h: ^¹H NMR (200 MHz, CDCl₃): δ = 3.86 (s, 3 H, OCH₃), 4.61 (dd, J = 12.2, 4.9 Hz, 1 H, H-5′), 4.78 (dd, J = 12.2, 3.7 Hz, 1 H, H-5′), 4.94 (dd, J = 10.9, 5.3 Hz, 1 H, H-4′), 6.35 (dd, J = 7.0, 5.1 Hz, 1 H, H-3′), 6.40 (d, J = 2.0 Hz, 1 H, H-1′), 6.50 (dd, J = 5.1, 2.0 Hz, 1 H, H-2′), 7.00 (d, J = 8.9 Hz, 2 H, H-Ar), 7.30-7.65 (m, 9 H, H-Ar), 7.85-8.10 (m, 8 H, H-Ar). ^¹³C NMR (50 MHz, CDCl₃): δ = 55.4, 63.7, 71.9, 75.1, 81.2, 88.2, 114.3, 121.5, 128.1, 128.5, 128.6, 128.7, 130.0, 133.3, 133.7, 134.0, 142.3, 160.1, 165.2, 166.3.
MS (ES): m/z = 75.8 [M + Na].

19

To a solution of 2a (1 mmol) in toluene (10 mL) were successively added 2-(tributylstannyl)furan (2 equiv), Pd(PPh₃)₂Cl₂ (5 mol%), CuI (5 mol%) and Et₃N (1 equiv). The reaction mixture was stirred for 30 min at 80 ˚C. After the reaction was complete (^¹H NMR monitoring), the mixture was filtered through Celite and the solvent was removed. The crude product was purified by flash silica gel chromatography (cyclohexane-EtOAc, 9:1→1:1) to afford the desired compound in 95% isolated yield. ^¹H NMR (200 MHz, CDCl₃): δ = 1.37 (t, J = 7.1 Hz, 3 H, CH₃), 2.00 (s, 3 H, Ac), 2.09 (s, 3 H, Ac), 2.10 (s, 3 H, Ac), 4.11 (dd, J = 12.1, 4.4 Hz, 1 H, H-5′), 4.30-4.50 (m, 4 H, H-4′, H-5′ and CH₂ ester), 5.82 (t, J = 6.2 Hz, 1 H, H-3′), 6.17 (dd, J = 5.2, 2.9 Hz, 1 H, H-2′), 6.39 (d, J = 2.9 Hz, 1 H, H-1′), 6.60 (dd, J = 3.4, 1.8 Hz, 1 H, H-furan), 7.45 (d, J = 3.4 Hz, 1 H, H-furan), 7.66 (d, J = 1.8 Hz, 1 H, H-furan). ^¹³C NMR (50 MHz, CDCl₃): δ = 14.4, 20.6, 20.8, 61.6, 62.9, 71.2, 74.4, 81.4, 89.7, 112.4, 117.6, 139.0, 145.3, 151.5, 157.9, 160.8, 169.4, 169.5, 170.7. HRMS (ESI): m/z [M + H]⁺
calcd for C₂₀H₂₄N₃O₁₀: 466.1462; found: 466.1456. This compound was then dissolved in MeOH (8 mL) and the solution was saturated with ammonia at 0 ˚C and stirred for 1 h at r.t. The crude product was evaporated and purified by flash silica gel chromatography (CH₂Cl₂-MeOH, 9:1) to afford nucleoside 4 in 91% yield. Free nucleoside 4: ^¹H NMR (200 MHz, CD₃OD): δ = 3.60 (dd, J = 12.1, 5.6 Hz, 1 H, H-5′), 3.75 (dd, J = 12.2, 3.7 Hz, 1 H, H-5′), 3.88 (s, 3 H, OMe), 4.13 (dd, J = 9.2, 5.5 Hz, 1 H, H-4′), 4.51 (t, J = 5.4 Hz, 1 H, H-3′), 4.87 (t, J = 1.7 Hz, 1 H, H-2′), 6.17 (d, J = 2.9 Hz, 1 H, H-1′), 6.69 (dd, J = 3.4, 1.8 Hz, 1 H, H-furan), 7.36 (d, J = 3.4 Hz, 1 H, H-furan), 7.82 (d, J = 1.8 Hz, 1 H, H-furan). ^¹³C NMR (50 MHz, CD₃OD): δ = 52.6, 63.3, 72.2, 76.0, 87.3, 93.3, 113.0, 118.0, 139.8, 147.0, 159.0, 161.7, 162.2. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₅N₃O₇Na: 348.0808; found: 348.0807.

20

The Eicar analogue 5 was prepared using standard Sonogashira coupling to give the protected nucleoside intermediate: ^¹H NMR (200 MHz, CDCl₃): δ = 0.27 (s, 9 H, TMS), 1.37 (t, J = 7.2 Hz, 3 H, CH₃), 2.02 (s, 3 H, Ac), 2.09 (s, 3 H, Ac), 2.10 (s, 3 H, Ac), 4.12 (dd, J = 12.9, 5.4 Hz, 1 H, H-5′), 4.32-4.52 (m, 4 H, H-4, H-5′ and CH₂ ester), 5.73 (t, J = 6.2 Hz, 1 H, H-3′), 5.90 (dd, J = 5.2, 2.8 Hz, 1 H, H-2′), 6.16 (d, J = 2.8 Hz, 1 H, H-1′). ^¹³C NMR (50 MHz, CDCl₃): δ = -0.6, 14.3, 20.4, 20.5, 20.7, 61.5, 62.6, 70.7, 74.1, 81.1, 88.8, 113.6, 124.6, 140.6, 159.6, 169.2, 169.4, 170.6. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₃₀N₃O₉Si: 496.1751; found: 496.1746.
Methanolysis of this intermediate as described above (MeOH, NH₃, 48 h) led to the free nucleoside 5: ^¹H NMR (200 MHz, CD₃OD): δ = 3.40 (s, 1 H, H-alkyne), 3.60 (dd, J = 12.1, 5.7 Hz, 1 H, H-5′), 3.74 (dd, J = 12.1, 3.8 Hz, 1 H, H-5′), 4.11 (dd, J = 9.3, 5.4 Hz, 1 H, H-4′), 4.45 (t, J = 5.4 Hz, 1 H, H-3′), 4.75 (t, J = 3.4 Hz, 1 H, H-2′), 6.09 (d, J = 3.4 Hz, 1 H, H-1′). ^¹³C NMR (50 MHz, CD₃OD): δ = 63.3, 72.2, 75.8, 87.4, 92.5, 94.5, 123.8, 144.3, 159.1, 163.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₃N₄O₅: 269.0886; found: 269.0882.