Design and Synthesis of 3′-Deoxy-3′-Fluoro-2′-O,3′-C-Vinylene-Linked ­Bicyclic Purine Nucleoside

Abstract

Starting from d-xylose via a 3-deoxy-3α-C-ethynyl-3-fluoro sugar as a key intermediate, a novel fluorinated bicyclic purine nucleoside has been synthesized. A neighboring-group participation pathway and a mechanism involving an intramolecular cycloaddition induced by fluorine are proposed for the formation of the key intermediate and the bicyclic nucleoside, respectively.

Key words

ethynyl group - fluorine - bicyclic nucleoside - neighboring-group participation - intramolecular cyclization

References and Notes

• 1a Patani GA. Lavoie EJ. Chem. Rev.  1996,  96:  3147 
• 1b De Clereq E. Antiviral Res.  2005,  67:  56 
• 1c Nair V. Jahnke TS. Antimicrob. Agents Chemother.  1995,  39:  1017 
• 2a Chen X. Zhou W. Schinazi RF. Chu CK. J. Org. Chem.  2004,  69:  6034 
• 2b Ohrui H. Kohgo S. Kitano K. Sakata S. Kodama E. Yoshimura K. Matsuoka M. Shiro S. Mitsuya H. J. Med. Chem.  2000,  43:  4516 
• 2c Yoshimura Y. Asami K. Matsui H. Tanaka H. Takahata H. Org. Lett.  2006,  8:  6015 
• 3a Watanabe KA. Reichman U. Hirota K. Lopez C. Fox JJ. J. Med. Chem.  1979,  22:  21 
• 3b Hertel LW. Kroin JS. Misner JW. Tustin JM. J. Org. Chem.  1988,  53:  2406 
• 3c Marquez VE. Tseng CK.-H. Mitsuya H. Aoki S. Kelley JA. Ford H. Driscoll JS. J. Med. Chem.  1990,  33:  978 
• 3d Pai SB. Liu S.-H. Zhu Y.-L. Chu CK. Cheng Y.-C. Antimicrob. Agents Chemother.  1996,  40:  380 
• 3e Chun BK. Schinazi RF. Cheng Y.-C. Chu CK. Carbohydr. Res.  2000,  328:  49 
• 4a Agrofoglio L. Suhas E. Farese A. Condom R. Guedj R. Tetrahedron  1994,  50:  10611 
• 4b Scharer OD. Verdine GL. J. Am. Chem. Soc.  1995,  117:  10781 
• 5a Kando JC. Kalunian DA. Hosp. Formul.  1990,  25:  849 
• 5b Harada S. Takayama S. Yakuri to Chiryo  1991,  19:  S789 
• 5c Graul A. Rabasseda X. Castaner J. Drugs Future  1998,  23:  133 
• 6a Minakawa N. Takeda T. Sasaki T. Matasuda A. Ueda T. J. Med. Chem.  1991,  34:  778 
• 6b De Clercq E. Cools M. Balzarini J. Snoeck R. Andrei G. Hosoya M. Shigeta S. Ueda T. Minakawa N. Matasuda A. Antimicrob. Agents Chemther.  1991,  679 
• 6c Minakawa N. Matasuda A. Curr. Med. Chem.  1999,  6:  615 
• 7a Matasuda A. Hattori H. Tanaka M. Sasaki T. Bioorg. Med. Chem. Lett.  1996,  6:  1887 
• 7b Hattori H. Tanaka M. Fukushima M. Sasaki T. Matasuda A. J. Med. Chem.  1996,  39:  5005 
• 7c Hattori H. Nozawa E. Lino T. Yoshimura Y. Shuto S. Shimamoto M. Nomura Y. Fukushima M. Tanaka M. Sasaki T. Matsuda A. J. Med. Chem.  1998,  41:  2892 
