PROJECT SUMMARY/ABSTRACT Synthesis, Structure, and Mechanism of Biorelevant Molecules and Reactions Our MIRA-supported research program encompasses synthetic, mechanistic, and structural organic chem- istry. We address unresolved contemporary problems through studies that lead to i) new ways of deducing the structures of novel chemical entities, often through innovative use of NMR methodologies, ii) new insights about how chemical reactions, including spontaneous biosynthetic transformations, proceed, and iii) new ways to make molecules that have structural features of interest to researchers pursuing targets with promising bio- logical properties. We will capitalize on recent accomplishments and launch new efforts as follows. I. Natural Products Chemistry A. We remain interested in unraveling key steps in the biosynthesis of natural products that proceed in the absence of enzymatic catalysis—that is, spontaneously. Two specific hypotheses related to the origin of the unique skeleton of ottelione A drive current work: i) an unprecedented, low-barrier Cope rearrangement fashions the strange, dearomatized 4-methylenecyclohexenone present in this secondary metabolite and ii) a simple, achiral diarylheptanoid is oxidatively transformed into the strained and preorganized Cope substrate. The engagement of an outstanding collaborator to use genome mapping approaches will be of great benefit. B. We frequently engage in natural product structure determination studies and the development of methodologies of value to those who do the same. These studies have had impact extending well beyond the specific questions that we address. Our record in doing this is strong. One notable example teaches methodol- ogy for calculation of chemical shifts to the experimentalist who may be a novice computationalist. Our ap- proach was the same as that used in the newest developments of probabilistic methods for comparison of computed vs. experimental NMR chemical shifts to validate structure assignments (DP4, DP4+, DP4-AI, DP5). We find a gap in that some communities have yet to embrace these approaches. We propose to evaluate the effectiveness (and limitations) of these methods for structural assessment of various cyclic peptides and then to communicate, advertise if you will, these outcomes to benefit future structural studies by peptide chemists. II. HDDA-Benzyne Chemistry Our discovery of the broad scope of the hexadehydro-Diels–Alder (HDDA) reaction is both exciting and en- abling. This work has advanced significantly since the onset of our MIRA funding four years ago. The opportu- nities in this arena show no sign of abating. To the contrary, it seems that every month or so a coworker arrives at my doorstep with yet another new result that elicits from me something to the effect of “Wow, HDDA- benzynes will also do that!” Myriad new directions are presented in pages 4–6 of the Research Strategy. Many will lead to products containing a greater preponderance of heteroatoms, thereby demonstrating new ap- proaches for consideration and use by researchers engaged in drug discovery activities. (30 lines)

PROJECT NARRATIVE Natural products chemistry and organic synthesis are two enabling disciplines that fuel the engine of small- molecule drug discovery. These fields impact existing pharmaceutical agents, compounds currently in the clinical pipeline heading toward approved therapeutics, and basic research to develop the improved drugs of tomorrow. In our research program (i) we provide new knowledge about the structures of natural products as well as an understanding of how they are created by their producing organisms and (ii) we develop new paradigms that researchers can use for the synthesis of novel compounds having potential as new, clinically relevant drug candidates. (3 sentences)