Synthesis and reactivity of 14-membered keto lactones

A convergent synthesis using dithiane alkylations to produce a long chain hydroxy acid, and subsequent macrolactonization of the latter, yielded the 14-membered macrolides 47 and 58. [ Formulas omitted ] Alkylation of 47 with methyl iodide gave a diastereomeric product mixture of α-methylated lactones with the major product having the 2R*,13S* stereochemistry (71). The product ratio was explained by using low energy starting material conformations combined with MM2 calculations. Alkylation of 58 in the same manner also yielded a mixture with the major product having the 2R*,13S* stereochemistry (77a). [ Formulas omitted ] Hydrolysis of the dithiane ring on 47 and 58 gave the keto lactones 28 and 29 respectively. Reduction of the ketone in 28 yielded a mixture of diastereomeric hydroxy lactones of which the major product had the 5S*,13S* stereochemistry (61); this stereochemistry was confirmed by the X-ray crystallographic structure of the p-bromobenzene sulfonate derivative. Reduction of the ketone in 29 also yielded a diastereomeric mixture of hydroxy lactones; the 7S*,13S* stereochemistry of the major product 67 was suggested by MM2 calculations. [ Formulas omitted ] Treatment of both 28 and 29 with trimethylsilyl trifluoromethanesulfonate and tert-butyldimethylsilyl trifluoromethanesulfonate in the presence of triethylamine gave rise to mixtures of isomeric enol ethers; the product distribution could be partly explained by MM2 calculations based on product conformations.Science, Faculty ofChemistry, Department ofGraduat