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UBC Theses and Dissertations

Selective reactions of 14-membered macrolides-a conformational approach using MM2 calculation Neeland, Edward George


A number of 14-membered lactones, derived from 42 or 43 were used to investigate a series of alkylation, hydride reduction and hydrogenation reactions. These reactions yielded diastereoselective product distributions which were rationalized as proceeding through a [3434] conformation. A simple model for determining these low energy conformations was developed using MM2 calculations, energy trends of acyclic molecules, X-ray crystallography and NMR spectroscopy. In order to unambiguously identify ring conformations, a method to generate polar maps of the large ring lactones was developed. These polar maps quickly differentiated complex ring conformations as well as identifying the symmetry elements of a conformation. With the aid of polar maps, a new solid state conformation for 14-membered rings was discovered for two macrolides synthesized in this project. Furthermore, three additional unidentified examples of this conformation were recognized from the literature. Energy calculations showed this twisted conformation to be of very low energy. The discovery of the twist conformation led to an improved nomenclature for large rings which considers the number of bonds separating both corner and pseudo corner atoms. Under this proposed nomenclature, the twist conformation was designated the [34'3'4'] conformation. During this investigation, a useful technique for assigning the stereochemistry of E and Z-trimethylsilyl (TMS) enol ethers was developed using ¹H NMR nuclear Overhauser effect difference spectroscopy (NOEDS) experiments. One advantage of this technique over the widely used ¹³C NMR method is that only one isomer is required to accurately assign the Eor Z. stereochemistry. [Formula Omitted]

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