Recent advances in hapalindole-type cyanobacterial alkaloids: biosynthesis, synthesis, and biological activity

Covering: 1984 up to the end of 2020 Hapalindoles, fischerindoles, ambiguines and welwitindolinones are all members of a class of indole alkaloid natural products that have been isolated from the Stigonematales order of cyanobacteria. These compounds possess a polycyclic ring system, unique functional groups and various stereo- and regiochemical isomers. Since their initial isolation in 1984, they have been explored as potential therapeutics due to their wide variety of biological activities. Although numerous groups have pursued total syntheses of these densely functionalized structures, hapalindole biosynthesis has only recently been unveiled. Several groups have uncovered a wide range of novel enzymes that catalyze formation and tailoring of the hapalindole-type metabolites. In this article, we provide an overview of these natural products, their biological activities, highlight general synthetic routes, and provide an extensive review on the surprising biosynthetic processes leading to these structurally diverse metabolites. This review covers isolation, biological activity, an overview of total synthesis efforts and recent biosynthetic discoveries related to hapalindole-type indole alkaloids.