The Application of Mitsunobu Cyclization for the Synthesis of 2′,3′-Dideoxy-C-Nucleosides Designed as Didanosine Analogues

Abstract

The synthesis of new 2′,3′-dideoxy-C-nucleosides structurally related to didanosine has been achieved. Their preparation involved condensation of a suitably substituted, lithiated 2- or 4-picoline with 2′,3′-dideoxy-5′-benzylribonolactone, followed by borohydride reduction of the resulting hemiacetals, intramolecular Mitsunobu cyclization of the derived diols, formation of the pyrazolo[3,4-c] or [4,3-b]pyridine ring-system and subsequent removal of the protecting groups.

Key words

C-nucleosides - heterocycles - pyrazolo[3,4-c]pyridine - pyrazolo[4,3-b]pyridine - dideoxynucleosides

References and Notes

• 1a Balzarini J. De Clercq E. Biochemical pharmacology. Nucleoside and nonnucleoside reverse transcriptase inhibitors active against HIV, In Textbook of AIDS Medicine   Merigan TC. Bartlett JG. Bolognesi D. Williams and Wilkins; Philadelphia: 1998.  Chap. 47. p.815-847  
• 1b Balzarini J. Pharm. World Sci.  1994,  16:  113 
• 2 De Clercq E. Antiviral Res.  2005,  67:  56 
• 3a Wu O. Simons C. Synthesis  2004,  1533 
• 3b Watanabe KA. In Chemistry of Nucleosides and Nucleotides   Vol. 3:  Townsend LB. Plenum Press; New York: 1994.  p.421-535  
• 4a Guianvarc’h D. Fourrey J.-L. Maurisse R. Sun J.-S. Benhida R. Org. Lett.  2002,  4:  4209 
• 4b Haberli A. Leumann CJ. Org. Lett.  2002,  4:  3275 
• 4c Heinrich D. Wagner T. Diederichsen U. Org. Lett.  2007,  9:  5311 
• 4d Matulic-Adamic J. Beigelman L. Portmann S. Egli M. Usman N. J. Org. Chem.  1996,  61:  3909 
• 5a Redpath P. Macdonald S. Migaud ME. Org. Lett.  2008,  10:  3323 
• 5b Wellington KW. Benner SA. Nucleosides, Nucleotides Nucleic Acids  2006,  25:  1309 
• 5c Simons C. Nucleoside Mimetics: Their Chemistry and Biological Properties   Gordon and Breach; Amsterdam: 2001. 
• 5d Togo H. He W. Waki Y. Yokoyama M. Synlett  1998,  700 
• 5e Levy DE. Tang C. The Chemistry of C-Glycosides   Pergamon; Oxford: 1995. 
• 5f Postema MHD. C-Glycoside Synthesis   CRC; Boca Raton FL: 1995. 
• 5g Jaramillo C. Knapp S. Synthesis  1994,  1 
• 6a Kourafalos VN. Marakos P. Pouli N. Townsend LB. Synlett  2002,  1479 
• 6b Kourafalos VN. Marakos P. Pouli N. Townsend LB. J. Org Chem.  2003,  68:  6466 
• 6c Korouli S. Lougiakis N. Marakos P. Pouli N. Synlett  2008,  181 
• 7a Faulds D. Drogden D. Drugs  1992,  44:  94 
• 7b De Clercq E. J. Clin. Virol.  2004,  30:  115 
• 8 Chapman D. Hurst J. J. Chem. Soc., Perkin Trans. 1  1980,  2398 
• 9a Taniguchi M. Koga K. Yamada S. Tetrahedron  1974,  30:  3547 
• 9b Kang S.-K. Jeon J.-H. Yamaguehi T. Hong R.-K. Ko B.-S. Tetrahedron: Asymmetry  1995,  6:  97 
• 9c Okabe M. Sun R.-C. Tam SY.-K. Todaro LJ. Coffen DL. J. Org. Chem.  1988,  53:  4780 
• 10a Mitsunobu O. Synthesis  1981,  1 
• 10b Hughes DL. Org. Prep. Proced. Int.  1996,  28:  127 
• 11a Weizman H. Tor Y. J. Am. Chem. Soc.  2001,  123:  3375 
• 11b Guianvarc’h D. Fourrey J.-L. Tran Huu Dau M.-E. Guerineau V. Benhida R. J. Org. Chem.  2002,  67:  3724 
• 12a Harusawa S. Araki L. Imazu T. Ohishi H. Sakamoto Y. Kurihara T. Chem. Pharm. Bull.  2003,  51:  325 
• 12b Harusawa S. Araki L. Terashima H. Kawamura M. Takashima S. Sakamoto Y. Hashimoto T. Yamamoto Y. Yamatodani A. Kurihara T. Chem. Pharm. Bull.  2003,  51:  832 
• 13 Marakos P. Pouli N. Wise D. Townsend LB. Synlett  1997,  561 
• 16a Olah GA. Narang SC. Gupta BGB. Malhotra R. J. Org. Chem.  1979,  44:  1247 
• 16b Ramasany K. Imamura N. Robins RK. Revankar GR. J. Heterocycl. Chem.  1988,  25:  1893 
• 17 Lougiakis N. Marakos P. Pouli N. Balzarini J. Chem. Pharm. Bull.  2008,  56:  775 

