Leveraging Catalysis to Enable the Asymmetric Synthesis of Novel Cereblon E3 Ligase Modulatory Drug Cores Público

Abstract

Glutarimide-containing compounds, particularly immunomodulatory imide drugs (IMiDs), are an exceptional class of compounds that can degrade previously “undruggable” proteins of interest. The glutarimides ubiquitous in the class modulate Cereblon (CRBN), an E3 ubquitin ligase receptor. The synthetic challenges surrounding these structures such as hydrolytic instability, sensitive stereochemical elements, and insolubility make the development and adaptation of new methods for their preparation of high value. Rhodium carbene chemistry, catalyzed by chiral dirhodium complexes, is a powerful method for use in medicinally relevant contexts. Herein, we develop a new adaptation of the Suzuki-Miyaura cross-coupling to enable the synthesis of diverse and stereodefined IMiDs via asymmetric rhodium cyclopropanation and cyclopropenation. These novel and bioactive IMiDs comprise a study demonstrating the subtle interplay of regiochemistry and stereochemistry in neosubstrate degradation. Further exploration of the impact of rhodium carbenes on the study of IMiDs lead to the development of carbene precursors containing CBRN-modulatory cores, which are capable of not only effective cycloaddition chemistry but also selective C–H functionalization, for the creation of stereodefined molecular glue-like compounds and bioactive bifunctional degrader compounds. This work expands the current understanding of how catalysis—especially rhodium catalysis—can impact drug discovery efforts via the facile generation of different kinds of structural complexity, enhance the tools available to medicinal chemists, and by doing so develop further knowledge of the subtleties of rhodium carbene chemistry.

Table of Contents

Introduction ..................................................................................................................................... 1

References ................................................................................................................................. 14

Chapter 1: Development of an Anhydrous and Stereoretentive Fluoride-Enhanced Suzuki-Miyaura Reaction for the Synthesis of Derivatized Cereblon E3 ligase Modulatory Drug Cores........................................................................................................................................................ 22

Introduction ............................................................................................................................... 22

Results and Discussion ............................................................................................................. 24

Conclusions ............................................................................................................................... 36

References ................................................................................................................................. 37

Chapter 2: Asymmetric Dirhodium-Catalyzed Cyclopropanation and Cyclopropenation of Cereblon E3 Ligase Modulatory Drug Cores and their Biological Evaluation. ........................... 40

Introduction ............................................................................................................................... 40

Results and Discussion ............................................................................................................. 42

Conclusions ............................................................................................................................... 55

Reference .................................................................................................................................. 56

Chapter 3: Adapting Cereblon E3 Ligase Modulatory Drug Cores as Rhodium Carbene Precursors for C-H Functionalization and Cyclopropanation. ...................................................... 59

Introduction ............................................................................................................................... 59

Results and Discussion ............................................................................................................. 61

Conclusions ............................................................................................................................... 74

References ................................................................................................................................. 76

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School	Laney Graduate School
Department	Chemistry
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Chemistry, Organic
Palabra Clave	Rhodium Carbenes Asymmetric Catalysis Organic Synthesis Targeted Protein Degradation
Committee Chair / Thesis Advisor	Huw Davies, Emory University
Committee Members	Frank McDonald, Emory University William Wuest, Emory University

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