Research toward the total synthesis of lactonamycin and related type II polyketides

This work presents research toward the total synthesis of the promising antibiotic lactonamycin and related polyketides specifically, a scalable, inexpensive, and universal process to access this family of natural products. Lactonamycin exhibits a wide range of promising biological activity. Most notable among these is the potent activity displayed against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus.; Lactonamycin and each of the aforementioned structurally related polyketide natural products serve as good targets for synthetic efforts, particularly lactonamycin. Further impetus for total synthesis is provided by the interesting structural features of these related polyketides and the synthetic challenges associated with these features. The structure of lactonamycin contains several unique connectivities including a novel hexacyclic ring structure distinguished by a densely oxygenated DEF-ring system with three contiguous quaternary stereogenic centers. An approach to lactonamycin and its related polyketides has been developed, in particular two methodologies: (1) the tandem conjugate addition-Dieckmann condensation and (2) a quinone nitrile-oxide cycloaddition. These methods have allowed a unified approach to this class of biologically active natural products.; The synthesis of the ABCD-ring system of lactonamycin has been accomplished in eleven steps by utilizing a novel tandem cyanide conjugate addition/Dieckmann condensation as a 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 an application to the related polyketides tetracenomycin C, elloramycin, saintopin, saintopin E. This methodology has also allowed for a formal synthesis of 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 and implemented in the full ABCD-ring system of lactonamycin, providing rapid entry to an isoxazole intermediate possessing virtually all of the atoms necessary to construct the skeleton of lactonmycin. Diastereoselective installation of a final tertiary hydroxyl remained after [3+2] cycloaddition. Several methods geared toward solving this challenging synthetic problem are presented to better understand how it may be overcome.; This dissertation describes a plan and progress toward lactonamycin that has allowed for the synthesis of a unique substrate where these methodologies may be utilized to complete the first total synthesis of lactonamycin.