Novel Exocyclic Nucleoside Related to Clitocine: A Convergent Synthesis of 3′-Azido-2′,3′-dideoxy Clitocine

Abstract

The synthesis of a new clitocine derivative was achieved through a convergent strategy. A protected 4,6-diamino-5-nitro­pyrimidine was condensed with p-chlorobenzoyl (PCB)-protected methyl 3′-azido-2′,3′-dideoxyribofuranoside, followed by subsequently deprotection to give the desired product.

nucleoside analogues - exocyclic nucleosides - convergent synthesis - clitocine - antiviral drug

References and Notes

1 Kubo I. Kim M. Wood WF. Naoki H. Tetrahedron Lett.  1986,  27:  4277 

2a Moss RJ. Petrie CR. Meyer RB. Dee Nord L. Willis RC. Smith RA. Larson SB. Kini GD. Robins RK. J. Med. Chem.  1988,  31:  786 

2b Kamikawa T. Fujie S. Yamagiwa Y. Kim M. Kawaguchi H.
J. Chem. Soc., Chem. Commun.  1988,  195 

2c Choi H. Choi BS. Chang JH. Lee KW. Nam DH. Kim YK. Lee JH. Heo T. Shin H. Kim N. Synlett  2005,  1942 

3a Fortin H. Tomasi S. Delcros J. Bansard J. Boustie J. ChemMedChem  2006,  1:  189 

3b Ren G. Zhao YP. Yang L. Fu CX. Cancer Lett.  2008,  262:  190 

3c Shin H. Min C. Clitocine and its Analogues, In Modified Nucleosides   Herdewijn P. Wiley-VCH; Weinheim: 2008.  Chap. 22. p.567 

4a Lee CH. Daanen JF. Jiang M. Yu H. Kohlhaas KL. Alexander K. Jarvis MF. Kowaluk EL. Bhagwat SS. Bioorg. Med. Chem. Lett.  2001,  11:  2419 

4b Varaprasad CV. Habib Q. An H. Hong Z. Nucleosides, Nucleotides Nucleic Acids  2006,  25:  61 

4c Long MC. Parker WB. Biochem. Pharmacol.  2006,  71:  1671 

5 Liu FY, Ren G, Fu CX, and Wu P. inventors; CN  101333236.  ; Chem. Abstr. 2008, 150, 106103

6 Liu FY, Guo TD, Wu SH, Wu P, and Feng GP. inventors; CN  101347442.  ; Chem. Abstr. 2009, 150, 206311

7a Wilde RG, Kennedy PD, Almstead NG, Welch EM, Takasugi JJ, and Friesen WJ. inventors; WO  2004009609.  ; Chem. Abstr. 2004, 140, 128608

7b Wilde RG, Almstead NG, Welch EM, and Beckmann H. inventors; WO  2004009610.  ; Chem. Abstr. 2004, 140, 122839

7c Wilde RG, Almstead NG, Welch EM, and Beckmann H. inventors; US  2006166926.  ; Chem. Abstr. 2006, 145, 167496

8a Eger K. Klünder EM. Schmidt M. J. Med. Chem.  1994,  37:  3057 

8b Franchetti P. Cappellacci L. Abu Sheikha G. Grifantini M. Loi AG. De Montis A. Spiga MG. La Colla P. Nucleosides Nucleotides  1995,  14:  607 

8c Bacchelli C. Condom R. Patino N. Aubertin AM. Nucleosides, Nucleotides Nucleic Acids  2000,  19:  567 

9a Palmer CF. Parry KP. Roberts SM. Tetrahedron Lett.  1990,  31:  279 

9b Baxter AD. Penn CR. Storer R. Weir NG. Woods JM. Nucleosides Nucleotides  1991,  10:  393 

9c Marquez VE. Lim BB. Driscoll JS. Snoek R. Balzarini J. Ikeda S. Andrei G. De Clercq E. J. Heterocycl. Chem.  1993,  30:  1393 

9d Demaison C. Hourioux C. Roingeard P. Agrofoglio LA. Tetrahedron Lett.  1998,  39:  9175 

9e Agrofoglio LA. Demaison C. Toupet L. Tetrahedron  1999,  55:  8075 

10 Varaprasad CV. Habib Q. Li DY. Huang JF. Abt JW. Rong F. Hong Z. An HY. Tetrahedron  2003,  59:  2297 

11 Sharkin YA. Semizarov DG. Viktorova LS. Kukhanova MK. Russ. J. Bioorg. Chem.  2001,  27:  340 

12a Gryaznov SM. Biochem. Biophys. Acta  1999,  1489:  131-140  

12b Eglia M. Gryaznov SM. Cell. Mol. Life Sci.  2000,  57:  1440 

12c Ford LP. Zou Y. Pongracz K. Gryaznov SM. Shay JW. Wright WE. J. Biol. Chem.  2001,  276:  32198 

12d Herbert BS. Pongracz K. Shay JW. G ryaznov SM. Oncogene  2002,  21:  638 

12e Zielinska D. Pongracz K. Gryaznov SM. Tetrahedron Lett.  2006,  47:  4495 

13a Boon WR. Jones WGM. Ramage GR. J. Chem. Soc.  1951,  96 

13b Robins RK. Dille KJ. Willits CH. Christensen BE. J. Am. Chem. Soc.  1953,  75:  263 

14 Hansen P. Pedersen EB. Acta Chem. Scand.  1990,  44:  522 

15 Gold A. Sangaiah R. Nucleosides Nucleotides  1990,  9:  907 

16a Anderson NG. Lust DA. Colapret KA. Simpson JH. Malley MF. Gougoutas JZ. J. Org. Chem.  1996,  61:  7955 

16b Davis AP. Dresen SD. Lawless LJ. Tetrahedron Lett.  1997,  38:  4305 

17

The CCDC number of compound 12α is 777653.

