The plan of this investigation is twofold in nature. The overall goal is to develop concise and efficient syntheses of synthetically and technically challenging alkaloids possessing important biological activities. The current focus is on the development of new synthetic methodologies and strategies for the construction of 2-aminoimidazole- and related guanidine-based marine natural products having unique pharmacophoric entities. Notable representatives of this alkaloid group include the tricyclic marine pigments zoanthoxanthins and zoamides, the C11N5 family of oroidin alkaloids, the dimeric oroidin alkaloids, and the red-tide toxins saxitoxin and gonyautoxins. Collectively, these and other structurally related compounds possess a myriad of potent pharmacological effects that include antiviral, antibiotic, antileukemic, antineoplastic, antiserotonergic, immunosuppressive, cytotoxic as well as alpha-adrenoceptor and ion-channel blocking activities. In addition, a rare example of ATPase stimulating activities of myosin and actomyosin has been observed. Although each class of metabolites is structurally unique, they represent, however, a collection of structures whose diversity is related by the rich chemistry that they share in common. The proposed research focuses on developing methodologies and strategies that will have general applicability to synthesis of the above metabolites and related analogs. In particular, the utility of these methods is delineated in the proposed syntheses of the oroidin alkaloids, dibromoagelaspongin and agelastatin, the dimeric oroidin alkaloids ageliferin, sceptrin, and palau amine, the potent neurotoxins saxitoxin and gonyautoxins. The proposed methods and routes are essentially devoid of protecting groups and are based loosely on biogenetic considerations. An integral feature of the research plan is a criterion for substantiating possible biosynthetic pathways. The synthetic plan calls for the development of methods for transforming 2-aminoimidazoles into key intermediates for the synthesis of the naturally occurring compounds. The preparation of these intermediates and the facility of the ensuing molecular rearrangements would tend to support or disclaim the biogenetic hypothesis. Versatile and efficient syntheses of these metabolites would provide access to structurally modified or specifically labeled substrates for biomedical research.
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