High-throughput screening (HTS) is the dominant approach to identify lead compounds in drug development. However, most compound-screening collections provide little structural or stereochemical complexity, which do not offer enough diversity to merit the modulation of many drug targets. Here we describe a facile strategy for the creation of diverse compounds with high structural and stereochemical complexity using readily available natural products, β-caryophyllene, as a synthetic starting point. Our findings demonstrate that a cascaded Beckmann-transannular protocol transforms macrocyclic natural products into poly-heterocyclic unnatural skeletal types. These compounds are significantly more complex and diverse than those in standard screening collections.