Discovery and Bioinspired Synthesis of Neuroprotective Geranylated Chalcones From Artocarpus communis

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.