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Design and Synthesis of Natural and Unnatural Macrocycles

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Date
2019
Author
Lee, Hyunji
Advisor
Hong, Jiyong
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Abstract

Macrocycles have received growing appreciation for their potential in probing a broader biological space, and there are a significant number of bioactive macrocycles in nature. In addition, a macrocyclic scaffold provides interesting features, including high binding affinity and target selectivity due to the pre-organized conformation. Despite the therapeutic potential and valuable pharmacological characteristics, this class of scaffolds has been poorly exploited in the field of drug discovery because of synthetic challenges and incompatibility to the conventional Lipinski’s rule of five. Therefore, efficient approaches for the generation of diverse and complex macrocycles are needed to develop novel macrocyclic agents.

In an attempt to construct a diverse set of macrocycles, we designed a natural product-like macrocycle library containing a tetrahydropyran core. Our strategy for the generation of the library is based on the tandem allylic oxidation/oxa-conjugate addition for the stereoselective synthesis of a 2,6-cis-tetrahydropyran ring. The incorporation of various building blocks and the utilization of diverse macrocyclization methods were carried out to rapidly increase skeletal diversity and complexity. Appendage diversification was performed to further modulate the physicochemical properties of the macrocycles. Cheminformatic analyses demonstrated that our macrocycle library covers a distinct chemical space compared to drug-like space, while significantly overlapping

with macrocyclic natural product space.

We also explored a modular strategy for the synthesis of a macrocycle from nature, forazoline A, polyketide natural product. Forazoline A exhibits potent in vivo efficacy against the fungal pathogen Candida albicans displaying a synergistic effect with amphotericin B. Our approach towards the synthesis of forazoline A relied on the construction of three major fragments with the desired stereochemistry and the assembly of those fragments. In the dissertation, the synthetic studies of cyclohexane, thiazolidine, and alkyl chain fragments were introduced. Construction of the highly functionalized cyclohexane moiety was efficiently accomplished utilizing Mukaiyama aldol, Bayer–Villeger reaction, and addition of lithium dimethyl cuprate. Synthesis of the thiazolidine fragment was investigated via oxa-conjugate addition and Pummerer-type rearrangements. Finally, the alkyl chain fragment was synthesized through epoxidation, regioselective ring opening, and β-ketoester formation.

Description
Dissertation
Type
Dissertation
Department
Chemistry
Subject
Organic chemistry
Chemical Library
Macrocycle
Polyketide
Synthesis
Permalink
https://hdl.handle.net/10161/20147
Citation
Lee, Hyunji (2019). Design and Synthesis of Natural and Unnatural Macrocycles. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/20147.
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 United States License.

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