Synthesis of a Library of Terpenoid Alkaloid–Like Compounds Containing Medium‐Sized Rings via Reconstruction of the Humulene Skeleton

Abstract

AbstractThe construction of a chemical library based on natural products is a promising method for the synthesis of natural product‐like compounds. In this study, we synthesized a terpenoid alkaloid‐like compound library based on the humulene skeleton. Our strategy, which enables access to diverse ring systems such as 11‐membered monocyclic, oxabicyclic, and medium‐sized aza ring‐containing scaffolds, involves the introduction of a nitrogen atom, an intermolecular C−O bond formation via Lewis acid‐mediated epoxide‐opening transannulation, and a ring‐reconstruction strategy based on olefin metathesis. A cheminformatics analysis based on their structural and physicochemical properties revealed that the synthesized compounds have high three‐dimensionality and high natural product likeness scores but with structural novelty. The usefulness of the terpenoid alkaloid‐like compound library for drug discovery and the accessibility to structure‐activity relationship studies were validated by performing an assay for osteoclast‐specific tartrate‐resistant acid phosphatase activity, resulting in the identification of a seed compound for bone‐resorptive diseases such as osteoporosis.