Formal Synthesis of Uvaricin via Palladium-Mediated Double Cyclization

Abstract

[see reaction]. A novel palladium-mediated, ligand-controlled double cyclization is reported. The C2-symmetric diene produced was desymmetrized via Sharpless asymmetric dihydroxylation and was further transformed into a known intermediate in the synthesis of uvaricin.

Transition-Metal-Catalyzed Reactions in Heterocyclic Synthesis

“…265 The resulting diene 614 was further transformed into a known intermediate 615 for the synthesis of uvaricin. They demonstrated that palladium(0)-catalyzed desymmetrization of the C 2 diol 616 with Trost's ligand 607 afforded the tetrahydrofuran 617 diastereoselectively (Scheme 188).…”

Desymmetrization of pibrentasvir for efficient prodrug synthesis

“…For example, in Hoye's synthesis of the annonaceous acetogenin (+)-parviflorin, bis(epoxide) 5 was desymmetrized via reaction with a limited quantity of a lithium acetylide, giving alcohol 6 (29%) along with recovered 5 (53%). 10 Two syntheses from the Burke group utilized this approach, including a related annonaceous acetogenin, uvaricin (not shown), using a dihydroxylation, 11 and the C(37)-C(54) halichondrin B subunit, using an olefination/hydroboration/oxidation sequence to convert bis(lactone) 7 to desymmetrized primary alcohol 8 in 40% yield. 12 In a remarkably brief route to (+)-roxaticin that showcases this approach, the Krische group desymmetrized diol 9 via mono-selenide 10 formation in 50% yield.…”

Recent progress on the total synthesis of acetogenins from Annonaceae

“…In 2001, Burke’s group reported the synthesis of a known intermediate 232 in the synthesis of uvaricin ( 225 ) ( Scheme 31 ) [ 86 ]. A chiral DPPBA ligand controlled double cyclization of 230 allowed the selective formation of a single diastereomer 231 in one step, thus providing general access to annonaceous acetogenins containing trans / threo / trans or cis / threo / cis bis-THF core structures.…”