Pamamycin-607, a polyether antibiotic, owes its pharmacological activity to its ability to disrupt bacterial cellular transport processes, once bound to the cell membrane. Precisely how this occurs at the molecular level is not known. However, its structure strongly suggests that it functions as an ionophore. A long-term objective of ours, therefore, is to use 1H and 13C NMR to study the binding properties of this molecule, and designed structural relatives of this molecule, with a variety of mono- and divalent cations. It is hoped that such an investigation will provide valuable insight into the mechanism by which normal bacterial cellular activity is disrupted by this agent. moreover, by measuring ion affinities in relation to structural variations, the design of more efficient membrane transport inhibitors, and hopefully more effective antibiotics, should be possible. For this project to be viable, an efficient entry into the complex pamamycin framework is essential. To this and, our immediate goal, as described in this application, is to develop a stereoselective synthesis of pamamycin607. The key step in our approach involves the addition of a 2-oxetanone enolate to a tetrahydrofuran acetaldehyde derivative with chelation control. We intend to explore the feasibility of this strategy by carrying out a series of reactions in which a simple 2-oxetanone enolate is generated from its alpha-silylated precursor, by treatment with fluoride, and added to a beta-alkoxy aldehyde in the presence of different potential chelating agents such as LiClO4 and ZnBr2. With this novel four-center diastereoselective process at our disposal, we then wish to use a carbonyl-directed reductive ring opening of these stereoselectively constructed units to provide a unique entry into cis 2,5-disubstituted tetrahydrofurans bearing multiple side chain asymmetry. Using a model system, the application of this strategy to pamamycin-607 will be demonstrated by controlled addition of the enolate of 4-(3-methyl-3butenyl)-2-oxetanone to syn alpha-methyl tetrahydrofuran acetaldehyde. From the aldol product, a carbonyl group for reductive cyclization will be unleashed from the terminal alkene moiety by low temperature ozonolysis. Plans have been made to apply methodology developed in the model system to the synthesis of the natural product.
