PROJECT SUMMARY/ABSTRACT As a class, terpene-based natural products have long led to critical scientific discoveries and advances. For instance, the particular connectivity of longifolene served as the inaugural ground upon which to establish the power of retrosynthetic analysis, while larger molecules such as steroids have been valuable tools to treat and understand disease as well as a scaffold upon which to develop powerful bond-forming reactions such as electrophile-induced polyene cyclizations and site-specific functionalizations. We believe that numerous opportunities remain for further development within the class, and here we seek specifically to probe the potential of structurally complex, but relatively non-functionalized, members to contribute to the development of new reactions, strategies, and tactics of broad applicability. Our goal is to develop the means to both tailor and deliver molecular structure with high specificity, mirroring chemistry that Nature can accomplish enzymatically as well as contributing new reactions and tools that have no biological counterpart. As delineated within the proposal, we seek to explore several avenues for possible advances. First, drawing from a previously accomplished total synthesis of a strained molecule known as presilphiperfolan-8-ol, we have designed an array of Pd-based Heck relay cascades, in a variety of different formats, to generate a key patterning of atoms that is seemingly conserved across several different molecular collections despite having distinct plant, and likely biogenetic, origins. Key goals for the present study are to affect such reactions in contexts where competing β-hydride elimination pathways could preclude success, and to probe the viability of Heck-type processes in highly hindered settings, such as ones that would utilize tetrasubstituted olefins as acceptors. Second, we seek to utilize C-PdII intermediates in unprecedented trappings with intermolecular oxygen and nitrogen nucleophiles to access highly regio- and enantioselectively functionalized gem-dimethyl moieties. Finally, careful consideration of both how to synthesize and use quaternary centers has afforded what we believe to be critical insights pertinent to synthetic design. This concept is illustrated by the proposed generation of two different families of natural products in syntheses which either would be the only available route to date or which are marked improvements on past efforts in terms of overall step economy.