Homer-Wadsworth-Emmons condensation

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. 

Kozikowski, A.P., and Sorgi, K.L., Use of the anomeric allylation reaction in natural products synthesis. A stereocontrolled synthesis of methyl deoxypseudomonate B, Tetrahedron Lett., 25, 2085, 1984. Hammond, G.B., Cox, M.B., and Wiemer, D.F., Stereocontrol in Homer-Wadsworth-Emmons condensations of a gezw-dimethylcyclopropyl aldehyde with a-substituted phosphono acetates, J. Org. Chem., 55, 128, 1990. 

More elaborate 4-hydroxy-enals and -enones have been generated in a variety of ways, for example via alkynes or often via epoxides, " it being sometimes unnecessary to isolate the hydroxy-enone, " or via Homer-Wadsworth-Emmons condensation of P-ketophosphonates with a-acetoxyketones. Acetal, thioenolether or terminal aUcyne can be employed as surrogate for the carbonyl group. 1,2,3-Trienyl-... 

A small band gap poly(thienylene vinylene) macro-initiator 9 has been synthesized by Homer-Wadsworth-Emmons condensation. Rod-coil copolymers 10 have been obtained from it (Figure 7) they present red-shifted absorption spectra, which is very suitable for photovoltaic applications. 

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... 

Domino processes involving Homer-Wadsworth-Emmons (HWE) reactions constitute another important approach. Among others, HWE/Michael sequences have been employed by the group of Rapoport for the synthesis of all-cis-substituted pyrrolidines [143], and by Davis and coworkers to access new specific gly-coamidase inhibitors [144]. Likewise, arylnaphthalene lignans, namely justicidin B (2-281) and retrojusticidin B (2-282) [145], have been synthesized utilizing a domino HWE/aldol condensation protocol developed by Harrowven s group (Scheme 2.65) [146]. 

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. 

Homer-Wadsworth-Emmons reactions are C=C-forming condensation reactions between the Li, Na, or K salt of a /1-koto- or an a-(alkoxycarbonyl )phosphomc acid dialkyl ester and a carbonyl compound (see Figure 4.46). These reactions furnish a,/3-unsaturated ketones or 0 ,/3-unsaturated esters, respectively, as the desired products and a phosphoric acid diester anion as a water-soluble by-product. In general, starting from aldehydes, the desired compounds are produced /ra/ov-selectively or, in the case of alkenes with trisubstituted C=C double bonds, -selectively. 

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. 

Pommer et al.146) reported a synthesis of a stereoisomer mixture of JH1 using a Homer-Wadsworth-Emmons olefmation for introducing the double bond at C-2 of 184146). Three Wittig olefinations were applied in the condensation of C4 + C6 + + C5 + C2 synthons 147). The isomers obtained were separated by distillation (Scheme 35). 

Phenylalanine-derived oxazolidinone has heen used in O Scheme 52 as a chiral auxiliary for as)rmmetric cross-aldolization (Evans-aldol reactions [277,278,279,280,281,282,283,284, 285]). The 6-deoxy-L-glucose derivative 155 has heen prepared by Crimmins and Long [286] starting with the condensation of acetaldehyde with the chlorotitanium enolate of O-methyl glycolyloxazohdinethione 150. A 5 1 mixture is obtained from which pure 151 is isolated by a single crystallization. After alcohol silylation and subsequent reductive removal of the amide, alcohol 152 is obtained. Swem oxidation of 152 and subsequent Homer-Wadsworth-Emmons olefination provides ene-ester 153. Sharpless asymmetric dihydroxylation provides diol 154 which was then converted into 155 (O Scheme 60) (see also [287]). 

However, further synthetic investigations have shown that with piperidine/AcOH as catalyst, the reaction proceeds by several competitive processes to give complex mixtures containing the desired phosphonate, the Homer-Wadsworth-Emmons olefination product, the straight-condensation product, and other byproducts. 

A further purpose of experiment [Alb] is to investigate the use of the Homer-Wadsworth-Emmons modified V 4ttig reaction to complete the synthetic objective. You will also study a reaction that involves the condensation of an aldehyde and a phosphonate ester, using a highly effective phase-transfer catalyst. 

Just as in the example just cited, phenylalanine can be converted to an aldehyde (phenylalinal). N-Boc-Phenylalinal 1.226), for example, was condensed with an ylid to form an alkene, just as with any other aldehyde. In this example, Homer-Wadsworth-Emmons olefmationll of 1.226 gave the alkene, and removal of the N-Boc group with trifluoroacetic acid gave methyl 4-amino-5-phenylpent-2-enoale, 7.227.133... 

Carbonyl Condensations. Bis- or tris-TMS ketenimines condense with ketones, mediated by MgBr2, to produce an intermediate that loses hexamethylsiloxane, affording 2-alkenenitriles in high yield with high ( ) selectivity (eq 16). MgBr2 also enables the use of very mild bases like Triethylamine in Homer-Wadsworth-Emmons reactions, enabling the synthesis of unsaturated esters from aldehydes or ketones without the need for strongly basic conditions (eq 17). ... 

Cyelopropanation, Horner-Wadsworth Emmons Reaction, and Darzens Condensation Although induction in the cyelopropanation of alkenes was reported early, this work was disputed [49]. Other reports of cyclopropanations have yielded, at best, low asymmetric inductions [llh,50]. The first example of a catalytic asymmetric Homer-Wadsworth Emmons reaction, which is promoted by a chiral quaternary ammonium salt, was reported recently by the Shioiri group (Scheme 10.10) [51]. The reaction of the prochiral ketone 74 gives optically active a,p-unsaturated ester 76 with 57% ee. 

Muscone (40) is a sex pheromone of the musk deer and a chemical component of cosmetics. A 12-member library of racemic muscone analogs was synthesized by Nicolaou et al.," who anployed a cyclorelease method on solid support to form the macrocycle scaffold (Figure 11.17). A phosphonate-functionalized resin loaded on encoded SMART microreactors 36 was coupled to olelinic esters 35 to form the p-ketophosphonates 37. Sorting and cross olefin metathesis of 37 with two alkenols followed by oxidation with Dess-Martin reagent gave aldehydes 38. An intramolecular ketophosphonate-aldehyde condensation (Homer-Emmons-Wadsworth reaction) of 38 caused smooth cyclorelease of macrocyclic enones 39. Parallel solution-phase chemistry completed the sequence. 

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