Horner synthesis acid esters

Emmons reaction (Scheme 26). ° Horner-Wadsworth-Emmons reactions also feature in new routes to (diphenylphosphono)acetic acid esters and alkenes. The latter involve combining the Homer-Wadsworth-Emmons procedure with a Heck coupling reaction for the synthesis of tri-substituted alkenes. 

These optically active cyclopentanoids have been synthesized from tartaric acids or their derivatives employing a new phosphonate-based strategy for the construction of substituted cycloalkenones. Therefore, before presenting total syntheses of terreins it is desirable to outline this new strategy because it was used in the synthesis of other bioactive products. It was found [33, 34] that 3-(phosphorylmethyl)-2-cycloalkenones 23 are formed in good yields by intramolecular Horner-Wittig reaction of the corresponding bis- -ketophos-phonates which, in turn, are easily prepared from dicarboxylic acid esters and a-phosphonate carbanions (Scheme 10). 

The Horner-Wadsworth-Emmons reaction (or HWE reaction) is the reaction of stabilized phosphonate carbanions with aldehydes (or ketones) to produce predominantly -alkenes. In 1958, Horner published a modified Wittig reaction using phosphonate-stabilized carbanions [32]. Wadsworth and Emmons further defined the reaction [33]. Compared to phosphonium ylides used in the Wittig reaction, phosphonate-stabilized carbanions are more nucleophilic and more basic. Likewise, phosphonate-stabilized carbanions can be alkylated, unlike phosphonium ylides. The dialkylphosphate salt by-product is easily removed by aqueous extradion. A reliable and versatile synthesis of a stilbene derivative, 2,2-aryl-substituted cinnamic acid esters, using the Wittig reaction was reported [34—36] (Figure 1.3). 

A soln. of cyano(methylthio)methyltrimethylsilane in THF added over 5 min to a stirred soln. of LDA (1 M) in the same solvent at —78° under N2, treated dropwise after 30 min with a soln. of benzaldehyde in THF, the mixture stirred for 1 h, warmed slowly to room temp., and stirring continued for 3 h - product. Y 85% (E/Z mixture). The method is higher-yielding than the Wittig-Horner approach, and does not require strong base. F.e. with enolizable aldehydes and ketones s. D.I. Han, D.Y. Oh, Synth. Commun. 75, 2111-6 (1988) a-alkyIthio-a,p-ethylenephosphonic acid esters s. M. Mikotajczyk, P. Bafczewski, Synthesis 1989, 101-6. 

Isocyanoacrylic acid esters are useful as precursors of heterocyclic and unsaturated amino-acids. These compounds are prepared in a stereoselective manner and in good yield using the Wittig-Horner reaction of t-butyl(diphenylphosphinyl)isocyanoacetate with aldehydes. cw-Enoates have been prepared by the reaction of a-diazoesters with Rh(OAc)2. An interesting one-pot synthesis of a-fluoro-a,/3-unsaturated esters from ethyl chloromalonate and carbonyl compounds works well using spray dried potassium fluoride but not with other forms of this salt (Scheme 47) the E-ester was the major product with a stereoselectivity of 86—96%. 

A suspension of NaH in abs. tetrahydrofuran stirred and treated portionwise at 0° with diethyl methoxycarbonylmethylphosphonate, after completion of the Hg-evolution a soln. of cortexone in abs. tetrahydrofuran added whereupon the temp, rises to 40-50° then drops to ca. 30°, the product isolated after 35 min. stirring crude butenolide. Y 90.1%. F. e. s. W. Fritsch, U. Stache, and H. Ruschig, A. 699, 195 (1966) a, -ethylenecarboxyiic acid esters from ketones, labeled compounds, s. W. M. Walter, Jr., J. Labelled Compds. 3, 54 (1967) a,/ -ethylenephosphonic from methylenediphosphonic acid esters s. T. L. Hular, Tetrah. Let. 1967, 4921 a,y -ethylenealdehydes from oxo compounds by Horner synthesis cf. W. Nagata and Y. Hayase, Tetrah. Let. 1968, 4359. 