• 8a Sugimoto I. Shuto S. Mori S. Shigeta S. Matasuda A. Bioorg. Med. Chem. Lett.  1999,  9:  385 
• 8b Nomura M. Shuto S. Tanaka M. Sasaki T. Mori S. Shigeta S. Matasuda A. J. Med. Chem.  1999,  42:  2901 
• 9 Siddiqui MA. Hughes SH. Boyer PL. Mitsuya H. Van Q N. George C. Sarafinanos SG. Marquez VE. J. Med. Chem.  2004,  47:  5041 
• 10 Hrdlicka PJ. Jepsen JS. Nielsen C. Wengel J. Bioorg. Med. Chem.  2005,  13:  1249 
• 11 Moukhachafiq O. Tiwari KN. Secrist JA. Nucleosides, Nucleotides Nucleic Acids  2005,  24:  713 
• 12a Poopeiko NE. Kvasyuk EI. Mikhailopuio IA. Lidaks MJ. Synthesis  1985,  605 
• 12b Momura M. Sato T. Washinosu M. Tanaka M. Asao T. Shuto S. Matsuda A. Tetrahedron  2002,  58:  1279 
• 13a Binkley RW. Modern Carbohydrate Chemistry   Marcel Dekker Inc.; New York: 1988.  p.53-60  
• 13b Watts JK. Sadalapure K. Choubdar N. Pinto BM. Damha MJ. J. Org. Chem.  2006,  71:  921 
• 13c Ma TW. Lin J. Newton MG. Cheng YC. Chu CK. J. Med. Chem.  1997,  40:  2750 
• 13d Ma T. Pai B. Zhu YL. Lin JS. Shanmuganathan K. Du J. Wang C. Kim H. Newton MG. Cheng YC. Chu CK. J. Med. Chem.  1996,  39:  2835 
• 13e Takamatsu S. Maruyama T. Katayama S. Hirose N. Naito M. Izawa K. J. Org. Chem.  2001,  66:  7469 
• 14 Yoshimura Y. Endo M. Miuura S. Sakata S. J. Org. Chem.  1999,  64:  7912 
• 15a Wang Y. Inguaggiato G. Jasamai M. Shah M. Hughes D. Slater M. Simons C. Bioorg. Med. Chem.  1999,  7:  481 
• 15b Hudlicky M. Org. React.  1988,  35:  513 
• 16a Robins MJ. Zou R. Guo Z. Wnuk SF. J. Org. Chem.  1996,  61:  9207 
• 16b Garner P. Ramakanth S. J. Org. Chem.  1988,  53:  1294 
• 16c Wright GE. Dudycz LW. J. Med. Chem.  1984,  27:  175 
• 18 Shapiro SL. Bandurco V. Freedman L. J. Org. Chem.  1961,  26:  3710 
• 19a Nakagawa F. Okazaki T. Naito A. Iijima Y. Yamazaki M. J. Antibiot.  1985,  38:  823 
• 19b Arai M. Haneishi T. Kitahara N. Enokita R. Kawakubo K. Kondo Y. J. Antibiot.  1976,  29:  863 
• 19c Terahara A. Haneishi T. Arai M. Hata T. Kuwano H. Tamura C. J. Antibiot.  1982,  35:  1711 
• 20a Marquez VE. Ezzitouni A. Russ P. Sidiqui MA. Ford H. Feldman RJ. Mitsuya H. Geoge C. Barchi JJ. J. Am. Chem. Soc.  1998,  120:  2780 
• 20b Lescop C. Huet F. Tetrahedron  2000,  56:  2995 
• 20c Marquez VE. Siddiqui MA. Ezzitouni A. Russ P. Sidiqui MA. Wang J. Wagner RW. Matteucci MD. J. Med. Chem.  1996,  39:  3739 
• 20d Olsen AG. Rajwanshi VK. Nielsen C. Wengel J. J. Chem. Soc., Perkin Trans. 1  2000,  3610 
• 21a Kool ET. Chem. Rev.  1997,  97:  1473 
• 21b Meldgaard M. Wengel J. J. Chem. Soc., Perkin Trans. 1  2000,  3539 
• 21c Leumann CJ. Bioorg. Med. Chem.  2002,  10:  841 

