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Synlett 2004(5): 0823-0826  
DOI: 10.1055/s-2004-820033
LETTER
© Georg Thieme Verlag Stuttgart · New York

1,2-Ethylene-3,3-bis(4′,4′′-dimethoxytrityl Chloride) (E-DMT): Synthesis and Applications of a Novel Protecting Reagent

Natsuhisa Okaa, Yogesh S. Sanghvi*b, Emmanuel A. Theodorakisa
a Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0358, USA
b Rasayan Inc., 2802 Crystal Ridge Road, Encinitas, CA 92024-6615, USA
Fax: +1(760)9441543; e-Mail: rasayan@sbcglobal.net;
Further Information

Publication History

Received 5 January 2004
Publication Date:
10 March 2004 (online)

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Abstract

1,2-Ethylene-3,3-bis(4′,4′′-dimethoxytrityl chloride), (E-DMT) was developed as a novel, bifunctional protecting reagent. This new compound was found to have a potential as a multipurpose acid-labile protecting reagent which can afford a 5′,5′-tritylthymidine dimer and a unique 5′,3′-cyclic protected thymidine derivative in modest to good yields.

Key words

bis(trityl chloride) - bifunctional protecting reagent - acid-labile protecting group - solution-phase DNA synthesis - nucleo­side - thymidine

    References

  • 1 For a review, see: Greene TW. Wuts PGM. Protective Groups in Organic Synthesis   3rd Ed.:  Wiley; New York: 1999.  p.102-112  
    Google Scholar
  • 2a For a review, see: Seliger H. In Current Protocols in Nucleic Acid Chemistry   Beaucage SL. Bergstrom DE. Glick GD. Jones RA. Wiley; New York: 2000.  Chap. 2.3.1-2.3.34.
    CrossrefGoogle Scholar
  • 2b Successful use of trityl groups as acid-labile 5′-protecting groups was originally reported by Khorana et al. in: Gilman PT. Khorana HG. J. Am. Chem. Soc.  1958,  80:  6212-6222  
    CrossrefGoogle Scholar
  • 2c See also: Smith M. Rammler DH. Goldberg IH. Khorana HG. J. Am. Chem. Soc.  1962,  84:  430 
    CrossrefGoogle Scholar
  • 3 Biernat J. Wolter A. Köster H. Tetrahedron Lett.  1983,  24:  751 
    CrossrefGoogle Scholar
  • 4 For a review of the recent studies on bifunctional trityl chlorides, see: Shchepinov MS. Korshun VA. Chem. Soc. Rev.  2003,  32:  170 
    CrossrefPubMedGoogle Scholar
  • 5a Bonora GM. Rossin R. Zaramella S. Cole DL. Eleuteri A. Ravikumar VT. Org. Proc. Res. Dev.  2000,  4:  225 
    CrossrefGoogle Scholar
  • 5b Reese CB. Yan H. J. Chem. Soc., Perkin Trans. 1  2002,  2619 
    CrossrefGoogle Scholar
  • 6 Sanghvi YS. Andrade M. Deshmukh RR. Holmberg L. Scozzari AN. Cole DL. In Manual of Antisense Methodology   Hartmann G. Endres S. Kluwer Academic Publishers; Norwell, MA: 1999.  p.3-23  
    Google Scholar
  • 7 Pon RT. Current Protocols in Nucleic Acid Chemistry   Beaucage SL. Bergstrom DE. Glick GD. Jones RA. Wiley; New York: 2000.  Chap. 3.1.1-3.1.28. and references therein
    Google Scholar
  • 8 Mihaichuk JC. Hurley TB. Vagle KE. Smith RS. Yegge JA. Pratt GM. Tompkins CJ. Sebesta DP. Pieken WA. Org. Proc. Res. Dev.  2000,  4:  214 
    CrossrefGoogle Scholar
  • 9a Ravikumar VT. Wyrzykiewicz TK. Cole DL. Tetrahedron  1994,  50:  9255 
    CrossrefGoogle Scholar
  • 9b Krotz AH. Cole DL. Ravikumar VT. Tetrahedron Lett.  1996,  37:  1999 
    CrossrefGoogle Scholar
  • 9c Ravikumar VT. Cheruvallath ZS. Cole DL. Nucleosides Nucleotides  1997,  16:  1709 
    CrossrefGoogle Scholar
  • 9d Bhat B. Sanghvi YS. Tetrahedron Lett.  1997,  38:  8811 
    CrossrefGoogle Scholar
  • 10a Krotz AH. Carty RL. Scozzari AN. Cole DL. Ravikumar VT. Org. Proc. Res. Dev.  2000,  4:  190 
    CrossrefGoogle Scholar
  • 10b Pon RT. Yu S. Guo Z. Deshmukh R. Sanghvi YS. J. Chem. Soc., Perkin Trans. 1  2001,  2638 
    CrossrefGoogle Scholar
  • 10c Sanghvi YS. Guo Z. Pfundheller HM. Converso A. Org. Proc. Res. Dev.  2000,  4:  175 
    CrossrefGoogle Scholar
  • 11a Wen K. Chow S. Sanghvi YS. Theodorakis EA. J. Org. Chem.  2002,  67:  7887 
    CrossrefGoogle Scholar
  • 11b Chow S. Wen K. Sanghvi YS. Theodorakis EA. Bioorg. Med. Chem. Lett.  2003,  13:  1631 
    CrossrefGoogle Scholar
  • 12 Ramage R. Wahl FO. Tetrahedron Lett.  1993,  34:  7133 
    CrossrefGoogle Scholar
  • 13 Goswami S. Mahapatra AK. Tetrahedron Lett.  1998,  39:  1981 
    Google Scholar
  • 14 Windisch B. Vögtle F. Nieger M. Lahtinen T. Rissanen K. J. Prakt. Chem.  2000,  342:  642 
    Google Scholar
  • 17 Wakatsuki Y. Yamazaki H. Inorg. Synth.  1989,  26:  189 
    Google Scholar
  • 21a Furusawa K. Katsura T. Tetrahedron Lett.  1985,  26:  887 
    CrossrefGoogle Scholar
  • 21b Beijer B. Grøtli M. Douglas ME. Sproat BS. Nucleosides Nucleotides  1994,  13:  1905 
    CrossrefGoogle Scholar
  • 21c Wada T. Tobe M. Nagayama T. Furusawa K. Sekine M. Tetrahedron Lett.  1995,  36:  1683 
    CrossrefGoogle Scholar
15

Compound 3b was purchased from TCI (www.tciamerica.com).

