Wang Yi-Gui, Barnes Ericka C
Department of Chemistry, Southern CT State University , 501 Crescent Street, New Haven, Connecticut 06515, United States.
J Phys Chem A. 2017 Nov 22;121(46):8866-8883. doi: 10.1021/acs.jpca.7b06602. Epub 2017 Nov 9.
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 S2 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 nBuN 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 S1 mechanism) were also examined at the same level of theory. Because there were no "promoters" to extract Br in the PTC method, the S1 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 S1 mechanism: The former was explained by the neighboring group participation, and the latter was explained by the formation of ionic pairs between nBuN 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 nBuN and 2-O-substituted 5-FU anions.
通过计算研究了经由相转移催化（PTC）方法对2 - O - 取代的5 - 氟尿嘧啶（5 - FU）进行的N - 区域选择性糖基化反应。在MP2/6 - 311++G(2d,p)//B3LYP/6 - 31+G*水平上计算了5 - FU阴离子与1 - 溴 - 1 - 脱氧 - 2,3,4,6 - 四 - O - 乙酰基 - α - D - 吡喃葡萄糖之间N - 反应的吉布斯自由能反应势垒。一般来说，计算得到的过渡态相当“松散”，5 - FU上N3 - 或O4 - 位的两可亲核反应位点距离异头碳约2.0 Å。对于S2机制，β - 糖苷的形成通过过渡态的特征来解释，而N - 区域选择性通过三个方面来解释：（1）初始配合物的构象和反应的结构要求；（2）nBuN与2 - O - 取代的5 - FU阴离子之间离子对的形成；（3）O - 糖苷向N - 糖苷的热力学转化。在相同理论水平上也研究了氧鎓离子与2 - O - 取代的5 - FU阴离子之间的反应（S1机制的快速步骤）。由于在PTC方法中没有“促进剂”来提取Br，S1机制生成氧鎓离子的势垒可能高得不利。然而，β - 糖苷的形成和实验观察到的N - 区域选择性也可以用S1机制来解释：前者通过邻基参与来解释，后者通过nBuN与2 - O - 取代的5 - FU阴离子之间离子对的形成来解释。离子对的形成可能将扩散控制机制转变为活化控制机制。Marcus理论证明有两个因素对PTC方法中实验观察到的N - 区域选择性起重要作用：（1）N - 产物相对于O - 产物的热力学稳定性；（2）nBuN与2 - O - 取代的5 - FU阴离子之间离子对的形成。
