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Synthesis of [beta]-keto lactones and the synthetic consequences of the conformational preferences of 14-membered lactones Ounsworth, James Paul


The preparation of the β-keto lactones 1̲9̲ via intramolecular alcoholysis of hydroxy Meldrum's acid derivatives was examined. Good yields of the 6- and 14-membered compounds were obtained, but the method was completely unsuccessful for medium-size rings. An investigation was conducted on the conformational preference of substituted 14-merabered lactones with a view to understanding the stereochemical consequences of the reactions of these compounds. The conformational preferences of simple 14-membered cyclic compounds were first determined. These preferences are described in terms of steric and electronic interactions, with the support of computer-calculated steric energies. A number of 14-membered lactones were prepared, beginning with the β-keto lactone 3-oxo-13-tetradecanolide (1̲3̲8̲). Hydride reduction of (1̲3̲8̲) gave the diastereomeric alcohols 1̲4̲6̲ and 1̲4̲7̲, which were then elaborated to give a series of derivatives. The stereochemistry and conformations of these compounds were determined by X-ray crystallography and/or nmr analysis. The preferred conformation was found to be Dale's [3434] diamond lattice model. The relative rates of reaction were determined for several reactions of the alcohols 1̲4̲6̲ and 1̲4̲7̲ and for one reaction of the corresponding acetates. The conformational effects were found to be much smaller than those observed in 6-merabered rings. Explanations of this difference are given. The preparation of the ⍺, β-unsaturated lactones 1̲6̲3̲ and 1̲6̲4̲, the β-methyl-⍺, β-unsaturated lactones 1̲8̲5̲ and 1̲8̲̲6̲̲, the dimethyl lactones 1̲5̲4̲ and 1̲5̲5̲ and the epoxides 1̲9̲7̲ and 1̲9̲8̲ are described. The resulting geometry of double bonds and the stereochemistry of substituents are explained in terms of conformational preferences. [Formula Omitted]

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