Project Summary A major thrust of the proposed studies is founded on the principle that a molecule's contour is key to its ability to elicit biological response, making it crucial that methods for precise alteration of its three-dimensional shape are available. The PI's long-standing experience in the design and development of olefin metathesis strategies, catalysts and methods will serve toward establishing innovative ways of transforming highly complex but readily available (i.e., purchasable and inexpensive) bioactive natural products to their corresponding skeletally altered analogs. The resulting entities, as shown recently in the PI's NIH-funded program, will represent new drug leads for the same or a different disease area. Molecules containing a medium or large ring and at least one olefin will be at the center of the proposed investigations. A new class of catalysts will be designed to promote efficient ring-opening metathesis of otherwise unreactive rings; after chain extension by cross-metathesis or olefin isomerization, ring-closing metathesis will be used to access expanded or contracted cyclic structures, respectively. Another aspect of the proposed studies will entail developing ways of precisely altering the shape of complex and easily accessible cyclic or polycyclic compounds that do not contain a readily modifiable functional group. New strategies will thus be developed for introducing unsaturation and then using olefin metathesis-based processes to expand or contract their ring(s), resulting in precise alteration of the molecule's overall shape. Another key aim will be the development of catalytic multicomponent diastereo-, and enantioselective transformations that will transform readily accessible molecules to highly complex and readily modifiable products, which can be used as platforms for the generation of a variety of bioactive compounds and potential drug leads.