Symposium on the Chemistry of Natural Products, symposium papers
Online ISSN : 2433-1856
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Total Synthesis of Acetylaranotin and Structural Determination of Its Congeners
Hideto FujiwaraTaichi KurogiShun OkayaKaori YamadaMalipan SappanMasahiko IsakaKentaro OkanoHidetoshi Tokuyama
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Abstract

Acetylaranotin (1), which was isolated from a fungus Arachniotus aureus in 1968, displays intriguing biological activities such as inhibitory activity against viral RNA polymerase. In addition to these important biological activities, the unique dimeric structure, possessing highly functionalized dihydrooxepine rings fused to pyrrolidino-diketopiperazine skeleton, has attracted considerable attention as one of most challenging target from the synthetic community. Herein, we describe total synthesis of (–)-acetylaranotin featuring vinylogous Rubottom oxidation and formation of the characteristic dihydrooxepine ring and structural determination of its congener.

Synthesis of the dihydrooxepine bearing a hydroxyl group at the g-position commenced with introduction of a hydroxyl group at the g-position of cyclohexenone, which is a common structure in the related compounds. We developed a regio- and stereoselective introduction of the hydroxyl group at the g-position of the cyclohexenone derivative by a regioselective dienol silyl ether formation and subsequent unusual vinylogous Rubottom oxidation. After protection of the alcohol 17 as its TBS ether, regio-controlled Baeyer-Villiger oxidation of the silyl ether 18 provided seven-membered enol lactone 19, which was converted to dihydrooxepine 21 via reduction of the corresponding triflate 20. Next, we focused on the crucial condensation of two monomer units. Remarkably, the use of a monomer unit with unnatural stereochemistry was crucial for the smooth condensation and formation of the diketopiperazine 25. The remaining task was inversion of two hydroxyl groups, which was executed by an exceptionally efficient oxidation using Iwabuchi’s nor-AZADO and Luche reduction at low temperature. The facial selectivity in the reduction was completely controlled by the steric bias of the densely fused polycyclic skeleton, which led to the total synthesis of acetylaranotin (1). We also determined the stereochemistry of the related compound, hirsutellomycin (5).

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