DIVERGENT TOTAL SYNTHESIS OF THE HARZIANE DITERPENOIDS AND DEACYLATIVE C–C BOND FORMING TRANSFORMATIONS OF KETONES

Here, I describe the development of synthetic strategies for the total synthesis of complex harziane diterpenoid natural products, as well as radical-mediated carbon–carbon bond cleavage and functionalization reactions, including polyfluoroarylation and carbonyl isotope labeling of ketones.

Chapter 1 describes the divergent total synthesis of harziane diterpenoid natural products. The harziane family features a stereochemically dense 6/5/7/4 tetracyclic framework with up to six contiguous stereocenters, three all-carbon quaternary centers, and diverse oxidation patterns across ~50 isolated congeners. A concise strategy based on quaternary center analysis and common intermediate logic enabled access to three natural products and a proposed fourth, all obtained in 1–3 steps from a late-stage common intermediate. Four additional natural products were also accessed formally. Key steps include a Au(I)-catalyzed cycloisomerization to form a bicyclo[5.2.0]nonane framework, a semipinacol ring contraction, and late-stage site- and chemoselective redox manipulations.

Chapter 2 describes a deacylative polyfluoroarylation of alkyl ketones enabled by radical-mediated C–C bond cleavage. The method converts simple methyl ketones into alkyl-substituted polyfluoroarenes via aromatization-driven fragmentation to generate alkyl radical intermediates, which undergo coupling with polyfluoroaryl reagents. This transformation enables direct C(sp³)–C(sp²) bond formation from unactivated ketones under mild conditions and expands the utility of ketones in radical cross-coupling chemistry.

Chapter 3 highlights recent developments in the synthesis of carbon isotope-labeled bioactive molecules and pharmaceuticals. The focus is placed on late-stage isotope labeling of hydrocarbons, (hetero)arenes, nitriles, ketones, esters, amides, and related carbonyl-containing functional groups. Recent advances in carbon isotope exchange (CIE) and skeletal editing strategies are also discussed. These methods enable direct incorporation of isotopes into complex molecular scaffolds without the need for extensive pre-functionalization, expanding the scope of late-stage labeling approaches in complex molecule synthesis.

Chapter 4 describes a carbonyl carbon isotope exchange (CIE) strategy for cyclic ketones based on a dual-activation skeletal editing approach. A modified NAHA-2 reagent bearing an aryl bromide enables a second radical activation via halogen atom transfer (XAT), triggering sequential C–C bond cleavage and re-aromatization of cyclic ketones. This process allows replacement of the carbonyl carbon within the ring framework. A ¹³CO synthon (sulfonyl oxime reagent) was developed to enable isotope incorporation through the same sequence, providing isotopically labeled cyclic ketones in a three-step process.