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.

Conformational Design Principles in Total Synthesis

“…In 2014, Inoue and co-workers reported the first asymmetric total synthesis of (À)-4-hydroxyzinowol by tuning conformational preferences with different hydroxyl protecting groups (Scheme 9). [37] Thea uthors supposed that the tetrahydrofuran ring of (À)-4-hydroxyzinowol could be constructed by epoxide opening and subsequent etherification. When 9-1 was treated sequentially with CsOAc and pTSA, only the dehydration (at C11) product 9-3 was obtained.…”

“…Scheme 9. Conformational design by using substituent effects by Inoue and co-workers [37] (pTSA = para-toluenesulfonic acid).…”

Strategy of total synthesis based on the use of Rh-catalyzed stereoselective 1,4-addition

“…Among the most biologically active compounds isolated from the South American medical plant Zinowoewia costaricensis, the (−)-4-hydroxyzinowol 56 has shown a potent anticancer activity with a strong P-gp inhibitory activity. 21 This compound belong to the sesquiterpene family that possesses a transdecalin core and a tetrahydrofuran heterocycle (Scheme 13). The total synthesis of 56 remains still challenging due to the nine consecutive stereogenic centers on the trans-decalin backbone.…”

Synthesis of Alkynyl Sulfones

“…Sulfones are valuable structures that have attracted the interest of synthetic chemists due to their ability to stabilize α‐carbanions, their strong electron‐withdrawing properties, and their chameleonic abilities . Alkynyl sulfones are sulfone derivatives that have shown very important synthetic applications, e. g., as dienes in cycloadditions, in the synthesis of disubstituted alkynes and in the alkynylation of diverse structures of biological interest, which can subsequently be functionalized (Figure ) . Owing to the importance of these materials, different methodologies for the synthesis of alkynyl sulfones have been reported over the years.…”