PROJECT SUMMARY The goal of this proposal is to develop simplified approaches to the construction of diverse medium- sized oxygen and nitrogen heterocycles that can be applied to the synthesis and complexity-building diversification of bioactive small molecules. Medium-ring heterocycles are ubiquitous in naturally occurring bioactive molecules, however these scaffolds remain largely absent from pharmaceutical drug scaffolds due to challenges associated with their synthesis. In order to address rising concerns regarding the lack of chemical space explored by current therapeutic molecules, we propose methods that enable the use of readily available alcohols and amines as functional handles for the facile synthesis of medium-sized heterocycles. Preliminary work in our laboratory has discovered a novel electrophilic heteroatom rearrangement of benzylic alcohols facilitated by a unique class of (poly)cationic hypervalent iodine reagents that allows direct access to diverse medium-ring ethers. The first aim of this proposal is the continued development of this novel transformation to include secondary and tertiary alcohols as well as amine substrates, providing a general platform for medium- ring heterocycle synthesis. The second aim is the further development of our enabling (poly)cationic λ3- iodanes, both through detailed reactivity studies as well as novel derivative syntheses, in order to facilitate their adoption as broadly utilized synthetic reagents. We will also employ these reagents as a novel manifold for the synthesis of chiral hypervalent iodine scaffolds. The third aim of this proposal will utilize our methodology as an enabling platform for complex medium-sized ether analogues of the promising chemotherapeutic lead podophyllotoxin, a compound that has seen little clinical development to date due to limited tolerance for traditional medicinal chemistry diversification. The work is significant because the development of simplified approaches to medium-ring heterocycles will expand the chemical space available for drug discovery by providing previously inaccessible analogues and facilitating more rapid syntheses of complex bioactive natural products. Furthermore, the development of promising (poly)cationic λ3-iodanes will provide the synthetic community with a powerful new toolkit of synthetic reagents.