N,N-二(对氟苄基)-N'-(2',3'-二脱氧-3'-硫代胞苷)甲脒水解反应的理论研究

采用密度泛函理论方法B3LYP/6-31++G(d,p)//B3LYP/6-31G(d,p)和导体极化连续模型B3LYP/CPCM/6-31++G(d,p)方法对苯环对位上有F取代的N,N-二(对氟苄基)-N′-(2′,3′-二脱氧-3′-硫代胞苷)甲脒(FBFA-3TC)水解反应机理和溶剂效应进行了研究. 考虑两条可能反应途径: 水分子首先进攻C=N双键的途径(Path A)和先进攻C-N单键的途径(Path B). 计算结果表明, 气相和水中两条途径的第一步都是速率控制步骤, Path A 比Path B 更有利. 对优势途径Path A的第二步反应的进一步研究发现, 中间体的羟基H原子转移到双键N比单键N更容易, 从而形成2′,3′-二脱氧-3′-硫代胞苷(3TC)的最终水解产物.

Theoretical Study on the Hydrolysis of N, N-Bis(p-fluorobenzyl)-N'-(2', 3'-dideoxy-3'-thiacytidinyl) Formamidine

Theoretical study on the hydrolysis mechanism of N,N-bis(p-fluorobenzyl)-N′-(2′,3′- dideoxy-3′-thiacytidinyl)formamidine(FBFA-3TC) was carried out at the B3LYP/6-31G(d,p) level. The solvent effect was evaluated using the conductor polarizable continuum model(CPCM) through the single point energy calculations at the B3LYP/6-31++G(d,p) level. Two reaction pathways are considered. Path A is the addition of water molecule to the C=N double bond in the amidine group in its first step and Path B is the attack of water molecule to the C-N single bond in its first step. The calculated results indicate that the first step in both pathways is the rate-limiting process and Path A is more favorable than Path B in the gas phase and in water. The solvent effects are not distinct. It is also found that the second step in Path A proceeds preferably according to Channel a, in which the second H atom of water transfers to the N atom in double bond of the amidine group, leading to products the modified cytidine and N,N-dibenzyl formamide.