16

The purity of the complex can roughly be checked by the color of the complex and/or the solution of it since the green color of Co(I)Cl(PPh3)3 is changed into blue color of Co(II) species generated by degradation.

18

Experimental for Synthesis of 2: Ethyl ester 4a (1.96 g, 6.0 mmol) was dried by repeated coevaporations with dry toluene and dissolved in dry THF (30 mL) under argon. Freshly prepared 1 M p-anisyl magnesium bromide solution in dry THF was added drop wise to the mixture under reflux and stirred for 30 min. The mixture was cooled to r.t., diluted with Et2O (150 mL), and washed with sat. NH4Cl aq solution (150 mL). The aqueous layer was back-extracted with Et2O (2 × 150 mL). The combined organic layers were washed with sat. NaCl aq solution (150 mL), dried over MgSO4, filtered, and concentrated to dryness. The residue was dried by repeated coevaporations with dry toluene and dissolved in AcCl (3 mL). The mixture was heated under reflux for 1.5 h, and then cooled to r.t. The mixture was added to cyclohexane (30 mL), stirred for 5 min, and kept at 4 °C for 20 h. The mixture was warmed to r.t. and the resultant precipitate was collected by suction filtration. The collected solid was washed with dry cyclohexane (5 × 3 mL) and dried under vacuum to afford 2 (2.97 g, 4.22 mmol, 70%) as an orange powder. 1H NMR (400 MHz, CDCl3): δ = 7.16-7.11 (m, 4 H), 7.08 (d, J = 8.8 Hz, 8 H), 7.01 (d, J = 7.6 Hz, 2 H), 6.94 (d, J = 8.8 Hz, 2 H), 6.78 (d, J = 8.8 Hz, 8 H), 3.80 (s, 12 H), 2.86 (s, 4 H). 13C NMR (100 MHz, CDCl3): δ = 158.7, 145.4, 140.6, 137.6, 130.9, 129.9, 127.9, 127.3, 127.1, 112.8, 82.5, 55.3, 37.5. ESI-MS: m/z for C44H41Cl2O4 (M + H+) 703. Anal. Calcd. for C44H40Cl2O4: C, 75.10; H, 5.73; Cl, 10.08. Found: C, 74.68; H, 6.07; Cl, 9.51.

19

Analytical data for 7: 1H NMR (400 MHz, DMSO-d 6): δ = 11.3 (brs, 2 H), 7.50 (s, 2 H), 7.19-7.14 (m, 14 H), 6.94-6.93 (m, 2 H), 6.85-6.82 (m, 8 H), 6.20 (dd, J = 6.7, 6.7 Hz, 2 H), 5.32 (d, J = 4.4 Hz, 2 H), 4.33 (m, 2 H), 3.84 (m, 2 H), 3.71 (s, 12 H), 3.12 (m, 4 H), 2.72 (s, 4 H), 2.24 (ddd, J = 13.5, 6.7, 6.7 Hz, 2 H), 2.15 (ddd, J = 13.5, 6.7, 3.2 Hz, 2 H), 1.38 (s, 6 H). 13C NMR (100 MHz, DMSO-d 6): δ = 163.4, 157.8, 157.8, 150.1, 143.8, 140.4, 135.6, 135.4, 135.2, 129.5, 129.3, 127.8, 127.6, 126.7, 125.3, 113.0, 109.4, 85.7, 85.4, 83.6, 79.1, 70.5, 63.6, 55.0, 37.1, 11.7. HRMS: calcd for C64H65N4Na2O14 + (M - H+ +2 Na+) 1159.4287; found: 1159.4342.

20

Analytical data for 8: 1H NMR (400 MHz, CDCl3): δ = 8.04 (brs, 1 H), 7.54 (s, 1 H), 7.37-6.69 (m, 24 H), 6.56 (dd, J = 9.2, 5.2 Hz, 1 H), 4.34 (m, 1 H), 4.04 (m, 1 H), 3.80 (s, 3 H), 3.78 (s, 3 H), 3.76 (s, 3 H), 3.72 (s, 3 H), 3.15-2.57 (m, 6 H), 2.27 (dd, J = 10.8, 3.2 Hz, 1 H), 2.11 (m, 1 H), 1.41 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 163.3, 158.6, 158.2, 158.1, 157.8, 150.0, 141.6, 141.5, 140.5, 140.1, 139.8, 138.5, 136.9, 135.6, 133.9, 130.9, 130.8, 129.4, 129.3, 129.3, 128.2, 127.7, 127.7, 127.6, 127.4, 127.3, 127.1, 113.2, 113.1, 113.0, 112.9, 110.8, 87.6, 86.6, 86.2, 85.5, 75.5, 55.3, 55.3, 55.3, 55.2, 40.4, 37.6, 36.8, 11.8. HRMS: calcd for C54H53N2O9 (M + H+) 873.3745; found: 873.3732.

22

E-DMT is commercially available from Sai Dru Syn Laboratories, Hyderabad, India (www.saiintgroup.com).