Stereoselective Synthesis of 2,6- trans -Tetrahydropyrans via Tandem Horner–Wadsworth–Emmons Olefination of Lactols/Intramolecular Oxa-Conjugate Cyclization

Abstract

Tandem approaches based on intramolecular oxa-conjugate cyclization of ζ-hydroxy-α,β-unsaturated carbonyl compounds provide an efficient route to 2,6-disubstituted tetrahydropyrans (THPs). However, existing methods are limited to the synthesis of thermodynamically favored 2,6-cis-isomers. Here, we report a tandem stereoselective synthesis of 2,6-trans-THPs via a Horner–Wadsworth–Emmons olefination of lactols/intramolecular oxa-conjugate cyclization sequence under kinetically tailored reaction conditions. The developed protocol affords 4-methylene-2,6-trans-disubstituted THPs, bearing functionalized substituents, in good yields (50–84%) and with high diastereoselectivities (dr up to 95:5). The utility of the method was demonstrated through synthetic modifications of the 2,6-trans-THPs and the asymmetric synthesis of the natural products diospongins A and B.