Synthesis of Haptens for the Marine Toxin, Gymnodimine; Synthesis of Beta-lactone Fused Carbocycles and Nitrogen Heterocycles; Efforts Toward the Synthesis of the Proposed Structure of Thiolyngbyan

Abstract

Contamination of seafood by marine toxins has been a consistent public health problem. Gymnodimine (GYM) is a member of a family of spirocyclic imine containing marine natural products which was shown to be highly toxic (LD50 96 mg/kg, intraperitoneal injection); thus ensuring public safety requires stringent monitoring of gymnodimine. Current detection methods for GYM and spirolides include the mouse bioassay and LC-MS-based detection techniques which, however, have significant limitations. Therefore, more efficient and convenient detection methods are required. Building on our recently completed total synthesis of (-)-gymnodimine, the synthesis of two haptens were targeted for eventual production of monoclonal antibodies (mAb) to be used in an eventual Enzyme-Linked Immunosorbent Assay (ELISA) for gymnodimine. As an extension of the intramolecular nucleophilic catalyzed aldol lactonization (NCAL) process from aldehyde acid to keto acid substrates, carbocyclic and nitrogen heterocyclic B-lactones were synthesized. Demonstration of the utility of the NCAL process for keto acids was applied to the synthesis of dihydroplakevulin A and the core of tussilagine. In addition, although initial attempts to develop guanidine catalysts for the asymmetric NCAL process were unsuccessful, homobenzotetramisole (HBTM) was found to be a suitable asymmetric catalyst for keto acid substrates. Finally, synthetic studies toward the proposed structure of thiolyngbyan are described. Thiolyngbyan was isolated from a blue-green algae and it exhibited antifungal activity.