17

Compound 10: space group P212121 with cell parameters: a = 7.4156(15) nm, b = 20.417(4) nm, c = 23.585(5) nm; CCDC 701133.

22

Compound 3: white solid, mp 168 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 8.04-8.00 (m, 4 H, Ar), 7.60-7.57 (m, 1 H, Ar), 7.43-7.36 (m, 4 H, Ar), 6.02 (d, 1 H, J = 3.5 Hz, H-1), 5.31 (d, 1 H, J = 3.5 Hz, H-2), 4.82-4.79 (m, 1 H, H-5), 4.75-4.71 (m, 1 H, H-4), 4.66-4.64 (m, 1 H, H-5), 2.74 (s, 1 H, H-7), 1.51 (s, 3 H, H-9), 1.35 (s, 3 H, H-10). ^¹³C NMR (75 MHz, CDCl₃): δ = 165.4, 164.1, 139.7, 133.5, 131.3, 129.9, 129.1, 128.7, 128.4, 128.2, 113.6, 104.7, 82.6, 78.1, 77.9, 77.8, 77.2, 63.8, 26.8, 26.6.

23

Compound 4: light yellow solid, mp 106-107 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 8.09-8.07 (m, 4 H, Ar), 7.62 (m, 1 H, Ar), 7.43-7.50 (m, 4 H, Ar), 5.61 (d, 1 H, J = 2.0 Hz,
H-1), 5.17 (d, 1 H, J = 2.0 Hz, H-2), 4.74-4.71 (m, 1 H, H-5), 4.64-4.60 (m, 1 H, H-4), 4.47-4.44 (m, 1 H, H-5), 3.47 (s, 3 H, H-8), 2.76 (br s, 1 H, 2-OH), 2.74 (s, 1 H, H-7). ^¹³C NMR (75 MHz, CDCl₃): δ = 165.7, 165.5, 139.6, 133.8, 131.2, 130.0, 128.8, 128.6, 128.4, 107.1, 83.1, 81.4, 80.0, 77.2, 73.7, 65.2, 56.1.

24

Compound 6: light yellow oil. ^¹H NMR (500 MHz, CDCl₃): δ = 8.08-8.04 (m, 4 H, Ar), 7.64-7.61 (m, 1 H, Ar), 7.50-7.42 (m, 4 H, Ar), 5.59 (d, 1 H, J = 12.5 Hz, H-2), 5.13 (s, 1 H, H-1), 4.78-4.64 (3 H, m, H-4 and H-5), 3.50 (s, 3 H,
H-8), 2.79 (d, 1 H, J = 5.5 Hz, H-7). ESI-HRMS: m/z calcd for C₂₂H₁₈ClFO₆ [M + Na⁺]: 455.0674; found: 455.0672.

25

Compound 7: light yellow oil. ^¹H NMR (400 MHz, CDCl₃): δ = 8.07-8.02 (m, 4 H, Ar), 7.65-7.61 (m, 1 H, Ar), 7.50-7.41 (m, 4 H, Ar), 6.34 (s, 1 H, H-1), 5.72 (d, 1 H, J = 11.6 Hz, H-2), 4.85-4.62 (m, 3 H, H-4 and H-5), 2.81 (d, 1 H, J = 5.2 Hz, H-7), 2.15 (s, 3 H, H-9). ^¹³C NMR (100 MHz, CDCl₃): δ = 169.4, 165.4, 164.4, 140.0, 134.2, 131.4, 130.2, 129.0, 128.8, 128.7, 128.2, 99.3, 93.2, 84.8, 81.1, 80.0, 74.46, 62.1, 21.1. ^¹9F NMR (CDCl₃): δ = -185.7.

26

Compound 9: white solid, mp: 211-212 ˚C. ^¹H NMR (500 MHz, CDCl₃): δ = 8.94 (s, 1 H, H-2), 8.67 (s, 1 H, H-8), 8.11-8.09 (m, 2 H, Ar), 8.05-8.03 (m, 2 H, Ar), 7.70-7.67 (m, 1 H, Ar), 7.54-7.51 (m, 2 H, Ar), 7.46-7.44 (m, 2 H, Ar), 6.88 (s, 1 H, H-1′), 5.92 (dd, 1 H, J = 13.5, 1.0 Hz, H-2′), 4.98-4.93 (m, 1 H, H-4′), 4.90-4.82 (m, 2 H, H-5′), 2.94 (d, 1 H, J = 6.0 Hz, H-7′). ^¹³C NMR (125 MHz, CDCl₃): δ = 165.4, 164.2, 162.6, 153.2, 146.7, 142.8, 140.4, 134.7, 131.4, 130.3, 129.1, 128.0, 127.8, 122.0, 93.8, 90.3, 84.0, 83.0, 80.9, 72.7, 60.9.

27

Compound 10: white solid, mp 112-115 ˚C. ^¹H NMR (500 Hz, DMSO-d ₆): δ = 8.86 (s, 1 H), 8.62 (s, 1 H), 7.03 (t, J = 2.5 Hz, 1 H), 5.95 (d, J = 6.0 Hz, 1 H), 5.68 (dd, J = 6.0, 26.5 Hz), 5.62 (d, J = 2.5 Hz, 1 H), 5.01 (t, J = 5.0 Hz, 1 H), 4.25-4.20 (m, 1 H), 4.06 (s, 3 H), 3.82-3.77 (m, 1 H), 3.71-3.66 (m, 1 H). ^¹³C NMR (75 Hz, DMSO-d ₆): δ = 162.86, 157.15, 153.48 (d, J = 9.0 Hz, C-2), 152.88, 147.27, 112.07, 111.17 (d, ^² J _C-F = 202.1 Hz, C-3a), 103.91 (d, ^³ J _C-F = 24.5 Hz, C-3), 91.16 (d, ^³ J _C-F = 25.3 Hz, C-4), 90.63 (d, J = 13.0 Hz, C-6), 86.39 (d, J = 31.3 Hz, C-6a), 60.07 (d, J = 9.0 Hz, CH₂OH), 55.60 (OCH₃). ^¹9F NMR (400 Hz, DMSO-d ₆): δ = -167.61. ESI-HRMS: m/z calcd for C₁₃H₁₃FN₄O₄ [M + Na⁺]: 331.0819; found: 331.0811.