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Synlett 2004(12): 2147-2150  
DOI: 10.1055/s-2004-832807
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis and Reactions of Allenic Sulfone-Modified Thymidine: The First Allenic Sulfone to Alkylate Deoxyadenosine

Sanjib Bera, Tanmaya Pathak*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Fax: +91(3222)282252; e-Mail: tpathak@chem.iitkgp.ernet.in;
Further Information

Publication History

Received 29 June 2004
Publication Date:
21 September 2004 (online)

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Abstract

3′-(S)-(allenic sulfonyl)-5′-benzoyl-3′-deoxythymidine has been synthesized from 1-(5-O-trityl-3-O-mesyl-2-deoxy-β-d-threopentofuranosyl) thymine via 3′-(S)-(propargylthio)-5′-trityl-3′-deoxythymidine in six steps. 3′-(S)-(allenic sulfonyl)-3′-deoxy­thymidine reacts very efficiently with a wide array of nucleophiles. This is also the first report on the alkylation of adenine moiety by some allenic sulfone modified compounds.

Key words

reactive nucleosides - allenic sulfone - alkylating nucleo­side

    References

  • 1 Present address: New River Pharmaceuticals, 1861 Pratt Drive, Suite 1090, Blacksburg, VA 24060, USA
  • For a discussion on the importance of alkylating agents in biological systems, see:
  • 2a Silverman RB. The Organic Chemistry of Drug Design and Drug Action   Elsevier; Amsterdam, Boston: 2004.  Chap. 5.
    Google Scholar
  • 2b Silverman RB. The Organic Chemistry of Drug Design and Drug Action   Elsevier; Amsterdam, Boston: 2004.  Chap. 6.
    Google Scholar
  • 3a Lyttle DA. Petering HG. J. Am. Chem. Soc.  1958,  80:  6459 
    CrossrefGoogle Scholar
  • 3b Evans JS. Mengel GD. Proc. Soc. Exptl. Biol. Med.  1958,  99:  620 
    CrossrefGoogle Scholar
  • 3c Kennedy BJ. Torkelson JL. Torlakovic E. Cancer  1999,  85:  2265 
    CrossrefGoogle Scholar
  • 4a De las Heras FG. Alonso R. Alonso G. J. Med. Chem.  1979,  22:  496 
    CrossrefGoogle Scholar
  • 4b Alonso R. Camarasa MJ. Alonso G. De las Heras FG. Eur. J. Med. Chem.  1980,  15:  105 
    CrossrefGoogle Scholar
  • 4c De las Heras FG. Sanchez-Perez RM. Aguado ML. Eur. J. Med. Chem.  1981,  16:  339 
    CrossrefGoogle Scholar
  • 4d Garcia-Lopez MT. Herranz R. Mendez-Castrillon PP. Nucleosides Nucleotides  1982,  1:  127 
    CrossrefGoogle Scholar
  • 4e Garcia-Lopez MT. Herranz R. Andres JI. J. Chem. Soc., Perkin Trans. 1  1983,  2303 
    CrossrefGoogle Scholar
  • 5 Talebian AH. Schein PS. Green DC. Vincent T. Nucleosides Nucleotides  1990,  9:  721 
    Google Scholar
  • 6 Schreiber SL. Ikemoto N. Tetrahedron Lett.  1988,  29:  3211 
    CrossrefGoogle Scholar
  • 7a Catalano CE. Benkovic SJ. Biochemistry  1989,  28:  4374 
    CrossrefGoogle Scholar
  • 7b Semizarov DG. Victorova LS. Krayevsky AA. Kukhanova MK. FEBS Lett.  1993,  327:  45 
    CrossrefGoogle Scholar
  • 7c Gurskaya GV. Bochkarev AV. Zdanov AS. Papchikhin AV. Purygin PP. Kraevskii AA. FEBS Lett.  1990,  265:  63 
    CrossrefGoogle Scholar
  • 8a Bera S. Sakthivel K. Pathak T. Langley GJ. Tetrahedron  1995,  51:  7857 
    CrossrefGoogle Scholar
  • 8b Bera S. Langley GJ. Pathak T. J. Org. Chem.  1998,  63:  1754 
    CrossrefGoogle Scholar
  • 8c Pathak T. Eur. J. Org. Chem.  2004,  3361 
    CrossrefGoogle Scholar
  • 9 For a review on allenic sulfones, see: Back TG. Tetrahedron  2001,  57:  5263 
    CrossrefGoogle Scholar
  • 10a Nicolaou KC. Wendeborn S. Isshiki K. Zein N. Ellestad G. Angew. Chem., Int. Ed. Engl.  1991,  30:  418 
    Google Scholar
  • 10b Dai W.-M. Chow CW. Zhou L. Ishii A. Lau CW. Li Q. Hamaguchi W. Nishimoto S.-I. Bioorg. Med. Chem.  1999,  9:  2789 
    Google Scholar
  • 10c McPhee MM. Kern JT. Hoster BC. Kerwin SM. Bioorg. Chem.  2000,  28:  98 
    Google Scholar
  • 10d McPhee MM. Kerwin SM. Bioorg. Med. Chem.  2001,  9:  2809 
    Google Scholar
  • 10e Braverman S. Cherkinsky M. Birsa ML. Zafrani Y. Eur. J. Org. Chem.  2002,  3198 
    Google Scholar
  • 10f Suzuki I. Shigenaga A. Manabe A. Nemoto H. Shibuya M. Tetrahedron  2003,  59:  5691 
    Google Scholar
  • 10g Haruna K.-i. Tanabe K. Ishii A. Min-Dai W. Hatta H. Nishimoto S.-i. Bioorg. Med. Chem.  2003,  11:  5311 
    Google Scholar
  • 11 Herdewijn P. Balzarini J. Baba M. Pauwels R. Aerschot AV. Janssen G. Clercq ED. J. Med. Chem.  1988,  31:  2040 
    CrossrefGoogle Scholar
  • 14a Mackle H. Steele WV. Trans. Faraday Soc.  1969,  65:  2073 
    CrossrefGoogle Scholar
  • 14b Back TG. Parvez M. Wulff JE. J. Org. Chem.  2003,  68:  2223 
    CrossrefGoogle Scholar
12

