New Insights into Cyclobutenone Rearrangements: A Total Synthesis of the Natural ROS‐Generating Anti‐Cancer Agent Cribrostatin 6

Aryl‐ and heteroarylcyclobutenone rearrangements proceed in excellent yield under continuous‐flow conditions. The former shows a Hammett correlation with σ I providing strong evidence that electrocyclisation is the rate‐determining step and has a late transition state. The reaction has been modelled by using DFT and CCSD(T) methods, with the latter giving excellent correlation with the experimental rate constant. A short and efficient total synthesis of cribrostatin 6, an anti‐neoplastic and anti‐microbial agent, provides a topical demonstration of the value of this method.