Horner-Emmons reagents

The direct reduction of esters with diisobuty laluminum hydride in the presence of the Horner-Emmons reagent prepared from ethyl diethylphosphon-ofluoroacetate avoids the necessity to work with sensitive aldehydes in the olefi-nation procedure [72, 75] (equation 62) (Table 23). 

The preparation of 1 started with the addition of lithiated 4 to the enantiomcrically-pure epoxide 5, which was prepared from the racemate using the Jacobsen protocol. Reduction followed by selective protection of the primary alcohol gave the monosilyl ether, which was further protected with MOM chloride to give 7. Pd-mediated oxidation to the methyl ketone followed by condensation with the Horner-Emmons reagent gave the unsaturated ester 8 as an inconsequential mixture of geometric isomers. Oxidation then set the stage for the crucial cyclization. 

Horner-Emmons reagents react with trifluoromethyl ketones to form trifluoromethylated al-kenes however, the C = C bond can isomcrize out of conjugation with the carboxylic ester group when the product alkcnc bears a > -proton, e.g. to produce 33. ... 

Ando, K. Practical synthesis of Z-unsaturated esters by using a new Horner-Emmons reagent, ethyl diphenylphosphonoacetate. Tetrahedron Lett. 1995, 36, 4105-4108. 

Silyl migration can be used advantageously as in a disorazole Ci synthesis by Meyers. Treatment of the hydroxyl with NaH results in TBS migration with concomitant liberation of an aldehyde which then reacts with the Horner-Emmons reagent to form the unsaturated ester. "... 

Further work showed that stabilized ylides can also react with acylphosphonates. Ethoxycarbonyltriphenylphosphorane and triethyl phosphonoacetate carbanion (Horner-Emmons reagent) give trisubstituted vinylphosphonates of the opposite stereochemistry as main products (equation 64)... 

In an effort to evaluate general synthetic routes to polyenes, the authors [93] compared the usage, among others, of Horner-Emmons reagent 127 and Wollenberg vinyl ether reagent 128 [95] (Scheme 16). In a model olefination... 

Simple unfunctionalized ketones such as aryl alkyl ketones 36 can be olefinated by ynolates to provide tetrasubstituted olefins 37-42 in good to excellent yield (Fig. 12) [56]. While the Wittig and the Horner-Emmons reagents are not suitable reagents for this type of olefination, especially for ferf-butyl phenyl ketone (43), the ynolate affords the corresponding olefin 41 in 74% yield (Fig. 13). Ynolates are actually much better reagents for the olefination of ketones than the conventional... 

Chiral Horner-Emmons reagents have also been documented. In a study by researchers at Schering directed towards the synthesis of stable prostacyclin analogues, the stereoselective olefmation of ketone 115 was necessary (Equation 14) [70]. Condensation of 115 with the traditional Horner-Wads-worth-Emmons reagent, trimethyl phosphonoacetate, afforded a 1 1 mixture of ester diastereomers. Interestingly, use of the optically active phosphonoacetate 116 furnished 117 selectively (dr=86 14). 

There do not appear to be any simple phosphines that bear a CH2F group. However, fluorine NMR spectra of phosphonates, phosphane oxides, and phosphonium compounds with CH2F and —CHF- bound to phosphorous have been reported. Examples are given in Scheme 3.26, including spectral data for the useful Horner-Wadsworth-Emmons reagent, triethyl 2-fluoro-2-phosphonoacetate. 

Tanaka et al.50 also reported that chiral Horner-Wadsworth-Emmons reagent (S )-51 reacted with an alternative carbonyl group of the meso-a-diketones... 

Sharpless asymmetric dihydroxylation procedure was applied to the synthesis of the side chain of azinomycin A (equation 26)43. Horner-Emmons condensation of phospho-nate 36 with a /J-aziridine substituted acrolein afforded dehydroamino acid diene 37. Treatment of the diene with catalytic amounts of an osmium reagent and dihydroquini-dine (DHQD) p-chlorobenzoate resulted in asymmetric dihydroxylation, producing diol 38. Diol 38 was further converted to the naphthyl ester. 

