Synthetic and Theoretical Studies Towards Unravelling the Basis of Diastereoselectivity in Triptycene Macrocycle Synthesis

Details

Supervisors

Singleton, Michael L. ; de Wergifosse, Marc

Faculty

Faculté des sciences

Degree label

Master [120] en sciences chimiques, à finalité approfondie

Abstract

This thesis investigates the use of aromatic oligoamide building blocks for the synthesis of macrocycles, with a focus on diastereoselectivity and overall efficiency. The specific objectives of this study were to assess the role of conformational preorganization, cavity size, and connectivity in enhancing the efficiency and diastereoselectivity of macrocycle synthesis. By expanding the understanding of factors impacting diastereoselectivity, this work lays the groundwork for future advancements in macrocycle synthesis. The experimental work involved the synthesis of various diazatriptycene-functionalized building blocks and tetrameric (or hexameric) aromatic oligoamide macrocycles. These compounds were characterized using 1H-NMR spectroscopy and high-resolution mass spectrometry. The efficiency of the macrocyclization process was quantitatively analyzed using 1H-NMR by varying concentrations to evaluate the impact of conformational preorganization, while diastereoselectivity was assessed through 1H-NMR and, in select cases, X-ray diffraction spectroscopy. Host-guest chemistry investigations were conducted using UV-vis spectroscopy. Additionally, cost-efficient quantum chemistry approaches, utilizing the GFN2-xTB as well as the density functional theory and metadynamics, were employed to identify different conformations of intermediates formed during the macrocyclization process. UV spectra of one macrocycle and monomeric unit were computed with the exact integral simplified time-dependent density functional theory and compared to experimental results. While preorganization was found to be important for the yield of the macrocycle formation, the diastereoselectivity, measured as the ratio of diastereomers, remained largely unchanged for the macrocycles synthesized in this study. Theoretical results suggest that diastereoselectivity is driven by conformational preorganization only when building blocks capable of forming specific π-stacked conformations in the penultimate intermediate are used. These findings have broader implications for designing synthetic routes in aromatic oligoamide macrocycles, potentially aiding in developing new macrocycles with tailored properties. Future research could explore the influence of alternative building blocks and varying macrocycle sizes on diastereoselectivity, as well as investigate the applicability of these findings to other types of macrocyclic systems. Overall, this thesis underscores the potential of conformational preorganization in enhancing the efficiency of macrocycle synthesis and highlights the significant role of building block structure in determining intermediate conformations. Ultimately, this work advances the field of macrocycle synthesis by providing new insights into the roles of building block design and preorganization strategies, paving the way for more efficient and selective synthetic methodologies.