title: Total synthesis of (-)-4-hydroxyzinowol.
abstract: (-)-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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo , Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Todoroki
authors.forename: Masafumi
authors.initials: M
authors.lastname: Iwatsu
authors.forename: Daisuke
authors.initials: D
authors.lastname: Urabe
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D061565:Cycloaddition Reaction; D005663:Furans; D015394:Molecular Structure; D009279:Naphthacenes / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: C000595484:4-hydroxyzinowol; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005663:Furans; D009279:Naphthacenes; C018674:tetrahydrofuran