Skeletally remoulded analogues of natural products enrich compound libraries, accelerating hit identification and drug discovery. Here we present a divergent alkaloid remodelling strategy that is centred on isolable platforms generated by Hofmann elimination. Piperidine deconstruction is thus effected through site-selective cleavage of a C–N σ-bond concomitant with the formation of a second alkene moiety. Ensuing alterations involving Stevens and/or Meisenheimer rearrangements and reconstruction by ring-closing metathesis or intramolecular hydroamination deliver expanded and contracted frameworks, respectively. By using a small selection of readily accessible catalysts and reagents, we prepared 26 altered frameworks in a total of 48 steps (~1.8 steps per reshaped structure). The utility of the approach is highlighted by the discovery of a reverse-Meisenheimer rearrangement and observation of a rare case of anionic [1,6]-sigmatropic rearrangement. In cellulo studies involving ten cancer cell lines reveal that an expanded amine-bridged and a deconstructed tricyclic framework exhibit micromolar and nanomolar activity, respectively.