18

6-Amino-5-nitro-4-(3′-azido-5′- O - p -chloro-benzoyl-2′,3′-dideoxy-β- d -ribofuranosylamino) Pyrimidine (16)
TMS-protected 4,6-diamino-5-nitropyrimidine 8 (0.86 g, 2.9 mmol) was dissolved in DCE (10 mL). To this solution, methyl 3′-azido-5′-O-p-chlorobenzoyl-2′,3′-dideoxy-β-d-ribofuranoside (13, 0.75 g, 2.4 mmol) and TMSOTf (0.72 mL, 4.0 mmol) were added, the mixture was stirred for 48 h at r.t., and 10% NaHCO₃ (15 mL) was added. After 20 min stirring, CH₂Cl₂ (20 mL) was added to the resulting suspension; the mixture was filtered through Hyflo Super Cel; the organic layer was separated, washed with H₂O (10 mL), and dried with Na₂SO₄. Nucleoside 16 (0.11 g) and recovered sugar 13 (0.27 g) were isolated by silica gel chromatography (elution with EtOAc-PE = 1:2). The yield was 16% based on recovered starting material. A white solid was afforded after recrystallizaion in EtOAc; mp 178-180 ˚C. IR (KBr): ν = 3440, 3332, 2109, 1389, 1344, 1290, 1245 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆): δ = 9.57 (1 , d, J _{NH-H1 ′} = 8.51 Hz, NH), 8.61 (2 H, d, J _NH2 = 15.10 Hz, NH₂), 8.00 (1 H, s, C2-H), 7.98 (2 H, m, ArH), 7.61 (2 H, m, ArH), 6.32 (1 H, m, C1′-H), 4.56 (1 H, m, C4′-H), 4.36 (3 H, m, C5′-H, C3′-H), 2.62 (1 H, dd, J = 5.69, 12.80 Hz, C2′-H), 2.20 (1 H, m, C2′-H) ppm. ^¹³C NMR (500 MHz, DMSO-d ₆): δ = 164.66 (C=O), 159.29 (C-2), 158.58 (C-6), 156.02 (C-4), 138.46 (CCl), 131.11 (2 C, Ar), 128.98 (2 C, Ar), 128.17 (CC=O), 112.03 (C-5), 81.11 (C-1′), 80.62 (C-4′), 64.83 (C-5′), 61.68 (C-3′), 36.77 (C-2′) ppm.

19

6-Amino-5-nitro-4-(3′-azido-2′,3′-dideoxy-β- d -ribofuranosylamino) Pyrimidine 6
To a solution of nucleoside 16 (90 mg, 0.2 mmol) in MeOH (10 mL) cooled to 0 ˚C was added 0.1 M NaOMe in MeOH (0.64 mL), and the mixture was stirred at r.t. for 18 h in the argon atmosphere. The reaction mixture was neutralized with Dowex 50 (H⁺), and the resin was rapidly filtered. After evaporation under vacuum to dry, a light yellow solid product 6 was isolated from the residue by silica gel chromatography, elution with an EtOAc-PE (3:2). The yield was 40 mg (65%). ^¹H NMR (500 MHz, DMSO-d ₆): δ = 9.39 (1 H, d, J _{NH-H1 ′} = 8.2 Hz, NH), 8.56 (2 H, br s, NH₂), 8.00 (1 H, s, C2-H), 6.22 (1 H, td, J = 6.0 Hz, J _{NH-H1 ′} = 8.2 Hz, C1′-H), 5.23 (1 H, t, J = 5.0 Hz, OH), 4.33 (1 H, td, J = 4.2 Hz, J _{H2 α ′ -H3 ′} = 7.0 Hz, C3′-H), 3.88 (1 H, q, J = 3.58, 3.58, 3.60 Hz, C4′-H), 3.51 (2 H, t, J = 4.2 Hz, C5′-H), 2.39 (1 H, ddd, J _{H2 α ′ -H1 ′} = 6.0 Hz, J _{H2 α ′ -H3 ′} = 7.0 Hz, J _{H2 β ′ -H2 α ′} = 13.0 Hz, C2′-H_α), 2.27 (1 H, ddd, J _{H2 β ′ -H3 ′} = 4.2 Hz, J _{H2 β ′ -H1 ′} = 6.0 Hz, J _{H2 β ′ -H2 α ′} = 13.0 Hz, C2′-H_β) ppm. ^¹³C NMR (500 MHz, DMSO-d ₆): δ = 159.98 (C-2), 159.29 (C-6), 156.49 (C-4), 109.99 (C-5), 84.62 (C-1′), 82.21 (C-4′), 62.14 (C-5′), 62.08 (C-3′), 38.40 (C-2′) ppm.