The Center for Combinatorial Chemistry and Drug Discovery, The School of Pharmaceutical Sciences and The College of Chemistry, Jilin University, 1266 Fujin Road, Changchun, Jilin 130021, P. R. China.
J Org Chem. 2010 Dec 3;75(23):8147-54. doi: 10.1021/jo101798p. Epub 2010 Nov 9.
To understand the detailed mechanism of a recently reported tandem iminium cyclization and Smiles rearrangement, the reaction processes of a chiral substrate were investigated by monitoring its stereochemical courses. Under the tandem reaction conditions, chiral aldehyde 1 derived from l-prolinol led to two surprising results. First, the iminium cyclization gave a diastereomeric mixture with the cis-configured product as the predominant one. Second, Smiles rearrangement of both cis- and trans-2 led to the same product 3a directly derived from the trans isomer. The former was rationalized by the postulation of a Cram's chelate transition state leading to the cis product as kinetically favored. The latter was due to the equilibration between the trans/cis pair involving a carbocation intermediate and the steric hindrance, which prevented the cis isomer from undergoing the intramolecular nucleophilic substitution. This hypothesis was further supported by the results of a competition experiment in which the addition of 1 equiv of p-methoxyaniline in the rearrangement step led to a significant amount of anilinyl-exchanged rearrangement product.
为了深入理解最近报道的串联亚胺环化和斯迈尔斯重排的详细机理，通过监测手性底物的立体化学过程，研究了反应过程。在串联反应条件下，来源于 L-脯氨酸的手性醛 1 产生了两个令人惊讶的结果。首先，亚胺环化生成了具有顺式构型产物为主的非对映混合物。其次，顺式和反式 2 的斯迈尔斯重排都直接生成了来自反式异构体的相同产物 3a。前者通过假定 Cram 的螯合过渡态来合理化，该过渡态导致动力学上有利的顺式产物。后者是由于涉及碳正离子中间体的反式/顺式对的平衡以及空间位阻，阻止了顺式异构体进行分子内亲核取代。这一假设通过在重排步骤中加入 1 当量对甲氧基苯胺的竞争实验结果得到进一步支持，该实验导致了大量的苯胺基交换重排产物。