14

1,6-Dihydro-3-(2,3-dideoxy-β-d-ribofuranosyl)-7H-pyrazolo[3,4-c]pyridin-7-one (15): mp 270-272 ˚C (CH₂Cl₂-MeOH); ^¹H NMR (400 MHz, CD₃OD): δ = 1.88-2.02 (m, 1 H, H-3′), 2.08-2.25 (m, 2 H, H-2′, H-3′), 2.28-2.40 (m, 1 H, H-2′), 3.63 (dd, 1 H, H-5′, J_{5 ′ ,4 ′} = 5.48 Hz, J_{5 ′ ,5 ′} = 11.35 Hz), 3.70 (dd, 1 H, H-5′, J_{5 ′ ,4 ′} = 4.30 Hz, J_{5 ′ ,5 ′} = 11.35 Hz), 4.13-4.22 (m, 1 H, H-4′), 5.22 (t, 1 H, H-1′, J_{1 ′ ,2 ′} = 7.04 Hz), 6.87 (d, 1 H, H-4, J_4,5 = 6.65 Hz), 6.95 (d, 1 H, H-5, J_5,4 = 6.65 Hz). ^¹³C NMR (50 MHz, CD₃OD): δ = 28.54 (C-3′), 32.97 (C-2′), 65.59 (C-5′), 77.27 (C-1′), 81.94 (C-4′), 101.72 (C-4), 125.69 (C-3α), 125.93 (C-5), 134.94 (C-7α), 148.07 (C-3), 156.55 (C-7). Anal. Calcd for C₁₁H₁₃N₃O₃: C, 56.16; H, 5.57; N, 17.86. Found: C, 56.01; H, 5.69; N, 17.68

15

1,4-Dihydro-3-(2,3-dideoxy-β-d-ribofuranosyl)-7H-pyrazolo[4,3-b]pyridin-7-one (30): Oil. ^¹H NMR (400 MHz, CD₃OD): δ = 2.00-2.23 (m, 3 H, 2 × H-3′, 1 × H-2′), 2.35-2.46 (m, 1 H, H-2′), 3.71 (dd, 1 H, H-5′, J_{5 ′ ,4 ′} = 3.13 Hz, J_{5 ′ ,5 ′} = 11.74 Hz), 3.89 (dd, 1 H, H-5′, J_{5 ′ ,4 ′} = 2.74 Hz, J_{5 ′ ,5 ′} = 11.74 Hz), 4.22-4.29 (m, 1 H, H-4′), 5.29 (t, 1 H, H-1′, J_{1 ′ ,2 ′} = 7.04 Hz), 6.26 (d, 1 H, H-6, J_6,5 = 7.04 Hz), 7.77 (d, 1 H, H-5, J_5,6 = 7.04 Hz). ^¹³C NMR (50 MHz, CD₃OD): δ = 28.46 (C-3′), 34.19 (C-2′), 69.95 (C-5′), 77.95 (C-1′), 81.76 (C-4′), 110.23 (C-6), 128.49 (C-3α), 134.58 (C-7α), 138.77 (C-5), 142.86 (C-3), 171.12 (C-7). Anal. Calcd for C₁₁H₁₃N₃O₃: C, 56.16; H, 5.57; N, 17.86. Found: C, 56.38; H, 5.39; N, 17.99