Horner-Emmons

The reaction has been extended to include carbanions generated from phosphonates. This is often referred to as the Horner-Wittig or Homer-Emmons reaction. The Horner-Emmons reaction has a number of advantages over the conventional Wittig reaction. It occurs with a wider variety of aldehydes and ketones under relatively mild conditions as a result of the higher nucleophilicity of the phosphonate carbanions. The separation of the olefinic product is easier due to the aqueous solubility of the phosphate by-product, and the phosphonates are readily available from the Arbusov reaction. Furthermore, although the reaction itself is not stereospecific, the majority favor the formation of the trans olefin and many produce the trans isomer as the sole product. 

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). 

This method, sometimes called the Horner-Emmons, Wadsworth-Emmons, or... 

Alkylation of cyanohydrin acetonide 79 with the iodide 78 proceeded smoothly to give pentaacetonide 80 in 70% yield (Scheme 10). This represents the entire polyol framework of roflamycoin. An eight-step sequence involving installation of the polyene, macrocyclization via Horner-Emmons reaction, and protecting group machinations, completed the first total synthesis of roflamycoin. 

Based on information accrued during the stereochemical elucidation, macrolactone 85 was identified as a viable synthetic intermediate (Scheme 12). The authors were cognizant of the potential challenges that could arise. First, the required formation of a trisubstituted alkene in a projected Horner-Emmons macrocyclization was without strong precedent. Also, this strategy would necessitate a stereoselective reduction of the Cl5 ketone, which was predicted to be feasible based on MM2 calculations. 

The synthetic P-o-glucopyranoside 30 was converted to the cyanoglucoside rho-diocyanoside A (38a), which was isolated from the underground part of Rhodiola quadrifida (Pall.) Fisch. et Mey. (Crassulaceae) and found to show antiallergic activity in a passive cutaneous anaphylaxis test in rat. Acetylation of 30 gave an acetate (98% yield) which was subjected to ozonolysis to afford the aldehyde 39. The Horner-Emmons reaction of 39 using diethyl (l-cyanoethyl)phosphonate furnished (Z)-40a (32% yield from 30) and ( )-40b (10% yield from 30). The physical... 

The synthetic 31 was converted to the cyanoglucoside osmaronin (41a) which was isolated from a methanolic extract of the leaves of Osmaronia cerasi-formis. Acetylation of 31 gave an acetate (99% yield) which was subjected to ozonolysis to afford a ketone 42. The Horner-Emmons reaction of 42 using diethyl cyanomethylphosphonate furnished (Z)-43a (22% yield from the acetate of 31) and ( )-43b (10% yield from the acetate of 31). Deprotection of (Z)-43a and ( )-43b gave the (3-D-glucosides 41a (83% yield) and 41b (94% yield), respectively. The spectral data of the synthetic 41a were identical with those ( H- and C-NMR) of the natural osmaronin (41a) (Fig. 5). 

Oiganic synthesis 79 [OS 79] Methyl diethoxyphosphonoacetate and 4-methoxybenzaldehyde (Wittig-Horner-Emmons)... 

Methoxybenzaldehyde and methyl diethoxyphosphonoacetate were reacted via the Wittig-Horner-Emmons route to give the corresponding alkene product [85] (see a more detailed description in [42]). 

OS 79] ]R 17] ]no protocol] 4-Methoxybenzaldehyde and methyl diethoxyphos-phonoacetate were reacted by means of the Wittig-Horner-Emmons reaction [85] (see a more detailed description in [42]). A modified micro reaction system consisting of two mixers, for deprotonation of the phosphonates and introduction of the aldehyde, connected to an HPLC capillary of 0.8 m length and 0.25 mm diameter was employed. The micro reactor showed higher yields than laboratory batch synthesis. 

The synthesis of quadrupolar chromophores has also been achieved from 2,6-DTT-dicarboxaldehyde 117. Push-push (i.e., bis-donor) compound 118 was prepared via a double Wittig reaction carried out under solid-liquid phase transfer conditions. Pull-pull (i.e., bis-acceptor) compounds 119 were obtained from a symmetrical bis-aldehydes via a double Horner-Emmons-Wittig condensation (Scheme 9) <2002SM17, 1999CC2055>. 

The remaining section highlights various other methods of generating piperidine cores. The scheme below depicts a simple route to piperidines heterocycles, such as 196, via an intramolecular Horner-Emmons cyclization of phosphonate 197 <06JA12743>. 

An intramolecular cycloaddition also occurred with 3-ylidenepiperazine-2,5-diones such as 124 or 125, obtained by Wittig-Horner-Emmons reaction from phosphonate 121 and aldehydes 122 or 123, respectively. The products of the Diels-Alder reaction are the bridged bicyclo[2.2.2]diazaoctane rings 126 and 127 that have been found in biologically active secondary metabolite such as VM55599 and brevianamide A. The different type of structures employed in this case requires a chemoselective reaction in order to produce the expected products as single diastereoisomers after 20 days (Scheme 18) <2001JOC3984>. 

Esters attached to the pyridine were used as precursors of amides <2003TL1675> and aldehydes on the pyridine ring underwent Horner-Emmons conversion to acrylates <1995JHC787>. 

Only a few reactions of the substituents attached to ring carbon atoms of bicyclic systems 1-34 have been reported. Methylation of compound 100 occurs at sulfur to give 101 (Equation 6) <2005BMC1847>. Horner-Emmons reaction of phosphonate 102 with benzaldehyde leads to triazole 103 as a single /. -stereoisomer (Equation 7) <2004TL1877>. 

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. 

A variant of the Horner-Emmons reaction using bis(trifluoroethyl)phosphonate to give Z-olefins. 

In the asymmetric addition to alkenylphosphonate 33 (Eq. 2) [25], the yield is dependent on the amount of water present. The combination of boroxine and water (1 equiv. relative to boron) gave a high yield of the desired product 34, with 96% enantiomeric excess. The alkylphosphonate 34 can be used as a chiral building block for the synthesis of optically active alkenes, using a Horner-Emmons type of reaction. 

An interesting example of biocatalysis and chemical catalysis is the synthesis of a derivative of y-aminobutyric acid (GABA) that is an inhibitor for the treatment of neuropathic pain and epilepsy (Scheme 10.4). The key intermediate is a racemic mixture of cis- and trons-diastereoisomer esters obtained by a hydrogenation following a Horner-Emmons reaction. The enzymatic hydrolysis of both diaste-reoisomers, catalyzed by Candida antarctica lipase type B (CALB), yields the corresponding acid intermediate of the GABA derivative. It is of note that both cis- and trans-diastereoisomers of the desired enantiomer of the acid intermediate can be converted into the final product in the downstream chemistry [10]. 

Horner-Emmons. The use of (diphenylphosphinoyl)fluoroacetonitrile (48) to introduce the amino group... 

Horner-Emmons. Replacement of a nonpeptidomimetic amide (32) with the fluoroolefin isostere (33)... 

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