Selective Introduction of Four Contiguous Stereocenters on the B-Ring of 4-Hydroxyzinowol

(-)-4-Hydroxyzinowol (1) is a potent inhibitor of P-glycoprotein, which has been implicated in multi-drug resistance in the treatment of cancer. The highly oxygenated structure of 1 comprises a trans-decalin (AB-ring) and a tetrahydrofuran (C-ring) and possesses six acyloxy, one hydroxy, and one alkoxy groups. The challenge of synthesizing 1 is particularly heightened by the nine consecutive stereogenic centers on the 10-carbon decalin skeleton. The total synthesis of this extremely complex structure was achieved in 36 steps from 5-acetoxynaphthalen-1-ol by the judicious application of powerful chemo- and stereoselective reactions. The rhodium-catalyzed asymmetric 1,4-addition of the isopropenyl group set the C7-stereocenter, and the remaining three cis-oriented hydroxy groups (C6, 8, and 9) of the B-ring were stereoselectively constructed in a stepwise fashion. The C5-tetra-substituted and C10-quaternary carbons at the juncture of the AB-ring were then introduced by oxidative dearomatization and Diels-Alder reaction, respectively. After acid-promoted formation of the C-ring ether, the C1-, 2-, 4- and 6-oxygen-based functional groups were stereoselectively installed to deliver the fully functionalized tricycle. Finally, the polyhydroxylated structure was converted to the polyacylated target molecule 1 via regioselective acetylation and benzoylation.

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Total Synthesis of (−)-4-Hydroxyzinowol

Todoroki

Iwatsu

Urabe

et al. 2014

J. Org. Chem.

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Concise Synthesis of the Multiply Oxygenated ABC-Ring System of the Dihydro-β-agarofurans

et al. 2013

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The multiply oxygenated ABC-ring system of the dihydro-β-agarofurans was synthesized by employing two highly stereoselective reactions. The quinidine-catalyzed Diels-Alder reaction between a chiral dienophile and 3-hydroxy-4-methyl-2-pyrone simultaneously installed the C2-stereogenic center and two contiguous tetrasubstituted carbon centers (C5 and C10) of the A-ring. After 12 additional transformations, the aldol reaction of the resulting spiral AC-ring cyclized the B-ring with stereoselective introduction of the C7- and C8-centers.

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Construction of the septahydroxylated ABC-ring system of dihydro-β-agarofurans: application of 6-exo-dig radical cyclization

et al. 2017

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A synthetic route to the septahydroxylated ABC-ring system of dihydro-β-agarofurans was established. The B-ring was formed by a base-promoted diastereoselective Diels-Alder reaction between 3-hydroxy-2-pyrone and a d-glyceraldehyde-derived dienophile, while the C-ring was cyclized by PhSeCl-mediated etherification. The remaining A-ring was constructed via a 6-exo-dig radical reaction. Selective transformations gave rise to the ABC-ring system 1 with nine contiguous stereocenters. The thus obtained 1 corresponded to the enantiomer of the densely oxygenated core structure of dihydro-β-agarofurans.

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Selective Introduction of Four Contiguous Stereocenters on the B-Ring of 4-Hydroxyzinowol

Cited by 4 publications

References 40 publications

Total Synthesis of (−)-4-Hydroxyzinowol

Total Synthesis of (−)-4-Hydroxyzinowol

Concise Synthesis of the Multiply Oxygenated ABC-Ring System of the Dihydro-β-agarofurans

Construction of the septahydroxylated ABC-ring system of dihydro-β-agarofurans: application of 6-exo-dig radical cyclization

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