UC Irvine

This dissertation describes the development of synthesis strategies for the lissoclimide natural product syntheses starting from either sclareolide or geranyl acetate. Chapter 1 focuses on the isolation and biological activity of lissoclimide terpenoid natural products. Previous synthesis efforts from the Vanderwal lab and other groups are described.

Chapter 2 focuses on the semi-synthesis of chlorolissoclimide, haterumaimide N, and haterumaimide Q from sclareolide. Development of a reliable Evans auxiliary based aldol approach to the hydroxysuccinimide moiety common to all lissoclimide natural products is described. The C–H chlorination of sclareolide is vastly improved with the use of a new chlorinating protocol co-developed with the Alexanian lab, enabling the first synthesis of chlorolissoclimide in 9 steps and 14% overall yield.

Chapter 3 focuses on a fully synthetic route towards the lissoclimides from geranyl acetate featuring an epoxide-initiated bicyclization. This strategy provides access to a readily diversifiable intermediate that is converted to haterumaimide Q and key analogues. A key finding was that the preference for Fürst–Plattner addition of chlorine across an alkene on a rigid decalin system is partially reversed in the presence of a homoallylic trifluoroacetate. The resulting diequatorial dichlorides are found in several of the most potent lissoclimides.

Chapter 4 focuses on four key biological investigations our syntheses have enabled: (1) the Yusupov group elucidated the biological mode of action via a co-crystal structure of chlorolissoclimide in the E-site of the eukaryotic large ribosomal subunit (2); our synthetic lissoclimide natural products and analogues were screened against several cell lines to determine structure activity relationships (SAR); (3) the structural information was used to computationally rationalize the observed SAR; and (4) these compounds were evaluated for their ability to eradicate several viral infections, including Ebola, exhibiting EC50 values of 20 nM.

Chapter 5 focuses on the exploration of 2,2-disubstituted epoxide-initiated bicyclizations to access haterumaimide J. A Ti(III) radical cyclization strategy is first explored using several cyclization precursors. Lewis-acid-catalyzed bicyclizations are described for our efforts towards both haterumaimide J and hydroxytotarol.