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Abstract
By emulating the universal biosynthetic strategy, which employs modular assembly and divergent cyclizations, we have developed a four-step synthetic process to yield a collection of natural-product-inspired scaffolds. Modular assembly of building blocks onto a piperidine-based manifold 6, having a carboxylic acid group, was achieved through Ugi condensation, N-acetoacetylation and diazotransfer, leading to cyclization precursors. The rhodium-catalyzed tandem cyclization and divergent cycloaddition gave rise to tetracyclic and hexacyclic scaffolds by the appropriate choice of dipolarophiles installed at modules 3 and 4. A different piperidine-based manifold 15 bearing an amino group was successfully applied to demonstrate the flexibility and scope of the unified four-step process for the generation of structural diversity in the fused scaffolds. Evaluation of in vitro antitrypanosomal activities of the collections and preliminary structure–activity relationship (SAR) studies were also undertaken.
Highlights
Intriguing natural products often possess cyclic scaffolds bearing dense arrays of functional groups and hydrogen-bond donors or acceptors
Intramolecular Claisen condensation and subsequent enolization produce phloracetophenone, while aldol condensation followed by enolization and hydrolysis of the thioester yield orsellinic acid. Inspired by this simple yet universal biosynthetic strategy, which generates structural variation among natural products, we envisioned the construction of chemical libraries featuring modular assembly for the rapid connection of simple building blocks, as well as divergent cyclization of a common precursor leading to distinct skeletons with complex molecular architectures
We devised a modular assembly of five components employing manifold 6 and subsequent installation of a diazoimide group
Summary
Intriguing natural products often possess cyclic scaffolds bearing dense arrays of functional groups and hydrogen-bond donors or acceptors. Inspired by this simple yet universal biosynthetic strategy, which generates structural variation among natural products, we envisioned the construction of chemical libraries featuring modular assembly for the rapid connection of simple building blocks, as well as divergent cyclization of a common precursor leading to distinct skeletons with complex molecular architectures.
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