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. 

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]. 

Various methods have been used to lengthen a carbon side chain, in the syntheses of quinuclidyl-3-acetic acid (113) (Scheme 1). The lowest yield is in the sodiomalonic ester synthesis (13.4% ).125 Much better results are afforded by the Reformatsky reaction (40%)125 and Knoevenagel condensation (65-70%).129 The best yield (nearly quantitative) may be obtained by application of the Wittig-Horner reaction.155... 

Butenolides. The fmnal steps in a synthesis of jolkinolide E (4) involve formation of the butenolide ring by reaction of the a-hydroxy ketone 1 with the mixed anhydride of trichloroacetic acid amd a-(diethylphosphono)propionic acid (2) with catalysis by DMAP. The ester 3 undergoes an intramolecular Wittig-Horner reaction in the presence of NaH to give 4. ... 

The Wittig-Horner reaction of protected 3-formylindazoles with iV-(benzyloxycarbonyl)-a-phosphonoglycine trimethyl ester has been developed as a new practical synthesis of dehydro 2-azatryptophans and amino acid derivatives <2007TL2457>. Nucleophilic addition of Grignard or lithiated reagents of 3-A -methoxy-A -methyl-amides of indazole afforded a library of 3-keto and 3-formylindazoles <2007T419>. 

In a novel synthesis of pyridazinones, a Wittig-Horner reaction is used to prepare an intermediate hydrazone of an a,)S-unsaturated y-keto ester, which undergoes geometrical isomerization and cyclization when heated under reflux in DMF (Scheme 91). The starting a-formylhydrazone is prepared from ascorbic acid <87H(26)2loi>. 

The ketophosphonate chemistry briefly discussed above indicates that the cycloalkenones 23 can be easily functionalized and, therefore, can serve as synthetic intermediates in the synthesis of bioactive products. Having this in mind, Altenbach and Holzapfel [35] devised an elegant and short synthesis of natural (+)-terrein (21) from the protected ethyl ester of (+)-(l)-tartaric acid 24. Upon reaction of 24 with diethyl lithiomethanephosphonate in the presence of acetic acid under strictly controlled reaction conditions a mixture of two cyclic products 25 and 26 was formed. The first of them, readily separated chromatograph-ically, was the desired product of an intramolecular Horner-Wittig reaction of the transiently formed bis-jS-ketophosphonate. Introduction of the unsaturated side chain was achieved via Horner-Wittig reaction with acetaldehyde. Subsequent deprotection of the chiral diol moiety with fluoride ion gave (+)-terrein (21) in 26% overall yield (Scheme 12). 

For the linear synthesis of spheroidene (97) [20] that is described in Section B.4, the Cig-ketone 51 is used as starting material. This is prepared (Scheme 17) from commercially available (5jF)-6,10-dimethylundeca-5,9-dien-2-one (geranylacetone) (52). This ketone 52 is coupled in an Horner-Emmons reaction with the commercially available triethyl phosphonocrotonate (53), in the presence of BuLi as base. Yields for this reaction are almost doubled (from 45 to 85%) when HMPA is added. The ester 54 is converted in one step into the Ci8-ketone 51 by addition of an excess of MeLi (55) in the presence of five equivalents of trimethylsilyl chloride at -100°C, giving, after acidic work-up, the all-E" Cig-ketone 51 in 69% yield [20]. 

As has been shown in previous Chapters the Wittig and the Horner-Emmons reactions are of utmost importance for the coupling of carotenoid end groups with the polyene chain. In the following example, the synthesis of the naturally occurring C25-apocarotenal 507 (12 -apo-P-caroten-12 -al, (3-apo-12 -carotenal) and also ethyl 8 -apo-P-caroten-8 -oate (1) (P-apo-8-carotenoic acid ethyl ester), which is produced industrially by means of these reactions, is described. 

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