Asymmetric Transformations from Palladium Enolates and Progress Toward the Total Synthesis of Hypermoin A

Citation

Flesch, Kaylin Nicole (2025) Asymmetric Transformations from Palladium Enolates and Progress Toward the Total Synthesis of Hypermoin A. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/jfcn-4r24. https://resolver.caltech.edu/CaltechTHESIS:05122025-153409748

Abstract

Research in the Stoltz group is centered around developing new methodologies for the asymmetric formation of stereocenters and the application of these technologies in complex natural product total synthesis. Herein we describe the development of new enantioselective transformations from Pd enolate intermediates and efforts toward the total synthesis of hypermoin A. Chapter 1 reports the development of an asymmetric intramolecular decarboxylative [4+2] cycloaddition from a catalytically generated chiral Pd enolate, forging four contiguous stereocenters in a single transformation. Mechanistic studies including quantum mechanics calculations, Eyring analysis, and KIE studies offer insight into the reaction mechanism. Appendix 2 discloses efforts toward the development of an asymmetric intermolecular decarboxylative double Michael addition. Chapter 2 describes an enantioselective cyclization of Pd enolates and isocyanates to form spirocyclic γ-lactams. This reaction proceeds under mild reaction conditions and utilizes a novel Meldrum’s acid derivative to achieve catalyst turnover, delivering enantioenriched products in up to 97% yield and 96% ee. Chapter 3 outlines the ongoing progress toward the total synthesis of hypermoin A. A [4+2] cycloaddition and ring expansion strategy has been developed in a model system to form the key [3.2.2] bicycle and current efforts are dedicated to the application of this sequence in a more complex setting.

Thesis Files