Wadsworth-Emmons phosphonate condensation

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

Intramolecular condensation of phosphonate carbanions with carbonyl groups carried out under conditions of high dilution have been utilized in macrocycle syntheses. Entries 7 and 8 show macrocyclizations involving the Wadsworth-Emmons reaction. Entries 9 to 11 illustrate the construction of new double bonds in the course of a multistage synthesis. The LiCl/amine conditions are used in Entries 9 and 10. 

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... 

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. 

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. 

Horner-Wadsworth-Emmons reactions are C—C-forming condensation reactions between the Li, Na, or K salt of a /J-keto- or an -(alkoxycarbonyl)phosphonic acid dialkyl ester and a carbonyl compound (cf. Figure 4.41). These reactions furnish a,f)-unsaturated ketones or a j8-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 fraus-selectively or in the case of olefins with trisubstituted C—C double bonds -selectively. 

Horner-Wadsworth-Emmons procedures are also commonplace in synthetic materials chemistry, recent examples including donor-acceptor substituted molecules with bicyclo-spacers, which require napthalene-, anthracene-, and pyrene-substituted phosphonates, (112), (113) and (114) respectively, well-defined, electroactive PPE/PPV copolymers through the condensation of dialdehydes and bisphosphonate (115), ° and triphenylamine-substituted PPV. ° ... 

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. 

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 Wadsworth-Emmons reaction of the phosphonate (250) with the aldehyde (251) has been used as a key step in a total synthesis of analogues (252) and (253) of topostin B-1, an inhibitor of mammalian DNA topoisomerase The enzyme-catalysed aldol condensation between the phosphonate aldehyde (254) and dihydroxyacetone phosphate is followed by spontaneous intramolecular olefination of the product to give the cyclitol (256) in spite of the reaction being below pH 7 at all times.Attempts at a similar reaction of the homologue (255) were unsuccessful probably because (255) is a poor substrate for the aldolase. 

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. 

A selective metalation of co-sulphonyl substituted phosphonates (338) resulted in sufficiently stable carbanions that underwent the chemoselec-tive Julia-Kocienski condensation with various aldehydes to provide ( )-allylic phosphonates (339) in good yields (up to 85%) and selectivities (up to 95 5). Synthesis of trans-dienes, trienes, and tetraenes (340) based on the Horner-Wadsworth-Emmons olefination of the resulting allylic phosphonates (339), has been also described (Scheme 115). ... 

Emmons-Wadsworth reaction. Conjugate bases of these reagents condense with aldehydes to give dienes with good fEj-selectivity. Diphenyl phosphonates are not suitable because of low yields of their reactions. 

Use in synthesis. Wadsworth and Emmons condensed diethyl phosphonate with carbon tetrachloride and cyclohexylamine according to A. R. Todd (1945) to produce diethyl cyclohexylaminephosphoramidate (3). The initially formed trichloro-methylphosphonate (2) reacts with a second mole of amine with elimination of chloroform to give (3). Treatment of this phosphoramidate with sodium hydride in... 

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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