Part I. Total synthesis of the marine cyclodepsipeptide apratoxin A. Part II. Structural determination and total synthesis of spongidepsin. Part III. Improved synthesis of the C3-C17 domain of phorboxazole A and synthesis of a fluorescent phorboxazol

Apratoxin A is representative of a growing class of marine cyanobacterial cyclodepsipeptides wherein discrete polypeptide and polyketide domains are merged via ester and amide or amide-derived linkages. The Dtna domain was assembled in the biogenetic direction beginning with a Brown allylation of pivaldehyde to establish the C39 alcohol configuration. Diastereofacial selective addition of a higher order dimethylcuprate upon an RCM derived alpha,beta-unsaturated valerolactone installed the C37 methyl-bearing center. A Paterson anti-aldol process was used to incorporate the remaining two ketide stereogenic centers at C34 and C35. The thiazoline moiety was constructed via an intramolecular Staudinger reduction---aza-Wittig process using an alpha-azido thioester. Late stage macrocycle closure proceeded successfully via lactam formation between Pro and N-Me-Ile residues. Optimization of C35 hydroxyl group protection-deprotection completed the effort, which culminated in the fist total synthesis of apratoxin A.; Spongidepsin was isolated from the genus Spongia of marine Porifera. It showed potent cytotoxic and antiproliferative activities against several cancer cell lines. We determined the absolute stereochemistry assignment and accomplished the first and second total syntheses of spongidepsin via a stereochemically divergent strategy that employed macrolide closure via ring-closing metathesis as a key step. Catalytic hydrogenation of the RCM alkene products provided eight targeted diastereomers for spectroscopic comparison. The assignment of absolute configuration to the natural product was corroborated by the incorporation of (S)-N-methylphenylalanine in the diastereomeric probe and the close match in specific rotations between the final synthetic and natural products.; Phorboxazoles A and B were isolated from the extracts of the marine sponge Phorbas sp off the coast of western Australia. Preliminary biological data against the National Cancer Institute's 60 tumor cell line suggests phorboxazole A to be among one of the most cytotoxic compounds yet discovered. We developed a convergent and efficient synthesis of the C3--C17 domain via iterative hetero-Diels-Alder cycloaddition and retro-Michael and Michael addition. To explore structure-activity relationships, a total synthesis of a fluorescent phorboxazole A derivative was accomplished using alkylation with a coumarin derivative, Takai methylenation and Sonogashira coupling as key steps.