Phosphonate 99, Homer-Wadsworth-Emmons

Aldehyde 170 is to serve as the electrophile in an intermolecular Homer-Wadsworth-Emmons (HWE) reaction70 with enantiomeri-cally pure phosphonate 169. Compounds 169 and 170 can in fact be joined efficiently under the mild reaction conditions shown in Scheme 50 to give a,/ -unsaturated imide 206 (96 % yield). The use... 

Intramolecular phosphonate-ketone condensation (Homer-Wadsworth-Emmons)... 

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 efficient one-pot synthesis of mikanecic acid derivatives was accomplished from allylic phosphonates, ClC02Et, and aqueous HCHO (Eq. 12.38).100 The overall process involves a cascade sequence linking together metalation-alkoxycarbonylation, Homer-Wadsworth-Emmons,... 

In 2000, the Merlic research group reported concise total syntheses of calphostins A and D and the first total syntheses of calphostins B and C [33]. This original approach to the naphthalene fragment relied on a chromium carbene intermediate to obtain the required regioselection. The synthesis began with phosphonate 39 (three steps), followed by a Homer-Wadsworth-Emmons olefination of 39 with... 

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. 

When the substituent becomes very anion-stabilising, as in 42, the ylid may not react with ketones and anions of phosphonate esters are usually preferred in the Homer-Wadsworth-Emmons (HWE) variant.11 The reagent triethyl phosphonoacetate 46 is made by combining a phosphite (EtO)3P instead of a phosphine, with ethyl bromoacetate. Displacement of bromide 44 gives a phosphonium ion that is dealkylated by bromide 45. 

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. 

Fig. 11.20. Still-Gennari olefination of a racemic a-chi-ral aldehyde with an enan-tiomerically pure phosphonate as kinetic resolution II—Use of the unreactive enantiomer ent-B of the aldehyde (R stands for the phenylmenthyl group in the Homer-Wadsworth-Emmons products).

Alternatives to the standard Wittig reaction have been developed, including the Homer-Wadsworth-Emmons (HWE) reaction which involves the reaction of a phosphonate stabilized carbanion with a carbonyl compound (Scheme 2). These carbanions are generally more reactive than the traditional phosphoranes and they will often react with ketones that are unreactive to stabilized phosphoranes.2 3,8... 

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. 

One striking example is the use of 1-azadiene 92 as intermediate to scaffold diversity which is generated in situ from a phosphonate 89, a nitrile 90 and an aldehyde 91 via a 3CR involving a Homer-Wadsworth-Emmons (HWE) reaction (Scheme 9) [77, 78]. 

Some stabilized ylides are too stable to be very reactive. In this case phosphonates are used instead of phosphonium salts. For the Homer-Wadsworth-Emmons-r action see Chapter 2. 

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-... 

The Homer-Wadsworth-Emmons (HWE) reaction involves the addition of a stabilized phosphonate anion to an aldehyde or ketone to afford an intermediate which undergoes an elimination reaction to form predominately the ( )-alkene. The HWE reaction has been applied inter- and intramolecularly to simple as well as highly functionalized systems. 

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. 

Benayoud, R, deMendonca, D.J., Digits. C.A.. Moniz, G.A., Sanders, T.C., and Hammond, G.B., Efficient syntheses of (a-fluoropropargyl)phosphonate esters, 7. Org. Chem., 61, 5159, 1996. Sanders, T.C., Golen, J.A., Williard, PG.. and Hammond, G.B., The crystal structure of 2-fluoro-l-(/)-methoxyphenyl)-l-penten-3-yne, a fluorinated vinylacetylene prepared via Homer-Wadsworth-Emmons condensation, J. Fluorine Chem.. 85. 173. 1997. 

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). 

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