Theoretical Studies of the Glycosidation of 2-O-Substituted 5-Fluorouracil: N-Regioselective Synthesis with the Phase-Transfer-Catalysis Method.

The observed N-regioselective glycosidation of 2-O-substituted 5-fluorouracil (5-FU) via the phase-transfer-catalysis (PTC) method was investigated computationally. The Gibbs free energy reaction barrier of the N-reaction between the 5-FU anion and 1-bromo-1-deoxy-2,3,4,6-tetra-O-acetyl-α-d-glucopyranose was computed at the MP2/6-311++G(2d,p)//B3LYP/6-31+G* level. The calculated transition states were, in general, quite "loose", with the ambident reaction sites at the N3- or O4-positions on 5-FU located approximately 2.0 Å from the anomeric carbon. With the SN 2 mechanism, the formation of β-glycosides was explained by the characteristics of transition states, and the N-regioselectivity was explained by three considerations: (1) the conformations of initial complexes and the structural requirement of the reactions; (2) the formation of an ionic pair between nBu4 N+ and 2-O-substituted 5-FU anions; and (3) the thermodynamic conversion of O-glycosides to N-glycosides. The reactions between the oxocarbenium ion and the 2-O-substituted 5-FU anions (the fast step of SN 1 mechanism) were also examined at the same level of theory. Because there were no "promoters" to extract Br in the PTC method, the SN 1 mechanism might have an unfavorably high barrier to produce oxocarbenium ion. However, both the formation of β-glycosides and the experimentally observed N-regioselectivity could also be explained by the SN 1 mechanism: The former was explained by the neighboring group participation, and the latter was explained by the formation of ionic pairs between nBu4 N+ and 2-O-substituted 5-FU anions. The formation of ionic pairs possibly changed the diffusion-controlled mechanism into an activation-controlled mechanism. Two factors were demonstrated by Marcus theory to play an important role for the experimentally observed N-resioselectivity in the PTC method: (1) the thermodynamic stability of N-products over O-products; (2) the formation of ionic pair between nBu4 N+ and 2-O-substituted 5-FU anions.