A Facile Synthesis of Novel Chiral Phosphonoacetates Bearing a Stereogenic Phosphorus Atom

Abstract

Asymmetric Horner-Wadsworth-Emmons (HWE) reaction of prochiral cyclic ketones is of current interest.1-4) Several useful chiral HWE reagents such as phosphonates, [5][6][7][8][9] phosphonoamides, 10) and phosphonoamidates 11) have been developed for the synthesis of olefins possessing an axis of chirality. However, most of these reagents are restricted to the compounds with non-stereogenic phosphorus atom. Although Motoyoshiya et al. reported geometrical selectivity of HWE reactions of aldehydes with racemic phosphonoacetates, 12) the asymmetric HWE reaction of P-stereogenic phosphonoacetates has never been established. Herein we describe a facile synthesis of novel chiral phosphonoacetates bearing a stereogenic phosphorus atom utilizing the enzymecatalyzed kinetic resolution of racemic phosphonoacetates derived from two kinds of Z-selective HWE reagents, methyl bis(2,2,2-trifluoroehtyl)phosphonoacetate (Still's reagent, 1)13) and ethyl diphenylphosphonoacetate (2). 14)Recently, we reported a new and efficient stereoselective HWE reaction of aldehydes and ketones with bis(2,2,2-trifluoroehtyl)phosphonoacetic acid and found oxophilicity of a phosphorus atom of phosphonoacetate 1. 15,16) That is to say, the phosphonate moiety of 1 was found to be more easily hydrolyzed than the ester moiety of 1 under aqueous alkaline conditions. Thus, the phosphonoacetic acid was readily prepared by enzymatic hydrolysis of 1 with porcine liver esterase (PLE). Although attempts to hydrolyze the ester moiety of 1 under aqueous alkaline conditions were unsuccessful, reactions of 1 with various alcohols in the presence of triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave the corresponding phosphonoacetate rac-3a-d as the major product (Chart 1). The similar transformation of 2 using various alcohols gave rac-4a-d as shown in Chart 2. Attempts to hydrolyze 2 under aqueous alkaline conditions were also unsuccessful, though phosphonoacetates 4a and 5-7 were obtained (Chart 2). It can be concluded that the high oxophilicity of phosphorus atoms of these HWE reagents 1 and 2 appears to be necessary for Z-selective HWE reaction with aldehydes. [17][18][19] The phosphonoacetates rac-3a-d were subjected to enzymatic hydrolysis utilizing PLE (Sigma, E-2884), as follows. Phosphonoacetates rac-3a-d were dissolved in 1/15 M phosphate buffer solution (pH 7.4) and acetone (9 : 1). After addition of PLE (800 units/mmol), the mixture was stirred at room temperature for the appropriate time. The reaction mixture was treated with 10% HCl and then extracted with AcOEt. After evaporation of the extraction in vacuo, the residue was purified on a silica gel column with CHCl 3 -MeOH as eluent to give the corresponding carboxylic acid 8 and unreacted ester 3. The enantiomeric excess of resolution product 8 was determined by means of HPLC analysis with chiral-stationary-phase (CSP) after methylation with (trimethylsilyl)diazomethane (TMSCHN 2 ). 20) Unreacted resolution compound 3 was also subjected to HPLC analysis with CSP. As the result of enz...

Enzymatic synthesis of chiral P-stereogenic phosphonoacetates

“…However, most of these chiral HWE reagents are restricted to the compounds with non-stereogenic phosphorus atom, which are more easily available than P-stereogenic HWE reagents. We have already reported the facile synthesis of two kinds of chiral P-stereogenic phosphonoacetates (>99% ee) by porcine liver esterase (PLE)-catalyzed kinetic resolution of the corresponding racemic mixed phosphonoacetates [5]. 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.…”

“…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.…”

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

“…In the first step, nucleophilic substitution of the 1st alcohol 2 at the phosphorus center of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (StillGennari reagent, 1) 28,29 furnishes the common key intermediate The reaction of the Still-Gennari reagent (1) and chiral alcohol 2 was conducted in the presence of a 1 equiv of DBU and molecular sieves (type 3A) based on our previous report. 30,31 As a result, mixed phosphonoacetate 3 was obtained as an inseparable diastereomeric mixture (ca. 1:1) in 82% yield (Scheme 4).…”

Synthesis of 1,2-Dihexadecyl-sn-glycero-3-phosphoethanolamine

“…One strategy of synthesizing DHPE 化合物 9 中的羟基在三乙胺或 DBU[18,19] 存在的条 件下作为亲核试剂与 O,O'-双(2,2,2-三氟乙基)磷乙酸甲 酯反应, 室温下搅拌 2 h 后生成产物 10-1(产率 66%), 核 磁共振检测结构正确. 接着再用 10-1 与 5 反应 20 h, 薄 层色谱(TLC)检测发现产物点复杂, 有较多的副产物生 成, 用硅胶色谱柱分离纯化后, 质谱检测发现目标化合 物 11-1 的分子离子峰, 但核磁共振检测分析发现产物仍 含有杂质峰.…”