Theoretical Studies of the Glycosidation of 2-O-Substituted 5-Fluorouracil: N-Regioselective Synthesis with the Phase-Transfer-Catalysis Method,The Journal of Physical Chemistry A

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Theoretical Studies of the Glycosidation of 2-O-Substituted 5-Fluorouracil: N-Regioselective Synthesis with the Phase-Transfer-Catalysis Method
The Journal of Physical Chemistry A ( IF 2.7 ) Pub Date : 2017-11-09 00:00:00 , DOI: 10.1021/acs.jpca.7b06602
Yi-Gui Wang ₁ , Ericka C. Barnes ₁

Affiliation

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 S_N2 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 nBu₄N⁺ 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 S_N1 mechanism) were also examined at the same level of theory. Because there were no “promoters” to extract Br in the PTC method, the S_N1 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 S_N1 mechanism: The former was explained by the neighboring group participation, and the latter was explained by the formation of ionic pairs between nBu₄N⁺ 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 nBu₄N⁺ and 2-O-substituted 5-FU anions.

中文翻译：

相转移催化方法2-O取代的5-氟尿嘧啶糖苷化的理论研究：N-区域选择性合成

通过相转移催化（PTC）方法对2 - O-取代的5-氟尿嘧啶（5-FU）的N-区域选择性糖基化进行了计算研究。在MP2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-吡喃葡萄糖之间的N反应的吉布斯自由能反应势垒/ 6-311 ++ G（2d，p）// B3LYP / 6-31 + G *等级。通常，所计算的过渡态非常“松散”，在5-FU的N3-或O4-位置处的环境反应位相对于异头碳约2.0Å。带有S _Ñ2机制中，β-糖苷的形成是通过过渡态的特征来解释的，N-区域选择性是通过三个方面的考虑来解释的：（1）初始配合物的构型和反应的结构要求；（2）在n Bu ₄ N ⁺和2-O-取代的5-FU阴离子之间形成离子对；（3）O-糖苷向N-糖苷的热力学转化。还以相同的理论水平检查了氧碳鎓离子与2-O-取代的5-FU阴离子之间的反应（S _N 1机理的快速步骤）。因为在PTC方法中没有“促进剂”来提取Br，所以S _N一种机理可能对产生氧碳en离子具有不利的高阻隔作用。但是，β-糖苷的形成和实验观察到的N-区域选择性也可以通过S _N 1机理来解释：前者是通过邻近基团的参与来解释的，后者是通过n之间离子对的形成来解释的。Bu ₄ N ⁺和2-O-取代的5-FU阴离子。离子对的形成可能会将扩散控制机制转变为激活控制机制。Marcus理论证明了以下两个因素在PTC方法中对实验观察到的N-重氮选择性起着重要作用：（1）N产物相对于O产物的热力学稳定性；（2）在n Bu ₄ N ⁺和2-O-取代的5-FU阴离子之间形成离子对。

更新日期：2017-11-09

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