Diastereoselective formation of glycoluril dimers:: Isomerization mechanism and implications for cucurbit[n]uril synthesis
Diastereoselective formation of glycoluril dimers:: Isomerization mechanism and implications for cucurbit[n]uril synthesis
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DOI：
10.1021/ja025876f
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发表时间：
2002-07-17
影响因子：
15
通讯作者：
Isaacs, L
中科院分区：
文献类型：
--
作者：
Chakraborty, A;Xu, AX;Isaacs, L
葫芦[6]脲（CB[6]）是由甘脲和甲醛一锅法合成的大环化合物，其分子识别特性使其成为研究的热点。CB[n]形成机制的研究，这可能会提供见解，允许定制的CB[n]同系物和衍生物的合成，已被CB[n]的复杂结构所阻碍。通过降低反应的复杂性，形成S-形（12 S-18 S）和C-形（12 C-18 C）亚甲基桥连甘脲二聚体，我们已经能够探测CB[n]合成机制的基本步骤，达到以前不可能的水平。例如，我们提出了强有力的证据表明，CB[n]合成的机制通过S形和C形二聚体的中间性进行。S形和C形二聚体的相对自由能的第一次实验测定表明C形非对映体的热力学偏好（1.55-3.25 kcal mol（-1））。这种热力学偏好不是因为自缔合、溶剂化或模板效应。此外，标记实验使我们能够阐明这种酸催化的S-形和C-形非对映异构体之间的平衡的机制。平衡是一个分子内过程，具有高的非对映选择性和构型保留。基于这些结果对CB[n]合成的广泛影响，我们提出了新的合成策略，可以改进从官能化甘脲制备CB[n]（n > 8）和CB[n]衍生物。
Cucurbit[6]uril (CB[6]) is a macrocyclic compound, prepared in one pot from glycoluril and formaldehyde, whose molecular recognition properties have made it the object of intense study. Studies of the mechanism of CB[n] formation, which might provide insights that allow the tailor-made synthesis of CB[n] homologues and derivatives, have been hampered by the complex structure of CB[n]. By reducing the complexity of the reaction to the formation of S-shaped (12S-18S) and C-shaped (12C-18C) methylene bridged glycoluril dimers, we have been able to probe the fundamental steps of the mechanism of CB[n] synthesis to a level that has not been possible previously. For example, we present strong evidence that the mechanism of CB[n] synthesis proceeds via the intermediacy of both S-shaped and C-shaped dimers. The first experimental determination of the relative free energies of the S-shaped and C-shaped dinners indicates a thermodynamic preference (1.55-3.25 kcal mol(-1)) for the C-shaped diastereomer. This thermodynamic preference is not because of self-association, solvation, or template effects. Furthermore, labeling experiments have allowed us to elucidate the mechanism of this acid-catalyzed equilibrium between the S-shaped and C-shaped diastereomers. The equilibration is an intramolecular process that proceeds with high diastereoselectivity and retention of configuration. On the basis of the broad implications of these results for CB[n] synthesis, we suggest new synthetic strategies that may allow for the improved preparation of CB[n] (n > 8) and CB[n] derivatives from functionalized glycolurils.