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Methoxymethyl (MOM) Group Nitrogen Protection of Pyrimidines Bearing C-6 Acyclic Side-Chains
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 20, HR-10000 Zagreb, Croatia
Slovenian NMR centre, National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
EN-FIST Centre of Exellence, Dunajska 156, SI-1000 Ljubljana, Slovenia
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva cesta 5, SI-1000 Ljubljana, Slovenia
Radiopharmaceutical Chemistry, Institute of Nuclear Chemistry, Johannes Gutenberg-Universität, Fritz-Strassmann Weg 2, 55128 Mainz, Germany
Center for Radiopharmaceutical Sciences, ETH Zurich (Swiss Federal Institute of Technology), Wolfgang-Pauli Strasse 10, CH-8093 Zurich, Switzerland
* Authors to whom correspondence should be addressed.
Received: 26 May 2011; in revised form: 15 June 2011 / Accepted: 16 June 2011 / Published: 20 June 2011
Abstract: Novel N-methoxymethylated (MOM) pyrimidine (4-13) and pyrimidine-2,4-diones (15-17) nucleoside mimetics in which an isobutyl side-chain is attached at the C-6 position of the pyrimidine moiety were synthesized. Synthetic methods via O-persilylated or N-anionic uracil derivatives have been evaluated for the synthesis of N-1- and/or N-3-MOM pyrimidine derivatives with C-6 acyclic side-chains. A synthetic approach using an activated N-anionic pyrimidine derivative afforded the desired N,N-1,3-diMOM and N-1-MOM pyrimidines 4 and 5 in good yield. Introduction of fluorine into the side-chain was performed with DAST as the fluorinating reagent to give a N,N-1,3-diMOM pyrimidine 13 with a 1-fluoro-3-hydroxyisobutyl moiety at C-6. Conformational study of the monotritylated N-1-MOM pyrimidine 12 by the use of the NOE experiments revealed the predominant conformation of the compound to be one where the hydroxymethyl group in the C-6 side-chain is close to the N-1-MOM moiety, while the OMTr is in proximity to the CH3-5 group. Contrary to this no NOE enhancements between the N-1-MOM group and hydroxymethyl or fluoromethyl protons in 13 were observed, which suggested a nonrestricted rotation along the C-6 side-chain. Fluorinated N,N-1,3-diMOM pyrimidine 13 emerged as a model compound for development of tracer molecules for non-invasive imaging of gene expression using positron emission tomography (PET).
Keywords: N-methoxymethyl protecting group; C-6 isobutyl pyrimidine derivatives; N-1 and N-3 regioisomers; NOE experiments; positron emission tomography (PET)
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Kraljević, T.G.; Petrović, M.; Krištafor, S.; Makuc, D.; Plavec, J.; Ross, T.L.; Ametamey, S.M.; Raić-Malić, S. Methoxymethyl (MOM) Group Nitrogen Protection of Pyrimidines Bearing C-6 Acyclic Side-Chains. Molecules 2011, 16, 5113-5129.
Kraljević TG, Petrović M, Krištafor S, Makuc D, Plavec J, Ross TL, Ametamey SM, Raić-Malić S. Methoxymethyl (MOM) Group Nitrogen Protection of Pyrimidines Bearing C-6 Acyclic Side-Chains. Molecules. 2011; 16(6):5113-5129.
Kraljević, Tatjana Gazivoda; Petrović, Martina; Krištafor, Svjetlana; Makuc, Damjan; Plavec, Janez; Ross, Tobias L.; Ametamey, Simon M.; Raić-Malić, Silvana. 2011. "Methoxymethyl (MOM) Group Nitrogen Protection of Pyrimidines Bearing C-6 Acyclic Side-Chains." Molecules 16, no. 6: 5113-5129.