Progress towards the total synthesis of bastadin 5, a novel RyR-1 calcium(2+) channel modulator from the marine sponge Ianthella basta (Pallas)

Bastadin 5 is a novel modulator of the RyR-1 Ca2+ channel in skeletal muscle from the marine sponge Ianthella basta (Pallas). The structure of bastadin 5 contains the 13,32-dioxa-4,22-diazabastarane (i.e. bastarane) skeleton, comprised of four 2,6-dibromotyrosine residues linked through two amide bonds and two diphenyl phenolic ethers. The activity demonstrated by bastadin 5 is unique in this class of compounds, with bastadin 5 as the most active congener. This dissertation research describes work towards the total synthesis of bastadin 5 and the development of methodology to achieve the bastadin skeleton.; Chapter Two describes the synthesis of a diphenyl ether diamine used to create the bastadin skeleton through a tandem amide coupling reaction from the two halves of the bastadin ring. Both halves of the bastadin ring were developed from a common diphenyl ether dialdehyde intermediate. The tandem Erlenmeyer condensation macrolactamization (TECM) methodology is presented in this chapter.; Chapter Three develops the methodology presented in Chapter Two by synthesis of the bis-Erlenmeyer azlactone through the common dialdehyde intermediate. Model studies are presented using the bis-azlactone to explore the tandem macrolactamization process. The limitations in realizing isodityrosine metabolites and the barriers associated with a tandem macrolactamization strategy are also described.; Chapter Four describes a revised strategy to synthesize bastadin 5 using Nucleophilic Aromatic Substitution (S_NAr) to form the diphenyl phenolic ethers and a directed macrolactamization amide coupling strategy. The synthesis of a mono-protected diamine is presented using methodology distinct from the syntheses in Chapter Two.; Chapter Five continues the syntheses of mono-protected intermediates leading to macrolactamization. The strategies to synthesize a mono-protected diphenyl ether dicarboxylate are described using a Horner-Emmons olefination to create an α-oximino ester. The synthesis of a bastadin macrolactam is described, but the natural product is not obtained.