Effects of substituting a OH group by a F atom in D-glucose. Ab initio andDFT analysis

High-level ab initio and DFT methods up to MP2/6-311++G**//B3LYP/6-31G* and B3LYP/6-311++G**B3LYP/6-31G* levels have been used to assess the relative energies of 17 different structures of (D)-glucose and 13 different structu res of 4-deoxy-4-fluoro-(D)-glucose. The structures were confirmed to corre spond to minima on the potential energy surface at the RHF/6-31G* level. So lvation Model 5.4/AM1 was used to calculate the effects of aqueous solution . The substitution of a OH group by a F atom does not much change the shape and electrostatic potential around corresponding conformers, but in the ga s phase it destabilizes the cooperative network of intramolecular hydrogen bonds. This destabilization mostly affects structures with a chain of intra molecular hydrogen bonds oriented counterclockwise, as fluorine is unable t o donate a hydrogen bond and therefore causes a gap in the chain. In contra st, for clockwise-oriented networks of hydrogen bonds, the fluorine can act as an acceptor at the end of a chain of cooperative hydrogen bonds. A slig htly higher energy of anomeric and exo-anomeric stabilization is another ef fect of substituting the fourth hydroxyl group by a fluorine atom in D-gluc ose, observed both in the gas phase and in aqueous solution. For this reaso n, the a anomers contribute more to the equilibrium population of structure s of 4-deoxy-4fluoro-(D)-glucose than D-glucose. In aqueous solution, both D-glucose and its 4-deoxy-4-fluoro analogue are present as a mixture of mai nly three corresponding structures. This indicates that 4-deoxy-4-fluoro-D- glucose is a good substitute for D-glucose in terms of its biochemical and biological activity. Moreover, this suggests that, for molecules with limit ed conformational freedom, the substitution of a OH group by a F atom is ve ry likely to lead to a potential new drug. In contrast, it had already been shown that, for conformationally labile aliphatic compounds, replacement o f a hydroxyl by a fluorine increases conformational diversity, so the fluor ine-containing aliphatic molecules were not likely to be an example of a su ccessful drug design. On the other hand, this work shows that. among molecu les with limited conformational freedom, such as cyclic compounds. one is v ery likely to find targets for a successful rational drug design.