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

Abstract

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 α‐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

Chemical Evolution of Natural Product Structure

“…A diverse collection of compounds was produced by merging the principles of complexity to diversity and pseudo-NPs. 68 The strategy employed six fragment-sized sesquiterpenoid lactones that are either NPs or were obtained via ring distortion and can be considered to be biosynthetically related scaffolds but are yet chemically diverse ( Figure 5 a). The pseudo-NP principle was then applied by combining the sesquiterpenoid fragments with the biosynthetically unrelated alkaloid fragment pyrrolidine via a 1,3-dipolar cycloaddition to arrive at sesquiterpenoid alkaloid pseudo-NPs.…”

“…A diverse collection of compounds was produced by merging the principles of complexity to diversity and pseudo-NPs . The strategy employed six fragment-sized sesquiterpenoid lactones that are either NPs or were obtained via ring distortion and can be considered to be biosynthetically related scaffolds but are yet chemically diverse (Figure a).…”

Synthesis of 20‐Membered Macrocyclic Pseudo‐Natural Products Yields Inducers of LC3 Lipidation

“…Thus, we have recently shown that de novo fragment combination can advantageously be combined with Hergenrother's ring‐distortion complexity‐to‐diversity strategy. [11] …”

Catalytic asymmetric Michael/cyclization reaction of 3-isothiocyanato thiobutyrolactone: an approach to the construction of a library of bispiro[pyrazolone-thiobutyrolactone] skeletons

“…Consequently, developing an efficient methodology for the construction of these stereochemically rich scaffolds has been the focus of organic chemists. 3–5 To the best of our knowledge, most reports on constructing spirobutyrolactone derivatives are based on butyrolactone-derived cyclic imino esters 4 and 3-unsaturated substituted butyrolactones 5 as starting substrates. Although butyrolactone-derived cyclic imino esters have been developed as nucleophilic cascade building blocks, the use of other butyrolactone-derived bifunctional donor–acceptor reagents for the asymmetric construction of spirobutyrolactone derivatives with structural complexity and diversity has rarely been reported.…”