Abstract
Fungal indole alkaloids bearing a bicyclo[2.2.2]diazaoctane (BCDO) core structure are a fascinating family of natural products that exhibit a wide spectrum of biological activities. These compounds also display remarkable structural diversity, with many different diastereomers and enantiomers produced by specific fungal strains. The biogenesis of the unique BCDO moiety has long been proposed to involve an intramolecular [4+2] hetero-Diels-Alder (IMDA) reaction, but the exact mechanisms for this hypothetical transformation have remained elusive until recently. This review aims to summarize the whole history of synthetic and biosynthetic studies of fungal BCDO indole alkaloids, by covering the discovery, biomimetic syntheses, total syntheses, biosynthetic pathway elucidation, and biological activities of representative compounds. We highlight the mutual inspiration and corroboration between biological and synthetic chemists in exploring the intriguing biosynthetic mysteries of this family of natural products. We also provide perspectives and clues for the remaining biosynthetic problems.