Author ORCID Identifier

https://orcid.org/0009-0004-1491-1013

Date of Award

Summer 9-5-2025

Document Type

Thesis (Ph.D.)

Department or Program

Chemistry

First Advisor

Jimmy Wu

Abstract

An important aspect for the research and development of new drug therapies is the ability to use modular synthetic methods to rapidly access structurally diverse drug-like building blocks. Nitrogen-containing heterocycles represent one of the most prevalent structural motifs found in pharmaceutical agents and biologically active natural products. However, despite their ubiquity, existing methods for accessing these structures often remain limited in scope, efficiency, and structural diversity, particularly when targeting densely functionalized or sterically demanding scaffolds from simple starting materials.

To address this problem, the research described in this dissertation focuses on the design and development of (3+2) annulation reactions for the direct synthesis of diverse cyclohexa-fused indoline compounds This reaction technology enables rapid and regioselective construction of indoline cores with unique substitution patterns that would be challenging or cannot be easily accessed with existing methods. Key to this approach is the use of mechanistically informed reaction design to control regiochemical outcomes under mild conditions with a broad substrate scope.

Moreso, using previously published methodologies by our lab, these annulative products serve as highly functionalized intermediates amenable to further structural elaboration. In particular, they can be modified to incorporate bridged azacycles within the gross structure; thereby expanding the accessible chemical space and enabling the exploration of novel three-dimensional architectures. This capacity for modular diversification aligns with the broader goal of generating compound libraries with maximized structural diversity, favorable for drug discovery.

Overall, the methodologies described herein not only expand the synthetic toolbox for nitrogen heterocycle construction but also invite new opportunities for accessing molecular architectures that are both challenging to prepare and relevant to pharmaceutical research. By enabling the streamlined synthesis of complex, stereochemically rich scaffolds from simple starting materials, these strategies contribute to the efficient exploration of underrepresented regions of biologically relevant chemical space.

Original Citation

Protich, Zachary, "Advances in Indole Chemistry: Regiodivergent Annulations and Bridged Azacycle Synthesis" (2025). Dartmouth College Ph.D Dissertations.

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