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| - Expedient Access to the Okadaic Acid Architecture: A NovelSynthesis of the C1−C27 Domain
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| Abstract
| - A newly designed synthetic entry to the C1−C27 domain of okadaic acid has been developed. Thisincorporates substantial improvements in the preparations of the key okadaic acid building blocksrepresenting the C3−C8, C9−C14, and C16−C27 portions. The synthesis of the C3−C8 lactoneused (R)-glycidol as the origin of the C4 stereogenic center and featured a late-stage optionalincorporation of the C7 hydroxyl group. The complementary C9−C14 fragment was synthesized ina concise route from (R)-3-tert-butyldimethylsilyloxy-2-methylpropanal and propargyl bromide.Assembly of the C3−C14 spiroketal-containing intermediate from the constituent fragments revealeda dramatic effect of C7 functionalization upon spiroketalization efficiency. In contrast, both (9E)-and (9Z)-enones converged readily to the C8 spiroketal upon treatment with acid. Modifications tothe central C16−C27 fragment of okadaic acid included the early replacement of benzylic protectinggroups by more suitable functionalities to facilitate both the generation of the C15−C27 intermediateand the deprotection of the final products. These modular building blocks were deployed for thesynthesis of the C1−C27 scaffold of 7-deoxyokadaic acid. This work demonstrates improvementsin the formation of versatile okadaic acid intermediates, as well as a reordering of fragmentcouplings. This alternative order of coupling was designed to promote the late stage incorporationof nonnatural lipophilic extensions from the C27 terminus.
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