Harnessing Vanadium-Dependent Haloperoxidases for Oxindole Formation and Heterocycle Halogenation Open Access

Abstract

Biocatalysis provides a selective and sustainable approach to chemical synthesis by using enzymes to perform complex transformations under mild conditions. In this work, vanadium- dependent haloperoxidases (VHPOs) are explored as versatile biocatalysts for both oxidative transformations and heterocycle halogenation. Using Curvularia inaequalis chloroperoxidase (CiVCPO), indole substrates were converted to oxindoles across a range of functionalized molecules, demonstrating tolerance to diverse functional groups and structurally complex substrates. Additionally, VHPO-mediated halogenation was investigated across a range of heterocyclic substrates, with systematic screening used to identify optimal conditions for selective reactivity. This approach enables halogenation under mild, controlled conditions, offering a safer alternative to traditional methods that rely on hazardous reagents. Together, these studies highlight the versatility of VHPOs and their potential as practical tools for heterocycle functionalization in synthetic chemistry. 

Table of Contents

Chapter 1: Introduction (1)

1.1 Principles and Advantages of Biocatalysis (1)

1.2 Classes and Mechanisms of Halogenase Enzymes (3)

1.3 Structure and Reactivity of Vanadium-Dependent Haloperoxidase (5)

Chapter 2: Oxindole and Spirooxindole Formation (9)

2.1 Medicinal Relevance of Oxindole and Spirooxindole Scaffolds (9)

2.2 Current Chemical and Enzymatic Methods for Indole Oxidation (11)

2.3 Proposed VHPO-Catalyzed Oxidative Rearrangement of Indoles (13)

2.4 Reaction Optimization for VHPO-Catalyzed Indole Oxidation (15)

2.5 Substrate Scope for VHPO-Catalyzed Oxindole Formation (18)

2.6 Chloride-Mediated Oxidation and Halide Recycling (19)

2.7 Investigation of a C–C Semipinacol Rearrangement (19)

Chapter 3: Heterocycle Halogenation (24)

3.1 Importance of Halogenation in Drug Discovery (24)

3.2 Chlorine Substitution and the “Magic Chloro” Effect (24)

3.3 Aryl Bromides as Versatile Handles for Late-Stage Functionalization (26)

3.4 Initial Halogenation Studies on Indazole Substrates (27)

3.5 Reactivity Differences Between 1- and 2-Methyl Indazole (31)

3.6 High-Throughput Screening of Heterocycle Halogenation Conditions (34)

3.7 Screening of Heterocyclic Substrates (35)

3.8 Validation of the 96-Well Screening Method (38)

3.9 Scale-Up Reactions for Pyrazole Halogenation (40)

Chapter 4: Conclusion (44)

Supporting Information for Chapter 2 (45)

Supporting Information for Chapter 3 (72)

References (92)

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Organic
Keyword	Biocatalysis Halogenation Vanadium-dependent haloperoxidase
Committee Chair / Thesis Advisor	Biegasiewicz, Kyle, Emory University
Committee Members	Weinschenk, Matthew , Emory University McKnelly, Kate , Emory University

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