Wang Yi-Gui, Barnes Ericka C
Department of Chemistry, Southern CT State University, 501 Crescent Street, New Haven, Connecticut 06515, United States.
ACS Omega. 2018 Apr 26;3(4):4557-4572. doi: 10.1021/acsomega.8b00361. eCollection 2018 Apr 30.
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--acetyl-α-d-glucopyranose and the silver salts of 5-FU, 2--butyl-5-FU, and 2--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.
通过银盐法对具有双亲性的2 - O - 取代5 - 氟尿嘧啶（5 - FU）进行糖苷化反应时，其出色的O - 区域选择性在MP2/6 - 311++G(2d,p):DZP//B3LYP/6 - 31+G(d):DZP理论水平上进行了计算研究。所研究的反应是1 - 溴 - 1 - 脱氧 - 2,3,4,6 - 四 - 乙酰基 - α - D - 吡喃葡萄糖与5 - FU、2 - 丁基 - 5 - FU和2 - 苄基 - 5 - FU的银盐之间的反应。考虑了两条途径如下：（A）银离子和溴离子不相互作用的途径，以及（B）银离子和溴离子在过渡态相互作用的途径。由于在两条途径中O - 反应势垒都比N - 反应势垒低得多（低13.3 - 22.2 kcal/mol），所以银盐法的O - 区域选择性可以通过途径A或途径B得到满意的解释。此外，在N - 和O - 反应中，银离子和溴离子持续相互作用的途径B比相应的途径A具有更低的活化势垒（低6.8 - 17.4 kcal/mol）。这一计算结果可归因于以下原因：（1）在反应混合物中加入碳酸银对柯尼希斯 - 克诺尔反应的加速作用；（2）如科恩布卢姆及其同事所提出的，银离子将卤化物中的卤素拉走；以及（3）氧鎓离子参与糖苷化反应。N - 和O - 过渡态之间的巨大能量差异源于银离子与双亲性单元（-N3 - C4 = O4）的N - （O - ）之间的缔合，这种缔合表现出显著的共价性质，使得银盐法的O - 反应过渡态受益于有利的离子相互作用（C···O）和有利的共价相互作用（Ag···N）。这两种有利的相互作用符合软硬酸碱原理；前者是硬 - 硬相互作用，后者是软 - 软相互作用。
