The drimane sesquiterpene alkaloid halichonine B was isolated more than a decade ago, while only a very limited structure-activity relationship (SAR) was achieved in chemicobiology due to tedious synthesis (> 10 steps) and inefficient modular derivatizations. Herein, a practical synthesis and divergent optimization of halichonine B is presented from the commercially inexpensive (+)-sclareolide, aiming at advancing chemicobiological exploration. A step-economy access (3 steps) to the core scaffold drimanyl amine was conceived and realized through intramolecular Hofmann rearrangement, enabling 6-step facile preparation of halichonine B. The first agrochemical potentials of this natural product and mimics were disclosed facilitated by the function-oriented rapid and modular diversifications including alkylated amines, amides, sulfamides, thioureas, and ureas. The unnatural mimic 10 and analog 12d were more effective against the cancer cell line HepG2 than cisplatin. The analog 12d was protruded as a novel antifungal lead demonstrating >25-fold improvement than halichonine B against Rhizoctonia solani. Molecular docking differentiates halichonine B and the analog 12d in interacting with the predictive target.

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