Iboga alkaloids, a family of natural products including the anti-addictive compound ibogaine and the chemotherapeutic precursor catharanthine, have inspired chemists and biologists for over 120 years. This review covers advances from 2000 to 2020 in their biosynthesis and chemical synthesis, as well as their development as next-generation neurotherapeutics for mental illness. The authors provide historical context for recent discoveries and highlight unresolved questions. Although significant progress in chemistry and pharmacology has occurred since the 1960s, the iboga alkaloids continue to drive scientific innovation.
Salvinorin A, a hallucinogenic compound from the plant Salvia divinorum, is a potent and selective activator of the kappa-opioid receptor (KOR), a promising target for new painkillers. Unlike typical opioids, it lacks a basic nitrogen, enters the brain rapidly, and has a short duration of action. Since 2000, extensive medicinal chemistry using semi-synthesis from plant extracts has explored its properties. Total synthesis efforts have produced multiple routes to create salvinorin A and related analogs, aiming to improve its activity for various therapeutic effects. This review covers those total syntheses and identifies remaining challenges for future synthetic chemistry to address.