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 method, making it highly amenable to large-scale production.

Bioinspired Asymmetric Total Synthesis of Emeriones A–C**

“…[11] Therefore, angelic aldehyde was immediately used in a Still-Gennari olefination with 31 to give dienoate 32, which was then reduced to give allylic alcohol 20. [12,13] Sharpless asymmetric epoxidation of 20 proceeded in excellent yield to give 33, but with a modest 81 % ee, [15] as previously observed with Zconfigured allylic alcohols. [16] While Upjohn oxidation of epoxide 33 to give triol 19 was moderately diastereoselective (72 : 28 dr), Sharpless asymmetric dihydroxylation (SAD) proceeded with an improved dr of 86 : 14.…”

Total Synthesis of Meayamycin B

“…To test this hypothesis, we developed a mole-scale protocol for the preparation of phosphonate 3 (Scheme ). Ester 1 was reduced to the aldehyde and subjected to this phosphonate and KO t Bu to form Z -enoate 2 in 80% yield as a single isomer. Subsequently, this enoate underwent acid-catalyzed acetonide deprotection–transesterification to provide the unsaturated lactone 4 in 77% yield in a 9 g scale.…”

Improved Synthesis of the Amine Fragment of FR901464 and Thailanstatins through the Development of a Convenient N-Detosylation Method

“…The preparation of ethyl 2-(bis­(2-( tert -butyl)­phenoxy)­phosphoryl)­propanoate followed the reported procedure …”

“…To achieve high conversion, it was critical to heat the reaction mixture. This ester was then reduced by DIBALH to the corresponding aldehyde 4-Ts in situ , which was subjected to the Ando-type phosphonate 5 , to afford an inseparable mixture of enoate 6-Ts and phosphonate-derived byproducts. The mixture of products was separated after treatment with acetic acid under reflux to afford the unsaturated lactone 7-Ts in a 64% yield over three steps.…”