An asymmetric approach to the synthesis of neurotrophic seco-prezizaane sesquiterpenes is described that is based on the strategic application of a hydroxyl directed metallacycle-mediated [2 + 2 + 2] annulation and an intramolecular radical cyclization cascade. Targets prepared are among the most potent members of the natural product class and include (1R,10S)-2-oxo-3,4-dehydroneomajucin, (2S)-hydroxy-3,4-dehydroneomajucin, and (-)-jiadifenin. In addition to representing the first application of the alkoxide-directed metallacycle-mediated hydrindane-forming annulation reaction in natural product synthesis and the first total synthesis of (2S)-hydroxy-3,4-dehydroneomajucin, these pursuits have resulted in the elucidation of a complex radical cascade process for installation of the CS quaternary center common to the natural product class.