UC San Diego

This dissertation discusses the structural elucidation and total synthesis of bioactive marine natural products. Separation of the MeOH extracts of three Verongida sponges provided novel bromotyrosine alkaloids (BTAs), the structures of which revealed oxidative and non-oxidative dimerization and other unprecedented structural motifs. The Caribbean Aplysina lacunosa and Western Australian Pseudoceratina verrucosa furnished eight novel BTAs characterized by a spirocyclohexadienyl-isoxazoline (SIO) ring system. Evaluation of the MeOH extract of the Bahamian Pseudoceratina crassa revealed the presence of nine new BTAs embodied by an O-methyl-2,6-dibromotyrosyl ketoxime. The planar structures of the 17 alkaloids were determined by interpretation of MS, 1D and 2D NMR data, and the absolute configuration of the SIO unit was ascertained by ECD. Analysis of the compounds by specific rotation, Cotton effects and chiral-phase HPLC revealed that BTAs are configurationally heterogenous. Extracts from A. lacunosa showed inhibitory activity against -chymotrypsin. Alkaloids from P. verrucosa and P. crassa selectively inhibited acetylcholinesterase and butyrylcholinesterase, respectively. The structure of the unusually complex glycolipid axinoside-1 was elucidated by integrated spectroscopic analysis, MS, degradation, and derivatization to reveal a tetrasaccharide, comprising three D-xylose units and one D-glucose, linked to a C28-aglycone. The identities of the sugar units were established after acidic methanolysis, conversion to persilylated ethers and GCMS analysis with comparison to authentic standards. Linkage analysis was performed by HMBC, and anomeric configurations were established from interpretation of 1JCH coupling constants. The location of the 2º OH groups in the aglycone and the site of glycosylation were ascertained through MS fragmentation. The absolute configuration of the terminal -butyrolactone in the aglycone was determined by ECD. Configurational assignment of the three free 2º OH groups was achieved from interpretation of the colossal 1H NMR anisotropy induced in the values of their corresponding tri-(naphth-1-yl)methoxyacetic acid (NMA) esters, and comparative analysis of values of the corresponding tri-NMA derivatives of two stereodefined synthetic models, prepared by multistep synthesis. Lastly, extensive efforts towards the total synthesis of lepadin I, a selective butyrylcholinesterase inhibitor, were carried out leading to an advanced intermediate through tandem Robinson annulation–aza-Michael cyclization, setting the stage for the end-game and completion of the natural product.