Enantioselective Syntheses of Tetrahydroisoquinolines (THIQs) via Iridium-Catalyzed Asymmetric Hydrogenation and Progress Toward the Total Synthesis of (+)-Cyanocycline A

Citation

Kim, Alexia Nahyun (2023) Enantioselective Syntheses of Tetrahydroisoquinolines (THIQs) via Iridium-Catalyzed Asymmetric Hydrogenation and Progress Toward the Total Synthesis of (+)-Cyanocycline A. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/4xty-8711. https://resolver.caltech.edu/CaltechTHESIS:06022023-190747966

Abstract

Described herein are two reviews and three projects related to the asymmetric syntheses of tetrahydroisoquinoline (THIQs) alkaloids, and the progress toward the total synthesis of (+)-cyanocycline A. In Chapter 1, a review of the development of asymmetric methodologies for the preparation of enantioenriched N-heteroarenes is detailed. In Chapter 2, the development of an iridium-catalyzed enantio- and diastereoselective hydrogenation of 1,3-disubstituted isoquinolines to achieve cis-THIQs is reported. Chapter 3 describes the iridium-catalyzed asymmetric hydrogenation of 1,3-disubstituted isoquinolines that can afford trans-THIQs in a single transformation. Preliminary mechanistic insights to the iridium-catalyzed asymmetric hydrogenation method using deuterium experiments are detailed.

Chapter 4 details a comprehensive review of the advances in the total syntheses of complex THIQ alkaloids from 2000 – 2020, ranging from simple benzyl THIQ natural products to complex THIQ alkaloids such as Ecteinascidin-743. In Chapter 5, efforts toward the total synthesis of (+)-cyanocycline A are described, harnessing a non- biomimetic synthetic route through a convergent cross-coupling of two heterocyclic fragments followed by a global hydrogenation event.

Thesis Files