Palladium Catalyzed Amination and Suzuki-Miyaura Cross-coupling Reactions of Nucleosides

Palladium Catalyzed Amination and Suzuki-Miyaura Cross-coupling Reactions of Nucleosides

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Palladium catalyzed coupling reactions of arene arylsulfonates and halides with amines and arylboronic acids a powerful and general methodology in contemporaty organic synthesis. The application of this methodology to nucleosides is particularly interesting due to the central role of modified nucleosides in biochemical systems and in medicine. We have committed substantial effort in understanding and developing Pd-catalyzed C-N and C-C bond forming reactions of nucleosides because these compounds exhibit some remarkable reactivities that are often not comparable to simpler molecules. Our studies clearly demonstrate that a family of N6-aryl-2, 6-diaminopurine nucleoside analogues could be expediently synthesized in good yields via palladium catalysis. This was the first study pertaining to a general utility of O6-arylsulfonate derivatives of 2'-deoxyguanosine in the Pd-catalyzed C-N bond formation. The dependence of the reaction on ligand/palladium ratios and concentration has also been assessed. Spurred by these novel findings, we directed our attention towards the development of broadly applicable C-C bond forming reactions at room temperature also utilizing the O6-arylsulfonate derivatives of 2'-deoxyguanosine. To the best of our knowledge this is the first study on the C-C cross-coupling reactions of such nucleoside derivatives at room temperature. This study also entailed the detailed investigation of the effect of solvent, effect of substituents on the arylsulfonate moiety and substitution on the arylboronic acids on the cross coupling reaction. We have also performed structural studies that provide insight into the reactive nature of the catalyst. Based upon the results from the C-N and C-C bond-forming reactions, synthetic methodology to a new biphenyl based phosphine ligand has been developed. This new ligand has been evaluated for its ability to effectively promote C-N and C-C bond forming reactions and was found to provide a generally useful catalyst. We also studied Pd-catalyzed C-N bond formation involving halo nucleosides and the axially constrained amino benzoate from the tetrahydroepoxide of benzo[ a]pyrene. This results offer a facile approach to the biologically important epoxide-nucleoside adducts. These adducts were converted to 5'- O-DMT 3'-O-phosphoramidites and site-specifically incorporated into the human N-ras sequence 5'-CGGAC A*AGAAG-3' via semi-automated procedures. The ensuing adducted oligomers have been used for thermal denaturation and circular dichroism studies.10S refers to the absolute configuration at the C-10 of BaP in the adducted oligomer 234 19 CD spectra at 0 AdC and 50 AdC of the N-ras duplex containing BaP H4 E-10R adduct with a normal complementary strand 235 20 CD spectra at 0 AdCanbsp;...

Title:Palladium Catalyzed Amination and Suzuki-Miyaura Cross-coupling Reactions of Nucleosides
Author:Padmaja Gunda
Publisher:ProQuest - 2007


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