Combination of Pseudo-Natural Product Design and Formal Natural Product Ring Distortion Yields Stereochemically and Biologically Diverse Pseudo-Sesquiterpenoid Alkaloids

We describe the synthesis and biological evaluation of a new natural product-inspired compound class obtained by combining the conceptually complementary pseudo-natural product (pseudo-NP) design strategy and a formal adaptation of the complexity-to-diversity ring distortion approach. Fragment-sized alpha-methylene-sesquiterpene lactones, whose scaffolds can formally be viewed as related to each other or are obtained by ring distortion, were combined with alkaloid-derived pyrrolidine fragments by means of highly selective stereocomplementary 1,3-dipolar cycloaddition reactions. The resulting pseudo-sesquiterpenoid alkaloids were found to be both chemically and biologically diverse, and their biological performance distinctly depends on both the structure of the sesquiterpene lactone-derived scaffolds and the stereochemistry of the pyrrolidine fragment. Biological investigation of the compound collection led to the discovery of a novel chemotype inhibiting Hedgehog-dependent osteoblast differentiation

Automated summary

This study describes the synthesis and biological evaluation of a new compound class inspired by natural products, combining the pseudo-natural product design strategy and ring distortion approach. The resulting pseudo-sesquiterpenoid alkaloids are chemically and biologically diverse, with their biological performance dependent on the structure of sesquiterpene lactone-derived scaffolds and the stereochemistry of pyrrolidine fragments. The compound collection led to the discovery of a novel chemotype inhibiting Hedgehog-dependent osteoblast differentiation.