PROJECT SUMMARY Chemical Synthesis of Complex Natural Products for Translational Science The goals of the continuing MIRA (R35GM118173) research program are to continue focus on chemical syntheses of bioactive molecules for translational studies. The MIRA effort will allow flexibility and stability to enable new research directions that come up during the course of research. The first four years of the R35 program have been highly productive and have led to 30 publications in high impact journals. This includes 17 collaborative manuscripts with clinical and biological investigators. As part of our studies, we have taken opportunities to address key questions and contemporary needs in organic chemistry including asymmetric catalysis of photocycloadditions, biomimetic cascade reactions and cycloadditions, and chemoenzymatic synthesis. Key accomplishments in the past four years include synthesis of amidino rocaglates (ADRs) as highly potent translation inhibitors, synthesis of meroterpenoids using reactive enetriones, biomimetic synthesis of meroterpenoids by dearomatization-driven polycyclization, and computational investigation of chiral ion-pairs using parallel tempering (PT) computation. As part of the MIRA renewal project, the Principal Investigator Professor John Porco and colleagues will continue development of novel synthetic methodologies for concise entry to bioactive classes of natural products including rocaglates, oxaphenalenones, meroterpenoids, spiro- PPAPs, polycyclic xanthones and tetrahydroxanthones, xanthone dimers, trichothecenes, and pyrroloiminoquinone alkaloids. The project will continue major emphasis on collaborations to study biological properties and mode of action (MoA) of target molecules for use as pharmacological therapies for human cancers as well as viral, fungal, and bacterial illnesses. It is anticipated that the MIRA program will allow us to continue development of innovative syntheses of complex natural products and derivatives and work to aggressively interface these studies with applications in clinical and translational research.