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

Author: Kim, Alexia Nahyun

Year: 2023

Degree: Dissertation (Ph.D.)

Advisor: Stoltz, Brian M.

Committee Members: Robb, Maxwell J.; Reisman, Sarah E.; Hsieh-Wilson, Linda C.; Stoltz, Brian M.

Option: Chemistry

DOI: 10.7907/4xty-8711

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.

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