Azaspiracid is a potently toxic natural product that represents a human health hazard due to its seasonal contamination of mussels (Mytilus edulis) that have been cultivated for human consumption. This unique toxin was isolated recently from Irish mussels (2 mg/20 kg mussel tissue) and is responsible for the acute poisoning of several humans. The structure of azaspiracid has been only partially assigned on the basis of spectroscopic studies, but the actual structure may be one of four possible isomers. Azaspiracid is an 842 MW. omega-amino acid with a 40 carbon backbone that is punctuated by an unprecedented array of two fused polycyclic domains connected via a 2,6-disubstituted pyranyl hemiketal and terminating in a spiroaminal. The lethal dose in mice was determined to be 0.2 mg/kg (i.p. injection). Although the mechanism of action remains to be explored, azaspiracid does not inhibit the protein serine/threonine phosphatase 2A that is affected by other diarrhetic shellfish toxins. The complex yet undefined structure of azaspiracid, coupled with its potent vertebrate toxicity, presents unique opportunities for synthetic, structural, and biological study. The primary goals of this proposal are to develop and apply novel synthetic strategies for the rapid and convergent assembly of azaspiracid's component polycyclic domains, and to utilize these synthetic products to assign the complete structure of the natural product and provide an alternative source via total synthesis for further biological evaluation and environmental monitoring. Azaspiracid has been retrosynthetically divided into two major domains representing carbons 1-20 and 21-40 of the natural product. The C1-C20 portion of azaspiracid contains 8 stereogenic centers and is comprised of a tetrahydrofuran-fused 6-5-6 trioxaspirotetracyclic ring system (rings A-B-C-D) that is linked via a single acyclic carbinol carbon (C20) to a hemiketal, pyranyl E ring. The spiro-fused A-B-C ring system is representative of similar structural motifs in several other biologically active natural products. It will be assembled in a novel convergent approach that involves the nucleophilic coupling of an A-B ring precursor with a C-D ring lactone, followed by an acid triggered transketalization to close the B ring and complete the trioxaspiroketal system. The C21-C40 domain of azaspiracid consists of the isolated hemiketal E ring and the unique spiroaminal-fused 2,9-dioxabicyclo(3.3.1)nonane ring system (rings F-G-H-I) and contains 12 stereogenic centers. The F-I system presents an opportunity to develop a novel, biomimetic polycyclization cascade sequence that will provide unique synthetic access to this polycyclic array that will be instrumental for assigning the stereochemistry and developing a total synthesis of the natural product.
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