Compound 9: 1H NMR (360 MHz, CDCl3 + D2O): δ = 7.55 (s, 1 H, H-6), 6.13 (dd, J = 4.7, 7.0 Hz, 1 H, H-1′), 4.06-3.96 (m, 2 H), 3.87 (dd, J = 2.6, 11.9 Hz, 1 H), 3.73 (q, 1 H, J = 7.9 Hz), 3.36 (m, 2 H, SCH2), 2.65 (m, 1 H), 2.51 (m, 1 H), 2.32 (t, J = 2.6 Hz, 1 H, acetylenic), 1.91 (s, 3 H, CH3). 13C NMR (90 MHz, CDCl3): δ = 164.2, 150.5, 136.6, 110.7, 85.5 (C-1′), 85.5 (acetylene), 79.6 (C-4′), 72.0 (acetylene), 61.3 (C-5′), 40.9 (C-3′), 39.6 (C-2′), 19.4 (SCH2), 12.4 (CH3). HRMS (FAB+): m/z calcd for C13H17N2O4S [M + H]+: 297.0909; found: 297.0911.

13

Compound 12: mp 86-87 °C. 1H NMR (360 MHz, CDCl3): δ = 9.67 (s, 1 H, NH), 8.01-7.41 (m, 5 H, phenyl), 7.15 (s, 1 H, H-6), 6.26 (t, J = 6.2 Hz, 1 H, allene CH), 6.07 (t, J = 6.5 Hz, 1 H, H-1′), 5.59 (m, 2 H, =CH2), 4.79 (m, 2 H, H-4′, H-5′a), 4.56 (dd, J = 4.1, 12.2 Hz, 1 H, H-5′b), 4.07 (m, 1 H, H-3′), 2.97 (m, 1 H, H-2′a), 2.52 (m, 1 H, H-2′b), 1.64 (s, 3 H, CH3). 13C NMR (90 MHz, CDCl3): δ = 211.8 (=C=), 165.9 (ester CO), 163.8 (C-4), 150.1 (C-2), 135.4 (C-6), 133.6, 129.5, 129.1, 128.6 (phenyl), 111.3 (C-5), 96.3 (HC=), 86.5 (C-1′), 84.3 (=CH2), 77.0 (C-4′), 64.7 (C-5′), 63.7 (C-3′), 33.4 (C-2′), 12.1 (CH3). HRMS (FAB+): m/z calcd for C20H21N2O7S [M + H]+: 433.1061; found: 433.1061.

