Synthetic studies on bromotyrosine natural products and their analogs. Pyridinium salt photochemistry and its application to the synthesis of novel glycomimetics.

摘要

Bromotyrosine marine natural products are a structurally diverse class of metabolites embodying a broad spectrum of interesting biological activities. Many bromotyrosine metabolites have been found to be cytotoxic, as well as antibacterial, anti-HIV and antifouling. The uniquely functionalized antifoulant ceratinamine 21 has been synthesized. A proposal for the biogenesis of 21 has been suggested. Total syntheses of several other bromotyrosine natural products, including the antifoulant moloka'iamine 20 and the anti-HIV mololipids 52–54 and 56, have been completed. Mololipids 52–54 and 56 were investigated for their interactions with gp120 towards an understanding of the mechanism of their anti-HIV activity. Structural analogs of moloka'iamine 20 were prepared and screened as antifoulants in a settlement inhibition assay against cyprids of the barnacle Balanus amphitrite . Structureactivity relationships were evaluated and then utilized in the design of novel antifoulants. Among the new compounds synthesized, Noctylbromotyramine 72 was found to be an especially potent inhibitor of cyprid settlement in subsequent assays.; Glycosidases, enzymes that carry out the hydrolysis of glycosidic bonds, are an essential class of specific carbohydrate modifying enzymes. Inhibitors of those enzymes have proven useful both in the study of glycobiology as well as in the development of new therapeutic agents. The rich photoelectrocyclization chemistry of N-alkylpyridinium salts has been utilized in the concise syntheses of novel glycomimetics with potential as glycosidase inhibitors. Aziridinylcyclopentitols 160, 164, and 166 have been prepared from simple N-methylpyridinium perchlorates in two steps. A key transformation was found to be the stereoselective, vicinal dihydroxylation of aziridinylcyclopentenols 102, 147, and 148. Novel trehazolin mimics 185 and 193 were similarly prepared from the appropriate N-glycosylpyridinium salts.; The synthetically powerful transformations enabled by pyridinium salt photochemistry prompted additional studies on heteroatom-directed photosolvolyses. Those studies resulted in the preparation of aziridinylacetals 206 and 211. The potential for solvolysis of photogenerated intermediates by solvents other than water or alcohols was also investigated. The photosolvolysis reactions of unfunctionalized pyridinium salts in wet acetonitrile led to the syntheses of aminooxazoline 220 and acetamidoaminoalcohol 223.