Microwave-Assisted Selective 5′-O-Trityl Protection of Inosine Derivatives

Abstract

The efficient microwave-assisted synthesis of 5′-O-trityl inosine derivatives is described. The reported protocol allows the protection of inosine derivatives in significantly higher yields and shorter reaction times than the standard thermal conditions. This procedure is particularly suitable for modified inosines where the 5′-OH is sterically hindered (i.e. 8-bromoinosine).

protecting groups - microwave synthesis - nucleosides - tritylether - medicinal chemistry

References and Notes

1 Muramatsu N. Takenishi T. J. Org. Chem.  1965,  30:  3211 

2 Hampton A. Nichol AW. Biochemistry  1966,  5:  2076 

3 Green R. Szostak JW. Benner SA. Rich A. Usman N. Nucleic Acids Res.  1991,  19:  4161 

4 Matulic-Adamic J. Beigelman L. Synth. Commun.  2000,  30:  3963 

5 Liekens S. Hernández AI. Ribatti D. De Clercq E. Camarasa MJ. Pérez-Pérez MJ. Balzarini J. J. Biol. Chem.  2004,  279:  29598 

6 Pankiewicz KW. Krzeminski J. Ciszewski LA. Ren WY. Watanabe KA. J. Org. Chem.  1992,  57:  553 

7 Takamatsu S. Maruyama T. Katayama S. Hirose N. Izawa K. Tetrahedron Lett.  2001,  42:  2321 

8 Casanova E. Hernández AI. Priego EM. Liekens S. Camarasa MJ. Balzarini J. Pérez-Pérez MJ. J. Med. Chem.  2006,  49:  5562 

9 Kappe CO. Angew. Chem. Int. Ed.  2004,  43:  6250 

10 This paper mostly reports on the tritylation reaction in the presence of DABCO in molten TBAB. Attempted microwave irradiation produces low yields and the nucleobase is lost. See: Khalafi-Nezhad A. Moktari B. Tetrahedron Lett.  2004,  45:  6737 

11 Hyde RM. Broom AD. Buckheit RW. J. Med. Chem.  2003,  46:  1878 

12 Watanabe KA, Pankiewicz KW, Krzeminski J, and Nawrot B. inventors; WO  9211276.  ; Chem. Abstr. 1993, 118, 7325

13

Spectroscopic data for N ¹-benzylinosine (4): ¹H NMR (360 MHz, DMSO-d ₆): δ = 3.60 (m, 2 H, H-5′), 3.93 (m, 1 H, H-4′), 4.11 (m, 1 H, H-3′), 4.48 (m, 1 H, H-2′), 5.05 (t, J = 5.7 Hz, 1 H, OH), 5.21-5.23 (m, 3 H, CH₂, OH), 5.49 (m, 1 H, OH), 5.85 (d, J = 5.8 Hz, 1 H, H-1′), 7.24-7.36 (m, 5 H, Ph), 8.36, 8.62 (s, 2 H, H-2, H-8). MS (ES, positive mode): m/z = 358 [M + 1]⁺.

14 Fukuoka M. Shuto S. Minakawa N. Ueno Y. Matsuda A. J. Org. Chem.  2000,  65:  5238 

15 Holmes RE. Robins RK. J. Am. Chem. Soc.  1964,  86:  1242 

16

Spectroscopic data for 8-bromo-5′-O-tritylinosine (8): white solid, mp 175-178 °C (MeOH). ¹H NMR (300 MHz, DMSO-d ₆): δ = 3.16 (m, 2 H, H-5′), 4.05 (m, 1 H, H-4′), 4.42 (m, 1 H, H-3′), 5.06 (m, 1 H, H-2′), 5.22 (d, J = 4.8 Hz, 1 H, OH), 5.56 (d, J = 5.7 Hz, 1 H, OH), 5.83 (d, J = 4.2 Hz, 1 H, H-1′), 7.19-7.30 (m, 15 H, Ph), 7.88 (s, 0.66 H, H-2), 7.93 (s, 0.33 H, H-2), 12.56 (br s, 1 H, NH). MS (ES, positive mode): m/z = 589 [M + 1]⁺.