Photo- and Electrochemical Activation of Sulfur(VI) Hexafluoride for the Deoxyfluorination of Glycosides and the Progress Towards the Synthesis of Tronocarpine
Creators: name: Kim, Sungjin
Publisher: name: My University
Year: 2023
Subjects: subject: Total synthesis
subject: Fluorination
subject: Carbohydrate chemistry
subject: Photochemistry
subject: Electrochemistry
subject: Flow chemistry
subject: Chemistry
subject: Science

description: Synthetic chemistry has enabled the development of strategies to make bioactive molecules by studying natural products. The bioactivity of glycosylated natural products, such as cardiac steroids, is determined by the identity of the glycosyl moiety as it affects the solubility and binding affinity of a molecule. Thus, modification of the bioactivity for the desired outcome can be accomplished through glycosylation reactions with appropriate glycosyl donors. Glycosyl fluorides are robust donors that can be activated under mild conditions. The compatibility of glycosyl fluorides with aqueous solution enables the enzymatic studies and versatile glycosylation reactions. The synthesis of glycosyl fluorides can be efficiently achieved with commercially available deoxyfluorination reagents, such as DAST and HF∙Pyridine. However, these reagents raise safety issues as they form explosive, toxic, and corrosive side products. This dissertation describes the photo- and electro-activation of sulfur(VI) hexafluoride (SF6) for the deoxyfluorination of glycosides. The methods that are demonstrated in this dissertation provide safe, mild, and efficient reaction conditions by implementing a flow-system and engineering an electrochemical cell for the practical scale-up for the synthesis of glycosyl fluorides. The study of natural products with N-heterocycles has advanced the field of medicinal chemistry due to their pharmacological activities. Especially, the indole alkaloids extracted from the species, Tabernaemontana corymbosa, have been shown to possess antimicrobial and antiviral properties, cytotoxicity against cancer cells, and capabilities of reversing multi-drug resistance. Despite the numerous numbers of isolated indole alkaloids from T. corymbosa, only a few of them are investigated for their bioactivities. This dissertation also describes our approach towards the synthesis of a 6/5/7/6 tetracyclic spirocycle core with the ABCE-ring system of tronocarpine, which has not been explored in previous studies. Chapter 1 introduces an overview of carbohydrate chemistry and SF6. The first section discusses the mechanism of glycosylation, arming and disarming of glycosides, leaving groups and activation methods for the glycosyl donors, with a particular focus on the synthesis and reactivity of glycosyl fluoride donors. The second section explores a brief history of SF6 and its related reactivity studies. This chapter is designed to establish a foundation for chapters 2 and 3. Chapter 2 describes the photoactivation of SF6 using 4,4’-dimethoxybenzophenone as an organo-photocatalyst and UV-A (365 nm) as a light source for the deoxyfluorination of glycosides. The development of a flow-system for a multi-gram scale synthesis is demonstrated as well. Chapter 3 describes the electroactivation of SF6 using the tin cathode and zinc anode in an undivided cell under galvanostatic conditions for the deoxyfluorination of glycosides. Engineering an electrochemical cell for a multi-gram scale synthesis is discussed as well. Chapter 4 introduces the structures and syntheses of indole alkaloids extracted from the species Tabernaemontana corymbosa, with a particular focus on the previous model studies and total syntheses of tronocarpine. Chapter 5 discloses our strategies including the AuI-catalyzed 7-exo cyclization and the Diels-Alder reaction for the synthesis of a 6/5/7/6 tetracyclic spirocycle core with an ABCE-ring system. Future directions to complete the total synthesis of tronocarpine is discussed as well.