Phosphonate 99, Homer-Wadsworth-Emmons reaction

A tandem enzymatic aldol-intramolecular Homer-Wadsworth-Emmons reaction has been used in the synthesis of a cyclitol.310 The key steps are illustrated in Scheme 8.33. The phosphonate aldehyde was condensed with dihydroxyacetone phosphate (DHAP) in water with FDP aldolase to give the aldol adduct, which cyclizes with an intramolecular Horner-Wadsworth-Emmons reaction to give the cyclo-pentene product. The one-pot reaction takes place in aqueous solution at slightly acidic (pH 6.1-6.8) conditions. The aqueous Wittig-type reaction has also been investigated in DNA-templated synthesis.311... 

An asymmetric synthesis of phosphonylated thiazolines has been described. The phosphonodithioacetate 46 was aminated with a chiral amino alcohol 47 to give the phosphonylated thioamide 48 in good yield. This was then cyclised using a Mitsunobu procedure to give the chiral thiazoline phosphonate 49 in good yields under mild conditions. Homer-Wadsworth-Emmons reaction of these phosphonylated thiazolines gave chiral vinylic thiazolines 50 <00S1143>. 

The first example of a catalytic asymmetric Horner-Wadsworth-Emmons reaction was recently reported by Arai et al. [78]. It is based on the use of a chiral quaternary ammonium salt as a phase-transfer catalyst, 78, derived from cinchonine. Catalytic amounts (20 mol%) of organocatalyst 78 were initially used in the Homer-Wadsworth-Emmons reaction of ketone 75a with a variety of phospho-nates as a model reaction. The condensation products of type 77 were obtained in widely varying yields (from 15 to 89%) and the enantioselectivity of the product was low to moderate (< 43%). Although yields were usually low for methyl and ethyl phosphonates the best enantioselectivity was observed for these substrates (43 and 38% ee, respectively). In contrast higher yields were obtained with phosphonates with sterically more demanding ester groups, e.g. tert-butyl, but ee values were much lower. An overview of this reaction and the effect of the ester functionality is given in Scheme 13.40. 

You will learn about the reaction of a-metalated phosphonic acid esters with aldehydes in Section 11.3 in connection with the Homer-Wadsworth-Emmons reaction. This reaction also seems to give a Irans-con figured oxaphosphetane (Figure 4.46). Again, a. vyn-selective /3-elim-ination of a compound with P=0 double bond should occur. One of the elimination products is (EtO)2P(=O)O0. As a second product an alkene is produced that is predominantly or exclusively irans-configured. 

Condensations between aldehydes and metalated phosphonic acid dialkyl esters other than those mentioned previously are also referred to as Homer-Wadsworth-Emmons reactions. Nevertheless, in these esters, too, the carbanionic center carries a substituent with a pi electron withdrawing group, for example, an alkenyl group, a polyene or a C=N group. The Homer-Wadsworth-Emmons reactions of these reagents are also stereoselective and form the new C=C double bond /ra/ ,v-selectively. 

The Michaelis-Arbuzov reaction is generally performed without solvent (as one or other, or both, of the reactants is usually a liquid), and the product phosphonate purified by distillation if a solvent is required THF, acetonitrile, benzene or toluene are suitable. Lawrence has collected details of the syntheses and Homer-Wadsworth-Emmons reactions of some common Michaelis-Arbuzov products 6 4 many such phosphonates are commercially available. 

Preparation of Derivatives. A -Acyl- and A-enoylsul-tam derivatives are routinely prepared in good yields using either sodium hydride-acid chloride or trimethyl-aluminum-methyl ester single-step protocols. A variant of the former method employing in situ stabilization of labile enoyl chlorides with CuCl/Cu has also been reported. A two-step procedure via the A-TMS derivative (1) is useful when a nonaqueous work-up is desirable and for synthesis of the A-acryloyl derivative. A-Enoyl derivatives may also be prepared via the phosphonate derivative (2) by means of an Homer-Wadsworth-Emmons reaction (eq... 

The use of anions derived from a phosphine oxide (132) or a diethyl phosphonate (133) to form al-kenes was originally described by Homer.Although these papers laid the foundations for the use of phosphoryl-stabiliz carbanions for alkene synthesis, it was not until Wadsworth and Emmons published a more detailed account of the general applicability of the reaction that phosphonates bet e widely used. Since the work of Wadsworth and Emmons was significant and crucial to the acceptance of this methodology, the reaction of a phosphonate caibanion with a carbonyl derivative to form an alkene is referred to as a Homer-Wadsworth-Emmons reaction (abbreviated HWE). The phosphine oxide variation of the Wittig alkenation is called the Homer reaction. 

Of course, the main interest in the Homer-Wadsworth-Emmons reaction is its application in synthesis. New biologically active molecules synthesised include endothelin receptor antagonist S-0139, which requires phosphonate... 

Ethyl phosphonoacetate reacts with 3-keto-substituted thiophenes to give 81 which are precursors to bridged dithienylethylenes such as 82. The synthesis of a-ylidene-y-amidobutyronitriles, RCONH(CH2)2C(CN) = CR R" (R = NPh2, r2 = R" rz Me R = R = Ph, R" = H, Me, Ph), has been achieved by the reaction of the phosphonates RC0NH(CH2)2CHCNP(0)(0Et)2 (R = NPh2, Ph) with ketones. The enantioselective synthesis of allenecarboxylates is accomplished by asymmetric Homer-Wadsworth-Emmons reaction of chiral phosphonoacetate-... 

