Climbing the Oxidase Phase Ladder by Using Dioxygen as the Sole Oxidant: The Case Study of Costunolide

Abstract

Natural sesquiterpenoid lactones are prominent scaffolds in drug discovery. Despite the progress made in their synthesis, their extensive oxidative decoration makes their chemo-and stereoselective syntheses highly challenging. Herein, we report our effort to mimic part of the oxidase phase used in the costunolide pathway to achieve the protecting-group-free total synthesis of santamarine, dehydrocostus lactone, estafiatin, and nine more related natural sesquiterpenoid lactones by using dioxygen as the sole oxidant.

Expanding Natural Diversity: Tailored Enrichment of the 8,12-Sesquiterpenoid Lactone Chemical Space through Divergent Synthesis

“… 7 Recognizing the scarcity of those members, compared to the isolated diversity of 6,12-isomers, we questioned whether it would be possible to enrich the sesquiterpenoid lactone chemical space by non-natural 8,12-congeners by utilizing an optimum divergency scaffold. 3 Despite our extensive experience in the synthesis of furosesquiterpenoids 3 and related congeners, 8 extending this approach to access 8,12-SQLs poses several challenges. These primarily stem from the enhanced sterics introduced by the highly electrophilic α- methylene-γ-butenolide core and our objective of achieving access to all possible diastereoisomers across diverse positions of the carbocycle.…”

“…The critically positioned tertiary hydroxyl at position C5 was projected as the pinpoint for inducing selectivity, according to earlier findings of our group. 8 Then, the products were further elaborated to achieve the maximum diversity.…”

“…Decoration of the guaianolide core of 2 was pursued following three main axes: reductive, redox neutral (dehydration), and oxidative at the initial stage of the transformation, aiming for optimal reaction selectivity (Scheme ). The critically positioned tertiary hydroxyl at position C5 was projected as the pinpoint for inducing selectivity, according to earlier findings of our group . Then, the products were further elaborated to achieve the maximum diversity.…”