Tandem Nucleophilic Addition/Oxy-2-azonia-Cope Rearrangement for the Formation of Homoallylic Amides and Lactams: Total Synthesis and Structural Verification of Motuporamine G

In the presence of a Lewis acid, β,γ-unsaturated ketones and oximes or imines undergo nucleophilic addition to produce zwitterion intermediates, and subsequent oxy-2-azonia-Cope rearrangements give homoallylic amides. In the case of 2-vinylcycloalkanones, the process results in ring enlargement, providing a novel route to 9- to 16-membered lactams. The preparative significance of this protocol was evidenced by a short synthesis of macrocyclic alkaloid motuporamine G. The stereochemistry-defining step of this oxy-azonia-Cope rearrangement was further studied computationally. Despite a high-energy preequilibrium in the formation of zwitterionic intermediates, the [3,3]-sigmatropic step is the rate- and product-determining step. Chairlike transition states are generally preferred over boatlike ones.

在路易斯酸（Lewis acid）存在的条件下，β,γ-不饱和酮与肟（oxime）或亚胺（imine）可发生亲核加成反应，生成两性离子中间体（zwitterion intermediate）；随后经oxy-2-氮杂-Cope重排（oxy-2-azonia-Cope rearrangement）得到高烯丙基酰胺（homoallylic amide）。当底物为2-乙烯基环烷酮（2-vinylcycloalkanone）时，该反应可发生环扩环，为9至16元内酰胺（lactam）的合成提供了全新路径。该合成策略的制备价值通过大环生物碱motuporamine G的简短全合成得以验证。针对本次oxy-2-氮杂-Cope重排的立体化学决定步骤，研究人员开展了进一步的计算化学研究：尽管两性离子中间体的形成过程存在高能预平衡，但[3,3]-σ迁移步骤才是决定反应速率与产物构型的决速步。相较于船式过渡态，椅式过渡态通常更具优势。