Research toward the total synthesis of lactonamycin and related polyketides
Deville, Jay Paul
Doctor of Philosophy
Research toward the total synthesis of the promising antibiotic lactonamycin is reported. Lactonamycin exhibits a wide range of potentially useful biological activities. Most notable among these, is the potent activity displayed against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus. The first reported synthesis of the ABCD-ring system of lactonamycin has been accomplished in nine steps in 15.3% overall yield utilizing a novel tandem cyanide conjugate addition/Dieckmann condensation as the key step. This powerful annulation reaction was developed in a model system prior to application to the synthesis of the ABCD-rings of lactonamycin. Flexibility was observed in the nucleophile used to initiate the cyclization, holding promise for application to the related polyketides tetracenomycin C, elloramycin, saintopin, saintopin E, and tetracenomycin A2. Model studies on the highly oxygenated DEF-ring system were conducted. A high-yielding, regioselective dipolar cycloaddition of a hydroxymethyl-substituted naphthoquinone with an appropriately substituted nitrile oxide was developed, providing rapid entry to an isoxazole intermediate possessing virtually all of the atoms necessary for the DEF-rings of lactonamycin. Diastereoselective installation of a final tertiary hydroxyl remained after [3+2] cycloaddition. Several methods geared toward solving this challenging synthetic problem are presented. In the course of studies on the ABCD-ring system, a methodology for the clay-catalyzed deprotection of acetal-type phenolic ethers was developed. This method proved selective for phenolic acetal-type ethers with an ortho heteroatom, prompting the proposal of a mechanism involving chelation-controlled selectivity.