In 1968, Peterson made the important discovery that the anions resulting from lithiation of [(meth-ylthio)methyl]trimethylsilane and [(trimethylsilyl)methyl]diphenylphosphine sulfide reacted with benzophenone to produce lithiated P-hydroxysilanes, which decompose to give olefins by loss of McgSiOLi. " This olefination reaction resulting in functionally substituted alkenes has been extended to phosphonates and can be considered as an alternative to the Homer-Wadsworth-Emmons reaction. 

A -FluorohiXtrifluoromethanesulfonyl)imide is one of the most powerful electrophilic fluori-nating agents. It was successfully used to fluorinate diethyl cyanomethylphosphonate in the presence of w-BuLi (1 eq), and the resulting diethyl 1-fluoro-1-cyanomethylphosphonate can be isolated (51% yield) or metallated in situ and reacted with carbonyl compounds in a Homer-Wadsworth-Emmons reaction to give a-fluoroacrylonitriles in 30-58% overall yields (Scheme 3.21). 2 These results aie especially noteworthy because the fluorination of diethyl cyanomethylphosphonate with NFBS in the presence of LiHMDS (2 eq) produces the A -fluoro and not the expected C-fluoro phosphonate. 

Long-chain phosphonylated aldehydes aie generally prepared to achieve the formation of macro-cycles via an intramolecular Homer-Wadsworth-Emmons reaction. The phosphonate group is frequently incorporated at one extremity of the chain by a carbanionic approach. Thus, displacement of iodide of the alkyl chain containing epoxide by the sodium enolate of diethyl l-(ethoxycarbo-nyl)methylphosphonate at 50°C in DMF leads to diethyl l-(ethoxycarbonyl)-4,5-epoxyalkylphos-phonate in 78% yield (Scheme 4.21). 

An added and valuable advantage found in this attractive and mild approach to dialkyl cyanoalkylphosphonates is the possibility of trapping the phosphonate carbanions in situ by reaction with an aldehyde or ketone when the desired product is the olefin resulting from the Homer-Wadsworth-Emmons reaction (Scheme 6.6). 

Addition of charged nucleophiles to diethyl 1-cy anovinyl phosphonate leads to the generation of a-substituted cyanomethylphosphonate carbanions. In the presence of carbonyl compounds, they undergo Homer-Wadsworth-Emmons reaction to produce the a,p-unsaturated nitriles in fair to good yields as a mixture of ( )- and (Z)-isomers. ... 

Homer-Wadsworth-Emmons reaction/Still-Gennari phosphonate reaction... 

Applicable to base-sensitive aldehydes and phosphonates for the Homer-Wadsworth-Emmons reaction. a-Keto or a-alkoxycarbonyl phosphonate required. 

The Homer—Wadsworth—Emmons reaction involves use of a phosphonate ester instead of a triphenylphosphonium salt. The major product is usually the (A)-alkene isomer. 

The Homer-Wadsworth-Emmons reaction is an important variant of the Wittig reaction and involves using a phosphonate ester in place of a phosphonium salt. Like the phase-transfer Wittig reaction just discussed, these reactions may be easily performed in the undergraduate laboratory. In one of the procedures that follows, the phosphonate ester 12 is deprotonated with potassium tert-butoxide in the polar, aprotic solvent N,N-dimethylformamide, (CH3)2NCHO (DMF), to provide the resonance-stabilized, nucleophilic phosphonate anion 13 (Eq. 18.7). 

The use of the phosphonate ester (Homer-Wadsworth-Emmons reaction) allows much easier separation of the product alkene, since the sodium phosphate byproduct is water soluble the byproduct of fhe Wiffig reaction, tri-phenylphosphine oxide, is not water soluble. In the Horner-Wadsworth-Emmons modification, a conjugated, or electron-withdrawing, substituent (such as a phenyl or carbonyl group) on the nucleophilic carbon is used to assist in the stabilization of the carbanion. This modification (Experiment [19B]) maybe used as an alternative to Experiment [19A] for the preparation of (E)-stilbene. The "instant-ylide" Wittig reaction yields predominantly the E isomer of... 

A modification of the above reaction, known as the Wittig-Homer reaction or Homer-Wadsworth-Emmons reaction uses phosphonate esters. Thus, the reaction of ethyl bromoacetate with triphenylphosphite gives the phosphonate ester, which on treatment with base (NaH) and reaction with cyclohexanone... 

Ylids are also convenient sources of carbanions and they react with aldehydes and ketones to give alkenes. With a suitable reactant, alkenyl amino acids can be prepared using this approach. One example used a phosphonate ester ylid in a Homer-Wadsworth-Emmons reaction 12 with amino aldehyde 1.189. The product... 

The commonly accepted mechanism for the Homer-Wadsworth-Emmons reaction is as depicted in Scheme 1.6. Here, reaction of the phosphonate stabilized carbanion with an aldehyde forms the oxyanion intermediates 4 under reversible conditions. Rapid decomposition of 4, via the four-centered intermediates 5, then affords alkenes 6. 

The stereochemical outcome of the Homer-Wadsworth-Emmons reaction is primarily dependent on the nature of the phosphonate used. In general, bulky substituents at both the phosphoms and the carbon adjacent to the carbanion favor formation of the -alkene. This selectivity has been rationalized in terms of a lowering of steric strain in intermediate SB as compared to intermediate SA. Z-Selectivity in HWE reactions can, however, be achieved using the Still-Gennari modification [20]. Here, the use of a (2,2,2-trifluoroethyl) phosphonate enhances the rate of elimination of the originally formed adduct SA (Scheme 1.6) relative to equilibration of the intermediates 4 and S. An example of the Still-Gennari modification is illustrated in Scheme 1.7. 

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