UC Riverside

Annotinolides A and B are 7,8-seco¬-lycopodane-derived 8,5-lactones isolated from the club moss Lycopodium annotinum. Preliminary investigations revealed amyloid-beta (Aβ) anti-aggregation properties that are not commonly observed in Lycopodium alkaloids, demonstrating potential as a therapeutic agent for Alzheimer’s disease (AD). AD is characterized by progressive cognitive decline and memory loss that remains a significant challenge in modern medicine. These derivatives show promise in mitigating AD pathology by modulating neurotransmitter levels, reducing oxidative stress, and inhibiting Aβ aggregation, a hallmark of AD progression. Given the history and knowledge of Lycopodium alkaloids in promoting healthier connections between nerve cells in the brain, a streamlined and targeted synthesis was conceived towards annotinolides A and B. Our synthesis design features an inverse electron-demand Diels–Alder reaction to access the tricyclic lycopodine-type skeleton, bioinspired radical cyclopropanation, and photochemical [2+2] cycloaddition. Efforts towards the synthesis of the key tricyclic intermediate will be described.Tetrahydroisoquinoline (THIQ) alkaloids belong to another class of natural products that are ubiquitous in nature, exhibiting multifaceted pharmacological properties, including anti-inflammatory, antioxidant, and anti-apoptotic activities. More specifically, numerous studies have identified protoberberine natural products as potent modulators of AMP-activated protein kinase (AMPK), a key enzyme involved in energy metabolism regulation. Although AMPK activation is widely recognized, its counterpart remains underexplored, demanding the use of powerful synthetic tools to access novel AMPK inhibitors. To this end, a concise synthetic strategy was developed that showcases novel oxidative C–H functionalization and anionic aza-6π electrocyclization methodologies. Heteroatom-substituted alkynes, categorized as subgroups of alkynes, have recently found extensive use in the development of synthetic methods. Ynamides in particular, characterized by their polarized triple bonds directly linked to a nitrogen atom, have recently emerged in C–H functionalization processes. The challenge of effectively and selectively transforming C−H bonds stems from their high bond dissociation enthalpy and widespread occurrence throughout organic molecules. To overcome this challenge, a common strategy involves utilizing a weakly coordinating Lewis-basic directing group. Building on the oxidative rhodium-catalyzed C−H functionalization of electron-rich alkenes (Chapter 2), the combination of N-methoxybenzamides with underexplored electron-rich ynamides is examined, unveiling unique regioselectivity that features cobalt-catalyzed C–H activation.