O-Regioselective Synthesis with the Silver Salt Method

[Image: see text] The excellent O-regioselectivity of the glycosidation of the ambident 2-O-substituted 5-fluorouracil (5-FU) via the silver salt method is computationally investigated at the MP2/6-311++G(2d,p):DZP//B3LYP/6-31+G(d):DZP level of theory. The reactions studied are those between 1-bromo-1-deoxy-2,3,4,6-tetra-O-acetyl-α-d-glucopyranose and the silver salts of 5-FU, 2-O-butyl-5-FU, and 2-O-benzyl-5-FU. Two pathways are considered as follows: (A) one where the silver and bromide ion do not interact, and (B) another where the silver and bromide ion interact in the transition states. Because the O-reaction barriers are much lower (by 13.3–22.2 kcal/mol) than N-reaction barriers in both pathways, the O-regioselectivity of the silver salt method can be satisfactorily explained by either path A or path B. Furthermore, path B, where Ag and Br interact consistently, has lower activation barriers than the corresponding path A (by 6.8–17.4 kcal/mol) in both N- and O-reactions. This computational result can be attributed to the following reasons: (1) the speeding-up effect in Koenigs–Knorr reactions due to the addition of silver carbonate into the reaction mixture; (2) the halogens being pulled away by silver ions from halides, as proposed by Kornblum and co-workers; and (3) the oxocarbenium ion involvement in the glycosidation reactions. The large energy difference between N- and O-transition states originates from the association between Ag and N–(O−) of the ambident unit (−N3–C4=O4) that shows significant covalent character so that the O-reaction transition states of the silver salt method benefit from favorable ionic interaction (C(+)···O(–)) and favorable covalent interaction (Ag···N). These two favorable interactions are in agreement with the hard and soft acids and bases principle; the former is a hard–hard interaction and the latter is a soft–soft interaction.