Synthesis and biological evaluation of conformationally restricted adenine bicycloribonucleosides

Organic and Biomolecular Chemistry

Volumn 13, Issue 35, 2015, Pages 9300-9313

  Hřebabecký, Hubert ^a   Procházková, Eliška ^a   Šála, Michal ^a   Plačková, Pavla ^a   Tloušt'ová, Eva ^a   Barauskas, Ona ^b   Lee, Yu Jen ^b   Tian, Yang ^b   Mackman, Richard ^b   Nencka, Radim ^a  

^a INSTITUTE OF ORGANIC CHEMISTRY AND BIOCHEMISTRY   (Czech Republic)

^b GILEAD SCIENCES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

POSITIVE IONS;

BIOLOGICAL EVALUATION; BIOLOGICAL PROPERTIES; CELL-BASED ASSAYS; CONFORMATIONAL RESTRICTIONS; CYTOSTATIC ACTIVITIES; METHYLENE GROUPS; PHOSPHORAMIDATES; SYNTHETIC APPROACH;

BIOMOLECULES;

ADENINE; ANTIVIRUS AGENT; NUCLEOTIDE; PRODRUG;

CHEMICAL STRUCTURE; CHEMISTRY; CONFORMATION; DRUG DESIGN; DRUG EFFECTS; HEPACIVIRUS; HUMAN; METABOLISM; SYNTHESIS; TUMOR CELL LINE;

ADENINE; ANTIVIRAL AGENTS; CARBOHYDRATE CONFORMATION; CELL LINE, TUMOR; CHEMISTRY TECHNIQUES, SYNTHETIC; DRUG DESIGN; HEPACIVIRUS; HUMANS; MODELS, MOLECULAR; NUCLEOTIDES; PRODRUGS;

EID: 84940375965     PISSN: 14770520     EISSN: None     Source Type: Journal    
DOI: 10.1039/c5ob00987a     Document Type: Article

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30. In situ structure determination of intermediate 20b was performed during approximately the first two hours of the reaction, when the concentration of the intermediate was above 50%. The structure determination is based on the in situ analysis of C-P spin-spin interactions across 1-3 bonds visible in 13C NMR spectra as a line splitting. It is clear that the methylester was hydrolyzed; the intensity of the signals corresponding to the methyl of the methylester group (two signals = two diastereoisomers around 52.55 ppm) decreased whereas the intensity of methanol single signal (52.45 ppm) increased. The phenyl moiety is still attached to the molecule, signals corresponding to the carbon atoms in ortho position are still two doublets (two, because of the two diastereoisomers and doublets because of the C-P interaction). After several hours, the phenyl ring was cleaved and the stable final product was obtained. The two doublets around 120.3 ppm, corresponding to ortho carbons, disappeared and one singlet signal around 118.9 ppm corresponding to ortho carbons of phenol appeared. After the phenol release, there is no chiral center at the phosphorus atom, thus no two diastereoisomers exist. It is visible, for instance, in 13C NMR spectra of carbon atom 8a, where the two doublets (87.8 ppm) corresponding to the two diastereoisomers of the intermediate disappeared and one doublet (88.6 ppm) coming from carbon atom 8a of the final product appeared (ESI Fig. S1 and S2†)
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