In the broader context of spiroketals as privileged bioactive scaffolds, the lycibarbarines provide an interesting case study in preventing isomerisation of the spirocentre. In doing so, the lycibarbarines resist convergence to the thermodynamic isomer of the scaffold, allowing three distinct isomers to exist and exhibit unique bioactivity profiles. This lesson may hold value in the future design of synthetic bioactive spiroketals, to enable greater exploration of isomeric pockets of spiroketal chemical space. These insights were enabled by the development of a 10 step (longest linear sequence) synthesis of lycibarbarines A-C (1-3), which provided practical access to these unusual scaffolds for the first time.