Synthesis and conformational analysis of d-2'-deoxy-2',2'-difluoro-4'-dihydro-4'-thionucleosides.
An efficient synthesis of d-2'-deoxy-2',2'-difluoro-4'-dihydro-4'-thionucleosides is described. The conformations of d-2'-deoxy-2',2'-difluoro-4'-dihydro-4'-thiouridine were studied by X-ray crystallography, NMR spectroscopy and molecular modeling in an attempt to explore the roles of the two gem-difluorine atoms in the puckering preferences of the thiosugar ring. No matter which conformation (south or north) the thiosugar adopts, there is always one fluorine in a pseudoaxial position, with the other in a pseudoequitorial position and thus the strong antiperiplanar (ap) effects from C-H and C-C sigma-bonds to sigma*C-F are equal to each other in these two conformers. Therefore, the other weak effects, such as dipole-dipole interactions and electrostatic attractions, become more important for determining the overall conformation of the sugar ring. Based on the results of NMR spectroscopy, high-level quantum computations and molecular dynamic simulations were performed to study the preferred pucker of the thiosugar ring in solution. Our results showed that the strong antiperiplanar preference of C-H and C-C sigma-bonds to sigma*C-F and sigma*C-O seemed to be responsible for the favored S-conformation in solution, and the weak electrostatic attractions between (delta+)C2-Fbeta(delta-) and (delta+)H6-C6(delta-) may stabilize the preferred structure further, and keep the base moiety in a high anti-rotamer population in solution. In contrast, the packing forces (hydrogen bond OH...O=C, dipole-dipole interaction C-F..C=O) in the solid state compensated the energetic disadvantage of the relatively less stable N-conformation, and drove the thiouridine to crystallize in the N-conformation. These results, along with the earlier empirical rules regarding proton chemical shifts in carbohydrates and nucleosides, were used to propose a method based on proton chemical shifts for the analysis of the N<==>S equilibrium of the fluorinated sugar ring.
Zheng
Feng
F
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China.
Fu
Lin
L
Wang
Renxiao
R
Qing
Feng-Ling
FL
D018360:Crystallography, X-Ray; D005461:Fluorine / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D019906:Nuclear Magnetic Resonance, Biomolecular; D013872:Thionucleosides / Q000138:chemical synthesis / Q000737:chemistry*
D013872:Thionucleosides; D005461:Fluorine