Ergot alkaloids belong to a diverse group of fungal-derived natural compounds with a range of biological activities that have important applications in medicine and agriculture. Cycloclavine, a complex ergot alkaloid containing a cyclopropyl moiety, which possesses a very broad insecticidal activity, was produced in high levels in Saccharomyces cerevisiae. It is the first ergot alkaloid downstream of chanoclavine to be successfully synthesized in a heterologous host in excellent yields. The insecticidal activity of the natural product itself was not sufficient for commercial use, but the broad activity in combination with the insect-specific mode of action motivated us to initiate a chemistry program. First, we undertook the modification of cycloclavine itself, followed by synthesis of simpler analogs in order to find compounds with enhanced insecticidal activity. © 2021 Elsevier Inc. All rights reserved.