UC Santa Barbara

Natural products are varieties of naturally occurring compounds that possess wide range of useful biological activities. Their intricate structures and activities are often the inspiration behind designs of medicinally significant molecules and new methodologies to perform chemical transformations. Through total synthesis of natural products, organic chemists discover how complex molecules behave in flasks and develop creative ways to build them. This dissertation describes findings and challenges from the effort towards total synthesis of portimine A, a complex marine natural product that is a highly selective inducer of apoptosis towards several cancer cells.

The first part of this dissertation details a new method in creating contiguous quaternary and tertiary carbon stereocenters through remote stereocontrol in Ireland-Claisen rearrangement. This new method enables stereocontrol in the rearrangement through a distant acetonide as an internal stereocontrol unit instead of transferring chirality from a chiral secondary alcohol, providing a rapid access to an extensively functionalized framework.

The second part of this dissertation describes efficacy of employing enyne metathesis in constructing cyclohexene diene motif commonly present in many members of cyclic imine family. This strategy is elegantly staged by the proceeding remote Ireland-Claisen rearrangement and is a convenient way to gain access to conjugated cyclic dienes.

The third part of this dissertation demonstrates the unprecedented use of N-heterocyclic carbene catalysis in complex macrocyclization. This strategy, with a large potential to be further optimized, is a useful method for large-membered macrocyclization baring various functionalities. The most recent discoveries on the total synthesis of portimine A following the successful macrocyclization are also discussed, and the remainder of synthesis is in progress.