15

Methoxide ion adds to MeCCSO2Ph to produce MeC(OMe)2CH2SO2Ph, see ref. [8]

16

Compound 15: mp 169-170 °C. 1H NMR (360 MHz, DMSO-d 6): δ = 11.38 (s, 1 H), 8.30-7.08 (m, 10 H), 6.22 (t, J = 6.5 Hz, 1 H), 4.73-4.37 (m, 4 H), 2.83 (m, 1 H), 2.69 (s, 3 H), 2.64 (m, 1 H), 1.56 (s, 3 H). 13C NMR (90 MHz, DMSO-d 6): δ = 165.4 (benzoyl CO), 163.5, 150.3, 148.5, 136.5, 135.5, 133.6, 130.5, 129.3, 129.1, 128.8, 117.4, 111.7, 110.0, 84.3, 75.3, 65.1 (C-5′), 63.4, 31.4 (C-2′), 15.4, 11.8. HRMS (FAB+): m/z calcd for C23H25N4O7S [M + H]+: 501.1444; found: 501.1449. Compound 16: mp 103-104 °C. 1H NMR (360 MHz, CDCl3): δ = 10.57 (br s, 1 H), 7.95-7.02 (m, 9 H), 5.98 (t, J = 6.4 Hz, 1 H), 5.52 (s, 1 H), 5.37 (s, 1 H), 4.82 (m, 1 H), 4.69 (d, J = 12.2 Hz, 1 H), 4.58 (d, J = 14.7 Hz, 1 H), 4.50 (dd, J = 4.2, 12.2 Hz, 1 H), 4.33 (d, J = 14.7 Hz, 1 H), 3.86 (m, 1 H), 2.96 (m, 1 H), 2.33 (m, 1 H), 1.58 (s, 3 H). 13C NMR (90 MHz, CDCl3): δ = 165.9, 164.1, 150.5, 136.1, 135.4, 133.6, 130.4, 130.0, 129.5, 129.0, 128.6, 118.0, 114.1 (=CH2), 111.2, 86.5, 75.8, 64.9 (C-5′), 60.8, 56.8 (SO2CH2), 33.5 (C-2′), 12.1. HRMS (FAB+): m/z calcd for C23H25N4O7S [M + H]+: 501.1444; found: 501.1431.

17

Compound 20: A solution of 12 (0.140 g, 0.32 mmol) and 2′-deoxyadenosine (0.095 g, 0.36 mmol) in dioxane (15 mL) was stirred at r.t. for 2 d. Solvent was evaporated to dryness and the residue was purified over silica gel to give 19. Ac2O (0.6 mL, 6.40 mmol) was added to a solution of 19 in pyridine (15 mL) and the mixture was stirred at r.t. After 15 h the reaction mixture was worked-up in the usual way and the product was purified over silica gel to give 20 (0.120 g, 46%); mp 137-138 °C. 1H NMR (360 MHz, CDCl3): δ = 9.52 (s, 1 H), 7.97-7.07 (m, 8 H), 6.27 (dd, J = 6.1, 8.0 Hz, 1 H), 5.93 (t, J = 6.8 Hz, 1 H), 5.83 (s, 1 H), 5.66 (s, 1 H), 5.33 (m, 1 H), 4.79-4.12 (m, 9 H), 2.88-2.73 (m, 2 H), 2.58 (m, 2 H), 2.27 (s, 3 H), 2.09 (s, 3 H), 2.05 (s, 3 H), 1.61 (s, 3 H). 13C NMR (90 MHz, CDCl3): δ = 184.0, 170.4, 170.2, 165.9, 163.6, 149.9, 147.4, 144.2, 143.2, 138.0, 136.0, 134.5, 133.5, 129.6, 129.1, 128.6, 124.7 (=CH2), 121.2, 111.2, 87.1, 84.4, 82.7, 76.1, 74.3, 64.8 (CH2), 63.6 (C-5′, CH2), 61.3, 55.1 (CH2), 37.8 (CH2), 33.6 (CH2), 26.5, 20.8, 20.7 (2 peaks), 12.1. HRMS (FAB+): m/z calcd for C36H40N7O13S [M + H]+: 810.2405; found: 810.2410.