Whitfield Dennis M, Nukada Tomoo
Institute for Biological Sciences, NRC Canada, 100 Sussex Drive, Ottawa, ON, Canada.
Carbohydr Res. 2007 Jul 23;342(10):1291-304. doi: 10.1016/j.carres.2007.03.030. Epub 2007 Apr 14.
Although the synthetic utility of the 1,2-trans relationship of the products of neighboring group participation is well established, it is still common to find glycosylation reactions where the stereochemical purity of the products is not 100%. As part of an ongoing series of density functional theory (DFT) studies of the factors that affect glycosylation reactions which are aimed at allowing synthetic chemists to achieve such selectivities, the structures of four oxacarbenium ions and eight methanol complexes of these ions were optimized for the prototypical ions 2-O-acetyl-3,4,6-tri-O-methyl-D-gluco- (1) and mannopyranos-1-yl (2). These studies corroborate the two-conformer hypothesis and further demonstrate that glycopyranosyl oxacarbenium ions exhibit facial selectivity that depends on, besides the inherent steric and Van der Waals effects, the conformational effect associated with the change from sp(2) to sp(3) hybridization at C-1 during nucleophilic attack and H-bonding between the incoming nucleophile and the electronegative atoms of the electrophile. Further studies based on systematic C-2-O-2 bond rotations found TSs that connect the monocyclic ions with the bicyclic ions associated with neighboring-group participation. It was also possible to find two TSs that connect nucleophilic attack at C-1 with C-2-O-2 bond rotation ultimately leading to 1,2-trans O-glycosides, that is, the probable TS that determines the stereochemistry of neighboring-group participation. Both of these TSs exhibit intramolecular H-bonding, which is considered the first step in proton transfer. It is further hypothesized that this coupling of proton transfer and nucleophilic attack is integral to glycosylation. It is further hypothesized that in many cases analogous intermolecular H-bonding is also favorable with the most likely acceptor the anion that is ion-paired to the oxacarbenium ion. These general features are found for both 1 and 2, but characteristic features of each isomer are found that provide further insights into the origins of stereoselectivity.
尽管相邻基团参与反应产物的1,2-反式关系在合成应用方面已得到充分确立，但在糖基化反应中，产物的立体化学纯度并非100%的情况仍很常见。作为正在进行的一系列旨在让合成化学家实现此类选择性的密度泛函理论（DFT）研究的一部分，针对原型离子2-O-乙酰基-3,4,6-三-O-甲基-D-葡糖-（1）和甘露吡喃糖-1-基（2），优化了四种氧碳鎓离子及其八种甲醇配合物的结构。这些研究证实了双构象体假说，并进一步表明，除了固有的空间效应和范德华效应外，糖吡喃糖基氧碳鎓离子还表现出表面选择性，这种选择性取决于亲核进攻过程中C-1处从sp(2)到sp(3)杂化转变所关联的构象效应，以及亲核试剂与亲电试剂的电负性原子之间的氢键作用。基于C-2-O-2键的系统旋转进行进一步研究时，发现了连接单环离子与与相邻基团参与相关的双环离子的过渡态。还发现了两个连接C-1处亲核进攻与C-2-O-2键旋转最终生成1,2-反式O-糖苷的过渡态，即决定相邻基团参与反应立体化学的可能过渡态。这两种过渡态均表现出分子内氢键作用，这被认为是质子转移的第一步。进一步推测，这种质子转移与亲核进攻的耦合对于糖基化反应至关重要。还进一步推测，在许多情况下，类似的分子间氢键作用也很有利，最有可能的受体是与氧碳鎓离子形成离子对的阴离子。对于1和2均发现了这些一般特征，但也发现了每种异构体的特征，这些特征为立体选择性的起源提供了进一步的见解。
