I. Development of Nickel- and Palladium-Catalyzed Asymmetric Allylic Alkylation Reactions. II. Enantioselective Syntheses of Tetrahydroisoquinoline–Based Natural Products and Unnatural Analogs

Described in this thesis are four projects related to the development of synthetic methodologies for the preparation of enantioenriched building blocks, and the total syntheses of complex tetrahydroisoquinoline natural products. In Chapter 1, the development of nickel-catalyzed asymmetric allylic alkylation of lactones and lactams with allylic alcohols is presented. In Chapter 2, the development of palladium-catalyzed enantioselective decarboxylative allylic alkylation of silicon-containing heterocycles is detailed. In these chapters, the utilization of prochiral enolates as nucleophiles has enabled access to enantioenriched all-carbon quaternary stereocenters. Chapter 3 describes the total syntheses of bis-tetrahydroisoquinoline alkaloids, (–)-jorumycin and (–)-jorunnamycin A. A general synthetic strategy, which exploits the tandem cross-coupling/hydrogenation approach, represents the first non-biomimetic synthetic route and allows for an efficient construction of the pentacyclic core in a highly modular fashion. Additional bis-tetrahydroisoquinoline analogs were prepared, and preliminary studies to probe their cytotoxicity against cancer cell lines were conducted. Finally, an extension of the enantioselective and diastereoselective hydrogenation technology to include simple 1,3-disubstituted isoquinolines is described in Chapter 4.