Scalable Preparation of Methylated Ando-Type Horner–Wadsworth–Emmons Reagent

Abstract

The Horner–Wadsworth–Emmons (HWE) reactions are vital to the chemical synthesis of complex molecules, forging a carbon–carbon double bond in the generation of α,β-unsaturated enoates from aldehydes or ketones. Despite their frequent use, the Z-stereoselective formation of α,β-unsaturated esters from aldehydes have been mostly limited to the use of the commercially available Still–Gennari reagent. Ando developed an alternative reagent to achieve the same formation with less expensive reagents. However, an α-methylated Ando-HWE reagent has remained difficult to prepare, hindering a reliable route to α,β-disubstituted Z-enoates. Here, we report the development of a preparative synthesis of a methylated Ando-HWE reagent for the highly Z-selective HWE reaction. Costing $0.49/mmol, this synthesis is significantly cheaper than the currently available Still–Gennari reagent ($11/mmol, Millipore Sigma 2018). The purification procedure does not require chromatography, with recrystallization as the only purification ...