Discovery and Bioinspired Synthesis of Neuroprotective Geranylated Chalcones From Artocarpus communis

ABSTRACT

Two geranylated chalcone oligomers, artocarpusones A ( 1 ) and B ( 2 ), featuring a highly functionalized 6/5/6/5/6‐fused pentacyclic hemiketal, were discovered from the medicinal plant Artocarpus communis , along with six related compounds 3 − 8 . Their structures with absolute configurations were established using comprehensive spectroscopic analyses that were supported by computational calculations. Biosynthetic considerations suggest that 1 − 7 could be derived from a single precursor 8 . Guided by this insight, a bioinspired synthesis of 1 − 7 was achieved in a total of 7−9 steps from 8 . The synthesis is enabled by bioinspired cascade reactions encompassing oxidative rearrangement, Michael additions, hemiketalizations, 6π‐electrocyclization, and hetero‐Diels–Alder reaction. Notably, congener 2 exhibited anti‐ischemic stroke activity both in vitro and in vivo, suggesting its potential as a neuroprotective candidate for further therapeutic evaluation.