Cannogenol and Related Cardiotonic Steroids: Concise Synthesis and their Anticancer Activity Evaluation

Small molecules that are approved as drugs are largely the result of extensive synthetic efforts. A robust synthetic method is required to access the natural products and their analogs to study their biological activities. This thesis largely focuses on the synthesis of cardiotonic steroids, the steroids that are known for the treatment of heart conditions and more recently has shown promising prospect in anticancer studies against various human cancer cell lines. Furthermore, the anti-cancer activities of the molecules of this class were studied and substantial data on structure-activity relationship (SAR) were obtained. In addition, this thesis also presents an anion binding catalysis, the process by which anions are selectively transported between membranes in human body, of a new class of catalyst thiophosphoramide that showed promising ability to bind with anions. The first chapter describes the utility of three hydrogen-bond donor, thiophosphoramide-based catalyst anion binding catalysis. The study illustrates that the thiophosphoramide-based HBDs could significantly accelerate Cu(II)-catalyzed reactions of potassium carboxylates with diaryliodonium salts. The scope of counterion on both the diaryliodonium salt and the copper salt is explored, followed by the application of this method in a wide-variety of carboxylic acid including some naturally available carboxylic acid. The second chapter introduces cardiotonic steroids and the discusses the relevant prior synthesis. Impressive synthesis of digitoxigenin by Yoshii and Nakada followed by the synthesis of strophanthidin by Yoshii and Kočovsky are discussed in detail. The total synthesis of cannogenol-3-O-α-L-rhamnoside that will be discussed in following chapter is inspired by the work previously published by Nagorny and coworkers on enantioselective synthesis of oxygenated steroids by copper-catalyzed Michael reaction followed by double aldol reaction and the utilization of this method in the total synthesis of 19-hydroxysermentogenin and trewianin aglycone are discussed in this chaper. The third chapter describes the development of a robust and divergent synthetic pathway to access natural product of the class called cardiotonic steroids. The chapter highlights the first enantioselective total synthesis of two cardiotonic steroids that have been recently of interest because of their anti-cancer activities: 1) cannogenol 2) cannogenol-3-O-α-L-rhamnoside. The challenges during the development of this method, that could provide analogs with different heterocycles and sugar moieties with minimum deviations, are described in detail. Finally, the fourth chapter focuses on the generation of natural products and analogs using the method developed in chapter 3. Another natural product cannogenol-3-O-glucopyranoside and an analog of cannogenol-3-O-α-L-rhamnoside with alkyne incorporation in the sugar moiety for the target identification studies were synthesized. In addition to the molecules synthesized in our group, other commercial steroids of diverse functional group at different part of the molecule were collected. The collaboration with Dr. Yimon Aye’s group at Cornell University presented us with significant structure-activity relationship (SAR) data. In addition, an analog of strophanthidin with amine incorporation instead of alcohol at C19 was synthesized by reductive amination of aldehyde.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/147616/1/btbhat_1.pd

Total Synthesis of the Potent Antibiotic Platensimycin

Ph.DDOCTOR OF PHILOSOPH

Enantiopure bromonium ion-induced cation-π cyclisations

There has been an astonishing variety of sesqui- and diterpene metabolites isolated—mainly from Laurencia species, or their predators—which possess the enantiopure α,α-dimethylcyclohexyl bromide moiety. The key step in their biogenesis is generally considered to be an enzyme-mediated formation of an asymmetric bromonium ion which initiates a cation-π cyclisation. This diverse array of terpene natural products is explored in the introduction to this thesis and their biogenesis via cation-π cyclisations analysed. Synthetic sources of electrophilic bromine such as NBS, TBCO and BDSB have been shown to initiate brominative polyene cyclisations with excellent control of relative stereochemistry albeit as necessarily racemic products. At the start of this work no asymmetric bromonium ion-induced polyene cyclisations had been demonstrated. Studies on a model system for the key in situ enantiopure bromonium ion generation and intramolecular trapping are described. Sharpless asymmetric dihydroxylation provides access to enantiopure diols of a trisubstituted alkene which can be manipulated to enantiopure bromohydrins. These are activated as 2,3,4,5-tetrafluorobenzoate esters which cyclise cleanly under the action of catalytic triflic acid to give enantiopure bromo-bicycles without racemisation from bromonium ion to alkene transfer. The mechanism of this reaction is investigated, it is practically demonstrated and shorter routes are explored. The synthesis of high purity linear terpene: homogeranyl 4-methoxybenzene is discussed, from which the synthesis of enantiopure bromo-tetrafluorobenzoate esters is carried out. The use of Lewis acid, in this case dimethylaluminium triflate, was found to successfully enact the cyclisation of these alkene containing substrates. Full conversion to cyclic products was achieved and the desired tricyclic product was isolated as a mixture of enantiopure diastereomers. Absolute and relative configuration of both diastereomers were determined by radical dehalogenation and comparison of the sign of the optical rotation of the product to literature values. Finally, the synthesis of homofarnesyl 4-methoxybenzene derived substrates is detailed. The cyclisation of which has the potential to generate tetracyclic compounds. This forms the basis of future work to be carried out.Open Acces