Studies Toward an Asymmetric Synthesis of CP-263,114 and CP-225,917

Abstract

An enantioselective approach to construction of the complex framework of the CP compounds is presented. The synthesis relies on initial elaboration of the two sidechains. The "upper" appendage was asymmetrically dihydroxylated with both AD-mix reagents in order to lend flexibility to the scheme and provide the necessary handle for evolving the additional stereogenic centers. These fragments were linked to benzoic acid via Birch reduction-alkylation and subsequent cuprate addition. A series of functionalization reactions including dissolving metal reduction, Claisen rearrangement, iodolactonization, regioselective epoxide cleavage-oxidation, and intramolecular Wadsworth-Emmons cyclization took advantage of highly efficient stereocontrol. However, this flexibility was thwarted when deprotonation of a penultimate intermediate failed to be regioselective in the proper direction.

Total Synthesis of (±)-Aplykurodinone-1: Traceless Stereochemical Guidance

“…Having served its function in mediating the stereoselective installation of the C 3 center, the C 1 fragment was cleaved via a hydrolysis−retro-aldol sequence following exposure of 6 to the action of K 2 CO 3 in water at 100 °C. Subsequent iodolactonization of the resultant carboxylic acid ( 14 ) was accomplished in the same flask, to provide 15 in 75% yield from 6 . The re-emergence of the cis -junction was confirmed through NOESY analysis of the methyl ester derivative of 14 and by X-ray diffraction of the subsequent deiodinated intermediate, 16 .…”

Evolution of a Synthetic Approach to CP-263,114

“…An intriguing combination of complex structure and biological activity has resulted in a great deal of attention being focused on the nonadrides CP-263,114 (phomoidride B, Figure ) and CP-225,917 (phomoidride A). Since their isolation in 1995, numerous reports have appeared describing syntheses, approaches, and biosynthetic investigations 3o 1 …”

Discovery of Novel Synthetic Methodologies and Reagents during Natural Product Synthesis in the Post-Palytoxin Era

“…Additionally, unique structural features include a C14 quaternary stereocenter, a lactone ring system, and a fused maleic anhydride subunit. To date, more than 20 research groups have been inspired by this structural complexity and contributed synthetic studies toward the total syntheses of the CP molecules. − …”