The preparation of unsaturated phosphonates and phosphine oxides represents another class of reagents that are extensively used in organic synthesis. For example, allylic phosphonates are commonly employed in the preparation of dienes and polyenes via Horner-Emmons olefmation. Vinyl phosphonates have numerous uses as both synthetic intermediates" and bioactive compounds. 

A-Ethyl(diethylphosphono)methylketenimine, readily prepared from the amide, is of value as an annelating reagent (79CC900). The sodium salt of salicylaldehyde reacts at the activated central carbon atom of the ketene and a subsequent intramolecular Horner-Emmons reaction results in cyclization to the chromene. 

Shibasaki made several improvements in the asymmetric Michael addition reaction using the previously developed BINOL-based (R)-ALB, (R)-6, and (R)-LPB, (R)-7 [1]. The former is prepared from (R)-BINOL, diisobutylaluminum hydride, and butyllithium, while the latter is from (R)-BINOL, La(Oz -Pr)3, and potassium f-butoxide. Only 0.1 mol % of (R)-6 and 0.09 mol % of potassium f-butoxide were needed to catalyze the addition of dimethyl malonate to 2-cy-clohexenone on a kilogram scale in >99% ee, when 4-A molecular sieves were added [15,16]. (R)-6 in the presence of sodium f-butoxide catalyzes the asymmetric 1,4-addition of the Horner-Wadsworth-Emmons reagent [17]. (R)-7 catalyzes the addition of nitromethane to chalcone [18]. Feringa prepared another aluminum complex from BINOL and lithium aluminum hydride and used this in the addition of nitroacetate to methyl vinyl ketone [19]. Later, Shibasaki developed a linked lanthanum reagent (R,R)-8 for the same asymmetric addition, in which two BINOLs were connected at the 3-positions with a 2-oxapropylene... 

Both regioselectivity and enantioselectivity are efficiently controlled by ALB in the Michael addition of Horner-Wadsworth-Emmons reagents 17 with enones (Scheme 8D.12) [29]. Although the reaction catalyzed by ALB itself did not afford the product, the use of a combination of ALB (10 mol %) and NaC/Bu (0.9 equiv. to ALB) gave the Michael adduct of 17 to cyclohexenone in 64% yield and 99% ee. The reaction of cyclohexenone with 17 promoted by standard bases such as NaO Bu and BuLi gave the 1,2-adduct in only 8-9% yield. The adduct... 

Fig. 6.48. Preparation of Horner-Wadsworth-Emmons reagents (synthetic applications Section 11.3) by chemoselective acylation of a phosphonatestabilized "carb-anion" with an ester.

The precursors for these Horner-Wadsworth-Emmons reagents are /f-ketophosphomc acid dialkyl esters or a-(alkoxycarbonyl)phosphonic acid dialkyl esters. The first type of compound, i.e., a /3-ketophosphonic acid dialkyl ester is available, for example, by acylation of a metalated phosphonic acid ester (Figure 6.48). The second type of compound, i.e., an a-(alkoxycarbonyl)phosphonic acid dialkyl ester, can be conveniently obtained via the Arbuzov reaction (Figure 11.12). 

Fig. 11.14. Preparation of tmns- or f-configured a,/3-unsaturated esters by the Horner-Wadsworth-Em mons reaction (left) or preparation of their cis- or Z-isomers by the Still-Gennari variant of it (right). 18-Crown-6 is a so-called crown ether containing a saturated 18-membered ring that is made up from six successive —CH2—0—CH2-units. 18-Crown-6 dissociates the K ions of the Horner-Wadsworth-Emmons reagent by way of complexation.

In the example shown the deprotonation of the phosphonate can be achieved under much milder conditions than with the usually employed sodium hydride, which by the way also applies to the standard Horner-Wadsworth-Emmons reagents. Incorporation of the two doubly bound oxygen atoms of the reagent A into sodium chelate B does the trick. Being a cation, B is much more acidic than A and can thus already be deprotonated by an amidine. 

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