Shape is an inherent feature of a molecule, and for a macrocycle, it governs its chemical reactivity and affinity for biomolecules. Efforts are still being made to define rules that dictate the low energy conformations of macrocycles and their associated dynamics. Our group is investigating a class of [13]-macrodilactones including two ester groups and an alkene, which was assembled by two acylations and ring closure metathesis. We found that the stereogenic center, alpha to the ester carbonyl, C7, influences the topology of the [13]-macrodilactones. Therefore, Suzuki cross coupling reactions and peptide coupling reactions were conducted as the key reactions to functionalize C7 position. Two major classes of modified [13]-macrodilactones were obtained by the installation of aromatic heterocycles and amides. Also, their anti-proliferative activity on cells and a principal component analysis (PCA) have been performed. This case study allows us to link physiochemical and structural parameters to chemical space as well as cytotoxicity. It paves the way for developing new macrocycles with designed properties and activities.

Late-stage tailoring of natural product-like macrocycles: Structure and properties of functionalized [13]-macrolactones

2019 Fall National Meeting

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