A novel synthetic approach to glycerophospholipids via Horner–Wadsworth–Emmons reaction of mixed phosphonoacetate

Synthesis of Fluorine-Containing Analogues of 1-Lysoglycerophospholipids via Horner–Wadsworth–Emmons Reaction

“…Recently, we reported a novel approach to synthesize glycerophospholipids (PLs) based on the Horner-Wadsworth-Emmons (HWE) reaction of easily handled mixed phosphonoacetate, which serves as a masked precursor of PLs. 5 Herein we describe the facile synthesis of fluorine-containing analogues 1-3 using HWE reagent 6 as a key intermediate, which was derived from methyl bis(2,2,2- trifluoroethyl)phosphonoacetate (Still-Gennari reagent, 4) 6,7 and fluorine-containing chiral alcohol 5 as shown in Scheme 1.…”

“…1:1) in 87% yield as shown in Scheme 3. 5,11 1-F-LPA (1), the fluorine-containing analogue of 1-lysophosphatidic acid (1-LPA), was prepared using an HWE reaction of mixed phosphonoacetate 17 with benzaldehyde as the key reaction as shown in Scheme 4. The nucleophilic substitution of 2-(trimethylsilyl)ethanol 1412 at the phosphorus center of the key intermediate 6 in the presence of excess amounts of 14 and DBU gave phosphonoacetate 15 in 76% yield.…”

“…The oily residue was purified by column chromatography [Silica Gel 60N: CHCl 3 -MeOH (15:1)] to afford 9 (760 mg, 99%) as a white solid; mp 37. 5…”

Enzymatic synthesis of chiral P-stereogenic phosphonoacetates

“…To verify the generality of this synthetic method, a series of racemic mixed phosphonoacetates were synthesized and subjected to enzymatic hydrolysis in the presence of PLE, which has been widely used as a practical biocatalyst in organic synthesis. Nucleophilic substitution of symmetrical secondary alcohols 2a-j at the phosphorus center of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (Still-Gennari reagent, 1) [6,7] furnished racemic mixed phosphonoacetates rac-3a-j in 66-81% yields [5,8,9]. Enzymatic hydrolysis of rac-3a-j using PLE gave the corresponding carboxylic acids 4a-j and allowed recovery of unreacted esters 3a-j.…”

Selective Transesterification of 2,2,2-Trifluoroethyl Phosphates: Synthesis of Mixed Unsymmetrical Phosphates

“…The transesterification of 1 has not to our knowledge been previously reported. Sano et al reported that transesterification of phosphonate esters bearing 2,2,2-trifluoroethoxy groups took place at the phosphorus center . The phosphate 1 is expected to undergo transesterification with alcohols.…”