Yang, FengPorco, John A.2023-11-172023-11-172022-07-20F. Yang, J.A. Porco. 2022. "Unified, Asymmetric Total Synthesis of the Asnovolins and Related Spiromeroterpenoids: A Fragment Coupling Approach." Journal of the American Chemical Society, Volume 144, Issue 28, pp.12970-12978. https://doi.org/10.1021/jacs.2c053660002-78631520-5126https://hdl.handle.net/2144/476633,5-Dimethylorsellinic acid (DMOA)-derived spiromeroterpenoids are a unique natural product family with attractive structures, unconventional stereochemistry, and potent biological activities. Herein, we report the first asymmetric total syntheses of the asnovolins, DMOA-derived spiromeroterpenoids. The spirocyclic skeleton was efficiently assembled through a sterically hindered bis-neopentyl 1,2-addition coupling/oxidative Michael addition sequence. The unusual axial C12-methyl stereochemistry was established via metal hydrogen atom transfer (MHAT) reduction involving a chair-to-boat conformational change. The mechanism of the HAT process was studied through both deuterium labeling and computational studies. Attempted late-stage alkene isomerization of an exocyclic enone proved to be challenging and resulted in hetero-Diels-Alder dimerization, which ultimately led to development of an alternative desaturation/coupling sequence. Endgame core modifications including orthogonal desaturation, Sc(III)-promoted regioselective Baeyer-Villiger oxidation, and Meerwein-Ponndorf-Verley reduction enabled collective syntheses of five asnovolin-related natural products. This study demonstrates the utility of anionic fragment coupling to assemble a sterically congested molecular framework and provides a foundation for the synthesis of spiromeroterpenoid congeners with higher oxidation states for biological studies.12970-12978Print-ElectronicenChemical sciencesGeneral chemistryEngineeringAnionsBiological productsDimerizationOxidation-reductionStereoisomerismArticle2023-11-1510.1021/jacs.2c053660000-0001-6836-1062 (Yang, Feng)0000-0002-2991-5680 (Porco, John A)759380