The assignment of two stereocenters of the natural product haprolid through the application of a profile hidden Markov model (HMM) and its confirmation through total synthesis of the natural product and of two of its diastereomers are reported. The structure elucidation of this polyketide-peptide hybrid natural product is a telling showcase of how difficult it can be to determine the absolute configuration of isolated stereocenters and the benefits of a gene cluster analysis for structure determination. The key steps of the synthesis are a selective epoxidation of a terminal olefin and the stereodivergent macrolactonization strategy. Furthermore, the biological evaluation of all products showed that all diastereomers are potent inhibitors of hepatocellular carcinoma cell lines.
This review highlights why careful consideration of the biosynthetic origin (the how) and the biological function (the why) of a natural product can be so useful during the determination of its structure.
Divergent synthesis is a powerful but yet underdeveloped method to address the usual drawbacks of poor supply and confined diversity in the total synthesis of natural products. Herein, we describe the rational design behind the selection and the synthesis of a divergency scaffold for sesquiterpenoid lactones synthesis, as a case study, which provides access to a rich collection of carbocycles in different oxidation states within 8,12-sesquiterpenoids through simple, scalable transformations.
The isolation, total synthesis and structure elucidation of chlorofusin, a natural product inhibitor of the p53–MDM2 protein–protein interaction
