Fluorinated Pyrrolo[2,3-d]pyrimidine Nucleosides: 7- Fluoro-7-deazapurine 2′-Deoxyribofuranosides and 2′-Deoxy-2′-fluoroarabinofuranosyl Derivatives

Abstract

The syntheses of 7-deaza-7-fluoro-2′-deoxyadenosine (1a), 7-deaza-7-fluoro- 2′-deoxyinosine (3a) and 7-deaza-7-fluoro-2′-deoxyguanosine (3c) as well as of the 2′-deoxy-2′-fluoroarabinofuranosyl derivatives 1b, 3b are described. Starting materials were 6-chloro-7-fluoro-7-deazapurine (4-chloro-5-fluoropyrrolo[2,3-d]pyrimidine, 4b) and 2-pivaloylamino-6-chloro-7-fluoro-7-deaza­purine (2-pivaloylamino-4-chloro-5-fluoropyrrolo[2,3-d]pyrimidine, 6). Nucleobase anion glycosylation of 4b or 6 with the halogenoses 7 or 9 furnished the protected β-d-nucleosides 8, 10 and 11, which were converted to compounds 1a, 1b by ammonolysis and to 2a-c by sodium methoxide treatment. The 2′-deoxy­inosine derivatives 3a, 3b and the guanosine analogue 3c were obtained from 2a-c. Conformational analysis of the nucleosides 1a, 1b was performed in solution and in the solid state. Single-crystal X-ray analyses showed that the sugar moiety of 1a exhibits the S-conformation (P = 164.8°, τ = 40.1°). In solution the 2′-fluoro substituents shift the sugar conformation slightly towards N.

fluorine - glycosylations - pyrrolo[2,3-d]pyrimidines - nucleosides - sugar conformation

References

<A NAME="RT00806SS-1">1</A> Wang X. Seth PP. Ranken R. Swayze EE. Migawa MT. Nucleosides, Nucleotides Nucleic Acids  2004,  23:  161 

<A NAME="RT00806SS-2">2</A> Hinshaw BC. Gerster JF. Robins RK. Townsend LB. J. Heterocycl. Chem.  1969,  6:  215 

<A NAME="RT00806SS-3">3</A> Cook AF. Holman MJ. Nucleosides Nucleotides  1984,  3:  401 

<A NAME="RT00806SS-4">4</A> Henderson JF. Paterson ARP. Caldwell IC. Paul B. Chan MC. Lau KF. Cancer Chemother. Rep. 2  1972,  3:  71 

<A NAME="RT00806SS-5">5</A> Bhattacharya BK. Rao TS. Revankar GR. J. Chem. Soc., Perkin Trans. 1  1995,  1543 

<A NAME="RT00806SS-6">6</A> Bhattacharya BK. Ojwang JO. Rando RF. Huffman JH. Revankar GR. J. Med. Chem.  1995,  38:  3957 

<A NAME="RT00806SS-7">7</A> Ojwang JO. Bhattacharya BK. Marshall HB. Korba BE. Revankar GR. Rando RF. Antimicrob. Agents Chemother.  1995,  39:  2570 

<A NAME="RT00806SS-8">8</A> Seela F. Thomas H. Helv. Chim. Acta  1995,  78:  94 

<A NAME="RT00806SS-9">9</A> Ramzaeva N. Seela F. Helv. Chim. Acta  1996,  79:  1549 

<A NAME="RT00806SS-10">10</A> Seela F. Zulauf M. Chem. Eur. J.  1998,  4:  1781 

<A NAME="RT00806SS-11">11</A> Balow G. Mohan V. Lesnik EA. Johnston JF. Monia BP. Acevedo OL. Nucleic Acids Res.  1998,  26:  3350 

<A NAME="RT00806SS-12">12</A> Bondi A. J. Phys. Chem.  1964,  68:  441 

<A NAME="RT00806SS-13">13</A> Bergstrom DE. Brattesani AJ. Nucleic Acids Res.  1980,  8:  6213 

