Synthesis of Stereoenriched Polycyclic Scaffolds via Palladium Enolates and Progress toward the Total Synthesis of Hypermoin A

Author: Chen, Ruby Pengjui

Year: 2026

Degree: Dissertation (Ph.D.)

Advisor: Stoltz, Brian M.

Committee Members: Stoltz, Brian M.; Reisman, Sarah E.; Goddard, William A., III; Fu, Gregory C.

Option: Chemistry

Abstract

Research in the Stoltz lab is focused on the synergistic development of novel methodologies for the asymmetric formation of congested stereocenters and natural product total synthesis, while employing computations to aid mechanistic understanding. This thesis describes the development and mechanistic studies of novel asymmetric reactions from Pd enolates and progress toward the total synthesis of hypermoin A.

The first chapter details the development of an enantioselective intramolecular [4+2] cycloaddition from a chiral Pd enolate, allowing formation of highly stereoenriched polycyclic structures. Quantum mechanics calculations, Eyring analysis, and KIE studies allowed further mechanistic understanding of the reaction. The [4+2] cycloaddition was further investigated through molecular dynamics simulations, and studies of cyclohexenone-derived substrates are reported in chapter 2.

Chapter 3 describes the application of a chiral Pd enolate in an asymmetric intramolecular Michael spirocyclization, forging vicinal quaternary and tertiary stereocenters in a single step. Computational investigations provide mechanistic insights to the stereoselectivity of the process. In chapter 4, a branched-selective asymmetric decarboxylative allylic alkylation reaction is reported. The hypotheses informed by quantum mechanics calculations allow rational ligand design to achieve high regio-, diastereo-, and enantioselectivity in forming vicinal quaternary and tertiary stereocenters.

Chapter 5 outlines the ongoing progress toward the asymmetric total synthesis of hypermoin A. [2.2.2] bicycle formation through [4+2] cycloaddition or reductive Heck cyclization followed by ring expansion allows formation of a key [3.2.2] bicyclic core, and current efforts are focused on extending this approach to more elaborate substrates.