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, beta,gamma-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.