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Thesis/Dissertation
Date
2025-05
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Chemistry
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https://doi.org/10.34944/b09q-3w44
Abstract
This thesis presents the development of spiroligomer-based macrocycles, in terms of synthetic strategy and further applications. Spiroligomers are constructed by stereochemically pure bis-amino acids to generate pre-organized three-dimensional shape with diverse functionalities. These molecules have found applications in catalysis, ligand design, and molecular recognition. Previously, various protecting groups for proline amine have been used in solid-phase synthesis but failed to provide desirable yields. To overcome this limitation, we developed Fmoc-protected bis-amino acids that enabled the use of high-yield resin linkers. This synthetic routine combines the tens gram-scale precursors and one-pot methodology involving a temporary Cu2+ complexation strategy to enable the increasing scale and improving yield of building blocks. Four stereochemically pure Fmoc-protected bis-amino acids were synthesized and functionalized with different functional groups, which is the foundation for synthesis of diverse spiroligomers utilizing Fmoc/tBu solid-phase chemistry. This method yielded four tetramers with unique three-dimensional shapes, confirmed by two-dimensional NMR to possess constrained backbones and preferred functional group orientations. Based on the constrained and pre-organized nature of spiroligomers, we aimed to develop spiroligomer-based macrocycles with tunable cavity sizes. Macrocyclic triangles and rectangles were synthesized using a novel approach, with late-stage functionalization enabling chromophore incorporation to enhance water solubility and facilitate characterization. These structures were assembled via a modular solid-phase synthesis method using flexible spacers, with their well-defined and constrained architectures confirmed by 2D NMR. Membranes fabricated through interfacial polymerization of triangular macrocycles were characterized by SEM, showing a 17-fold reduction in water permeability and demonstrating size- and shape-selective sieving capabilities.
Although we developed spiroligomer-based macrocycles, their limited functionality and the complexity of previous methods highlighted the need for a more efficient and flexible synthetic approach. To address this, we introduced a streamlined method for synthesizing spiroligomer-based macrocycles, achieving four unique, highly functionalized, and well-defined macrocycles in significantly fewer steps. The modular solid-phase synthesis provided precise control over each stereocenter, the number of building blocks per segment, the number of segments per macrocycle, and their connectivity, greatly enhancing the diversity and feasibility of generating complex macrocycles.
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