Biomimetic Synthesis: Discovery of Xanthanolide Dimers

Starting from xanthatin, the biomimetic synthesis of 4β,5β‐epoxyxanthatin‐1α,4α‐endoperoxide, a novel monomeric xanthanolide, has been achieved. Moreover, four unprecedented xanthanolide dimers were synthesized by three different dimerizations of xanthatin, either in a head‐to‐head or head‐to‐tail fashion. Notably, these dimeric compounds were firstly identified as artifacts in the laboratory, and two of them, mogolides A and B, proved to be natural products present in the Xanthium mogolium Kitag plant.     

One‐Pot Enzymatic Synthesis of Merochlorin A and B

The polycycles merochlorin A and B are complex halogenated meroterpenoid natural products with significant antibacterial activities and are produced by the marine bacterium Streptomyces sp. strain CNH‐189. Heterologously produced enzymes and chemical synthesis are employed herein to fully reconstitute the merochlorin biosynthesis in vitro. The interplay of a dedicated type III polyketide synthase, a prenyl diphosphate synthase, and an aromatic prenyltransferase allow formation of a highly unusual aromatic polyketide‐terpene hybrid intermediate which features an unprecedented branched sesquiterpene moiety from isosesquilavandulyl diphosphate. As supported by in vivo experiments, this precursor is furthermore chlorinated and cyclized to merochlorin A and isomeric merochlorin B by a single vanadium‐dependent haloperoxidase, thus completing the remarkably efficient pathway.     

Synthesis of Cytotoxic Palmerolides

The chemical synthesis of the palmerolides is the subject of this review. The palmerolides are a family of Antarctic marine natural products, many of which display potent and selective cytotoxicity against melanoma cells. The confluence of promising bioactivities, limited natural supplies, and complex structures makes the palmerolides exciting targets for chemical synthesis. To date, several approaches have been reported, and a consensus strategy based on convergent fragment assembly has emerged. Collective wisdom from myriad approaches reviewed here may enable hybrid strategies capable of delivering larger amounts of synthetic palmerolides to support continued biological studies. Considering the relative lack of options for melanoma chemotherapy and the intriguing activity profile of the palmerolides, efforts aimed at developing an efficient, gram‐scale synthesis of palmerolide A and congeneric structures should be given a high priority.