Chemoselectivity\nin Pd-Based Dyotropic Rearrangement:\nDevelopment and Application in Total Synthesis of Pheromones

In the dyotropic rearrangement of\nmolecules with semiflexible structures,\ncharacterized by a freely rotating static C–C bond, the formation\nof a mixture of products is common due to the coexistence of several\nenergetically comparable conformers. Herein, we report that it is\npossible to modulate the shifting groups by adjusting the metal’s\ncoordination sphere in Pd-based dyotropic rearrangement. In the presence\nof a catalytic amount of Pd(II) salt, the reaction of γ-hydroxyalkenes\nor γ,δ-dihydroxyalkenes with Selectfluor affords fluorinated\ntetrahydropyranols or 6,8-dioxabicyclo[3.2.1]octanes (DOBCO), respectively.\nIn this domino process, two C(sp<sup>2</sup>) and one allylic C(sp<sup>3</sup>) are sequentially activated and functionalized through a\npivotal conformation-controlled chemoselective C(sp<sup>3</sup>)–C(sp<sup>3</sup>) and C(sp<sup>3</sup>)–Pd(IV) bond metathesis reaction.\nMechanistic studies suggest a reaction sequence including 5-<i>exo</i>-trig oxypalladation, Pd oxidation, and chemoselective\nring expansion 1,2-Csp<sup>3</sup>/Pd(IV) dyotropic rearrangement,\nfollowed by hydroxypalladation of in situ generated dihydropyrans.\nThese findings provide a unique retrosynthetic disconnection for the\nsynthesis of 6,8-DOBCO. We showcase its potential by developing a\nconcise synthesis of three important pheromones. Notably, (+)-frontalin\nis synthesized from a commercially available 1,5-diene in only two\nsteps, utilizing Sharpless catalytic asymmetric dihydroxylation and\nPd-catalyzed domino cyclization developed in this study.