PHD, Kent State University, 2025, College of Arts and Sciences / Department of Chemistry and Biochemistry
This dissertation discusses novel synthetic strategies for synthesizing complex natural products, such as cafestol and grayanane diterpenes. Ent-kaurene diterpenes, like cafestol, have a unique 6/6/6/5 tetracyclic skeleton, and their rearranged counterparts, grayanane diterpenes, feature a distinct 5/7/6/5 framework. These classes of diterpene show promising biological properties, including anti-inflammatory, anticancer, antidiabetic, and sodium channel-modulating activities, and are, therefore, of great interest to synthetic and medicinal chemists.
This dissertation details the total synthesis of cafestol in 14 steps from the ent-kaurenoic acid extracted from the mature sunflower heads, and in 19 steps from the commercially available stevioside, with an overall yield of 1.59 %. It streamlines the synthesis process using stevioside or ent-kaurenoic acid, which already have all the carbon skeleton and only needs the introduction of a furan ring and some functional group manipulation. A novel one-pot synthesis of furan ring has been accomplished through oxa-Michael Wittig annulation reaction. This work also provides a synthetic pathway to grayanane diterpenes, with a novel discovery of rearranging the ent-kauranes' 6,6 rings system to the grayanane 5,7-rings system to produce a universal intermediate that opens the gate for the synthesis of numerous grayanane diterpenes. Besides, this work also investigates the in-silico studies of synthesized grayanane and other related natural products with the membrane protein of human voltage-gated sodium channels (PDB:6j8h). It provides the insight into the structural features that are associated with biological activity.
Furthermore, this dissertation also explores the synthesis and lead optimization of 1,3,4-oxadiazole derivatives targeting methicillin-resistant Staphylococcus aureus (MRSA). The most promising lead compound has advanced into preclinical trials in beagles, demonstrating potential effective treatments in th (open full item for complete abstract)
Committee: Jeffrey D. Mighion (Advisor); Christopher J. Fenk (Committee Member); Thorsten-Lars Schmidt (Other); Sangeet Lamichhaney (Committee Member); Songping D. Huang (Committee Member)
Subjects: Biochemistry; Chemistry