EXPLORATIONS IN MEDIUM-RING ETHER SYNTHESIS VIA UMPOLUNG HETEROATOM ACTIVATION: TOTAL SYNTHESIS, METHODS DEVELOPMENT, AND REAGENT SYNTHESIS

Abstract

The Heliannuols are a family of structurally diverse allelochemicals produced by the common sunflower which hold potential as environmentally benign herbicides; however, their further study and development has been hampered by lack of efficient and divergent synthetic strategies. Key challenges include 7- and 8-membered medium-ring ethers and isolated stereogenic centers. A novel (bis)cationic nitrogen-ligated HVI (NHVI)-mediated oxidative rearrangement represents and innovative approach to the Heliannuols by providing expedient access to the challenging cyclic ether scaffold via umpolung reactivity of cyclic alcohols.This dissertation provides the unified synthesis and isolation of various electronically and sterically distinct N-HVIs to promote their continued investigation in the Wengryniuk group as well as synthetic groups across the globe. Additionally, synthetic efforts toward natural product targets led to new discoveries regarding the key electrophilic heteroatom rearrangement step which prompted a full study, resulting in improved yields, one-pot derivatization protocols, expanded scope, and a better understanding of substrate effects on reactivity. Finally, armed with improved access to medium-sized cyclic ethers, the 11-step total syntheses of Heliannuols D and A was accomplished in the most concise and highest yielding asymmetric syntheses to date. The divergent synthetic strategy has also enabled access to a library of unnatural analogues which are being screened for bioactivity in collaboration with agrochemical industry.