Divergent Total Syntheses of Elisapterane and Relevant Diterpenoids Assisted by <i>In Silico</i> Structure Reassignment

Herein, we describe our synthetic endeavors toward elisapterane and relevant diterpenoids through a bioinspired divergent strategy based on an unprecedented late-stage D-ring formation logic. The key tricyclic intermediate bearing a norneoelisabane skeleton could be efficiently prepared <i>via</i> an ODI-(5 + 2) cycloaddition/1,2-acyl migration cascade and a SmI₂-mediated pinacol coupling/Grob fragmentation/deoxygenation orchestration. The synthesis of the misassigned structure of elisapterosin F led us to revisit the structure elucidation of these natural products. Application of NMR calculation-based <i>in silico</i> structure reassignment disclosed several unheeded structural mutations for elisapterane diterpenoids and accurately revised the structures of elisapterosins A, D, and F. With a computation-rerouted synthetic blueprint, we eventually accomplished collective total syntheses of elisapterosins A-F, alongside biogenetically related aberrarone, elisabanolide, and 3-<i>epi</i>-elisabanolide. By integrating our inference aided by computational tools with validation through total synthesis, this work exemplifies a modern case of total synthesis detective stories, demonstrating the power of computer-assisted structure elucidation (CASE) and the risks of analogical approaches for the structure assignment of natural products.