UC Irvine

This dissertation describes synthetic strategies for the synthesis of lissoclimide and haterumaimide natural products. The development of both semi-synthesis and total synthesis routes will be highlighted. Chapter 1 provides a background on this family of cytotoxic diterpenoids including isolation, biological activity and general structure-activity-relationships. Previous efforts towards these products from the Vanderwal lab and other groups are described.

Chapter 2 focuses on the semi-synthesis of haterumaimide Q and chlorolissoclimide starting from commercially available sclareolide. An efficient and general strategy to for the elaboration of sclareolide to the lissoclimide scaffold was developed to access haterumaimide Q in high yields and was further implemented in synthesis of the potent chlorinated family member, chlorolissoclimide. These syntheses enabled investigations into the biological mode of action to gain further understanding into the key interactions that underly chlorolissoclimide’s high potency. Through analysis of the structural biology and computationally generated binding poses, the hydroxyimide group was identified as the key pharmacophore and the synthesis of hydroxyimide stereoisomers was pursued with the goal of generating potent analogues.

Chapter 3 describes our initial efforts towards the most potent members of the family, haterumaimide J and K. We envisioned accessing the pendent A-ring oxygenation of these products through a titanocene-mediated, radical bicyclization initiating on a 2,2-disubstituted epoxide. A model system synthesized from geranyl acetate was used to investigate this transformation.

Chapter 4 focuses on the development of a stereocontrolled, Lewis acid-mediated bicyclization of a 2,2-disubstutited epoxide to construct the core of haterumaimides J and K. A key finding was that the chlorine stereocenter could control the diastereoselectivity of this bicyclization regardless of the relative configuration of the epoxide. The completion of synthesis was achieved after optimization of a challenging Evans-auxiliary controlled aldol reaction to install the C12/C13 vicinal stereocenters and complete the formation of the succinimide motif.

Chapter 5 highlights the application of this chlorine-controlled, 2,2-disubstituted epoxide-initiated bicyclizations to access the C19-oxygenated scaffold of complex ent-kaurene natural products. Our efforts to develop rapid synthesis of enantioenriched 2,2-disubstituted epoxides for chiral -Lewis acid mediated cyclizations are described.