UC Berkeley

Bridged, polycyclic scaffolds present in both natural and unnatural targets have long captivated synthetic efforts. For natural products containing bicyclo[3.3.1]nonane cores (e.g., hyperforin, huperzine A and rugulosone), their promising bioactivities provide ample motivation, alongside longstanding synthetic challenges such as late-stage core functionalization. Additionally, fluxional organic molecules–such as barbaralones, bullvalones, and bullvalenes–have remained key targets for synthetic organic chemists due to their intriguing properties and potential applications.In Chapter 1, we first describe our efforts toward the modular, enantioselective synthesis of barbaralones via a known homoconjugated, α-halo ketone bicyclo[3.2.2]nonane building block. This building block was modulated via cross-coupling reactions and the resulting substrates were subjected to base-initiated or light-mediated rearrangement conditions to effect the synthesis of 3,4-disubstituted or 1,3-disubstituted enol triflate barbaralones, respectively. We demonstrate how these barbaralones can be further derivatized via traditional cross-coupling reactions, homologation sequences to afford bullvalones and bullvalenes, and C(sp2 )–P coupling to afford a barbaralone-based phosphine analogue of the dialkylbiaryl phosphine ligand, CyJohnPhos. In the final section of the chapter, we detail our efforts toward the synthesis of additional dialkylbiaryl phosphine ligand analogues using a didehydrobarbaralone intermediate. Finally, we report the synthesis of a bullvalene-based phosphine ligand and its corresponding oxidative addition complex.In Chapter 2, we describe our synthetic efforts toward the bicyclo[3.3.1]nonane-containing natural product, rugulosone. We outline our retrosynthetic analysis founded upon a Lewis acid-catalyzed cationic cyclization step to construct a functionalized bicyclo[3.3.1]nonane core. Initial efforts involved testing the key step via a synthetic model system substrate and, ultimately, allowed us to determine promising cyclization conditions to effect our desired cationic cyclization. Lastly, we outline our current work, which focuses on accessing the ideal cyclization precursor.