Two dimerized cyclic hexapeptides, antatollamides A (146) and B (147) were isolated from the colonial ascidian Didemnum molle collected in Pohnpei. The amino acid compositions and sequences were determined by interpretation of MS, 1D and 2D NMR data. Raney Ni reduction of antatollamide A cleaved the dimer to the corresponding monomeric cyclic hexapeptide with replacement of Cys by Ala. The amino acid configuration of 146 was established, after total hydrolysis, by derivatization with a new chiral reagent, (5-fluoro-2,4-dinitrophenyl)-N𝛼-L-tryptophanamide (FDTA), prepared from L-tryptophanamide, followed by LCMS analysis; all amino acids were L-configured except for D-Ala. The FDTA reagent was developed as an alternate reagent to Marfey’s reagent for the determination of the absolute configuration of amino acids. The improved resolution observed with FDTA is attributed to discrete π-cation interactions of the electron rich indole ring in Trp with the ammonium counterion in buffer. Additionally, six new cyclopentano[g]indoles, trans-herbindole A (147) and trikentramides E-I (155-159), were isolated from a West Australian sponge, Trikentrion flabbeliforme Hentschel, 1912 and their structures elucidated by integrated spectroscopic analysis. The compounds are analogs of previously described trikentrins, herbindoles and trikentramides from related Axinellid sponges. The assignment of absolute configuration of the new compounds was carried out largely by ECD – specifically, deconvolution of their Cotton effects by exploiting van’t Hoff’s principle of optical superposition – and by chemical interconversion of trans-herbindole A to trikentramide G and trikentramide G to trikentramides E, H and I.

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.