1. Project Summary/Abstract: Research Overview – Research is focused on organic synthesis, particularly on developing strategies and modes of reactivity that facilitate construction of complex molecules of medicinal and/or biological value. We have developed over thirty-five stereoselective reactions based on areas of reactivity that include metallacycle-mediated cross-coupling, [3+2] cycloaddition, vinylcyclopropane rearrangement, radical cascade chemistry, and tandem oxidative dearomatization/Wagner–Meerwein rearrangement. While some of these have been developed with the goal of realizing a wide range of unique “convergent” C–C bond forming processes, others have emerged in natural product synthesis projects. These combined activities, that aim to advance the fundamental backbone of organic chemistry through innovation within the field of stereoselective synthesis, are routinely embraced as enabling technology to fuel exploration in medicinally relevant science; examples included: (1) a non-opioid analgesic (conolidine), (2) paralog selective Hsp90 inhibitors (benzoquinone ansamycins), (3) selective anti multiple myeloma agents (lehualide B), (4) the first non-peptidic selective ligand to the DBD of p53 (natural product-inspired oligomerization), (5) the most potent and selective agonist of the estrogen receptor beta (ERb), (6) ent-steroids as potent and selective modulators of the glucocorticoid receptor, (7) substituted estranes and androstanes as antagonists of the androgen receptor (AR), (8) a designed enantiodefined hydrindane as the most potent inhibitor of the transcription factor ToxT, (9) steroidal ligands that interrupt the binding of NEMO to Ikkb, and (10) acyclic mimetics of oleic acid as potent and selective functional ligands to GPR40, GPR120 and TLX. Overall Vision for the Program – This seamless integration of reaction development, natural product synthesis, and efforts to employ our technology as an enabling tool for the discovery of molecules with unique biological properties defines the basic fabric of science that is the focus in my laboratory. Goals for the Next Five Years – Efforts will focus on natural product- and function-oriented synthesis, reaction development, and the design and synthesis of synthetic steroid- and fatty acid-like agents as potent and selective modulators of NRs and GPCRs. These activities will include target-oriented synthesis campaigns around limonoids, cardenolides, b-agarofurans, and the stelletin class of natural products. All of these planned efforts have, at their core, the ambition to establish and demonstrate novel synthesis designs and reaction methods to address a wide range of complex natural products and molecules of great potential biomedical relevance. Because our efforts include the exploration of new reactions and synthesis strategies as enabling tools/methods for the invention of molecules designed to modulate particular receptors (as summarized above), we will also continue to pursu...