<A NAME="RT00806SS-14">14</A> Seela F. Peng X. Synthesis  2004,  1203 

<A NAME="RT00806SS-15">15</A> Erian AW. J. Heterocycl. Chem.  2001,  38:  793 

<A NAME="RT00806SS-16">16</A> Nyffeler PT. Duron SG. Burkart MD. Vincent SP. Wong C.-H. Angew. Chem. Int. Ed.  2005,  44:  192 

<A NAME="RT00806SS-17">17</A> Winkeler H.-D. Seela F. J. Org. Chem.  1983,  48:  3119 

<A NAME="RT00806SS-18">18</A> Seela F. Westermann B. Bindig U. J. Chem. Soc., Perkin Trans. 1  1988,  697 

<A NAME="RT00806SS-19">19</A> Hoffer M. Chem. Ber.  1960,  93:  2777 

<A NAME="RT00806SS-20">20</A> Howell HG. Brodfuehrer PR. Brundidge SP. Benigni DA. Sapino C. J. Org. Chem.  1988,  53:  85 

<A NAME="RT00806SS-21">21</A> Gudmundsson KS. Freeman GA. Drach JC. Townsend LB. J. Med. Chem.  2000,  43:  2473 

<A NAME="RT00806SS-22">22</A> Tann CH. Brodfuehrer PR. Brundidge SP. Sapino C. Howell HG. J. Org. Chem.  1985,  50:  3644 

<A NAME="RT00806SS-23">23</A> Taylor EC. Kuhnt D. Shih C. Rinzel SM. Grindey GB. Barredo J. Jannatipour M. Moran RG. J. Med. Chem.  1992,  35:  4450 

<A NAME="RT00806SS-24">24</A> Barnett CJ. Kobierski ME. J. Heterocycl. Chem.  1994,  31:  1181 

<A NAME="RT00806SS-25">25</A> Revankar GR. Rao TS. Ramasamy K. Smee DF. Nucleosides Nucleotides  1995,  14:  671 

<A NAME="RT00806SS-26">26</A> Seela F. Thomas H. Helv. Chim. Acta  1994,  77:  897 

<A NAME="RT00806SS-27">27</A> Seela F. Zulauf M. Synthesis  1996,  726 

<A NAME="RT00806SS-28">28</A> Thomas H. Ph.D. Thesis   University of Osnabrück; Osnabrück: 1995. 

<A NAME="RT00806SS-29">29</A> Breitmaier E. Voelter W. In ¹³C NMR Spectroscopy Monographs in Modern Chemistry   2nd ed., Vol. 5:  Ebel HF. Verlag Chemie; Weinheim: 1978.  p.201 

<A NAME="RT00806SS-30">30</A> Albert A. Serjeant EP. The Determination of Ionization Constants   Chapman & Hall Ltd; London: 1971.  p.44 

<A NAME="RT00806SS-31">31</A> Plavec J. Thibaudeau C. Chattopadhyaya J. Pure Appl. Chem.  1996,  68:  2137 

<A NAME="RT00806SS-32">32</A> Van Wijk L. Haasnoot CAG. De Leeuw FAAM. Huckriede BD. Westra Hoekzema AJA. Altona C. PSEUROT 6.3   Leiden Institute of Chemistry, Leiden University; Leiden: 1999. 

<A NAME="RT00806SS-33">33</A> Thibaudeau C. Plavec J. Chattopadhyaya J. J. Org. Chem.  1998,  63:  4967 

<A NAME="RT00806SS-34">34</A> Rosemeyer H. Zulauf M. Ramzaeva N. Becher G. Feiling E. Mühlegger K. Münster I. Lohmann A. Seela F. Nucleosides Nucleotides  1997,  16:  821 

<A NAME="RT00806SS-35">35</A> Peng X. Seela F. Org. Biomol. Chem.  2004,  2:  2838 

<A NAME="RT00806SS-36">36</A> He J. Mikhailopulo I. Seela F. J. Org. Chem.  2003,  68:  5519 

<A NAME="RT00806SS-37">37</A> Seela F. Xu K. Eickmeier H. Acta Cryst.  2005,  C61:  o408