Biosynthesis of Complex Indole Alkaloids: Elucidation of the Concise Pathway of Okaramines

The okaramines are a class of complex indole alkaloids isolated from Penicillium and Aspergillus species. Their potent insecticidal activity arises from selectively activating glutamate‐gated chloride channels (GluCls) in invertebrates, not affecting human ligand‐gated anion channels. Okaramines B ( 1 ) and D ( 2 ) contain a polycyclic skeleton, including an azocine ring and an unprecedented 2‐dimethyl‐3‐methyl‐azetidine ring. Owing to their complex scaffold, okaramines have inspired many total synthesis efforts, but the enzymology of the okaramine biosynthetic pathway remains unexplored. Here, we identified and characterized the biosynthetic gene cluster (oka ) of 1 and 2 , then elucidated the pathway with target gene inactivation, heterologous reconstitution, and biochemical characterization. Notably, we characterized an α‐ketoglutarate‐dependent non‐heme Fe^II dioxygenase that forged the azetidine ring on the okaramine skeleton.     

An Asymmetric Pathway to Dendrobine by a Transition‐Metal‐Catalyzed Cascade Process

An asymmetric pathway to the caged tetracyclic pyrrolidine alkaloid, dendrobine, is reported. The successful synthetic strategy features a one‐pot, sequential palladium‐catalyzed enyne cycloisomerization and rhodium‐catalyzed diene‐assisted pyrrolidine formation by allylic CH activation. The developed transition‐metal‐catalyzed cascade process permits rapid access to the dendrobine core structure and circumvents the handling of labile intermediates. An intramolecular aldol condensation under carefully defined reaction conditions takes place with a concomitant detosylation, followed by reductive amine methylation, to afford a late‐stage intermediate (previously identified by several prior dendrobine syntheses) in only 10 synthetic steps overall.